Meta-Analysis of Suicide-Related Behavior Events in Patients Treated with Atomoxetine

ERIC Educational Resources Information Center

Bangs, Mark E.; Tauscher-Wisniewski, Sitra; Polzer, John; Zhang, Shuyu; Acharya, Nayan; Desaiah, Durisala; Trzepacz, Paula T.; Allen, Albert J.

2008-01-01

A study to examine suicide-related events in acute, double-blind, and placebo controlled trials with atomoxetine is conducted. Results conclude that the incidences of suicide were more frequent in children suffering from ADHD treated with atomoxetine as compared to those treated with placebo.

Atomoxetine's Effect on Societal Costs in Sweden

ERIC Educational Resources Information Center

Myren, Karl-Johan; Thernlund, Gunilla; Nylen, Asa; Schacht, Alexander; Svanborg, Par

2010-01-01

Objective: To compare societal costs between patients treated with atomoxetine and placebo in Sweden. Method: Ninety-nine pediatric ADHD patients were randomized to a 10-week double-blind treatment with atomoxetine (n = 49) or placebo (n = 50). All parents received four sessions of psycho-education. Parents filled out a resource utilization…

Atomoxetine Alone or Combined with Fluoxetine for Treating ADHD with Comorbid Depressive or Anxiety Symptoms

ERIC Educational Resources Information Center

Kratochvil, Christopher J.; Newcorn, Jeffrey H.; Arnold, L. Eugene; Duesenberg, David; Emslie, Graham J.; Quintana, Humberto; Sarkis, Elias H.; Wagner, Karen Dineen; Gao, Haitao; Michelson, David; Biederman, Joseph

2005-01-01

Objective: Symptoms of depression and anxiety are commonly comorbid with attention-deficit/hyperactivity disorder (ADHD). The authors assessed the safety and effectiveness of atomoxetine monotherapy compared with combined atomoxetine/fluoxetine therapy in a population of children and adolescents with ADHD and concurrent symptoms of depression or…

Differential effects of atomoxetine on executive functioning and lexical decision in attention-deficit/hyperactivity disorder and reading disorder.

PubMed

de Jong, Christien G W; Van De Voorde, Séverine; Roeyers, Herbert; Raymaekers, Ruth; Allen, Albert J; Knijff, Simone; Verhelst, Helene; Temmink, Alfons H; Smit, Leo M E; Rodriques-Pereira, Rob; Vandenberghe, Dirk; van Welsen, Inge; ter Schuren, Liesbeth; Al-Hakim, Mazim; Amin, Azad; Vlasveld, Laurens; Oosterlaan, Jaap; Sergeant, Joseph A

2009-12-01

The effects of a promising pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), atomoxetine, were studied on executive functions in both ADHD and reading disorder (RD) because earlier research demonstrated an overlap in executive functioning deficits in both disorders. In addition, the effects of atomoxetine were explored on lexical decision. Sixteen children with ADHD, 20 children with ADHD + RD, 21 children with RD, and 26 normal controls were enrolled in a randomized placebo-controlled crossover study. Children were measured on visuospatial working memory, inhibition, and lexical decision on the day of randomization and following two 28-day medication periods. Children with ADHD + RD showed improved visuospatial working memory performance and, to a lesser extent, improved inhibition following atomoxetine treatment compared to placebo. No differential effects of atomoxetine were found for lexical decision in comparison to placebo. In addition, no effects of atomoxetine were demonstrated in the ADHD and RD groups. Atomoxetine improved visuospatial working memory and to a lesser degree inhibition in children with ADHD + RD, which suggests differential developmental pathways for co-morbid ADHD + RD as compared to ADHD and RD alone. B4Z-MC-LYCK, NCT00191906; http://clinicaltrials.gov/ct2/show/NCT00191906.

Anxiety reduction on atomoxetine and methylphenidate medication in children with ADHD.

PubMed

Snircova, Eva; Marcincakova-Husarova, Veronika; Hrtanek, Igor; Kulhan, Tomas; Ondrejka, Igor; Nosalova, Gabriela

2016-06-01

Atomoxetine and methylphenidate are widely used to treat attention-deficit-hyperactivity disorder (ADHD) with similar effectiveness after 8 weeks of treatment, when atomoxetine has reached its a full effect. Both drugs have also been shown to have an effect on comorbid anxiety. To the best of our knowledge, no study has compared their effect on the dynamics of anxiety symptom reduction. The aim of this study was to compare the medication effect on core and comorbid anxiety symptom dynamics in children with ADHD. Sixty-nine patients participated in the study: 36 patients were taking atomoxetine and 33 patients, methylphenidate. Therapeutic effect on core symptoms of ADHD was measured on the ADHD-rating scale IV, and symptoms of anxiety were measured using the Conners Parent Rating Scale (CPRS). Symptoms were measured prior to and every 2 weeks during 8 weeks of treatment. There was a significant decrease in CPRS anxiety subscale score in both medication groups. Anxiety subscale score was significantly lower in the atomoxetine group in the fourth week, and lasted through to 8 weeks of medication. Both atomoxetine and methylphenidate reduced the symptoms of ADHD and anxiety. Atomoxetine was more effective in anxiety symptom reduction from the fourth week of treatment. © 2015 Japan Pediatric Society.

Efficacy and Safety of Atomoxetine Hydrochloride in Asian Adults With ADHD.

PubMed

Goto, Taro; Hirata, Yuko; Takita, Yasushi; Trzepacz, Paula T; Allen, Albert J; Song, Dong-Ho; Gau, Susan Shur-Fen; Ichikawa, Hironobu; Takahashi, Michihiro

2017-01-01

The efficacy and safety of atomoxetine was assessed in adult ADHD patients from Japan, Korea, and Taiwan in this first placebo-controlled Asian clinical study in adults of an ADHD medication. Atomoxetine was compared with placebo (195 atomoxetine, 196 placebo) over 10 weeks. The change from baseline to endpoint and changes over time in the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version total score (CAARS-Inv: SV total score) were assessed along with changes in quality of life (QoL) and executive function. Atomoxetine treatment resulted in a mean reduction of -14.3 (placebo, -8.8) in CAARS-Inv: SV total score and a steady increase of between-group differences from Week 2. Improvements in QoL and executive functioning were also observed. Treatment-emergent adverse events leading to discontinuation were infrequent (atomoxetine: 5.2%, placebo: 1.5%). Atomoxetine was tolerable and effective in improving QoL and executive function as well as ameliorating core ADHD symptoms in adult Asian patients.

Safety of Methylphenidate and Atomoxetine in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): Data from the Italian National ADHD Registry.

PubMed

Cortese, Samuele; Panei, Pietro; Arcieri, Romano; Germinario, Elena A P; Capuano, Annalisa; Margari, Lucia; Chiarotti, Flavia; Curatolo, Paolo

2015-01-01

The aim of this study was to assess the type and frequency of adverse events (AEs) in children with attention-deficit/hyperactivity disorder (ADHD) treated with methylphenidate or atomoxetine over a 5-year period in a large naturalistic study. We draw on data from the Italian ADHD Registry, a national database for postmarketing phase IV pharmacovigilance of ADHD medications across 90 centers. AEs were defined as severe or mild as per the classification of the Italian Medicines Agency. AE frequency in the two treatment groups was compared using incidence rates per 100 person-years (IR100PY) and incidence rate ratios (IRRs). Mantel-Haenszel adjusted IRRs were calculated to control for psychiatric comorbidity. A total of 1350 and 753 participants (aged 6-18 years, mean age 10.7 ± 2.8) were treated with methylphenidate and atomoxetine, respectively, from 2007 to 2012. Ninety participants (7 %) were switched from methylphenidate to atomoxetine, and 138 (18 %) from atomoxetine to methylphenidate. Thirty-seven children treated with atomoxetine and 12 with methylphenidate had their medication withdrawn. Overall, 645 patients (26.8 %) experienced at least one mild AE (including decreased appetite and irritability, for both drugs) and 95 patients (3.9 %) experienced at least one severe AE (including severe gastrointestinal events). IR100PY were significantly higher in the atomoxetine-treated group compared with the methylphenidate-treated group for a number of mild and severe AEs and for any severe or mild AEs. After controlling for comorbidities, IRR was still significantly higher in the atomoxetine group compared with the methylphenidate group for a number of mild (decreased appetite, weight loss, abdominal pain, dyspepsia, stomach ache, irritability, mood disorder and dizziness) and severe (gastrointestinal, neuropsychiatric, and cardiovascular) AEs. In this naturalistic study, methylphenidate had a better safety profile than atomoxetine.

Real-World Dosing Patterns of Atomoxetine in Adults with Attention-Deficit/Hyperactivity Disorder.

PubMed

Kabul, Samaneh; Alatorre, Carlos; Montejano, Leslie B; Farr, Amanda M; Clemow, David B

2015-12-01

The aim was to investigate the dosing patterns of atomoxetine monotherapy in adult patients with attention-deficit/hyperactivity disorder (ADHD) in a retrospective analysis. Adult (≥ 18 years) patients with ADHD newly initiated on atomoxetine with ≥ 1 outpatient pharmacy claim for atomoxetine between January 2006 and December 2011 were selected from the Truven Health MarketScan(®) Commercial database. After a 30-day titration period, dosing patterns of atomoxetine monotherapy were analyzed in the 12 months following initiation. In addition, patient demographic and clinical characteristics were compared to identify characteristics associated with suboptimal versus recommended dosing. Of the 12,412 adult patients with ADHD newly initiated on atomoxetine, 4548 (36.6%) were suboptimally dosed, whereas 3323 (26.7%) were treated at recommended dose. Overall, study patients were treated at a mean (standard deviation [SD]) dose of 68.5 (44.9) mg/day. The suboptimal dosing cohort included significantly more females (54% vs. 44%, P < 0.001) and had fewer patients with pre-index use of other ADHD medications (17% vs. 20%, P < 0.001) compared with the recommended dosing cohort. Adult patients with ADHD receiving atomoxetine therapy in a real-world setting are often dosed suboptimally. Increasing the awareness on optimal dosing strategy among clinicians and patients is warranted to maximize the therapeutic benefits of atomoxetine among adult patients with ADHD. © 2015 Eli Lilly and Company. CNS Neuroscience and Therapeutics published by John Wiley & Sons Ltd.

Atomoxetine versus Stimulants in the Community Treatment of Children with ADHD: An Electronic Diary Study

ERIC Educational Resources Information Center

Whalen, Carol K.; Henker, Barbara; Ishikawa, Sharon S.; Emmerson, Natasha A.; Swindle, Ralph; Johnston, Joseph A.

2010-01-01

Objective: To compare the morning and afternoon/evening functioning of children with ADHD treated in the community with either atomoxetine or long-acting stimulants and reported to be doing well. Method: 109 8- to 12-year-olds and their mothers participated in one of three groups: stimulants (STIM, N = 26), atomoxetine (ATMX, N = 25), or…

Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder.

PubMed

Spencer, Thomas; Heiligenstein, John H; Biederman, Joseph; Faries, Douglas E; Kratochvil, Christopher J; Conners, C Keith; Potter, William Z

2002-12-01

Atomoxetine is a nonstimulant drug being studied for the treatment of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine is a highly specific inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. Results of 2 proof-of-concept studies are reported that tested the hypothesis that a selective inhibitor of presynaptic norepinephrine uptake would be effective for the treatment of ADHD in school-aged children. Two identical 12-week, stratified, randomized, double-blind, placebo-controlled trials were conducted in children who met DSM-IV criteria for ADHD. The primary efficacy outcome measure was the mean change from baseline to endpoint in the Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD RS) total score. Secondary efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) and the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S). A total of 291 patients were randomized in the 2 trials combined (Study 1, N = 147; Study 2, N = 144). Stimulant-naive patients were randomized to atomoxetine, placebo, or methylphenidate. Patients with prior stimulant exposure were randomized to atomoxetine or placebo. Atomoxetine significantly reduced ADHD RS total scores compared with placebo in each study (p <.001). Changes in the CGI-ADHD-S (Study 1: p =.003; Study 2: p =.001) and CPRS-ADHD Index (Study 1: p =.023; Study 2: p <.001) also showed atomoxetine to be statistically significantly superior to placebo in reducing ADHD symptoms. Atomoxetine was found to be well tolerated in this population of pediatric patients. Two studies of atomoxetine early in its development confirmed that atomoxetine, a specific and selective inhibitor of noradrenergic uptake, was effective for the treatment of children with ADHD. In addition, atomoxetine was found to be well tolerated.

Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments*

PubMed Central

Jordan, Chloe J.; Harvey, Roxann C.; Baskin, Britahny B.; Dwoskin, Linda P.; Kantak, Kathleen M.

2014-01-01

Background Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown. Methods To investigate this, SHR, Wistar-Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post-natal day 28–55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule. Results Compared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains. Conclusions The SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD. PMID:24811203

Atomoxetine Increased Effect over Time in Adults with Attention-Deficit/Hyperactivity Disorder Treated for up to 6 Months: Pooled Analysis of Two Double-Blind, Placebo-Controlled, Randomized Trials.

PubMed

Wietecha, Linda A; Clemow, David B; Buchanan, Andrew S; Young, Joel L; Sarkis, Elias H; Findling, Robert L

2016-07-01

Changes in the magnitude of efficacy throughout 26 weeks of atomoxetine treatment, along with impact of dosing, were evaluated in adults with ADHD from two randomized, double-blind, placebo-controlled studies. Pooled placebo (n = 485) and atomoxetine (n = 518) patients, dosed 25, 40, 60, 80 (target dose), or 100 mg daily, were assessed. Change from baseline in Conners' Adult ADHD Rating Scale-Investigator Rated Scale: Screening Version (CAARS) total ADHD symptoms score and Adult ADHD Investigator Symptom Rating Scale (AISRS) total score were analyzed using mixed-model repeated measures, with least squares mean change, effect size, and response rate calculated at 1, 2, 4, 8, 12, 16, 22, and 26 weeks. Decreases on CAARS for atomoxetine- versus placebo-treated patients were consistently statistically significantly greater at every time point beginning at one week (P ≤ 0.006, 0.28 effect size). By 4 weeks, comparison was -13.19 compared with -8.84 (P < 0.0001, 0.45 effect size). By 26 weeks, mean change was -15.42 versus -9.71 (0.52 effect size); increase in effect size over time was most pronounced in the 80 mg group (0.82 effect size). AISRS demonstrated similar results. Atomoxetine response rate (CAARS 50% decrease) continued to increase throughout 26 weeks. Atomoxetine treatment in adults with ADHD was associated with small effect sizes after 4 weeks and moderate effect sizes by 6 months of treatment. The data support increased effect size and response rate over time during longer-term treatment at target dose. © 2016 Eli Lilly and Company. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

Effects of atomoxetine with and without behavior therapy on the school and home functioning of children with attention-deficit/hyperactivity disorder.

PubMed

Waxmonsky, James G; Waschbusch, Daniel A; Pelham, William E; Draganac-Cardona, Lillian; Rotella, Bryan; Ryan, Lynn

2010-11-01

To evaluate the effects of atomoxetine alone and in combination with behavior therapy on the school functioning of children with attention-deficit/hyperactivity disorder (ADHD). Most atomoxetine studies have not assessed school functioning other than by measuring the change in ADHD symptoms. Combining behavior therapy with atomoxetine may be particularly beneficial for the academic domain as medication has not been found to produce sustained benefits in this realm. However, there is little research examining the effects of combining atomoxetine and behavior therapy. In an 8-week open-label trial, 56 children aged 6-12 years with ADHD diagnosed according to DSM-IV-TR were randomly assigned to receive atomoxetine and behavior therapy or atomoxetine alone. Behavior therapy consisted of an 8-week parenting course, a child social skills course, and a teacher-implemented daily report card of classroom behavior. The primary outcome was direct observation of the subject's classroom behavior. Secondary outcomes included change in ADHD symptoms and functioning at home and school. All data were collected between March 2007 and May 2008. Classroom observations showed that atomoxetine decreased rule violations (P < .0001). Moreover, atomoxetine was associated with significant improvements in ADHD and oppositional defiant disorder symptoms at home and school and enhanced functioning in both domains (Impairment Rating Scale: all P < .001). Combined treatment led to greater improvements in parent-rated symptoms of inattention (P < .01), problem behaviors (P < .001), and academic impairment (P < .05). However, teachers did not report significant group differences. Atomoxetine improved ADHD symptoms and classroom functioning as measured by parents, teachers, and direct observation. The addition of behavior therapy led to further improvements at home but not at school. clinicaltrials.gov Identifier: NCT00918567. © Copyright 2010 Physicians Postgraduate Press, Inc.

Atomoxetine and Methylphenidate Treatment in Children with ADHD: The Efficacy, Tolerability and Effects on Executive Functions

ERIC Educational Resources Information Center

Yildiz, Ozlem; Sismanlar, Sahika G.; Memik, Nursu Cakin; Karakaya, Isik; Agaoglu, Belma

2011-01-01

The aim of this study was to compare the safety, efficacy, tolerability, and the effects of atomoxetine and OROS-MPH on executive functions in children with ADHD. This study was an open-label study that only included two medication groups. Children were randomized to open-label atomoxetine or OROS-MPH for 12 weeks. Primary efficacy measures were…

[Atomoxetine and piracetam in the treatment of attention deficit hyperactivity disorder in children].

PubMed

Zavadenko, N N; Suvorinova, N Iu

2008-01-01

Therapeutic effect of atomoxetine and piracetam has been assessed in the open controlled study included 42 patients with attention deficit hyperactivity disorder (ADHD), aged from 6 to 13 years. Group 1 (16 patients) received atomoxetine (strattera) in daily dosage 0,8-1,2 mg/kg as a monotherapy for 6 weeks. Patients of group 2 (14 children) received piracetam as a monotherapy in daily dosage 50-70 mg/kg for 6 weeks. No pharmacological therapy was conducted in group 3 (a control one) which included 12 patients with ADHD. The high effectiveness of both atomoxetine and piracetam has been shown. However, comparing to piracetam, the therapeutic effect of atomoxetine was reached earlier (two weeks after the beginning of therapy) and was more pronounced for all components of syndromes.

An Open-Label, Randomized Trial of Methylphenidate and Atomoxetine Treatment in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Shang, Chi-Yung; Pan, Yi-Lei; Lin, Hsiang-Yuan; Huang, Lin-Wan; Gau, Susan Shur-Fen

2015-09-01

The efficacy of both methylphenidate and atomoxetine has been established in placebo-controlled trials. The present study aimed to directly compare the efficacy of methylphenidate and atomoxetine in improving symptoms among children with attention-deficit/hyperactivity disorder (ADHD). The study sample included 160 drug-naïve children and adolescents 7-16 years of age, with DSM-IV-defined ADHD, randomly assigned to osmotic-release oral system methylphenidate (OROS-methylphenidate) (n=80) and atomoxetine (n=80) in a 24 week, open-label, head-to-head clinical trial. The primary efficacy measure was the score of the ADHD Rating Scale-IV Parents Version: Investigator Administered and Scored (ADHD-RS-IV). The secondary efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) and Chinese Swanson, Nolan, and Pelham IV scale (SNAP-IV), based on the ratings of investigators, parents, teachers, and subjects. At week 24, mean changes in ADHD-RS-IV Inattention scores were 13.58 points (Cohen's d, -3.08) for OROS-methylphenidate and 12.65 points (Cohen's d, -3.05) for atomoxetine; and mean changes in ADHD-RS-IV Hyperactivity-Impulsivity scores were 10.16 points (Cohen's d, -1.75) for OROS-methylphenidate and 10.68 points (Cohen's d, -1.87) for atomoxetine. In terms of parent-, teacher-, and self-ratings on behavioral symptoms, both of the two treatment groups significantly decreased on the SNAP-IV scores at the end-point, with effect sizes ranging from 0.9 to 0.96 on the Inattention subscale and from 0.61 to 0.8 on the Hyperactivity/Impulsivity subscale for OROS-methylphenidate; and from 0.51 to 0.88 on the Inattention subscale and from 0.29 to 0.57 on the Hyperactivity/Impulsivity subscale for atomoxetine. No statistically significant differences between treatment groups were observed on the outcome measures. Vomiting, somnolence, and dizziness were reported more often for atomoxetine than for OROS-methylphenidate, whereas insomnia was reported more often for OROS-methylphenidate than for atomoxetine. After 24 weeks of treatment, OROS-methylphenidate and atomoxetine had comparable efficacy in reducing core ADHD symptoms in drug-naïve children and adolescents with ADHD.

Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites.

PubMed

Byeon, Ji-Yeong; Kim, Young-Hoon; Na, Han-Sung; Jang, Jong-Hwa; Kim, Se-Hyung; Lee, Yun-Jeong; Bae, Jung-Woo; Kim, In Su; Jang, Choon-Gon; Chung, Myeon-Woo; Lee, Seok-Yong

2015-11-01

To investigate the effect of the variant CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (NAT), in healthy subjects, a single oral dose of atomoxetine was administered to 62 subjects with a CYP2D6*wt/*wt (*wt = *1 or *2, n = 22), CYP2D6*wt/*10 (n = 22) or CYP2D6*10/*10 (n = 18) genotype. Plasma samples were then collected for 24 h after atomoxetine administration. The concentrations of atomoxetine and its metabolites were assayed using LC-MS/MS. For atomoxetine, the Cmax, AUC0-∞, t1/2 and CL/F showed genotype-dependent differences. The CYP2D6*10/*10 and CYP2D6*wt/*10 groups showed 1.74- and 1.15-fold higher Cmax, 3.40- and 1.33-fold higher AUC0-∞, and 69.7 and 24.6 % lower CL/F, compared to those of the CYP2D6*wt/*wt group, respectively. The Cmax and t1/2 for 4-HAT were lower and longer in the CYP2D6*10/*10 group than those in the CYP2D6*wt/*wt group, but the AUC0-∞ was not different between these groups. The Cmax, AUC0-∞ and t1/2 for NAT were profoundly greater in the CYP2D6*10/*10 group than they were in the CYP2D6*wt/*wt group. The concentration of active moieties of atomoxetine (atomoxetine + 4-HAT) in the CYP2D6*10/*10 group was 3.32-fold higher than that in the CYP2D6*wt/*wt group. The mean exposure to active moieties of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6*wt/*wt genotype. The higher systemic exposure of the active atomoxetine moieties in CYP2D6*10/*10 individuals may increase the risk of concentration-related adverse events of atomoxetine, although this has not yet been clinically confirmed.

Atomoxetine Treatment for ADHD: Younger Adults Compared with Older Adults

ERIC Educational Resources Information Center

Durell, Todd; Adler, Lenard; Wilens, Timothy; Paczkowski, Martin; Schuh, Kory

2010-01-01

Objective: Atomoxetine is a nonstimulant medication for treating child, adolescent, and adult ADHD. This meta-analysis compared the effects in younger and older adults. Method: A post hoc analysis was conducted using data from two double-blind, placebo-controlled clinical trials. Data from patients aged 18-25 years were compared with data from…

Atomoxetine could improve intra-individual variability in drug-naïve adults with attention-deficit/hyperactivity disorder comparably with methylphenidate: A head-to-head randomized clinical trial.

PubMed

Ni, Hsing-Chang; Hwang Gu, Shoou-Lian; Lin, Hsiang-Yuan; Lin, Yu-Ju; Yang, Li-Kuang; Huang, Hui-Chun; Gau, Susan Shur-Fen

2016-05-01

Intra-individual variability in reaction time (IIV-RT) is common in individuals with attention-deficit/hyperactivity disorder (ADHD). It can be improved by stimulants. However, the effects of atomoxetine on IIV-RT are inconclusive. We aimed to investigate the effects of atomoxetine on IIV-RT, and directly compared its efficacy with methylphenidate in adults with ADHD. An 8-10 week, open-label, head-to-head, randomized clinical trial was conducted in 52 drug-naïve adults with ADHD, who were randomly assigned to two treatment groups: immediate-release methylphenidate (n=26) thrice daily (10-20 mg per dose) and atomoxetine once daily (n=26) (0.5-1.2 mg/kg/day). IIV-RT, derived from the Conners' continuous performance test (CCPT), was represented by the Gaussian (reaction time standard error, RTSE) and ex-Gaussian models (sigma and tau). Other neuropsychological functions, including response errors and mean of reaction time, were also measured. Participants received CCPT assessments at baseline and week 8-10 (60.4±6.3 days). We found comparable improvements in performances of CCPT between the immediate-release methylphenidate- and atomoxetine-treated groups. Both medications significantly improved IIV-RT in terms of reducing tau values with comparable efficacy. In addition, both medications significantly improved inhibitory control by reducing commission errors. Our results provide evidence to support that atomoxetine could improve IIV-RT and inhibitory control, of comparable efficacy with immediate-release methylphenidate, in drug-naïve adults with ADHD. Shared and unique mechanisms underpinning these medication effects on IIV-RT awaits further investigation. © The Author(s) 2016.

Pharmacokinetic Profile and Palatability of Atomoxetine Oral Solution in Healthy Japanese Male Adults.

PubMed

Nakano, Masako; Witcher, Jennifer; Satoi, Yoichi; Goto, Taro

2016-11-01

There is a clinical need for a liquid formulation of atomoxetine. We assessed the safety and bioequivalence of an atomoxetine oral solution. This was an open-label, randomized, crossover study. Healthy adult male Japanese subjects (n = 42) with a cytochrome P450 2D6 extensive (including intermediate and ultrarapid) metabolizer genotype were administered atomoxetine 50 mg as oral solution and capsules once each, with a washout period >5 days between doses. Blood samples were used to analyze pharmacokinetic parameters, particularly maximum observed drug concentration (C max ) and area under the concentration vs. time curve from time zero to the last time point with a measurable concentration (AUC 0-last ). Bioequivalence was concluded if the 90 % confidence interval of the ratio of geometric means between formulations for both C max and AUC 0-last were within the interval of 0.8-1.25. Safety assessments included determination of adverse events. Taste was evaluated via a five-item questionnaire immediately and 10 min after taking atomoxetine oral solution. Forty subjects completed the study. Plasma concentration-time profiles of atomoxetine oral solution and capsules were similar, and the statistical analysis of systemic exposure showed that the two formulations were bioequivalent. Adverse events were mild and similar in type and frequency between the formulations. For taste acceptability, only 7.1 % of subjects responded that the oral solution would be difficult to take every day. Atomoxetine oral solution is bioequivalent to atomoxetine capsules and potentially fulfills the need for an oral solution atomoxetine formulation that will facilitate treatment of children with attention-deficit hyperactivity disorder.

Effect of Atomoxetine on the Cognitive Functions in Treatment of Attention Deficit Hyperactivity Disorder in Children with Congenital Hypothyroidism: A Pilot Study.

PubMed

Yang, Rongwang; Gao, Weijia; Li, Rong; Zhao, Zhengyan

2015-04-19

With early initiation of thyroxine supplementation, children with congenital hypothyroidism (CH) retain some subtle deficits, such as attention and inhibitory control problems. This study assessed the effects of atomoxetine on cognitive functions in treatment of attention deficit hyperactivity disorder (ADHD) symptoms in children with CH. In a 6-month, open-labeled pilot study, 12 children were recruited and received atomoxetine. The measures of efficacy were scores on the Swanson, Nolan and Pelham Teacher and Parent Rating Scale, version IV (SNAP-IV) and Clinical Global Impression-Severity scale (CGI-S). The cognitive functions were evaluated with the Wechsler Intelligence Scale for Chinese Children, Digit Span, Wisconsin Card Sorting Test, and Stroop test. A statistically significant difference was found between the mean CGI-S and SNAP-IV scores before and after treatment (p < 0.01). All the indicators of cognitive functions at the endpoint were improved compared with those at baseline. No serious adverse events were reported. Atomoxetine appears to be useful in improving ADHD symptoms, as well as cognitive functions, in children with CH. Larger, randomized, double-blinded, clinical trials are required to replicate these results. © The Author 2015. Published by Oxford University Press on behalf of CINP.

The influence of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite.

PubMed

Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Chira, Ruxandra; Briciu, Corina

2015-01-01

To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers. 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period. Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively. Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

Does Comorbid Disruptive Behavior Modify the Effects of Atomoxetine on ADHD Symptoms as Measured by a Continuous Performance Test and a Motion Tracking Device?

PubMed

Wehmeier, Peter M; Kipp, Laura; Banaschewski, Tobias; Dittmann, Ralf W; Schacht, Alexander

2015-07-01

To compare the reduction of ADHD symptoms under atomoxetine in patients with and without comorbid oppositional defiant disorder (ODD) or conduct disorder (CD) using a computer-based continuous performance test (cb-CPT) combined with an infrared motion tracking (MT) device. Secondary analysis of a placebo-controlled study in ADHD patients (6-12 years old) treated with atomoxetine (target dose: 1.2 mg/kg per day). Cb-CPT/MT scores were analyzed using ANCOVA (last observation carried forward [LOCF]). The data (N = 125) suggested a more pronounced atomoxetine effect in the group with comorbid ODD/CD as measured by all cb-CPT/MT parameters except for "normalized variation of reaction time" (nVRT). The results showed that atomoxetine reduced ADHD severity as measured by cb-CPT and MT parameters regardless of whether comorbid ODD/CD was present. The treatment effect of atomoxetine on hyperactivity appears to be more pronounced in the subgroup of patients with comorbid ODD/CD than in the subgroup without this comorbidity. © 2012 SAGE Publications.

Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

PubMed

Brown, Jacob T; Bishop, Jeffrey R

2015-01-01

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

Atomoxetine in patients with ADHD: A clinical and pharmacological review of the onset, trajectory, duration of response and implications for patients.

PubMed

Clemow, David B; Bushe, Chris J

2015-12-01

This article reviews data providing new insight into the trajectory of response and maintenance of response of atomoxetine in the treatment of child and adult attention-deficit hyperactivity disorder (ADHD). This nonsystematic review includes: onset of action and duration of effect, response rate, effect size, time to optimal response and norepinephrine transporter blockade biomarker data. Atomoxetine can have an onset of action within 1-2 weeks of starting treatment, but there is an incrementally increasing response for up to 24 weeks or longer. Responder rates and effect sizes are similar to methylphenidate. Upon treatment discontinuation, relapse rates are lower than expected. In adults, 50% maintain their response for at least 6 months after stopping atomoxetine, following 6 months of treatment. Single-dose atomoxetine can provide 24-hour efficacy, despite a 5-hour plasma half-life. Hypotheses can be generated relating to neuroadaptive changes, to explain these findings. Atomoxetine has a trajectory of response that is incremental over a long period of time, with a greater than expected maintenance of response. This has implications for physician atomoxetine dosing and efficacy assessment, patient education and outcomes, and for clinical trial design and assessment of comparative efficacy with stimulant medications. © The Author(s) 2015.

Use of atomoxetine and suicidal ideation in children and adolescents: Results of an observational cohort study within general practice in England.

PubMed

Davies, M; Coughtrie, A; Layton, D; Shakir, S A S

2017-01-01

To investigate the association between atomoxetine, a drug used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and suicidal ideation, within a cohort of 2-18-year-old patients in England. The study was conducted using the observational cohort technique of Modified prescription event monitoring (M-PEM). Patients prescribed atomoxetine were identified from dispensed prescriptions issued by primary care physicians. A customised postal GP questionnaire was used to capture outcome data for suicidal ideation. A matched pair cohort analysis was performed within patients to compare the risk of suicidal ideation in the period after starting atomoxetine with the risk prior to starting atomoxetine; this was stratified by age and concomitant use of methylphenidate. Additional information on patient characteristics, and events of interest was also collected; individual cases of suicidal ideation were qualitatively assessed for drug relatedness. Of the final cohort (n=4509); 85.5% male (n=3857), median age 11 years (IQR: 9,14). Primary prescribing indication for atomoxetine was ADHD (n=4261, 94.6%). Almost a quarter of the cohort had been co-prescribed methylphenidate. Results of the matched pair cohort analysis indicated that the period after starting atomoxetine was not associated with an increase in the incidence of suicidal ideation compared to the period prior to starting treatment (RR: 0.71; CI: 0.48-1.07; P-value: 0.104). Individual case assessment of suicidal ideation suggested a causal association within a number of cases. This study found no evidence of an increased risk of suicidal ideation during treatment with atomoxetine, compared to the period prior to starting treatment. Amongst age specific subgroups, this risk may change. Nonetheless, individual case assessment suggested a causal relationship in some patients, hence physicians need to be aware of the possibility of developing this event, and furthermore consider how best to detect it in this paediatric population. This study demonstrates the importance of combining quantitative statistical analyses with a qualitative case series assessment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Atomoxetine restores the response inhibition network in Parkinson’s disease

PubMed Central

Rae, Charlotte L.; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E.; Jones, P. Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2016-01-01

Abstract Parkinson’s disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson’s disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson’s disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson’s disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson’s disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson’s disease. PMID:27343257

Neural correlates of atomoxetine improving inhibitory control and visual processing in Drug-naïve adults with attention-deficit/hyperactivity disorder.

PubMed

Fan, Li-Ying; Chou, Tai-Li; Gau, Susan Shur-Fen

2017-10-01

Atomoxetine improves inhibitory control and visual processing in healthy volunteers and adults with attention-deficit/hyperactivity disorder (ADHD). However, little is known about the neural correlates of these two functions after chronic treatment with atomoxetine. This study aimed to use the counting Stroop task with functional magnetic resonance imaging (fMRI) and the Cambridge Neuropsychological Test Automated Battery (CANTAB) to investigate the changes related to inhibitory control and visual processing in adults with ADHD. This study is an 8-week, placebo-controlled, double-blind, randomized clinical trial of atomoxetine in 24 drug-naïve adults with ADHD. We investigated the changes of treatment with atomoxetine compared to placebo-treated counterparts using the counting Stroop fMRI and two CANTAB tests: rapid visual information processing (RVP) for inhibitory control and delayed matching to sample (DMS) for visual processing. Atomoxetine decreased activations in the right inferior frontal gyrus and anterior cingulate cortex, which were correlated with the improvement in inhibitory control assessed by the RVP. Also, atomoxetine increased activation in the left precuneus, which was correlated with the improvement in the mean latency of correct responses assessed by the DMS. Moreover, anterior cingulate activation in the pre-treatment was able to predict the improvements of clinical symptoms. Treatment with atomoxetine may improve inhibitory control to suppress interference and may enhance the visual processing to process numbers. In addition, the anterior cingulate cortex might play an important role as a biological marker for the treatment effectiveness of atomoxetine. Hum Brain Mapp 38:4850-4864, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Efficacy and safety of atomoxetine hydrochloride in Korean adults with attention-deficit hyperactivity disorder.

PubMed

Lee, Soyoung Irene; Song, Dong-Ho; Shin, Dong Won; Kim, Ji Hoon; Lee, Young Sik; Hwang, Jun-Won; Park, Tae Won; Yook, Ki-Hwan; Lee, Jong Il; Bahn, Geon Ho; Hirata, Yuko; Goto, Taro; Takita, Yasushi; Takahashi, Michihiro; Lee, Sanghoon; Treuer, Tamás

2014-12-01

This article aims to assess the efficacy and safety of atomoxetine in Korean adults with attention-deficit hyperactivity disorder (ADHD). This post hoc double-blind, placebo-controlled study of atomoxetine (40-120 mg/day) over 10 weeks in adults with ADHD at 45 Japanese, Korean, and Taiwanese study sites focused on patient data from Korea (atomoxetine, n = 37; placebo, n = 37). Primary efficacy outcome was change in baseline-to-endpoint Conners' Adult ADHD Rating Scale-Investigator-rated: Screening Version (CAARS-Inv:SV) Total ADHD Symptoms score. Secondary efficacy outcomes included changes in Adult ADHD Quality of Life (AAQoL) total, Behavior Rating Inventory of Executive Function-Adult Version Self-Report (BRIEF-A:Self-Report), and Clinical Global Impression-ADHD-Severity (CGI-ADHD-S) scale scores. Atomoxetine-treated patients demonstrated a mean 18.9-point reduction in CAARS-Inv:SV total ADHD Symptoms score, compared with the 7.45-point reduction in placebo-treated patients (P ≤ 0.01). Significantly greater improvement was found for atomoxetine versus placebo in CGI-ADHD-S (P ≤ 0.01), BRIEF-A:Self-Report global executive composite (P ≤ 0.05), and metacognition index (P ≤ 0.01) executive function scores. Nausea, decreased appetite, and dry mouth were reported with significantly greater frequency by atomoxetine-treated patients, and only one placebo-treated patient discontinued because of adverse event. A 2.1-kg reduction in weight and a 7.5-beat/minute increase in pulse rate were observed in atomoxetine-treated patients. These data support a significant benefit of 80- to 120-mg once daily atomoxetine versus placebo for treatment of ADHD in adult Korean patients. A high placebo response rate was observed in this adult Korean sample; a higher discontinuation rate was also observed in atomoxetine-treated patients. These observations warrant further investigation. © 2014 Wiley Publishing Asia Pty Ltd.

A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients.

PubMed

Bushe, Chris; Day, Kathleen; Reed, Victoria; Karlsdotter, Kristina; Berggren, Lovisa; Pitcher, Ashley; Televantou, Foula; Haynes, Virginia

2016-05-01

The lack of head-to-head clinical studies powered to compare atomoxetine and osmotic release oral system (OROS) methylphenidate necessitates treatment comparison by methods that include indirect evidence such as network meta-analysis (NMA). A NMA assessing the relative treatment effects of atomoxetine and OROS methylphenidate in adults with attention-deficit/hyperactivity disorder (ADHD) was conducted. Studies were identified by systematic literature review. Analyses summarised improvements in efficacy, measured by ADHD-specific scales, using Cohen'sdto calculate the standardised mean difference (SMD), and all cause discontinuations. Results showed effect sizes (SMD, 95% credible interval (CrI)) relative to placebo that did not differ significantly between atomoxetine (0.46, 0.36-0.56) and OROS methylphenidate (0.51, 0.40-0.63) in clinical studies of up to 12 weeks' duration (SMD, 95% CrI for atomoxetine versus OROS methylphenidate: -0.05, -0.18-0.08). Patients treated with these medications responded better than those given placebo across all analyses. There was also no significant difference in discontinuation rates between atomoxetine and OROS methylphenidate (odds ratio, 95% CrI: 0.85, 0.53-1.35). Between-study heterogeneity was low overall. Results of this NMA suggest that the efficacy of atomoxetine and OROS methylphenidate in adults does not differ significantly. Clinical guidelines may require amendment to reflect these recent data. © The Author(s) 2016.

Atomoxetine, a selective norepinephrine reuptake inhibitor, improves short-term histological outcomes after hypoxic-ischemic brain injury in the neonatal male rat.

PubMed

Toshimitsu, Masatake; Kamei, Yoshimasa; Ichinose, Mari; Seyama, Takahiro; Imada, Shinya; Iriyama, Takayuki; Fujii, Tomoyuki

2018-03-30

Despite the recent progress of perinatal medicine, perinatal hypoxic-ischemic (HI) insult remains an important cause of brain injury in neonates, and is pathologically characterized by neuronal loss and the presence of microglia. Neurotransmitters, such as norepinephrine (NE) and glutamate, are involved in the pathogenesis of hypoxic-ischemic encephalopathy via the interaction between neurons and microglia. Although it is well known that the monoamine neurotransmitter NE acts as an anti-inflammatory agent in the brain under pathological conditions, its effects on perinatal HI insult remains elusive. Atomoxetine, a selective NE reuptake inhibitor, has been used clinically for the treatment of attention-deficit hyperactivity disorder in children. Here, we investigated whether the enhancement of endogenous NE by administration of atomoxetine could protect neonates against HI insult by using the neonatal male rat model. We also examined the involvement of microglia in this process. Unilateral HI brain injury was induced by the combination of left carotid artery dissection followed by ligation and hypoxia (8% O 2 , 2 h) in postnatal day 7 (P7) male rat pups. The pups were randomized into three groups: the atomoxetine treatment immediately after HI insult, the atomoxetine treatment at 3 h after HI insult, or the vehicle treatment group. The pups were euthanized on P8 and P14, and the brain regions including the cortex, striatum, hippocampus, and thalamus were evaluated by immunohistochemistry. HI insult resulted in severe brain damage in the ipsilateral hemisphere at P14. Atomoxetine treatment immediately after HI insult significantly increased NE levels in the ipsilateral hemisphere at 1 h after HI insult and reduced the neuronal damage via the increased phosphorylation of cAMP response element-binding protein (pCREB) in all brain regions examined. In addition, the number of microglia was maintained under atomoxetine treatment compared with that of the vehicle treatment group. To determine the involvement of microglia in the process of neuronal loss by HI insult, we further examined the influence of hypoxia on rat primary cultured microglia by the quantitative real-time polymerase chain reaction. Hypoxia did not cause the upregulation of interleukin-1beta (IL-1β) mRNA expression, but decreased the microglial intrinsic nitric oxide synthase (iNOS)/arginase1 mRNA expression ratio. NE treatment further decreased the microglial iNOS/arginase1 mRNA expression ratio. In contrast, no significant neuroprotective effect was observed at P14 when atomoxetine was administered at 3 h after HI insult. These findings suggested that the enhancement of intrinsic neurotransmitter NE signaling by a selective NE reuptake inhibitor, atomoxetine, reduced the perinatal HI insult brain injury. In addition, atomoxetine treatment was associated with changes of TUNEL, pCREB, and BDNF expression levels, and microglial numbers, morphology, and responses. Copyright © 2018. Published by Elsevier Ltd.

Improving response inhibition in Parkinson's disease with atomoxetine.

PubMed

Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

2015-04-15

Dopaminergic drugs remain the mainstay of Parkinson's disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Patients with Parkinson's disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson's disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson's disease. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Improving Response Inhibition in Parkinson’s Disease with Atomoxetine

PubMed Central

Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R.; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L.; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.; Rowe, James B.

2015-01-01

Background Dopaminergic drugs remain the mainstay of Parkinson’s disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. Methods This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Results Patients with Parkinson’s disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. Conclusions This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson’s disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s disease. PMID:24655598

An Open-Label, Randomized Trial of Methylphenidate and Atomoxetine Treatment in Adults With ADHD.

PubMed

Ni, Hsing-Chang; Lin, Yu-Ju; Gau, Susan Shur-Fen; Huang, Hui-Chun; Yang, Li-Kuang

2017-01-01

To directly compare the efficacy of methylphenidate and atomoxetine in improving symptoms, social functions, and quality of life among adults with ADHD. This was an 8-to-10-week, open-label, head-to-head, randomized clinical trial with two treatment arms: immediate-release methylphenidate (IR-methylphenidate; n = 31) and atomoxetine once daily ( n = 32). The outcome measures included ADHD symptom severity, quality of life, and functional impairments. We found a significant reduction in overall ADHD symptoms and improvement in social functions and quality of life for both groups at Weeks 4 to 5 and Weeks 8 to 10. There was no significant difference in the slope of improvements over time except that atomoxetine was superior to IR-methylphenidate in reducing hyperactive/impulsive symptoms at Weeks 4 to 5. There was no significant group difference in the rates of adverse effects. Both IR-methylphenidate and atomoxetine are well tolerated and efficacious in ethnic Chinese adults with ADHD.

A liquid chromatography/tandem mass spectrometry assay for the analysis of atomoxetine in human plasma and in vitro cellular samples

PubMed Central

Appel, David I.; Brinda, Bryan; Markowitz, John S.; Newcorn, Jeffrey H.; Zhu, Hao-Jie

2012-01-01

A simple, rapid and sensitive method for quantification of atomoxetine by liquid chromatography- tandem mass spectrometry (LC-MS/MS) was developed. This assay represents the first LC-MS/MS quantification method for atomoxetine utilizing electrospray ionization. Deuterated atomoxetine (d3-atomoxetine) was adopted as the internal standard. Direct protein precipitation was utilized for sample preparation. This method was validated for both human plasma and in vitro cellular samples. The lower limit of quantification was 3 ng/ml and 10 nM for human plasma and cellular samples, respectively. The calibration curves were linear within the ranges of 3 ng/ml to 900 ng/ml and 10 nM to 10 μM for human plasma and cellular samples, respectively (r2 > 0.999). The intra- and inter-day assay accuracy and precision were evaluated using quality control samples at 3 different concentrations in both human plasma and cellular lysate. Sample run stability, assay selectivity, matrix effect, and recovery were also successfully demonstrated. The present assay is superior to previously published LC-MS and LC-MS/MS methods in terms of sensitivity or the simplicity of sample preparation. This assay is applicable to the analysis of atomoxetine in both human plasma and in vitro cellular samples. PMID:22275222

A Cost-Utility Analysis of Lisdexamfetamine Versus Atomoxetine in the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Inadequate Response to Methylphenidate.

PubMed

Zimovetz, Evelina A; Beard, Stephen M; Hodgkins, Paul; Bischof, Matthias; Mauskopf, Josephine A; Setyawan, Juliana

2016-10-01

An economic analysis from the perspective of the UK National Health Service (NHS) evaluated the cost effectiveness of lisdexamfetamine dimesylate (LDX) compared with atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder who have had an inadequate response to methylphenidate. A 1-year decision-analytic model was constructed, with the health outcomes "response", "nonresponse", and "unable to tolerate". Clinical data were taken from a head-to-head, randomized controlled trial in inadequate responders to methylphenidate. Response to treatment was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Improvement subscale. Tolerability was assessed by discontinuation rates owing to adverse events. Utility weights were identified via a systematic literature review. Healthcare resource use estimates were obtained via a survey of clinicians. Daily drug costs were derived from British National Formulary 2012 costs and mean doses reported in the trial. One-way and probabilistic sensitivity analyses (PSAs) were performed. The comparison of LDX with atomoxetine resulted in an estimate of an incremental cost-effectiveness ratio of £1802 per quality-adjusted life-year (QALY). The result was robust in a wide range of sensitivity analyses; results were most sensitive to changes in drug costs and efficacy. In the PSA, assuming a maximum willingness to pay of £20,000 per QALY, LDX versus atomoxetine had an 86 % probability of being cost effective. In 38 % of PSA runs, LDX was more effective and less costly than atomoxetine. From the perspective of the UK NHS, LDX provides a cost-effective treatment option for children and adolescents who are inadequate responders to methylphenidate.

Atomoxetine for the Treatment of ADHD in Incarcerated Adolescents.

PubMed

Jillani, Sarah; Patel, Prina; Trestman, Robert; Kamath, Jayesh

2016-06-01

Effective interventions for adolescents with attention deficit/hyperactivity disorder (ADHD) in the correctional setting may improve care during incarceration, decrease risk of substance relapse, and reduce recidivism after release from the correctional setting of these individuals. The present report delineates the epidemiology of adolescent ADHD in the correctional setting and its association with substance use disorders and comorbid psychiatric illnesses. Evidence suggests that adolescents with ADHD have a higher risk of arrest and incarceration during adulthood. The present report examines evidence related to efficacy of atomoxetine, a nonstimulant medication for the treatment of adolescent ADHD, and presents data from a case series evaluating the effectiveness of atomoxetine for the treatment of adolescent ADHD in the Connecticut correctional setting. The results from the case series suggest that atomoxetine is effective for the treatment of adolescent ADHD in the context of significant past substance use. In summary, adolescents with ADHD have an elevated risk of incarceration and developing substance use disorders. The present review and pilot case series suggest that atomoxetine is an effective treatment for adolescents with ADHD in the correctional setting. © 2016 American Academy of Psychiatry and the Law.

Randomized, Controlled Trial of Atomoxetine for Attention-Deficit/Hyperactivity Disorder in Adolescents with Substance Use Disorder

ERIC Educational Resources Information Center

Thurstone, Christian; Riggs, Paula D.; Salomonsen-Sautel, Stacy; Mikulich-Gilbertson, Susan K.

2010-01-01

Objective: To evaluate the effect of atomoxetine hydrochloride versus placebo on attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) in adolescents receiving motivational interviewing/cognitive behavioral therapy (MI/CBT) for SUD. Method: This single-site, randomized, controlled trial was conducted between December…

Safety of atomoxetine in combination with intravenous cocaine in cocaine-experienced participants.

PubMed

Cantilena, Louis; Kahn, Roberta; Duncan, Connie C; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

2012-12-01

Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine and also whether cognitive function was affected by atomoxetine during short-term administration. In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 and 40 mg) was infused intravenously in sequential daily sessions. Preinfusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Preinfusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80- and 100-mg atomoxetine doses. All electrocardiogram parameters were unchanged. Visual Analog Scale (VAS) scores for "bad effect" in the atomoxetine group were significantly higher at baseline, then declined, and for "likely to use" declined with atomoxetine treatment. On the Addiction Research Center Inventory, the atomoxetine group scored significantly lower on amphetamine, euphoria, and energy subscales (P < 0.0001). Other VAS descriptors, Brief Substance Craving Scale, Profile of Moods State, and Brief Psychiatric Rating Scale showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine.

Safety of Atomoxetine in Combination with Intravenous Cocaine in Cocaine- Experienced Participants

PubMed Central

Cantilena, Louis; Kahn, Roberta; Duncan, Connie C.; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

2012-01-01

Objectives Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine, and also whether cognitive function was affected by atomoxetine during short-term administration. Methods In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 mg and 40 mg) was infused intravenously in sequential daily sessions. Results Pre-infusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Pre-infusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80 mg and 100 mg atomoxetine doses. All ECG parameters were unchanged. VAS scores for “bad effect” in the atomoxetine group were significantly higher at baseline, then declined, and for “likely to use” declined with atomoxetine treatment. On the ARCI the atomoxetine group scored significantly lower on amphetamine, euphoria and energy subscales (p<0.0001). Other VAS descriptors, BSCS, POMS, and BPRS showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Conclusions Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine. PMID:22987022

Open-label, dose-titration tolerability study of atomoxetine hydrochloride in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder.

PubMed

Takahashi, Michihiro; Goto, Taro; Takita, Yasushi; Chung, Sang-Keun; Wang, Yufeng; Gau, Susan Shur-Fen

2014-03-01

The primary objective of this study was to assess the overall safety and tolerability of atomoxetine in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder (ADHD). A total of 44 patients aged ≥18 years who met the Conners' Adult ADHD Diagnostic Interview for DSM-IV diagnostic criteria for ADHD were enrolled from China, Korea, and Taiwan. In this open-label, dose-escalation study, patients received atomoxetine orally once daily over a period of eight weeks, starting at 40 mg/day (one week) up to a maximum dosage of 120 mg/day. Tolerability was evaluated by rate of discontinuation due to adverse events. Safety was assessed by recording all adverse events, laboratory tests, vital signs, and electrocardiograms. ADHD symptoms were evaluated by the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) for efficacy assessment. Thirty-four patients (77.3%) completed the study. Atomoxetine was well tolerated with a discontinuation rate of 2.3% (1/44) due to adverse events. The most commonly reported adverse events were nausea, dizziness, and somnolence. The mean change from baseline to endpoint in CAARS-Inv:SV total ADHD symptom score was -12.5 (P < 0.001). A significant reduction in the CAARS-Inv:SV subscales (inattentive, hyperactive/impulsive, and ADHD index score, P < 0.001) was observed. This is the first atomoxetine clinical trial in adult patients with ADHD in China, Korea, and Taiwan. Atomoxetine was well tolerated in doses of up to 120 mg/day with no unknown safety concerns. Copyright © 2012 Blackwell Publishing Asia Pty Ltd.

Executive function in adults with attention-deficit/hyperactivity disorder during treatment with atomoxetine in a randomized, placebo-controlled, withdrawal study.

PubMed

Adler, Lenard; Tanaka, Yoko; Williams, David; Trzepacz, Paula T; Goto, Taro; Allen, Albert J; Escobar, Rodrigo; Upadhyaya, Himanshu P

2014-08-01

We assessed the executive function in adults with attention-deficit/hyperactivity disorder (ADHD) during atomoxetine treatment in a randomized withdrawal trial. Responders (Conners' ADHD Rating Scale-Investigator Rated: Screening Version [adult prompts] ≥30% reduction from baseline and Clinical Global Impression Scale-ADHD Severity score ≤3) to open-label atomoxetine (40-100 mg/d, 12 weeks) entered a 37-week double-blind maintenance period. Patients who maintained response (double-blind atomoxetine for 12 weeks) were randomized 1:1 to atomoxetine (80-100 mg/d, n = 266) or placebo (n = 258) for 25 weeks (total duration, 1 year). Patients and investigators were blinded to response criteria and randomization timing. Change in executive function was assessed with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Self-Report and Informant T scores from the randomization to the last-observation-carried-forward postrandomization week 25 (after week 17). Of the enrolled patients (n = 2017; mean age, 33.2 years; male, 58.7%), 524 responders were randomized. During open-label atomoxetine, subscales and individual items on both BRIEF-A questionnaires showed significant improvement (P < 0.001). After randomization, the following T scores improved significantly (P ≤ 0.05) with patients in the atomoxetine group versus those in the placebo group: global executive composite, behavioral regulation, and metacognition indices; plan/organize, working memory, inhibit, task monitor and shift (both BRIEF-A questionnaires), emotional control and organization of materials (BRIEF-A Informant), and initiate (BRIEF-A Self-Report). Atomoxetine significantly improved the executive function compared with placebo, which was maintained for 25 weeks or more; the executive function of patients in the placebo group worsened but did not return to baseline levels after randomization.

Effect of atomoxetine on hyperactivity in an animal model of attention-deficit/hyperactivity disorder (ADHD).

PubMed

Moon, Su Jin; Kim, Chang Ju; Lee, Yeon Jung; Hong, Minha; Han, Juhee; Bahn, Geon Ho

2014-01-01

Hyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention-deficit/hyperactivity disorder (ADHD). To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus. Young male spontaneously hypertensive rats (SHR), animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined. The motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D2 receptor immunohistochemistry, we observed significantly increased DA D2 receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D2 expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner. Hyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway.

Effect of Atomoxetine on Hyperactivity in an Animal Model of Attention-Deficit/Hyperactivity Disorder (ADHD)

PubMed Central

Moon, Su Jin; Kim, Chang Ju; Lee, Yeon Jung; Hong, Minha; Han, Juhee; Bahn, Geon Ho

2014-01-01

Background Hyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention-deficit/hyperactivity disorder (ADHD). Purpose To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus. Methods Young male spontaneously hypertensive rats (SHR), animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined. Results The motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D2 receptor immunohistochemistry, we observed significantly increased DA D2 receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D2 expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner. Conclusion Hyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway. PMID:25271814

Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder.

PubMed

Suzuki, Yutaro; Tajiri, Misuzu; Sugimoto, Atsunori; Orime, Naoki; Hayashi, Taketsugu; Egawa, Jun; Sugai, Takuro; Inoue, Yoshimasa; Someya, Toshiyuki

2017-02-01

The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.

Differential effects of methylphenidate and atomoxetine on intrinsic brain activity in children with attention deficit hyperactivity disorder.

PubMed

Shang, C Y; Yan, C G; Lin, H Y; Tseng, W Y; Castellanos, F X; Gau, S S

2016-11-01

Methylphenidate and atomoxetine are commonly prescribed for treating attention deficit hyperactivity disorder (ADHD). However, their therapeutic neural mechanisms remain unclear. After baseline evaluation including cognitive testing of the Cambridge Neuropsychological Test Automated Battery (CANTAB), drug-naive children with ADHD (n = 46), aged 7-17 years, were randomly assigned to a 12-week treatment with methylphenidate (n = 22) or atomoxetine (n = 24). Intrinsic brain activity, including the fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo), was quantified via resting-state functional magnetic resonance imaging at baseline and week 12. Reductions in inattentive symptoms were related to increased fALFF in the left superior temporal gyrus and left inferior parietal lobule for ADHD children treated with methylphenidate, and in the left lingual gyrus and left inferior occipital gyrus for ADHD children treated with atomoxetine. Hyperactivity/impulsivity symptom reductions were differentially related to increased fALFF in the methylphenidate group and to decreased fALFF in the atomoxetine group in bilateral precentral and postcentral gyri. Prediction analyses in the atomoxetine group revealed negative correlations between pre-treatment CANTAB simple reaction time and fALFF change in the left lingual gyrus and left inferior occipital gyrus, and positive correlations between pre-treatment CANTAB simple movement time and fALFF change in bilateral precentral and postcentral gyri and left precuneus, with a negative correlation between movement time and the fALFF change in the left lingual gyrus and the inferior occipital gyrus. Our findings suggest differential neurophysiological mechanisms for the treatment effects of methylphenidate and atomoxetine in children with ADHD.

Priapism associated with the use of stimulant medications and atomoxetine for attention-deficit/hyperactivity disorder in children.

PubMed

Eiland, Lea S; Bell, Edward A; Erramouspe, John

2014-10-01

To review the association of priapism with stimulant medications and atomoxetine commonly used in the treatment of attention-deficit/hyperactivity disorder (ADHD). A comprehensive literature search was conducted through PubMed (1966-May 15, 2014) using the search terms priapism, methylphenidate, amphetamine, atomoxetine, attention-deficit disorder with hyperactivity, and pediatrics. Google Scholar, Scopus, and the Food and Drug Administration (FDA) Web site were also searched. References from identified literature were also reviewed. All identified literature focused on ADHD treatment. Literature regarding priapism caused by methylphenidate, amphetamines, and atomoxetine were included. Stimulant medications and atomoxetine have been linked to the occurrence of priapism in children. Specifically, methylphenidate has been implicated in a recent FDA safety announcement warning as a result of 15 case reports (mean age = 12.5 years), and thus, the drug label and medication guides have been updated to reflect this concern. Prolonged erections and priapism occurred with immediate- and long-acting products, dose increases, and drug withdrawal periods. Priapism has also occurred in 4 patients taking amphetamines and one 11-year-old patient taking atomoxetine for ADHD. Priapism has been associated with stimulants, amphetamines, and atomoxetine use for ADHD in children. Providers and health care practitioners should educate male patients prescribed these ADHD medications as well as caregivers regarding the signs, symptoms, and complications with priapism. Discontinuation and evaluation of the medication is warranted if this adverse drug reaction occurs. Depending on the priapism subtype, other products may be initiated or medications not associated with priapism may be utilized. © The Author(s) 2014.

Atomoxetine restores the response inhibition network in Parkinson's disease.

PubMed

Rae, Charlotte L; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E; Jones, P Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

2016-08-01

Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Atomoxetine improved attention in children and adolescents with attention-deficit/hyperactivity disorder and dyslexia in a 16 week, acute, randomized, double-blind trial.

PubMed

Wietecha, Linda; Williams, David; Shaywitz, Sally; Shaywitz, Bennett; Hooper, Stephen R; Wigal, Sharon B; Dunn, David; McBurnett, Keith

2013-11-01

The purpose of this study was to evaluate atomoxetine treatment effects in attention-deficit/hyperactivity disorder (ADHD-only), attention-deficit/hyperactivity disorder with comorbid dyslexia (ADHD+D), or dyslexia only on ADHD core symptoms and on sluggish cognitive tempo (SCT), working memory, life performance, and self-concept. Children and adolescents (10-16 years of age) with ADHD+D (n=124), dyslexia-only (n=58), or ADHD-only (n=27) received atomoxetine (1.0-1.4 mg/kg/day) or placebo (ADHD-only subjects received atomoxetine) in a 16 week, acute, randomized, double-blind trial with a 16 week, open-label extension phase (atomoxetine treatment only). Changes from baseline were assessed to weeks 16 and 32 in ADHD Rating Scale-IV-Parent-Version:Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv); ADHD Rating Scale-IV-Teacher-Version (ADHDRS-IV-Teacher-Version); Life Participation Scale-Child- or Parent-Rated Version (LPS); Kiddie-Sluggish Cognitive Tempo (K-SCT) Interview; Multidimensional Self Concept Scale (MSCS); and Working Memory Test Battery for Children (WMTB-C). At week 16, atomoxetine treatment resulted in significant (p<0.05) improvement from baseline in subjects with ADHD+D versus placebo on ADHDRS-IV-Parent:Inv Total (primary outcome) and subscales, ADHDRS-IV-Teacher-Version Inattentive subscale, K-SCT Interview Parent and Teacher subscales, and WMTB-C Central Executive component scores; in subjects with Dyslexia-only, atomoxetine versus placebo significantly improved K-SCT Youth subscale scores from baseline. At Week 32, atomoxetine-treated ADHD+D subjects significantly improved from baseline on all measures except MSCS Family subscale and WMTB-C Central Executive and Visuo-spatial Sketchpad component scores. The atomoxetine-treated dyslexia-only subjects significantly improved from baseline to week 32 on ADHDRS-IV-Parent:Inv Inattentive subscale, K-SCT Parent and Teacher subscales, and WMTB-C Phonological Loop and Central Executive component scores. The atomoxetine-treated ADHD-only subjects significantly improved from baseline to Week 32 on ADHDRS-Parent:Inv Total and subscales, ADHDRS-IV-Teacher-Version Hyperactive/Impulsive subscale, LPS Self-Control and Total, all K-SCT subscales, and MSCS Academic and Competence subscale scores. Atomoxetine treatment improved ADHD symptoms in subjects with ADHD+D and ADHD-only, but not in subjects with dyslexia-only without ADHD. This is the first study to report significant effects of any medication on SCT. This study was registered at: http://clinicaltrials.gov/ct2/home, NCT00607919.

Atomoxetine Improved Attention in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Dyslexia in a 16 Week, Acute, Randomized, Double-Blind Trial

PubMed Central

Williams, David; Shaywitz, Sally; Shaywitz, Bennett; Hooper, Stephen R.; Wigal, Sharon B.; Dunn, David; McBurnett, Keith

2013-01-01

Abstract Objective The purpose of this study was to evaluate atomoxetine treatment effects in attention-deficit/hyperactivity disorder (ADHD-only), attention-deficit/hyperactivity disorder with comorbid dyslexia (ADHD+D), or dyslexia only on ADHD core symptoms and on sluggish cognitive tempo (SCT), working memory, life performance, and self-concept. Methods Children and adolescents (10–16 years of age) with ADHD+D (n=124), dyslexia-only (n=58), or ADHD-only (n=27) received atomoxetine (1.0–1.4 mg/kg/day) or placebo (ADHD-only subjects received atomoxetine) in a 16 week, acute, randomized, double-blind trial with a 16 week, open-label extension phase (atomoxetine treatment only). Changes from baseline were assessed to weeks 16 and 32 in ADHD Rating Scale-IV-Parent-Version:Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv); ADHD Rating Scale-IV-Teacher-Version (ADHDRS-IV-Teacher-Version); Life Participation Scale—Child- or Parent-Rated Version (LPS); Kiddie-Sluggish Cognitive Tempo (K-SCT) Interview; Multidimensional Self Concept Scale (MSCS); and Working Memory Test Battery for Children (WMTB-C). Results At week 16, atomoxetine treatment resulted in significant (p<0.05) improvement from baseline in subjects with ADHD+D versus placebo on ADHDRS-IV-Parent:Inv Total (primary outcome) and subscales, ADHDRS-IV-Teacher-Version Inattentive subscale, K-SCT Interview Parent and Teacher subscales, and WMTB-C Central Executive component scores; in subjects with Dyslexia-only, atomoxetine versus placebo significantly improved K-SCT Youth subscale scores from baseline. At Week 32, atomoxetine-treated ADHD+D subjects significantly improved from baseline on all measures except MSCS Family subscale and WMTB-C Central Executive and Visuo-spatial Sketchpad component scores. The atomoxetine-treated dyslexia-only subjects significantly improved from baseline to week 32 on ADHDRS-IV-Parent:Inv Inattentive subscale, K-SCT Parent and Teacher subscales, and WMTB-C Phonological Loop and Central Executive component scores. The atomoxetine-treated ADHD-only subjects significantly improved from baseline to Week 32 on ADHDRS-Parent:Inv Total and subscales, ADHDRS-IV-Teacher-Version Hyperactive/Impulsive subscale, LPS Self-Control and Total, all K-SCT subscales, and MSCS Academic and Competence subscale scores. Conclusions Atomoxetine treatment improved ADHD symptoms in subjects with ADHD+D and ADHD-only, but not in subjects with dyslexia-only without ADHD. This is the first study to report significant effects of any medication on SCT. Clinical Trials Registration This study was registered at: http://clinicaltrials.gov/ct2/home, NCT00607919. PMID:24206099

Time-to-onset and -resolution of adverse events before/after atomoxetine discontinuation in adult patients with ADHD.

PubMed

Upadhyaya, Himanshu; Tanaka, Yoko; Lipsius, Sarah; Kryzhanovskaya, Ludmila A; Lane, Jeannine R; Escobar, Rodrigo; Trzepacz, Paula T; Allen, Albert J

2015-01-01

Adults with attention-deficit/hyperactivity disorder treated with atomoxetine were examined for time-to-onset and -resolution of common treatment-emergent adverse events (TEAEs) and male sexual dysfunction, and for changes in blood pressure (BP) and heart rate (HR) upon atomoxetine discontinuation. 12-week open-label atomoxetine (40-100 mg/day) was followed by 12-week double-blind maintenance treatment (atomoxetine 80 or 100 mg/day). Responders were then randomized to atomoxetine (n = 266) or placebo (n = 258) for 25-week randomized withdrawal. Examined were (1) median time-to-onset and -resolution of TEAEs during atomoxetine treatment, and (2) within group, visitwise mean changes for sitting HR, systolic BP, and diastolic BP for the postrandomization placebo group. Common adverse events (AEs) appeared early, within week 1 of atomoxetine treatment. Some AEs resolve relatively rapidly, whereas others have a more lingering course of resolution (including male sexual side effects); median resolution times were 3 - 53 days. BP and HR increases during atomoxetine treatment returned to baseline upon atomoxetine discontinuation. Atomoxetine is associated with common AEs, with 3- to 53-day median resolution times. ClincialTrials.gov - NCT00700427.

Cost-effectiveness of pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: qualitative synthesis of scientific evidence.

PubMed

Catalá-López, Ferrán; Ridao, Manuel; Sanfélix-Gimeno, Gabriel; Peiró, Salvador

2013-01-01

To describe the cost-effectiveness analyses of medications launched in Spain for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. Systematic review of the literature without meta-analysis. A search was made in, PubMed/MEDLINE, SCOPUS, databases of the Centre for Reviews and Dissemination, and the websites of technology assessment agencies from Canada, the United Kingdom and the Spanish Platform AUnETS. Only full economic evaluations were included, considering at least methylphenidate or atomoxetine as pharmacological treatment alternatives in children and/or adolescents with ADHD. Eleven studies published in 9 articles or reports were included. The most frequent characteristics were: cost-utility analysis (82%), health system perspective (82%), short-term horizon (91%), and private funding (50%). Methylphenidate was included in all studies, and atomoxetine in 4 studies. Methylphenidate and atomoxetine are cost-effective alternatives compared to placebo or no treatment, although incremental cost-effectiveness ratios are variable. The few direct treatment-comparisons between methylphenidate and atomoxetine provided contradictory and potentially biased results. The pharmacological treatment of ADHD in children and adolescents, with the reservations arising from the generalization of results to different settings, is probably cost-effective in the short term. The existing studies do not allow the relative efficiency of different treatments to be established, either in the long-term treatment or in patient subgroups with specific characteristics or comorbidities. Copyright © 2012 SEP y SEPB. Published by Elsevier Espana. All rights reserved.

Efficacy and Safety of Atomoxetine in Childhood Attention-Deficit/Hyperactivity Disorder with Comorbid Oppositional Defiant Disorder

ERIC Educational Resources Information Center

Kaplan, S.; Heiligenstein, J.; West, S.; Busner, J.; Harder, D.; Dittmann, R.; Casat, C.; Wernicke, J. F.

2004-01-01

Objective: To compare the safety and efficacy of atomoxetine, a selective inhibitor of the norepinephrine transporter, versus placebo in Attention-Deficit/Hyperactivity Disorder (ADHD) patients with comorbid Oppositional Defiant Disorder (ODD). Methods: A subset analysis of 98 children from two identical, multi-site, double-blind, randomized,…

Atomoxetine Treatment for Pediatric Patients with Attention-Deficit/Hyperactivity Disorder with Comorbid Anxiety Disorder

ERIC Educational Resources Information Center

Geller, Daniel; Donnelly, Craig; Lopez, Frank; Rubin, Richard; Newcorn, Jeffrey; Sutton, Virginia; Bakken, Rosalie; Paczkowski, Martin; Kelsey, Douglas; Sumner, Calvin

2007-01-01

Objective: Research suggests 25% to 35% of children with attention-deficit/hyperactivity disorder (ADHD) have comorbid anxiety disorders. This double-blind study compared atomoxetine with placebo for treating pediatric ADHD with comorbid anxiety, as measured by the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored…

Differential therapeutic effects of 12-week treatment of atomoxetine and methylphenidate on drug-naïve children with attention deficit/hyperactivity disorder: A counting Stroop functional MRI study.

PubMed

Chou, Tai-Li; Chia, Seng; Shang, Chi-Yung; Gau, Susan Shur-Fen

2015-12-01

Methylphenidate and atomoxetine are effective in treating attention-deficit/hyperactivity disorder (ADHD) with underlying distinct pharmacological mechanisms. To relate neural mechanisms to clinical response, we conducted a comparative trial to differentiate the changes in brain activation of drug-naïve children with ADHD when performing neuropsychological tasks after 12 weeks of pharmacotherapy. We randomized 50 drug-naïve children with ADHD, aged 7-17, to treatment with methylphenidate (n=25) or atomoxetine (n=25). These children were scanned twice with functional magnetic resonance imaging (fMRI) during the counting Stroop task before and after treatment. Focused attention and impulsivity were assessed twice by using the Conner's Continuous Performance Test (CCPT). The final sample for fMRI analysis comprised 20 in the methylphenidate group and 22 in the atomoxetine group. Atomoxetine decreased activations in the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex, which correlated with improvement in focused attention assessed by the CCPT. In contrast, methylphenidate increased activations in the inferior frontal gyrus, which correlated with the decreasing severity of impulsivity assessed by the CCPT. The current findings suggest that differential therapeutic effects on neuronal changes induced by 12-week treatment atomoxetine and methylphenidate may contribute to behavioral improvement. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers

PubMed Central

Loghin, Corina; Haber, Harry; Beasley, Charles M; Kothare, Prajakti A; Kauffman, Lynnette; April, John; Jin, Ling; Allen, Albert J; Mitchell, Malcolm I

2013-01-01

Aim The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared. Methods Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days −2 and −1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QTcM) on day 7 was the primary endpoint. Results QTcM differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one-sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one-sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QTc was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QTcM for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration−QTc change observed was consistent with the literature. Conclusion Atomoxetine was not associated with a clinically significant change in QTc. However, a statistically significant increase in QTc was associated with increasing plasma concentrations. PMID:22803597

Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials.

PubMed

Camporeale, Angelo; Porsdal, Vibeke; De Bruyckere, Katrien; Tanaka, Yoko; Upadhyaya, Himanshu; Deix, Claudia; Deberdt, Walter

2015-01-01

The safety profile of atomoxetine in the treatment of attention deficit hyperactivity disorder has been studied in many clinical trials. We performed an integrated safety analysis of 15 clinical trials in adults with attention deficit hyperactivity disorder. The analysis pooled patient data into three groups: acute placebo-controlled trials; long-term placebo-controlled trials; all trials. In total, 4829 adults (18-77 years, median: 36 years) were exposed to atomoxetine. Statistically significantly more atomoxetine-treated than placebo-treated patients experienced treatment-emergent adverse events (81.3% vs. 68.3% acute; 90.6% vs. 76.8% long term) and discontinued due to adverse events (8.9% vs. 4.0% acute; 17.9% vs. 6.3% long term). No statistically significant differences were observed in the proportion of patients experiencing serious adverse events. No previously unknown adverse events were identified. The most common adverse events included nausea, dry mouth, decreased appetite, insomnia and erectile dysfunction. Mean increases in heart rate (+5.2 beats per min) and blood pressure (systolic +2 mmHg, diastolic +1.9 mmHg) were modest. The proportion of patients experiencing clinically significant increases in blood pressure and heart rate at any time was statistically significantly higher with atomoxetine (systolic blood pressure 13-17%, diastolic blood pressure 37-40%, heart rate 42-43%) compared to placebo (systolic blood pressure 8-13%, diastolic blood pressure 29-34%, heart rate 21-26%). There was no increased risk of suicidal ideation or behaviour. Our findings confirm atomoxetine's known safety profile. From a safety perspective, atomoxetine is a useful treatment option for adults with attention deficit hyperactivity disorder. © The Author(s) 2014.

Assessment of effects of atomoxetine in adult patients with ADHD: consistency among three geographic regions in a response maintenance study.

PubMed

Tanaka, Yoko; Escobar, Rodrigo; Upadhyaya, Himanshu P

2017-06-01

A previous study (Upadhyaya et al. in Eur J Psychiatry 2013b; 27:185-205) reported that adults with attention-deficit/hyperactivity disorder (ADHD) demonstrated maintenance of response for up to 25 weeks after initially responding to atomoxetine treatment. In the present report, the consistency of treatment effect across three geographic regions (Europe, United States/Canada [US/Can], and Latin America [Latin Am]) was explored. Data were analyzed from a phase 3, multicenter, randomized, double-blind, maintenance-of-response (randomized withdrawal) trial of atomoxetine versus placebo in adults with ADHD. Patients were randomized to atomoxetine (N = 266) or placebo (N = 258) for 25 weeks. Consistency assessments included the interaction test, pairwise t tests, noninferiority, and the criteria from Basic Principles on Global Clinical Trials (Ministry of Health, Labour and Welfare of Japan 2007). Atomoxetine-treated patients maintained the improved ADHD symptoms relative to placebo-treated patients on the Conners' Adult ADHD Rating Scale Investigator-Rated: Screening Version 18-Item (CAARS-Inv:SV) total score in all three regions (atomoxetine-placebo mean difference = -4.55, -3.18, and -0.07 for Europe, US/Can, and Latin Am, respectively). For the Latin Am region, the mean change in total score (0.41) was notably smaller for the placebo group than for Europe (5.87) and US/Can (4.39). Similar results were observed for the CAARS-Inv:SV hyperactivity/impulsivity and inattention subscale scores. Overall, patients maintained the response with atomoxetine treatment compared to placebo; however, the magnitude of treatment effect differed among the regions studied, being numerically higher in the EU and US/Can than Latin Am. Trial registration http://www.clinicaltrials.gov/(NCT00700427 ).

Atomoxetine Treatment Strengthens an Anti-Correlated Relationship between Functional Brain Networks in Medication-Naïve Adults with Attention-Deficit Hyperactivity Disorder: A Randomized Double-Blind Placebo-Controlled Clinical Trial

PubMed Central

Lin, Hsiang-Yuan

2016-01-01

Background: Although atomoxetine demonstrates efficacy in individuals with attention-deficit hyperactivity disorder, its treatment effects on brain resting-state functional connectivity remain unknown. Therefore, we aimed to investigate major brain functional networks in medication-naïve adults with attention-deficit hyperactivity disorder and the efficacy of atomoxetine treatment on resting-state functional connectivity. Methods: After collecting baseline resting-state functional MRI scans from 24 adults with attention-deficit hyperactivity disorder (aged 18–52 years) and 24 healthy controls (matched in demographic characteristics), the participants with attention-deficit hyperactivity disorder were randomly assigned to atomoxetine (n=12) and placebo (n=12) arms in an 8-week, double-blind, placebo-controlled trial. The primary outcome was functional connectivity assessed by a resting-state functional MRI. Seed-based functional connectivity was calculated and compared for the affective, attention, default, and cognitive control networks. Results: At baseline, we found atypical cross talk between the default, cognitive control, and dorsal attention networks and hypoconnectivity within the dorsal attention and default networks in adults with attention-deficit hyperactivity disorder. Our first-ever placebo-controlled clinical trial incorporating resting-state functional MRI showed that treatment with atomoxetine strengthened an anticorrelated relationship between the default and task-positive networks and modulated all major brain networks. The strengthened anticorrelations were associated with improving clinical symptoms in the atomoxetine-treated adults. Conclusions: Our results support the idea that atypical default mode network task-positive network interaction plays an important role in the pathophysiology of adult attention-deficit hyperactivity disorder. Strengthening this atypical relationship following atomoxetine treatment suggests an important pathway to treat attention-deficit hyperactivity disorder. PMID:26377368

Atomoxetine Treatment Strengthens an Anti-Correlated Relationship between Functional Brain Networks in Medication-Naïve Adults with Attention-Deficit Hyperactivity Disorder: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

PubMed

Lin, Hsiang-Yuan; Gau, Susan Shur-Fen

2015-09-16

Although atomoxetine demonstrates efficacy in individuals with attention-deficit hyperactivity disorder, its treatment effects on brain resting-state functional connectivity remain unknown. Therefore, we aimed to investigate major brain functional networks in medication-naïve adults with attention-deficit hyperactivity disorder and the efficacy of atomoxetine treatment on resting-state functional connectivity. After collecting baseline resting-state functional MRI scans from 24 adults with attention-deficit hyperactivity disorder (aged 18-52 years) and 24 healthy controls (matched in demographic characteristics), the participants with attention-deficit hyperactivity disorder were randomly assigned to atomoxetine (n=12) and placebo (n=12) arms in an 8-week, double-blind, placebo-controlled trial. The primary outcome was functional connectivity assessed by a resting-state functional MRI. Seed-based functional connectivity was calculated and compared for the affective, attention, default, and cognitive control networks. At baseline, we found atypical cross talk between the default, cognitive control, and dorsal attention networks and hypoconnectivity within the dorsal attention and default networks in adults with attention-deficit hyperactivity disorder. Our first-ever placebo-controlled clinical trial incorporating resting-state functional MRI showed that treatment with atomoxetine strengthened an anticorrelated relationship between the default and task-positive networks and modulated all major brain networks. The strengthened anticorrelations were associated with improving clinical symptoms in the atomoxetine-treated adults. Our results support the idea that atypical default mode network task-positive network interaction plays an important role in the pathophysiology of adult attention-deficit hyperactivity disorder. Strengthening this atypical relationship following atomoxetine treatment suggests an important pathway to treat attention-deficit hyperactivity disorder. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Investigator Ratings of ADHD Symptoms during a Randomized, Placebo-Controlled Trial of Atomoxetine: A Comparison of Parents and Teachers as Informants

ERIC Educational Resources Information Center

Bohnstedt, Bradley N.; Kronenberger, William G.; Dunn, David W.; Giauque, Ann L.; Wood, Elisabeth A.; Rembusch, Mary E.; Lafata, Deborah

2005-01-01

This study compared investigator ratings of ADHD symptoms based on interviews with parents and teachers during a doubleblind, placebo-controlled study of atomoxetine. Investigators completed the ADHD Rating Scale: Investigator (ADHDRS-I) based on separate semistructured interviews with the primary caretaker and teacher of the participant.…

Atomoxetine administration combined with intensive speech therapy for post-stroke aphasia: evaluation by a novel SPECT method.

PubMed

Yamada, Naoki; Kakuda, Wataru; Yamamoto, Kazuma; Momosaki, Ryo; Abo, Masahiro

2016-09-01

We clarified the safety, feasibility, and efficacy of atomoxetine administration combined with intensive speech therapy (ST) for patients with post-stroke aphasia. In addition, we investigated the effect of atomoxetine treatment on neural activity of surrounding lesioned brain areas. Four adult patients with motor-dominant aphasia and a history of left hemispheric stroke were studied. We have registered on the clinical trials database (ID: JMA-IIA00215). Daily atomoxetine administration of 40 mg was initiated two weeks before admission and raised to 80 mg 1 week before admission. During the subsequent 13-day hospitalization, administration of atomoxetine was raised to 120 mg and daily intensive ST (120 min/day, one-on-one training) was provided. Language function was assessed using the Japanese version of The Western Aphasia Battery (WAB) and the Token test two weeks prior to admission, on the day of admission, and at discharge. At two weeks prior to admission and at discharge, each patient's cortical blood flow was measured using (123)I-IMP-single photon emission computed tomography (SPECT). This protocol was successfully completed by all patients without any adverse effects. Four patients showed improved language function with the median of the Token Test increasing from 141 to 149, and the repetition score of WAB increasing from 88 to 99. In addition, cortical blood flow surrounding lesioned brain areas was found to increase following intervention in all patients. Atomoxetine administration and intensive ST were safe and feasible for post-stroke aphasia, suggesting their potential usefulness in the treatment of this patient population.

Meta-Analysis of Suicide-Related Behavior or Ideation in Child, Adolescent, and Adult Patients Treated with Atomoxetine

PubMed Central

Wietecha, Linda A.; Wang, Shufang; Buchanan, Andrew S.; Kelsey, Douglas K.

2014-01-01

Abstract Objective: This meta-analysis examined suicide-related events in the acute phases of double-blind, placebo-controlled atomoxetine trials in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 3883 pediatric and 3365 adult patients were included. Potential events were identified from the adverse events database using a text-string search. Mantel–Haenszel risk ratios (MHRR) were calculated for potential suicide-related events categorized according to United States Food and Drug Administration defined codes. Results: In this data set, no completed suicides were reported in the pediatric or adult populations. One pediatric (attempted suicide) (and no adult patient events) was categorized as suicidal behavior in the atomoxetine group. The frequency of combined suicidal behavior or ideation with atomoxetine treatment was 0.37% in pediatric patients (vs. 0.07% with placebo) and 0.11% in adults (vs. 0.12% with placebo) and the risk compared with placebo was not statistically significant (MHRR=1.57; p=0.42 and MHRR=0.96; p=0.96, respectively). In pediatric patients, suicidal ideation only was reported more frequently compared with placebo (MHRR=1.63; p=0.41). Conclusions: Overall in this data set, no completed suicides and 1 pediatric patient suicidal behavior event were reported in atomoxetine-treated pediatric and adult patients. Suicidal ideation was uncommon among atomoxetine-treated pediatric and adult patients, although it was reported more frequently in atomoxetine-treated pediatric patients compared with placebo; the reporting rate difference was not statistically significant. The MHRR of suicidal ideation was consistent with a previous meta-analysis of similar design. There was no evidence of increased risk for suicidal behavior in atomoxetine-treated pediatric or adult patients. Clinical trial registration information: http://www.clinicaltrials.gov. The data reported are from an analysis of 23 pediatric and 9 adult clinical trials completed between 1998 and 2011. Ten pediatric (Studies HFBD, HFBK, LYAC, LYAS, LYAT, LYAW, LYAX, LYBG, LYBI, and LYBP) and two adult trials (Studies LYAA and LYAO) were conducted before the requirement to post trials at initiation (ongoing as of July 1, 2005) and, therefore, do not have a registration number. The registration numbers for the 13 pediatric trials meeting this requirement are: NCT00191698 (LYBX), NCT00486122 (LYCC), NCT00386581 (LYCZ), NCT00485459 (S010), NCT00191542 (LY15), NCT00191295 (LYBC), NCT00191906 (LYCK), NCT00192023 (LYCY), NCT00191945 (LYDM), NCT00546910 (LYDV), NCT00406354 (LYDW), NCT00380692 (S017), and NCT00607919 (LYEB). For the seven adult trials, the registration numbers are: NCT00190931 (LYBV), NCT00190957 (LYBY), NCT00190736 (LYCU), NCT00190775 (LYCW), NCT00190879 (LYDQ), NCT00510276 (LYDZ), and NCT00962104 (LYEE). PMID:25019647

Atomoxetine hydrochloride in the treatment of children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: A placebo-controlled Italian study.

PubMed

Dell'Agnello, Grazia; Maschietto, Dino; Bravaccio, Carmela; Calamoneri, Filippo; Masi, Gabriele; Curatolo, Paolo; Besana, Dante; Mancini, Francesca; Rossi, Andrea; Poole, Lynne; Escobar, Rodrigo; Zuddas, Alessandro

2009-11-01

The primary aim of this study was to assess the efficacy of atomoxetine in improving ADHD and ODD symptoms in paediatric patients with ADHD and comorbid oppositional defiant disorder (ODD), non-responders to previous psychological intervention with parent support. This was a multicentre, randomised, placebo-controlled trial conducted in patients aged 6-15 years, with ADHD and ODD diagnosed according to the DSM-IV criteria by a structured clinical interview (K-SADS-PL). Only subjects who are non-responders to a 6-week standardized parent training were randomised to atomoxetine (up to 1.2 mg/kg/day) or placebo (in a 3:1 ratio) for the following 8-week double blind phase. Only 2 of the 156 patients enrolled for the parent support phase (92.9% of males; mean age: 9.9 years), improved after the parent training program; 139 patients were randomised for entering in the study and 137 were eligible for efficacy analysis. At the end of the randomised double blind phase, the mean changes in the Swanson, Nolan and Pelham Rating Scale-Revised (SNAP-IV) ADHD subscale were -8.1+/-9.2 and -2.0+/-4.7, respectively in the atomoxetine and in the placebo group (p<0.001 between groups); changes in the ODD subscale were -2.7+/-4.1 and -0.3+/-2.6, respectively in the two groups (p=0.001 between groups). The CGI-ADHD-S score decreased in the atomoxetine group (median change at endpoint: -1.0) compared to no changes in the placebo group (p<0.001 between groups). Statistically significant differences between groups, in favour of atomoxetine, were found in the CHIP-CE scores for risk avoidance domain, emotional comfort and individual risk avoidance subdomains. An improvement in all the subscales of Conners Parents (CPRS-R:S) and Teacher (CTRS-R:S) subscales was observed with atomoxetine, except in the cognitive problems subscale in the CTRS-R:S. Only 3 patients treated with atomoxetine discontinued the study due to adverse events. No clinically significant changes of body weight, height and vital signs were observed in both groups. Treatment with atomoxetine of children and adolescents with ADHD and ODD, who did not initially respond to parental support, was associated with improvements in symptoms of ADHD and ODD, and general health status. Atomoxetine was well tolerated.

The Effect of Myricetin on Pharmacokinetics of Atomoxetine and its Metabolite 4-Hydroxyatomoxetine In Vivo and In Vitro.

PubMed

Lan, Tian; Hu, Xiao-Xia; Liang, Bing-Qing; Pan, Wen-He; Zhou, Quan; Yuan, Ling-Jing; Hu, Guo-Xin

2017-04-01

Atomoxetine is the first non-stimulant drug to be approved for the treatment of ADHD, while the effect of myricetin on the pharmacokinetic of atomoxetine in rats or human is still unknown. The present work was to study the impact of myricetin on the metabolism of atomoxetine both in vivo and in vitro. Twenty healthy male Sprague-Dawley rats were randomly divided into four groups: A (control group), B (100 mg/kg myricetin), C (50 mg/kg myricetin), and D (25 mg/kg myricetin). A single dose of atomoxetine (10 mg/kg) was administrated half an hour later. In addition, human and rat liver microsomes were performed to determine the effect of myricetin on the metabolism of atomoxetine in vitro. Group B, C, D all increased the C max and AUC of atomoxetine, but decreased the C max and AUC of 4-hydroxyatomoxetine. Moreover, myricetin showed inhibitory effect on human and rat microsomes, the IC 50 of myricetin was 8.651 and 35.45 µmol/L, respectively. Our study showed that myricetin could significantly inhibit the formation of atomoxetine metabolite both in vivo and in vitro. It is recommended that the effect of myricetin on the metabolism of atomoxetine should be noted and atomoxetine plasma concentration should be monitored.

Forecasting Three-Month Outcomes in a Laboratory School Comparison of Mixed Amphetamine Salts Extended Release (Adderall XR) and Atomoxetine (Strattera) in School-Aged Children with ADHD

ERIC Educational Resources Information Center

Faraone, Stephen V.; Wigal, Sharon B.; Hodgkins, Paul

2007-01-01

Objective: Compare observed and forecasted efficacy of mixed amphetamine salts extended release (MAS-XR; Adderall) with atomoxetine (Strattera) in ADHD children. Method: The authors analyze data from a randomized, double-blind, multicenter, parallel-group, forced-dose-escalation laboratory school study of children ages 6 to 12 with ADHD combined…

Atomoxetine and stroop task performance in adult attention-deficit/hyperactivity disorder.

PubMed

Faraone, Stephen V; Biederman, Joseph; Spencer, Thomas; Michelson, David; Adler, Lenard; Reimherr, Fred; Seidman, Larry

2005-08-01

The aim of this study was to assess the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, for executive functioning in adults with attention-deficit/hyperactivity disorder (ADHD). Two identical studies using a double-blind, placebo-controlled, parallel design were conducted. Patients were adults (Study 1, n = 280; Study 2, n = 256) with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)-defined ADHD recruited by referral and advertising. They were randomized to 10 weeks of treatment with atomoxetine or placebo. Executive functions were measured by the Stroop task. There was no evidence of cognitive deterioration associated with atomoxetine treatment. Atomoxetine treatment was associated with an improvement of the Stroop colorword score. Our results provide further support for Spencer et al.'s (1998) report that atomoxetine improves inhibitory capacity, as measured by the Stroop task. The absence of cognitive deterioration from atomoxetine, along with improved performance in a subgroup of patients in this large study, supports the safety of atomoxetine in this regard and its potential for improving a significant source of impairment for adults with ADHD.

Impulsivity in Alcohol-Dependent Patients with and without ADHD: The Role of Atomoxetine.

PubMed

Coppola, Maurizio; Mondola, Raffaella

2018-06-07

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of hyperactivity, inattention, and impulsivity. As shown in the literature, this disorder is frequently associated with alcohol and drug abuse. Patients affected by ADHD show high levels of impulsivity and sensation seeking. These characteristics can significantly increase the risk of alcohol abuse, which is itself a clinical condition associated with high levels of impulsivity. Clinical studies suggest that atomoxetine is effective and safe in patients affected by both ADHD and alcohol dependence; however, information focused specifically on impulsivity is very limited. In an open-label study, we evaluated the difference in impulsivity level between alcohol-dependent patients with and without a diagnosis of ADHD. Furthermore, we hypothesized that, in patients with ADHD, atomoxetine could reduce the impulsivity trait.

Atomoxetine Prevents Dexamethasone-Induced Skeletal Muscle Atrophy in Mice

PubMed Central

Jesinkey, Sean R.; Korrapati, Midhun C.; Rasbach, Kyle A.; Beeson, Craig C.

2014-01-01

Skeletal muscle atrophy remains a clinical problem in numerous pathologic conditions. β2-Adrenergic receptor agonists, such as formoterol, can induce mitochondrial biogenesis (MB) to prevent such atrophy. Additionally, atomoxetine, an FDA-approved norepinephrine reuptake inhibitor, was positive in a cellular assay for MB. We used a mouse model of dexamethasone-induced skeletal muscle atrophy to investigate the potential role of atomoxetine and formoterol to prevent muscle mass loss. Mice were administered dexamethasone once daily in the presence or absence of formoterol (0.3 mg/kg), atomoxetine (0.1 mg/kg), or sterile saline. Animals were euthanized at 8, 16, and 24 hours or 8 days later. Gastrocnemius muscle weights, changes in mRNA and protein expression of peroxisome proliferator–activated receptor-γ coactivator-1 α (PGC-1α) isoforms, ATP synthase β, cytochrome c oxidase subunit I, NADH dehydrogenase (ubiquinone) 1 β subcomplex, 8, ND1, insulin-like growth factor 1 (IGF-1), myostatin, muscle Ring-finger protein-1 (muscle atrophy), phosphorylated forkhead box protein O 3a (p-FoxO3a), Akt, mammalian target of rapamycin (mTOR), and ribosomal protein S6 (rp-S6; muscle hypertrophy) in naive and muscle-atrophied mice were measured. Atomoxetine increased p-mTOR 24 hours after treatment in naïve mice, but did not change any other biomarkers. Formoterol robustly activated the PGC-1α-4-IGF1–Akt-mTOR-rp-S6 pathway and increased p-FoxO3a as early as 8 hours and repressed myostatin at 16 hours. In contrast to what was observed with acute treatment, chronic treatment (7 days) with atomoxetine increased p-Akt and p-FoxO3a, and sustained PGC-1α expression and skeletal muscle mass in dexamethasone-treated mice, in a manner comparable to formoterol. In conclusion, chronic treatment with a low dose of atomoxetine prevented dexamethasone-induced skeletal muscle wasting and supports a potential role in preventing muscle atrophy. PMID:25292181

Self-esteem evaluation in children and adolescents suffering from ADHD.

PubMed

Mazzone, Luigi; Postorino, Valentina; Reale, Laura; Guarnera, Manuela; Mannino, Valeria; Armando, Marco; Fatta, Laura; De Peppo, Lavinia; Vicari, Stefano

2013-01-01

Several recent studies investigated the relationship between self-esteem and ADHD, however, the results are still controversial. In the present study we analyze the characteristics of self-esteem in a sample of children and adolescents suffering from ADHD, with a particular focus on the relationship between ADHD symptoms severity and treatment strategies. A total of 85 patients with ADHD (44 drug-free and 41 drug-treated, 23 of which atomoxetine-treated and 18 Methylphenidate-treated) and 26 healthy controls were enrolled in the study in order to evaluate self-esteem using the Self-esteem Multidimensional Test (TMA). ADHD subjects revealed lower scores on all self-esteem domains compared to controls. Both ADHD drug-free (47.1%) and ADHD drug-treated (44.1%) groups showed significantly higher rates of subjects in the pathological range as compared to normal control group (8.8%) (p <.001) with a higher percentage of subjects in the pathological range. Among ADHD drug-treated subjects, the methylphenidate group showed higher self-esteem scores as compared to the atomoxetine group. A lower self-esteem profile is more common in subjects suffering from ADHD than in healthy controls, suggesting the importance of an early detection of psychological well-being in these children in order to reduce the ADHD symptoms long-term impacts.

Self-Esteem Evaluation in Children and Adolescents Suffering from ADHD

PubMed Central

Mazzone, Luigi; Postorino, Valentina; Reale, Laura; Guarnera, Manuela; Mannino, Valeria; Armando, Marco; Fatta, Laura; De Peppo, Lavinia; Vicari, Stefano

2013-01-01

Background: Several recent studies investigated the relationship between self-esteem and ADHD, however, the results are still controversial. In the present study we analyze the characteristics of self-esteem in a sample of children and adolescents suffering from ADHD, with a particular focus on the relationship between ADHD symptoms severity and treatment strategies. Methods: A total of 85 patients with ADHD (44 drug-free and 41 drug-treated, 23 of which atomoxetine-treated and 18 Methylphenidate-treated) and 26 healthy controls were enrolled in the study in order to evaluate self-esteem using the Self-esteem Multidimensional Test (TMA). Results: ADHD subjects revealed lower scores on all self-esteem domains compared to controls. Both ADHD drug-free (47.1%) and ADHD drug-treated (44.1%) groups showed significantly higher rates of subjects in the pathological range as compared to normal control group (8.8%) (p <.001) with a higher percentage of subjects in the pathological range. Among ADHD drug-treated subjects, the methylphenidate group showed higher self-esteem scores as compared to the atomoxetine group. Conclusion: A lower self-esteem profile is more common in subjects suffering from ADHD than in healthy controls, suggesting the importance of an early detection of psychological well-being in these children in order to reduce the ADHD symptoms long-term impacts. PMID:23878614

Atomoxetine for hoarding disorder: A pre-clinical and clinical investigation.

PubMed

Grassi, Giacomo; Micheli, Laura; Di Cesare Mannelli, Lorenzo; Compagno, Elisa; Righi, Lorenzo; Ghelardini, Carla; Pallanti, Stefano

2016-12-01

Despite several studies suggested that inattention and impulsivity-compulsivity could represent two core dimensions of hoarding disorder (HD), only a small case series study investigated the effectiveness of attention-deficit-hyperactivity-disorder (ADHD) medications in HD. The aim of the present study was to target attentional and inhibitory control networks in HD patients through the ADHD medication atomoxetine, moving from a preclinical investigation on an animal model of compulsive-like behavior (marble burying test) to a clinical investigation on both medicated and unmedicated patients with a primary diagnosis of HD without ADHD. Our preclinical investigation showed that acute administration of atomoxetine significantly reduced the compulsive-like behaviours of mice in the marble burying test without affecting neither locomotor activity and coordination nor exploration behaviours. When compared, atomoxetine and fluoxetine showed similar effects on the marble burying test. However, fluoxetine impaired both locomotor and exploratory activity. In our clinical investigation 12 patients were enrolled and 11 patients completed an open trial with atomoxetine at flexible dose (40-80 mg) for 12 weeks. At the endpoint the mean UCLA Hoarding Severity Scale score decreased by 41.3% for the whole group (p = 0003). Six patients were classified as full responders (mean symptom reduction of 57.2%) and three patients as partial responders (mean symptom reduction of 27.3%). Inattentive and impulsivity symptoms showed a significant mean score reduction of 18.5% from baseline to the endpoint (F (1,9) = 20.9, p = 0.0013). Hoarding symptoms improvement was correlated to reduction of patients' disability and increased in their global functioning. These preclinical and clinical data suggest that atomoxetine may be effective for HD and therefore should be considered for future controlled trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

Placebo-controlled trial of atomoxetine for weight reduction in people with schizophrenia treated with clozapine or olanzapine.

PubMed

Ball, M Patricia; Warren, Kimberly R; Feldman, Stephanie; McMahon, Robert P; Kelly, Deanna L; Buchanan, Robert W

2011-04-01

In recent years, several pharmacological and psychosocial interventions have examined ways to prevent or treat weight gain in people receiving second-generation antipsychotics. While there has been some success, in general, results have not been compelling. Atomoxetine is a selective norepinepherine reuptake inhibitor found to be associated with appetite suppression. Therefore, we examined whether atomoxetine may be of benefit for those who have gained weight on either clozapine or olanzapine. The study was a double-blind, placebo-controlled trial. All participants received the same psychosocial platform: a structured support and exercise group. People with schizophrenia or schizoaffective disorder, on olanzapine or clozapine, who had gained at least 7% of their pre-clozapine or pre-olanzapine weight were eligible for a 24-week, randomized, parallel group, double-blind comparison of adjunctive atomoxetine or placebo. Thirty-seven participants (20 atomoxetine, 17 placebo) were randomized and 26 participants (14 atomoxetine, 12 placebo; 70.2%) completed the study. There were no significant group differences in baseline BMI (atomoxetine: 34.5±4.9; placebo: 35.7±7.0) or weight (atomoxetine: 102.2±15.7 kg; placebo: 104.3±17.5 kg). Both treatment groups showed modest, not significant, trends in weight loss, averaging about 2 kg. Gender or baseline antipsychotic treatment did not modify treatment effects on weight. Secondary outcomes included neuropsychological assessments, symptom assessments (BPRS, SANS) and safety assessments. Of these, only the group difference in Gordon distractibility test scores was statistically significant and favored treatment with atomoxetine. Atomoxetine is not effective for weight loss in this population, but both olanzapine and clozapine participants can lose weight with structured group support and exercise.

Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial.

PubMed

Kelsey, Douglas K; Sumner, Calvin R; Casat, Charles D; Coury, Daniel L; Quintana, Humberto; Saylor, Keith E; Sutton, Virginia K; Gonzales, Jill; Malcolm, Sandra K; Schuh, Kory J; Allen, Albert J

2004-07-01

Atomoxetine seems to be as effective for treating attention-deficit/hyperactivity disorder (ADHD) when the daily dose is administered once in the morning as when the dose is divided and administered in the morning and evening. In the present study, the efficacy of atomoxetine administered once daily among children with ADHD was assessed throughout the day, including the evening and early morning. Another goal was to determine how early in treatment it was possible to discern a specific effect of the drug on ADHD symptoms. This study was a randomized, multicenter, double-blind, placebo-controlled trial conducted at 12 outpatient sites in the United States. A total of 197 children, 6 to 12 years of age, who had been diagnosed as having ADHD, on the basis of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria, were randomized to receive 8 weeks of treatment with atomoxetine or placebo, dosed once daily in the mornings. ADHD symptoms were assessed with parent and investigator rating scales. The primary outcome measure was the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score. Daily parent assessments of children's home behaviors in the evening and early morning were recorded with an electronic data entry system. This instrument measures 11 specific morning or evening activities, including getting up and out of bed, doing or completing homework, and sitting through dinner. Seventy-one percent of the children enrolled were male, 69% met criteria for the combined subtype (both inattentive and hyperactive/impulsive symptoms), and the most common psychiatric comorbidity was oppositional defiant disorder (35%). Once-daily atomoxetine (final mean daily dose of 1.3 mg/kg) was significantly more effective than placebo in treating core symptoms of ADHD. Mean reductions in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score were significantly greater for patients randomized to atomoxetine, beginning at the first visit after the initiation of treatment and continuing at all subsequent visits. Both inattentive and hyperactive/impulsive symptom clusters were significantly reduced with atomoxetine, compared with placebo. With continued treatment and dose titrations, core symptoms of ADHD continued to decrease throughout the 8-week study. Mean reductions in the daily parent assessment total scores for patients randomized to atomoxetine were superior during the first week, beginning with the first day of dosing, and were also superior at endpoint. Efficacy outcomes for the evening hours for atomoxetine-treated patients were superior to those for placebo-treated patients, as assessed with 2 different assessment scales. Decreases in the daily parent assessment morning subscores at endpoint showed a significant reduction in symptoms that lasted into the mornings. Rates of discontinuations attributable to adverse events were <5% for both groups. Adverse events reported significantly more frequently with atomoxetine were decreased appetite, somnolence, and fatigue. Among children 6 to 12 of age who had been diagnosed as having ADHD, once-daily administration of atomoxetine in the morning provided safe, rapid, continuous, symptom relief that lasted not only into the evening hours but also into the morning hours. Atomoxetine treatment was safe and well tolerated.

Pharmacodynamics of norepinephrine reuptake inhibition: Modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4-dihydroxyphenylglycol in humans.

PubMed

Kielbasa, William; Lobo, Evelyn

2015-12-01

Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker. © 2015, The American College of Clinical Pharmacology.

Improving visual memory, attention, and school function with atomoxetine in boys with attention-deficit/hyperactivity disorder.

PubMed

Shang, Chi-Yung; Gau, Susan Shur-Fen

2012-10-01

Atomoxetine is efficacious in reducing symptoms of attention- deficit/hyperactivity disorder (ADHD), but its effect on visual memory and attention needs more investigation. This study aimed to assess the effect of atomoxetine on visual memory, attention, and school function in boys with ADHD in Taiwan. This was an open-label 12 week atomoxetine treatment trial among 30 drug-naíve boys with ADHD, aged 8-16 years. Before administration of atomoxetine, the participants were assessed using psychiatric interviews, the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), the school function of the Chinese version of the Social Adjustment Inventory for Children and Adolescents (SAICA), the Conners' Continuous Performance Test (CPT), and the tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB) involving visual memory and attention: Pattern Recognition Memory, Spatial Recognition Memory, and Reaction Time, which were reassessed at weeks 4 and 12. Our results showed there was significant improvement in pattern recognition memory and spatial recognition memory as measured by the CANTAB tasks, sustained attention and response inhibition as measured by the CPT, and reaction time as measured by the CANTAB after treatment with atomoxetine for 4 weeks or 12 weeks. In addition, atomoxetine significantly enhanced school functioning in children with ADHD. Our findings suggested that atomoxetine was associated with significant improvement in visual memory, attention, and school functioning in boys with ADHD.

Relative bioequivalence evaluation of two oral atomoxetine hydrochloride capsules: a single dose, randomized, open-label, 2-period crossover study in healthy Chinese volunteers under fasting conditions.

PubMed

Shang, D-W; Guo, W; Zhou, F-C; Wang, X-P; Li, A-N; Zhang, L; Li, W-B; Lu, W; Wang, C-Y

2013-11-01

To evaluate the bioequivalence of a new formulation of atomoxetine hydrochloride (CAS 82248-59-7) capsules (test) and an available branded capsules (reference) after administration of a single 40 mg dose, randomized, open-label, 2-period crossover study was conducted in 22 healthy male Chinese subjects with a 1-week wash-out period. This study was designed for/the Honglin Pharmaceutical Co. Ltd and contracted to be done by the Beijing Anding Hospital in order to satisfy Chinese regulatory requirements to allow marketing of this generic product and performed according to the criteria of SFDA. Blood samples were collected before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detection. A non-compartmental method was used to calculate the pharmacokinetic parameters and evaluate bioequivalence of the 2 formulations. The 90% confidence interval (CI) of the ratios (test/reference) of atomoxetine for AUC0-24, AUC0-∞ and Cmax were 100.9% (93.6-108.8%), 103.1% (95.1-111.7%) and 105.2% (92.8-119.4%), respectively, which fell within the interval of 80-125% and 75-133%. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. From these results it can be concluded that the test formulation of atomoxetine capsules met the regulatory criterion for bioequivalence to the reference formulation. © Georg Thieme Verlag KG Stuttgart · New York.

Striatal Activation Predicts Differential Therapeutic Responses to Methylphenidate and Atomoxetine.

PubMed

Schulz, Kurt P; Bédard, Anne-Claude V; Fan, Jin; Hildebrandt, Thomas B; Stein, Mark A; Ivanov, Iliyan; Halperin, Jeffrey M; Newcorn, Jeffrey H

2017-07-01

Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD). A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response. Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F 1,30  = 17.00; p < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31-3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F 1,30  = 14.99; p < .001). Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach. Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/; NCT00183391. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

PubMed Central

Kobayashi, Toru; Washiyama, Kazuo; Ikeda, Kazutaka

2010-01-01

Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K+ (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A1 adenosine receptors or by intracellularly applied GTPγS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain- and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function. PMID:20393461

CYP2D6 predicted metabolizer status and safety in adult patients with attention-deficit hyperactivity disorder participating in a large placebo-controlled atomoxetine maintenance of response clinical trial.

PubMed

Fijal, Bonnie A; Guo, Yingying; Li, Si G; Ahl, Jonna; Goto, Taro; Tanaka, Yoko; Nisenbaum, Laura K; Upadhyaya, Himanshu P

2015-10-01

Atomoxetine, which is indicated for treatment of attention-deficit hyperactivity disorder (ADHD), is predominantly metabolized by genetically polymorphic cytochrome P450 2D6 (CYP2D6). Based on identified CYP2D6 genotypes, individuals can be categorized into 4 phenotypic metabolizer groups as ultrarapid, extensive, intermediate, and poor. Previous studies have focused on observed differences between poor and extensive metabolizers, but it is not well understood whether the safety profile of intermediate metabolizers differs from that of ultrarapid and extensive metabolizers. This study compared safety and tolerability among the different CYP2D6 metabolizer groups in the 12-week open-label phase of an atomoxetine study in adult patients with ADHD. Genotyping identified 1039 patients as extensive/ultrarapid metabolizers, 780 patients as intermediate metabolizers, and 117 patients as poor metabolizers. Common (≥5% frequency) treatment-emergent adverse events did not significantly differ between extensive/ultrarapid and intermediate metabolizers (odds ratios were <2.0 or >0.5). Poor metabolizers had higher frequencies of dry mouth, erectile dysfunction, hyperhidrosis, insomnia, and urinary retention compared with the other metabolizer groups. There were no significant differences between extensive/ultrarapid and intermediate metabolizers in changes from baseline in vital signs. These results suggest that data from CYP2D6 intermediate and extensive/ultrarapid metabolizers can be combined when considering safety analyses related to atomoxetine. © 2015, The American College of Clinical Pharmacology.

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research.

PubMed

Reed, Victoria A; Buitelaar, Jan K; Anand, Ernie; Day, Kathleen Ann; Treuer, Tamás; Upadhyaya, Himanshu P; Coghill, David R; Kryzhanovskaya, Ludmila A; Savill, Nicola C

2016-07-01

Atomoxetine is a noradrenergic reuptake inhibitor prescribed for attention-deficit/hyperactivity disorder (ADHD) that first gained approval in the USA in 2002 and has been authorized in 97 countries worldwide. The aim of this paper is to comprehensively review publications that addressed one or more of seven major safety topics relevant to atomoxetine treatment of children and adolescents (aged ≥6 years) diagnosed with ADHD. While the review focuses on children and adolescents, publications in which data from patients aged >18 years and from 6 to 18 years were analyzed in the same dataset were included. Using a predefined search strategy, including agreement of two reviewers when selecting papers, reduced the potential for bias. Using this process, we identified 70 eligible papers (clinical trials, epidemiological studies, and case reports) across the seven topics. We also referred to the European Summary of Product Characteristics (SPC) and US label. We found 15 papers about suicidality, three about aggression/hostility, seven about psychosis/mania, six about seizures, seven about hepatic effects, 29 about cardiovascular effects, and 28 about growth and development. The main findings (i.e., those from the largest and most well-conducted studies/analyses) are as follows. A large register-based study of pediatric and adult patients (6818 received atomoxetine) calculated a hazard ratio of 0.96 for suicide-related events during treatment with atomoxetine, and a meta-analysis of 23 placebo-controlled studies (N = 3883), published in 2014, found no completed suicides and no statistically significant association between atomoxetine and suicidality. The frequency of aggression/hostility was not statistically significantly higher with atomoxetine, e.g., experienced by 1.6 % (N = 21/1308) of atomoxetine-treated patients versus 1.1 % (N = 9/806) of placebo-treated patients in one meta-analysis. Symptoms of psychosis and mania were mainly observed in patients with comorbid bipolar disorder/depression. Based on spontaneous reports, during a 2-year period when 2.233 million adult and pediatric patients were exposed to atomoxetine, the reporting rate for seizures was 8 per 100,000 patients. In the manufacturer's database, atomoxetine was a "probable cause" of three hepatic adverse events (AEs) (all reversible hepatitis), and 133 hepatic AEs had possible confounding factors and were "possibly related" to atomoxetine, during 4 years when atomoxetine exposure had reached about 4.3 million patients. Rare cases of severe liver injury are described in the US label and European SPC; a case requiring liver transplantation is described in the US label. In a comprehensive review of a clinical trials database (N = 8417 received atomoxetine), most pediatric patients experienced modest increases in heart rate and blood pressure, and 8-12 % experienced more pronounced changes (≥20 bpm, ≥15 to 20 mmHg). However, in three long-term analyses (≥2 years), blood pressure was within age norms, and few patients discontinued due to cardiovascular AEs. As described in the European SPC, QT interval prolongation is uncommon, e.g., in an open-label study, 1.4 % of 711 children and adolescents had prolonged QTc intervals (≥450 ms in males, ≥470 ms in females) that were not clinically significant at ≥3 years of treatment with atomoxetine. The European SPC warns about potential QT interval prolongation in patients with a personal or family history, or if atomoxetine is administered with other drugs that potentially affect the QT interval. Decreases in growth (weight and height gain) occurred and were greatest in patients of above average weight and height, but appeared to recover over 2-5 years of atomoxetine treatment. In conclusion, suicidality, aggression/hostility, psychosis, seizures, liver injuries, and prolonged QT interval are uncommon or rare in children and adolescents treated with atomoxetine, based on data from the predefined search and from the European SPC. Overall, the data that we assessed from our search do not suggest that associations exist between atomoxetine and suicidality or seizures. The data also suggest that an association may not exist between atomoxetine and aggression/hostility. While atomoxetine may affect the cardiovascular system, the data suggest these effects are not clinically significant in most patients. Reductions in growth appear to be reversible in the long term.

Efficacy of atomoxetine for symptoms of attention-deficit/hyperactivity disorder in children with a history of child abuse.

PubMed

Sugimoto, Atsunori; Suzuki, Yutaro; Endo, Taro; Matsumoto, Keita; Sugiyama, Toshiro; Someya, Toshiyuki

2015-04-01

Recent studies suggest that the severity and drug response of depression and anxiety are correlated with childhood abuse. However, whether a history of child abuse can predict the severity and/or drug response of attention-deficit/hyperactivity disorder (ADHD) is unclear. Therefore, we conducted a retrospective study to assess the efficacy of atomoxetine in children with a history of child abuse. We reviewed 41 cases of children treated with atomoxetine. Specifically, we compared dissociation associating symptoms (DAS) and other symptoms (OS) measured via the ADHD Rating Scale (ADHD-RS) in abused and nonabused children at baseline and at 8 weeks after atomoxetine administration. At baseline, abused children had higher total scores (38.7±9.3 vs. 30.5±9.4, p=0.011), and greater levels of hyperactivity/impulsivity (17.3±5.8 vs. 11.3±6.0, p=0.004) on the ADHD-RS than did nonabused children, whereas the inattention scores were similar between the two groups (21.4±4.8 vs. 19.2±4.6). Additionally, the total score and the two subscores decreased at week 8 for both groups. In the nonabused group, DAS (5.5±2.3 vs. 3.9±1.7, p<0.001) and OS (25.0±8.1 vs. 17.4±6.7, p<0.001) significantly decreased after atomoxetine treatment. However, DAS in the abused group did not change after atomoxetine treatment (5.9±2.3 vs. 5.1±1.8), whereas OS significantly decreased (32.8±7.6 vs. 25.7±7.2, p=0.002). If DAS were caused by traumatic experiences in abused children, trauma treatment tools other than pharmacotherapy might be useful to treat DAS. These tools may include eye movement desensitization and reprocessing and trauma-focused cognitive behavioral therapy.

Efficacy and Safety Extrapolation Analyses for Atomoxetine in Young Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Upadhyaya, Himanshu; Kratochvil, Christopher; Ghuman, Jaswinder; Camporeale, Angelo; Lipsius, Sarah; D'Souza, Deborah; Tanaka, Yoko

2015-12-01

This extrapolation analysis qualitatively compared the efficacy and safety profile of atomoxetine from Lilly clinical trial data in 6-7-year-old patients with attention-deficit/hyperactivity disorder (ADHD) with that of published literature in 4-5-year-old patients with ADHD (two open-label [4-5-year-old patients] and one placebo-controlled study [5-year-old patients]). The main efficacy analyses included placebo-controlled Lilly data and the placebo-controlled external study (5-year-old patients) data. The primary efficacy variables used in these studies were the ADHD Rating Scale-IV Parent Version, Investigator Administered (ADHD-RS-IV-Parent:Inv) total score, or the Swanson, Nolan and Pelham (SNAP-IV) scale score. Safety analyses included treatment-emergent adverse events (TEAEs) and vital signs. Descriptive statistics (means, percentages) are presented. Acute atomoxetine treatment improved core ADHD symptoms in both 6-7-year-old patients (n=565) and 5-year-old patients (n=37) (treatment effect: -10.16 and -7.42). In an analysis of placebo-controlled groups, the mean duration of exposure to atomoxetine was ∼ 7 weeks for 6-7-year-old patients and 9 weeks for 5-year-old patients. Decreased appetite was the most common TEAE in atomoxetine-treated patients. The TEAEs observed at a higher rate in 5-year-old versus 6-7-year-old patients were irritability (36.8% vs. 3.6%) and other mood-related events (6.9% each vs. <3.0%). Blood pressure and pulse increased in both 4-5-year-old patients and 6-7-year-old patients, whereas a weight increase was seen only in the 6-7-year-old patients. Although limited by the small sample size of the external studies, these analyses suggest that in 5-year-old patients with ADHD, atomoxetine may improve ADHD symptoms, but possibly to a lesser extent than in older children, with some adverse events occurring at a higher rate in 5-year-old patients.

Do Children and Adolescents with ADHD Respond Differently to Atomoxetine?

ERIC Educational Resources Information Center

Wilens, Timothy E.; Kratochvil, Christopher; Newcorn, Jeffrey H.; Gao, Haitao

2006-01-01

Objective: Controversy exists over changes in tolerability and response to medications across the life span. Here the authors report data contrasting the efficacy and tolerability of atomoxetine between children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Method: Data were analyzed for children ages 6-11 (510 atomoxetine,…

Effects of atomoxetine on heart rhythm in children and adolescents.

PubMed

Tanidir, Ibrahim Cansaran; Tanidir, Canan; Ozturk, Erkut; Bahali, Kayhan; Gunes, Hatice; Ergul, Yakup; Uneri, Ozden Sukran; Akdeniz, Celal; Tuzcu, Volkan

2015-12-01

The aim of this study was to examine the effects of atomoxetine on heart rhythm using 12-lead electrocardiography (ECG) and 24 h Holter monitoring. Children and adolescents who were diagnosed with attention deficit-hyperactivity disorder according to DSM-IV-TR were referred to a pediatric cardiology clinic for cardiologic examination before and after 4 or 5 weeks of atomoxetine treatment. Cardiac examination, complete blood count, biochemistry, thyroid function tests, 12-lead ECG and 24 h Holter monitoring were performed routinely in all patients. Each subject underwent 24 h Holter ECG monitoring before atomoxetine was started and after 4 or 5 weeks of effective dose atomoxetine treatment. Forty-one patients were included in this prospective study. No statistically significant change was found in QT, QTc or QT interval dispersion or blood pressure before and after 4 or 5 weeks of atomoxetine treatment. There was a statistically significant increase in heart rate (both during the day and at night) and QRS duration, and a statistically significant decrease in P wave dispersion. Three patients had rhythm disturbances. All of these three patients were asymptomatic and none of these arrhythmias reached clinical significance. Atomoxetine did not cause significant changes in ECG or Holter variables. In two patients, who had undiagnosed subclinical extrasystoles, extra beats were increased after 4th week of treatment, but still remained clinically insignificant. Before and after atomoxetine treatment, listening to the heart sounds for a longer time, may help clinicians to notice an extra beat. If an extra beat is identified then 24 Holter monitoring is recommended. © 2015 Japan Pediatric Society.

Seizure Risk in Patients with Attention-Deficit-Hyperactivity Disorder Treated with Atomoxetine

ERIC Educational Resources Information Center

Wernicke, Joachim F.; Holdridge, Karen Chilcott; Jin, Ling; Edison, Timothy; Zhang, Shuyu; Bangs, Mark E.; Allen, Albert J.; Ball, Susan; Dunn, David

2007-01-01

The comorbidity of seizures, epilepsy, and attention-deficit-hyperactivity disorder (ADHD) prompted the examination of whether atomoxetine use for ADHD is associated with an increased risk of seizures. Seizures and seizure-related symptoms were reviewed from two independent Eli Lilly and Company databases: the atomoxetine clinical trials database…

Open-Label Trial of Atomoxetine Hydrochloride in Adults with ADHD

ERIC Educational Resources Information Center

Johnson, Mats; Cederlund, Mats; Rastam, Maria; Areskoug, Bjorn; Gillberg, Christopher

2010-01-01

Background: While atomoxetine is an established treatment for attention-deficit/hyperactivity disorder in children, few studies have examined its efficacy for adults. Methods: Open-label trial of atomoxetine in 20 individuals with ADHD, aged 19-47 years, for 10 weeks, and a total of one year for responders. Results: Ten patients met primary…

Atomoxetine in abstinent cocaine users: Cognitive, subjective and cardiovascular effects.

PubMed

DeVito, Elise E; Herman, Aryeh I; Konkus, Noah S; Zhang, Huiping; Sofuoglu, Mehmet

2017-08-01

No pharmacotherapies are approved for the treatment of cocaine use disorders (CUD). Behavioral treatments for CUD are efficacious for some individuals, but recovery rates from CUD remain low. Cognitive impairments in CUD have been linked with poorer clinical outcomes. Cognitive enhancing pharmacotherapies have been proposed as promising treatments for CUD. Atomoxetine, a norepinephrine transporter inhibitor, shows potential as a treatment for CUD based on its efficacy as a cognitive enhancer in other clinical populations and impact on addictive processes in preclinical and human laboratory studies. In this randomized, double-blind, crossover study, abstinent individuals with CUD (N=39) received placebo, 40 and 80mg atomoxetine, over three sessions. Measures of attention, response inhibition and working memory; subjective medication effects and mood; and cardiovascular effects were collected. Analyses assessed acute, dose-dependent effects of atomoxetine. In addition, preliminary analyses investigating the modulation of atomoxetine dose effects by sex were performed. Atomoxetine increased heart rate and blood pressure, was rated as having positive and negative subjective drug effects, and had only modest effects on mood and cognitive enhancement. Copyright © 2017. Published by Elsevier Inc.

Subchronic administration of atomoxetine causes an enduring reduction in context-induced relapse to cocaine seeking without affecting impulsive decision making.

PubMed

Broos, Nienke; Loonstra, Rhianne; van Mourik, Yvar; Schetters, Dustin; Schoffelmeer, Anton N M; Pattij, Tommy; De Vries, Taco J

2015-07-01

Previous work has established a robust relationship between impulsivity and addiction, and revealed that impulsive decision making predisposes the vulnerability to cocaine-seeking behavior in rats. An important next step is to assess whether elevated relapse vulnerability can be treated via the reduction of impulsive decision making. Therefore, this study explored whether subchronic atomoxetine treatment can reduce relapse vulnerability by reducing impulsive decision making. Rats were trained in the delayed reward task and were subjected to 3 weeks of cocaine self-administration. Following drug self-administration, animals were divided to different experimental groups and received the noradrenaline transporter inhibitor and attention-deficit/hyperactivity disorder drug atomoxetine or vehicle subchronically for 20 days. On days 1 and 10 after treatment cessation, a context-induced reinstatement test was performed. Throughout the entire experiment, changes in impulsive decision making were continuously monitored. Subchronic treatment with atomoxetine reduced context-induced reinstatement both 1 and 10 days after treatment cessation, only in animals receiving no extinction training. Interestingly, neither subchronic nor acute atomoxetine treatments affected impulsive decision making. Our data indicate that the enduring reduction in relapse sensitivity by atomoxetine occurred independent of a reduction in impulsive decision making. Nonetheless, repeated atomoxetine administration seems a promising pharmacotherapeutical strategy to prevent relapse to cocaine seeking in abstinent drug-dependent subjects. © 2014 Society for the Study of Addiction.

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition.

PubMed

Yu, Guo; Li, Guo-Fu; Markowitz, John S

2016-05-01

Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (≥6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed.

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

PubMed Central

Yu, Guo; Li, Guo-Fu

2016-01-01

Abstract Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (≥6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8–10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed. PMID:26859445

Atomoxetine Treatment in Children and Adolescents with Attention-Deficit/hyperactivity Disorder and Comorbid Oppositional Defiant Disorder

ERIC Educational Resources Information Center

Newcorn, Jeffrey H.; Spencer, Thomas J.; Biederman, Joseph; Milton, Denai R.; Michelson, David

2005-01-01

Objective: To examine (1) moderating effects of oppositional defiant disorder (ODD) on attention-deficit/hyperactivity disorder (ADHD) treatment response and (2) responses of ODD symptoms to atomoxetine. Method: Children and adolescents (ages 8-18) with ADHD were treated for approximately 8 weeks with placebo or atomoxetine (fixed dosing: 0.5,…

CYP2D60 and Clinical Response to Atomoxetine in Children and Adolescents with ADHD

ERIC Educational Resources Information Center

Michelson, David; Read, Holly A.; Ruff, Dustin D.; Witcher, Jennifer; Zhang, Shuyu; McCracken, James

2007-01-01

Background: Atomoxetine, a selective norepinephrine reuptake inhibitor effective in the treatment of attention-deficit/hyperactivity disorder (ADHD), is metabolized through the cytochrome P-450 2D6 (CYP2D6) enzyme pathway, which is genetically polymorphic in humans. Variations in plasma atomoxetine exposures can occur because of genetic variation…

A review of the efficacy of atomoxetine in the treatment of attention-deficit hyperactivity disorder in children and adult patients with common comorbidities

PubMed Central

Clemow, David B; Bushe, Chris; Mancini, Michele; Ossipov, Michael H; Upadhyaya, Himanshu

2017-01-01

Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder that is often diagnosed during childhood, but has also increasingly been recognized to occur in adults. Importantly, up to 52% of children (including adolescents) and 87% of adults with ADHD also have a comorbid psychiatric disorder. The presence of a comorbid disorder has the potential to impact diagnosis and could affect treatment outcomes. Atomoxetine is a nonstimulant treatment for ADHD. Despite numerous published studies regarding efficacy of atomoxetine in the treatment of ADHD in patients with comorbid disorders, there is limited information about the impact of individual common comorbid disorders on the efficacy of atomoxetine for ADHD, especially with regard to adults. Moreover, a cumulative review and assessment of these studies has not been conducted. For this reason, we performed a literature review to find, identify, and cumulatively review clinical studies that examined the efficacy of atomoxetine in the treatment of patients with ADHD and comorbid psychiatric disorders. We found a total of 50 clinical studies (37 in children; 13 in adults) that examined the efficacy of atomoxetine in patients with ADHD and a comorbid disorder. The comorbidities that were studied in children or in adults included anxiety, depression, and substance use disorder. Overall, the presence of comorbidity did not adversely impact the efficacy of atomoxetine in treatment of ADHD symptoms in both patient populations. In the studies identified and assessed in this review, atomoxetine did not appear to exacerbate any of the comorbid conditions and could, therefore, be an important therapy choice for the treatment of ADHD in the presence of comorbid disorders. PMID:28223809

Predictors of pharmacological treatment outcomes with atomoxetine or methylphenidate in patients with attention-deficit/hyperactivity disorder from China, Egypt, Lebanon, Russian Federation, Taiwan, and United Arab Emirates.

PubMed

Treuer, T; Feng, Q; Desaiah, D; Altin, M; Wu, S; El-Shafei, A; Serebryakova, E; Gado, M; Faries, D

2014-09-01

The reduced availability of data from non-Western countries limits our ability to understand attention-deficit/hyperactivity disorder (ADHD) treatment outcomes, specifically, adherence and persistence of ADHD in children and adolescents. This analysis assessed predictors of treatment outcomes in a non-Western cohort of patients with ADHD treated with atomoxetine or methylphenidate. Data from a 12-month, prospective, observational study in outpatients aged 6-17 years treated with atomoxetine (N = 234) or methylphenidate (N = 221) were analysed post hoc to determine potential predictors of treatment outcomes. Participating countries included the Russian Federation, China, Taiwan, Egypt, United Arab Emirates and Lebanon. Factors associated with remission were analysed with stepwise multiple logistic regression and classification and regression trees (CART). Cox proportional hazards models with propensity score adjustment assessed differences in atomoxetine persistence among initial-dose cohorts. In patients treated with atomoxetine who had available dosing information (N = 134), Cox proportional hazards revealed lower (< 0.5 mg/kg) initial dose was significantly associated with shorter medication persistence (p < 0.01). multiple logistic regression analysis revealed greater rates of remission for atomoxetine-treated patients were associated with age (older), country (United Arab Emirates) and gender (female) (all p < 0.05). CART analysis confirmed older age and lack of specific phobias were associated with greater remission rates. For methylphenidate, greater baseline weight (highly correlated with the age factor found for atomoxetine) and prior atomoxetine use were associated with greater remission rates. These findings may help clinicians assess factors upon initiation of ADHD treatment to improve course prediction, proper dosing and treatment adherence and persistence. Observational study, therefore no registration. © 2014 John Wiley & Sons Ltd.

The efficacy of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of clinical research.

PubMed

Savill, Nicola C; Buitelaar, Jan K; Anand, Ernie; Day, Kathleen Ann; Treuer, Tamás; Upadhyaya, Himanshu P; Coghill, David

2015-02-01

Atomoxetine was first licensed to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in the US in 2002. The aim of this paper is to comprehensively review subsequent publications addressing the efficacy of atomoxetine in 6- to 18-year-olds with ADHD. We identified 125 eligible papers using a predefined search strategy. Overall, these papers demonstrate that atomoxetine is an effective treatment for the core ADHD symptoms (effect sizes 0.6-1.3, vs. placebo, at 6-18 weeks), and improves functional outcomes and quality of life, in various pediatric populations with ADHD (i.e., males/females, patients with co-morbidities, children/adolescents, and with/without prior exposure to other ADHD medications). Initial responses to atomoxetine may be apparent within 1 week of treatment, but can take longer (median 23 days in a 6-week study; n=72). Responses often build gradually over time, and may not be robust until after 3 months. A pooled analysis of six randomized placebo-controlled trials (n=618) indicated that responses at 4 weeks may predict response at 6-9 weeks, although another pooled analysis of open-label data (n=338) suggests that the probability of a robust response to atomoxetine [≥40% decrease in ADHD-Rating Scale (ADHD-RS) scores] may continue to increase beyond 6-9 weeks. Atomoxetine may demonstrate similar efficacy to methylphenidate, particularly immediate-release methylphenidate, although randomized controlled trials are generally limited by short durations (3-12 weeks). In conclusion, notwithstanding these positive findings, before initiating treatment with atomoxetine, it is important that the clinician sets appropriate expectations for the patient and their family with regard to the likelihood of a gradual response, which often builds over time.

Effects of atomoxetine on attention and impulsivity in the five-choice serial reaction time task in rats with lesions of dorsal noradrenergic ascending bundle.

PubMed

Liu, Yia-Ping; Huang, Teng-Shun; Tung, Che-Se; Lin, Chen-Cheng

2015-01-02

Atomoxetine, a noradrenaline reuptake inhibitor (NRI), which is a non-stimulating medicine that is used for the treatment of patients with attention deficit hyperactivity disorder (ADHD), has been found to be effective in reducing behavioral impulsivity in rodents, but its efficacy in a dorsal noradrenergic ascending bundle (DNAB)-lesioned condition has not been examined. The present study aimed to investigate the effects of DNAB lesions on attention and impulsive control in the five-choice serial reaction time task (5-CSRTT) in rats treated with atomoxetine. The drug-induced changes in noradrenaline efflux in the medial prefrontal cortex were also measured. 5-CSRTT-trained rats were included in one of the following groups: N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)/Atomoxetine, Sham/Atomoxetine, DSP-4/Saline, or Sham/Saline. Acute atomoxetine (0.3 mg/kg) was administered 14 days after the DSP-4 regime. The behavioral testing included manipulations of the inter-trial interval (ITI), stimulation duration and food satiety. In vivo microdialysis of the noradrenaline efflux in the medial prefrontal cortex and the expression of the noradrenaline transporter (NAT) in the DNAB areas were examined. Atomoxetine reduced impulsivity and perseveration in the long-ITI condition with no effects on any other variables. This phenomenon was not influenced by DSP-4 pre-treatment. The DNAB-lesioned rats had lower noradrenaline efflux in the medial prefrontal cortex. DSP-4 caused no change in NAT expression in the DNAB areas. These findings suggested that noradrenaline reuptake may not be exclusively responsible for the atomoxetine effects in adjusting impulsivity. The role of DNAB should also be considered, particularly in conditions requiring greater behavioral inhibition. Copyright © 2014 Elsevier Inc. All rights reserved.

Neurophysiologic predictors of response to atomoxetine in young adults with attention deficit hyperactivity disorder: a pilot project.

PubMed

Leuchter, Andrew F; McGough, James J; Korb, Alexander S; Hunter, Aimee M; Glaser, Paul E A; Deldar, Ahmed; Durell, Todd M; Cook, Ian A

2014-07-01

Atomoxetine is a non-stimulant medication with sustained benefit throughout the day, and is a useful pharmacologic treatment option for young adults with Attention-Deficit/Hyperactivity Disorder (ADHD). It is difficult to determine, however, those patients for whom atomoxetine will be both effective and advantageous. Patients may need to take the medication for several weeks before therapeutic benefit is apparent, so a biomarker that could predict atomoxetine effectiveness early in the course of treatment could be clinically useful. There has been increased interest in the study of thalamocortical oscillatory activity using quantitative electroencephalography (qEEG) as a biomarker in ADHD. In this study, we investigated qEEG absolute power, relative power, and cordance, which have been shown to predict response to reuptake inhibitor antidepressants in Major Depressive Disorder (MDD), as potential predictors of response to atomoxetine. Forty-four young adults with ADHD (ages 18-30) enrolled in a multi-site, double-blind placebo-controlled study of the effectiveness of atomoxetine and underwent serial qEEG recordings at pretreatment baseline and one week after the start of medication. qEEG measures were calculated from a subset of the sample (N = 29) that provided useable qEEG recordings. Left temporoparietal cordance in the theta frequency band after one week of treatment was associated with ADHD symptom improvement and quality of life measured at 12 weeks in atomoxetine-treated subjects, but not in those treated with placebo. Neither absolute nor relative power measures selectively predicted improvement in medication-treated subjects. Measuring theta cordance after one week of treatment could be useful in predicting atomoxetine treatment response in adult ADHD. Copyright © 2014 Elsevier Ltd. All rights reserved.

Safety and improvement of movement function after stroke with atomoxetine: A pilot randomized trial

PubMed Central

Ward, Andrea; Carrico, Cheryl; Powell, Elizabeth; Westgate, Philip M.; Nichols, Laurie; Fleischer, Anne; Sawaki, Lumy

2016-01-01

Background: Intensive, task-oriented motor training has been associated with neuroplastic reorganization and improved upper extremity movement function after stroke. However, to optimize such training for people with moderate-to-severe movement impairment, pharmacological modulation of neuroplasticity may be needed as an adjuvant intervention. Objective: Evaluate safety, as well as improvement in movement function, associated with motor training paired with a drug to upregulate neuroplasticity after stroke. Methods: In this double-blind, randomized, placebo-controlled study, 12 subjects with chronic stroke received either atomoxetine or placebo paired with motor training. Safety was assessed using vital signs. Upper extremity movement function was assessed using Fugl-Meyer Assessment, Wolf Motor Function Test, and Action Research Arm Test at baseline, post-intervention, and 1-month follow-up. Results: No significant between-groups differences were found in mean heart rate (95% CI, –12.4–22.6; p = 0.23), mean systolic blood pressure (95% CI, –1.7–29.6; p = 0.21), or mean diastolic blood pressure (95% CI, –10.4–13.3; p = 0.08). A statistically significant between-groups difference on Fugl-Meyer at post-intervention favored the atomoxetine group (95% CI, 1.6–12.7; p = 0.016). Conclusion: Atomoxetine combined with motor training appears safe and may optimize motor training outcomes after stroke. PMID:27858723

Atomoxetine-Related Change in Sluggish Cognitive Tempo Is Partially Independent of Change in Attention-Deficit/Hyperactivity Disorder Inattentive Symptoms.

PubMed

McBurnett, Keith; Clemow, David; Williams, David; Villodas, Miguel; Wietecha, Linda; Barkley, Russell

2017-02-01

To evaluate effects of atomoxetine versus placebo on sluggish cognitive tempo (SCT) and determine factors affecting improvement of SCT in children with attention-deficit/hyperactivity disorder (ADHD) with dyslexia (ADHD+D) or dyslexia only. This is a post hoc analysis of a 16-week placebo-controlled, double-blind randomized phase of a previously reported atomoxetine study in children aged 10-16 years with ADHD+D, Dyslexia-only, or ADHD-only (no placebo arm). Least squares mean changes from baseline to endpoint for atomoxetine versus placebo on the Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) (Parent, Teacher, and Youth) were analyzed using analysis of covariance and multiple regression (partial R 2 ) analyses to test contributions of ADHD and dyslexia to improvements in K-SCT scores. Results were examined for the three informants within the three diagnostic groups (nine outcomes). Atomoxetine treatment was associated with significant reductions from baseline in seven of the nine outcomes using the p = 0.05 significance level, appropriate for exploratory analysis. When change in ADHD symptom severity was controlled, all of the seven SCT outcomes remained significant; changes in effect sizes were minimal. Regression analyses using SCT change as the criterion found a significant contribution by inattention change only for parent report, whereas, baseline SCT severity was a significant predictor in the randomized groups with the exception of teacher report in the Dyslexia-only group. Given that controlling for change in ADHD symptoms had little effect on change in SCT scores, findings suggest that change in SCT is substantially independent of change in ADHD. By inference, SCT and its response to treatment is a partially distinct phenomenon from ADHD response. Regression analyses did not reveal global effects of inattention change on SCT change; instead, baseline SCT severity was the strongest predictor of placebo-controlled treatment effect on SCT. Atomoxetine effects on SCT appear to be best predicted by how much room for improvement exists for SCT rather than by severity or improvement in inattention. NCT00607919, www.clinicaltrials.gov.

The Pharmacological Management of Oppositional Behaviour, Conduct Problems, and Aggression in Children and Adolescents With Attention-Deficit Hyperactivity Disorder, Oppositional Defiant Disorder, and Conduct Disorder: A Systematic Review and Meta-Analysis. Part 1: Psychostimulants, Alpha-2 Agonists, and Atomoxetine

PubMed Central

Pringsheim, Tamara; Hirsch, Lauren; Gardner, David; Gorman, Daniel A

2015-01-01

Objective: Children with attention-deficit hyperactivity disorder (ADHD) may have oppositional behaviour, conduct problems, and aggression. These symptoms vary in severity, and may be related to a comorbid diagnosis of oppositional defiant disorder (ODD) or conduct disorder (CD). Critical evaluation of the efficacy of ADHD medications may guide the clinician regarding the usefulness of medications for these symptoms. Method: We performed a systematic review and meta-analysis of psychostimulants, alpha-2 agonists, and atomoxetine for oppositional behaviour, conduct problems, and aggression in youth with ADHD, ODD, and CD. The quality of evidence for medications was rated using the Grading of Recommendations Assessment, Development and Evaluation approach. Results: Two systematic reviews and 20 randomized controlled trials were included. There is high-quality evidence that psychostimulants have a moderate-to-large effect on oppositional behaviour, conduct problems, and aggression in youth with ADHD, with and without ODD or CD. There is very-low-quality evidence that clonidine has a small effect on oppositional behaviour and conduct problems in youth with ADHD, with and without ODD or CD. There is moderate-quality evidence that guanfacine has a small-to-moderate effect on oppositional behaviour in youth with ADHD, with and without ODD. There is high-quality evidence that atomoxetine has a small effect on oppositional behaviour in youth with ADHD, with and without ODD or CD. Conclusions: Evidence indicates that psychostimulants, alpha-2 agonists, and atomoxetine can be beneficial for disruptive and aggressive behaviours in addition to core ADHD symptoms; however, psychostimulants generally provide the most benefit. PMID:25886655

The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 1: psychostimulants, alpha-2 agonists, and atomoxetine.

PubMed

Pringsheim, Tamara; Hirsch, Lauren; Gardner, David; Gorman, Daniel A

2015-02-01

Children with attention-deficit hyperactivity disorder (ADHD) may have oppositional behaviour, conduct problems, and aggression. These symptoms vary in severity, and may be related to a comorbid diagnosis of oppositional defiant disorder (ODD) or conduct disorder (CD). Critical evaluation of the efficacy of ADHD medications may guide the clinician regarding the usefulness of medications for these symptoms. We performed a systematic review and meta-analysis of psychostimulants, alpha-2 agonists, and atomoxetine for oppositional behaviour, conduct problems, and aggression in youth with ADHD, ODD, and CD. The quality of evidence for medications was rated using the Grading of Recommendations Assessment, Development and Evaluation approach. Two systematic reviews and 20 randomized controlled trials were included. There is high-quality evidence that psychostimulants have a moderate-to-large effect on oppositional behaviour, conduct problems, and aggression in youth with ADHD, with and without ODD or CD. There is very-low-quality evidence that clonidine has a small effect on oppositional behaviour and conduct problems in youth with ADHD, with and without ODD or CD. There is moderate-quality evidence that guanfacine has a small-to-moderate effect on oppositional behaviour in youth with ADHD, with and without ODD. There is high-quality evidence that atomoxetine has a small effect on oppositional behaviour in youth with ADHD, with and without ODD or CD. Evidence indicates that psychostimulants, alpha-2 agonists, and atomoxetine can be beneficial for disruptive and aggressive behaviours in addition to core ADHD symptoms; however, psychostimulants generally provide the most benefit.

Atomoxetine Does Not Alter Cocaine Use in Cocaine Dependent Individuals: A Double Blind Randomized Trial

PubMed Central

Middleton, Lisa S.; Wong, Conrad J.; Nuzzo, Paul A.; Campbell, Charles L.; Rush, Craig R.; Lofwall, Michelle R.

2016-01-01

Background Cocaine abuse continues to be a significant public health problem associated with morbidity and mortality. To date, no pharmacotherapeutic approach has proven effective for treating cocaine use disorders. Preclinical and clinical evidence suggests that noradrenergic activity may play a role in mediating some effects of cocaine and may be a rational target for treatment. Methods This double blind, placebo-controlled randomized, parallel group, 12-week outpatient clinical trial enrolled cocaine dependent individuals seeking treatment to examine the potential efficacy of the selective norepinephrine reuptake inhibitor, atomoxetine (80 mg/day; p.o.; n=25), compared to placebo (n=25). Subjects were initially stratified on cocaine use (<15 days or ≥15 days of the last 30), age and race using urn randomization. Attendance, medication adherence and study compliance were reinforced with contingency management, and weekly counseling was offered. An array of measures (vital signs, laboratory chemistries, cognitive and psychomotor tests, cocaine craving and urine samples for drug testing) was collected throughout the study and at follow-up. Results Survival analysis revealed no differences in study retention between the two groups, with approximately 56% of subjects completing the 12-week study (Cox analysis X2=.72; p=.40; Hazard Ratio 1.48 [CI 0.62–3.39]). GEE analysis of the proportion of urine samples positive for benzoylecgonine, a cocaine metabolite, revealed no differences between the atomoxetine and placebo groups (X2=0.2, p=.66; OR=0.89 [95% CI 0.41 – 1.74). Atomoxetine was generally well tolerated in this population. Conclusions These data provide no support for the utility of atomoxetine in the treatment of cocaine dependence. PMID:23200303

Safety and Tolerability of Atomoxetine over 3 to 4 Years in Children with ADHD

ERIC Educational Resources Information Center

Donnelly, Craig; Bangs, Mark; Trzepacz, Paula; Jin, Ling; Zhang, Shuyu; Witte, Michael M.; Ball, Susan G.; Spencer, Thomas J.

2009-01-01

Data from 13 double-blind, placebo-controlled trials and three open-label extension studies were pooled to examine the safety of atomoxetine for treating attention deficit hyperactivity disorder in children and adolescents for less than or equal to three or four years. Results show that atomoxetine is safe and well tolerated in the subjects.

Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor 'knockout' mice.

PubMed

Pillidge, Katharine; Porter, Ashley J; Vasili, Temis; Heal, David J; Stanford, S Clare

2014-12-01

Mice with functional ablation of the neurokinin-1 receptor gene (NK1R(-/-)) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT). Separate cohorts of mice were tested in the 5-CSRTT and LDEB after treatment with no injection, vehicle or atomoxetine (5-CSRTT: 0.3, 3 or 10mg/kg; LDEB: 1, 3 or 10mg/kg). Atomoxetine reduced the hyperactivity displayed by NK1R(-/-) mice in the LDEB at a dose (3mg/kg) which did not affect the locomotor activity of wildtypes. Atomoxetine (10mg/kg) also reduced impulsivity in NK1R(-/-) mice, but not wildtypes, in the 5-CSRTT. No dose of drug affected attention in either genotype. This evidence that atomoxetine reduces hyperactive/impulsive behaviours in NK1R(-/-) mice consolidates the validity of using NK1R(-/-) mice in research of the aetiology and treatment of ADHD. Copyright © 2014. Published by Elsevier Inc.

Reduced short interval cortical inhibition correlates with atomoxetine response in children with attention-deficit hyperactivity disorder (ADHD).

PubMed

Chen, Tina H; Wu, Steve W; Welge, Jeffrey A; Dixon, Stephan G; Shahana, Nasrin; Huddleston, David A; Sarvis, Adam R; Sallee, Floyd R; Gilbert, Donald L

2014-12-01

Clinical trials in children with attention-deficit hyperactivity disorder (ADHD) show variability in behavioral responses to the selective norepinephrine reuptake inhibitor atomoxetine. The objective of this study was to determine whether transcranial magnetic stimulation-evoked short interval cortical inhibition might be a biomarker predicting, or correlating with, clinical atomoxetine response. At baseline and after 4 weeks of atomoxetine treatment in 7- to 12-year-old children with ADHD, transcranial magnetic stimulation short interval cortical inhibition was measured, blinded to clinical improvement. Primary analysis was by multivariate analysis of covariance. Baseline short interval cortical inhibition did not predict clinical responses. However, paradoxically, after 4 weeks of atomoxetine, mean short interval cortical inhibition was reduced 31.9% in responders and increased 6.1% in nonresponders (analysis of covariance t 41 = 2.88; P = .0063). Percentage reductions in short interval cortical inhibition correlated with reductions in the ADHD Rating Scale (r = 0.50; P = .0005). In children ages 7 to 12 years with ADHD treated with atomoxetine, improvements in clinical symptoms are correlated with reductions in motor cortex short interval cortical inhibition. © The Author(s) 2014.

Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor ‘knockout’ mice

PubMed Central

Pillidge, Katharine; Porter, Ashley J.; Vasili, Temis; Heal, David J.; Stanford, S. Clare

2014-01-01

Background Mice with functional ablation of the neurokinin-1 receptor gene (NK1R−/−) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT). Methods Separate cohorts of mice were tested in the 5-CSRTT and LDEB after treatment with no injection, vehicle or atomoxetine (5-CSRTT: 0.3, 3 or 10 mg/kg; LDEB: 1, 3 or 10 mg/kg). Results Atomoxetine reduced the hyperactivity displayed by NK1R−/− mice in the LDEB at a dose (3 mg/kg) which did not affect the locomotor activity of wildtypes. Atomoxetine (10 mg/kg) also reduced impulsivity in NK1R−/− mice, but not wildtypes, in the 5-CSRTT. No dose of drug affected attention in either genotype. Conclusions This evidence that atomoxetine reduces hyperactive/impulsive behaviours in NK1R−/− mice consolidates the validity of using NK1R−/− mice in research of the aetiology and treatment of ADHD. PMID:25450119

A Pilot Study of the Effects of Atomoxetine on Driving Performance in Adults with ADHD

ERIC Educational Resources Information Center

Barkley, Russell A.; Anderson, Deborah L.; Kruesi, Markus

2007-01-01

Objective: There is a high risk of vehicular crashes, traffic citations, and poorer driving performance in adults with ADHD. This pilot study examines the value of a new nonstimulant (atomoxetine) for improving the driving performance of adults with ADHD. Method: Atomoxetine (1.2 mg/kg daily for 3 weeks) and a placebo are studied on 18 adults with…

Efficacy and Safety Extrapolation Analyses for Atomoxetine in Young Children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Kratochvil, Christopher; Ghuman, Jaswinder; Camporeale, Angelo; Lipsius, Sarah; D'Souza, Deborah; Tanaka, Yoko

2015-01-01

Abstract Objectives: This extrapolation analysis qualitatively compared the efficacy and safety profile of atomoxetine from Lilly clinical trial data in 6–7-year-old patients with attention-deficit/hyperactivity disorder (ADHD) with that of published literature in 4–5-year-old patients with ADHD (two open-label [4–5-year-old patients] and one placebo-controlled study [5-year-old patients]). Methods: The main efficacy analyses included placebo-controlled Lilly data and the placebo-controlled external study (5-year-old patients) data. The primary efficacy variables used in these studies were the ADHD Rating Scale-IV Parent Version, Investigator Administered (ADHD-RS-IV-Parent:Inv) total score, or the Swanson, Nolan and Pelham (SNAP-IV) scale score. Safety analyses included treatment-emergent adverse events (TEAEs) and vital signs. Descriptive statistics (means, percentages) are presented. Results: Acute atomoxetine treatment improved core ADHD symptoms in both 6–7-year-old patients (n=565) and 5-year-old patients (n=37) (treatment effect: −10.16 and −7.42). In an analysis of placebo-controlled groups, the mean duration of exposure to atomoxetine was ∼7 weeks for 6–7-year-old patients and 9 weeks for 5-year-old patients. Decreased appetite was the most common TEAE in atomoxetine-treated patients. The TEAEs observed at a higher rate in 5-year-old versus 6–7-year-old patients were irritability (36.8% vs. 3.6%) and other mood-related events (6.9% each vs. <3.0%). Blood pressure and pulse increased in both 4–5-year-old patients and 6–7-year-old patients, whereas a weight increase was seen only in the 6–7-year-old patients. Conclusions: Although limited by the small sample size of the external studies, these analyses suggest that in 5-year-old patients with ADHD, atomoxetine may improve ADHD symptoms, but possibly to a lesser extent than in older children, with some adverse events occurring at a higher rate in 5-year-old patients. PMID:25265343

Effects of stimulants and atomoxetine on emotional lability in adults: A systematic review and meta-analysis.

PubMed

Moukhtarian, T R; Cooper, R E; Vassos, E; Moran, P; Asherson, P

2017-07-01

Emotional lability (EL) is an associated feature of attention-deficit/hyperactivity disorder (ADHD) in adults, contributing to functional impairment. Yet the effect of pharmacological treatments for ADHD on EL symptoms is unknown. We conducted a systematic review and meta-analysis to examine the effects of stimulants and atomoxetine on symptoms of EL and compare these with the effects on core ADHD symptoms. A systematic search was conducted on the databases Embase, PsychInfo, and Ovid Medline ® and the clinicaltrials.gov website. We included randomised, double-blind, placebo-controlled trials of stimulants and atomoxetine in adults aged 18-60 years, with any mental health diagnosis characterised by emotional or mood instability, with at least one outcome measure of EL. All identified trials were on adults with ADHD. A random-effects meta-analysis with standardised mean difference and 95% confidence intervals was used to investigate the effect size on EL and compare this to the effect on core ADHD symptoms. Of the 3,864 publications identified, nine trials met the inclusion criteria for the meta-analysis. Stimulants and atomoxetine led to large mean weighted effect-sizes for on ADHD symptoms (n=9, SMD=-0.8, 95% CI:-1.07 to -0.53). EL outcomes showed more moderate but definite effects (n=9, SMD=-0.41, 95% CI:-0.57 to -0.25). In this meta-analysis, stimulants and atomoxetine were moderately effective for EL symptoms, while effect size on core ADHD symptoms was twice as large. Methodological issues may partially explain the difference in effect size. Reduced average effect size could also reflect heterogeneity of EL with ADHD pharmacotherapy responsive and non-responsive sub-types. Our findings indicate that EL may be less responsive than ADHD symptoms overall, perhaps indicating the need for adjunctive psychotherapy in some cases. To clarify these questions, our findings need replication in studies selecting subjects for high EL and targeting EL as the primary outcome. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Atomoxetine for Orthostatic Hypotension in an Elderly Patient Over 10 Weeks: A Case Report.

PubMed

Hale, Genevieve M; Brenner, Michael

2015-09-01

Several nonpharmacologic strategies for orthostatic hypotension exist including avoiding large carbohydrate-rich meals; limiting alcohol consumption; maintaining adequate hydration; adding salt to foods; and using compression stockings, tilt-table exercises, or abdominal binders. If these fail, however, only limited evidence-based pharmacologic treatment options are available including the use of fludrocortisone, midodrine, pyridostigmine, and droxidopa as well as pseudoephedrine, ocetreotide, and atomoxetine. This report discusses a case of atomoxetine use for 10 weeks in an elderly patient with primary orthostatic hypotension. An 84-year-old man with long-standing primary orthostatic hypotension presented to our ambulatory cardiology pharmacotherapy clinic after several unsuccessful pharmacologic therapies including fludrocortisone, midodrine, and pyridostigmine. Nonpharmacologic strategies were also implemented. Atomoxetine was initiated, and the patient showed gradual improvements in symptoms and blood pressure control over the course of 10 weeks. Our data suggest that low-dose atomoxetine is an effective and safe agent for symptom improvement and blood pressure control in elderly patients with primary orthostatic hypotension. © 2015 Pharmacotherapy Publications, Inc.

A Randomized Double-Blind Study of Atomoxetine versus Placebo for Attention-Deficit/Hyperactivity Disorder Symptoms in Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Harfterkamp, Myriam; van de Loo-Neus, Gigi; Minderaa, Ruud B.; van der Gaag, Rutger-Jan; Escobar, Rodrigo; Schacht, Alexander; Pamulapati, Sireesha; Buitelaar, Jan K.; Hoekstra, Pieter J.

2012-01-01

Objective: The efficacy of atomoxetine as treatment of symptoms of attention-deficit/hyperactivity disorder (ADHD) in patients with autism spectrum disorder (ASD) has not been established. Method: In this study, 97 patients aged 6 to 17 years with ADHD and ASD were randomly assigned to double-blind treatment with 1.2 mg/kg/day atomoxetine or…

The effect of atomoxetine on random and directed exploration in humans.

PubMed

Warren, Christopher M; Wilson, Robert C; van der Wee, Nic J; Giltay, Eric J; van Noorden, Martijn S; Cohen, Jonathan D; Nieuwenhuis, Sander

2017-01-01

The adaptive regulation of the trade-off between pursuing a known reward (exploitation) and sampling lesser-known options in search of something better (exploration) is critical for optimal performance. Theory and recent empirical work suggest that humans use at least two strategies for solving this dilemma: a directed strategy in which choices are explicitly biased toward information seeking, and a random strategy in which decision noise leads to exploration by chance. Here we examined the hypothesis that random exploration is governed by the neuromodulatory locus coeruleus-norepinephrine system. We administered atomoxetine, a norepinephrine transporter blocker that increases extracellular levels of norepinephrine throughout the cortex, to 22 healthy human participants in a double-blind crossover design. We examined the effect of treatment on performance in a gambling task designed to produce distinct measures of directed exploration and random exploration. In line with our hypothesis we found an effect of atomoxetine on random, but not directed exploration. However, contrary to expectation, atomoxetine reduced rather than increased random exploration. We offer three potential explanations of our findings, involving the non-linear relationship between tonic NE and cognitive performance, the interaction of atomoxetine with other neuromodulators, and the possibility that atomoxetine affected phasic norepinephrine activity more so than tonic norepinephrine activity.

An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder.

PubMed

Takahashi, Michihiro; Takita, Yasushi; Goto, Taro; Ichikawa, Hironobu; Saito, Kazuhiko; Matsumoto, Hideo; Tanaka, Yasuo

2011-02-01

The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen. This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores. Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time-dependent manner; the mean change from baseline to endpoint was -15.0 (P<0.001). This study showed that atomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients. © 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.

Reading outcomes of children and adolescents with attention-deficit/hyperactivity disorder and dyslexia following atomoxetine treatment.

PubMed

Shaywitz, Bennett A; Williams, David W; Fox, Bethany K; Wietecha, Linda A

2014-10-01

Abstract Objective: This study assessed the efficacy of atomoxetine on attention-deficit/hyperactivity disorder (ADHD) symptoms in children and adolescents having ADHD with comorbid dyslexia (ADHD+D) and the effects of the treatment on reading measures. The analyses in this report used data from a study designed to examine the effects of a nonstimulant pharmacological agent, atomoxetine, on reading in children with ADHD+D. Patients ages 10-16 years with ADHD or ADHD+D received open-label atomoxetine for 16 weeks. The ADHD Rating Scale (ADHD-RS) and reading subtests of the Kaufman Test of Educational Achievement (K-TEA) were assessed. Changes in ADHD symptoms and reading scores were also analyzed by ADHD subtype. Treatment effect sizes and correlations between changes in ADHDRS and K-TEA scores were calculated. After atomoxetine treatment, both ADHD and ADHD+D patient groups showed significant reduction in ADHD symptom and improvements in K-TEA reading scores. The range of treatment effect sizes on K-TEA scores was 0.35-0.53 for the ADHD group and 0.50-0.62 for the ADHD+D group. Pearson's correlation coefficients revealed only a few weak correlations between changes in ADHD symptoms and reading scores, regardless of diagnostic group. ADHD symptoms and K-TEA reading scores improved for both the ADHD and ADHD+D groups following atomoxetine treatment. Correlation analyses indicate that improvements in reading outcomes cannot be explained by a reduction of ADHD symptoms alone. These findings support further exploration of the potential effects of atomoxetine on reading in children with ADHD and dyslexia or dyslexia alone.

Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence

PubMed Central

Kenny, Jonathan D.; Taylor, Norman E.; Brown, Emery N.; Solt, Ken

2015-01-01

Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg IV), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg IV) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1–4 Hz) to θ (4–8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes significant neurophysiological changes, but does not promote behavioral arousal during general anesthesia. We hypothesize that dextroamphetamine is more likely than atomoxetine to be clinically useful for restoring consciousness in anesthetized patients, mainly due to its stimulation of dopaminergic neurotransmission. PMID:26148114

Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

PubMed

Kenny, Jonathan D; Taylor, Norman E; Brown, Emery N; Solt, Ken

2015-01-01

Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg i.v.), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg i.v.) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz) to θ (4-8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes significant neurophysiological changes, but does not promote behavioral arousal during general anesthesia. We hypothesize that dextroamphetamine is more likely than atomoxetine to be clinically useful for restoring consciousness in anesthetized patients, mainly due to its stimulation of dopaminergic neurotransmission.

Atomoxetine effects on executive function as measured by the BRIEF--a in young adults with ADHD: a randomized, double-blind, placebo-controlled study.

PubMed

Adler, Lenard A; Clemow, David B; Williams, David W; Durell, Todd M

2014-01-01

To evaluate the effect of atomoxetine treatment on executive functions in young adults with attention-deficit/hyperactivity disorder (ADHD). In this Phase 4, multi-center, double-blind, placebo-controlled trial, young adults (18-30 years) with ADHD were randomized to receive atomoxetine (20-50 mg BID, N = 220) or placebo (N = 225) for 12 weeks. The Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) consists of 75 self-report items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning. Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using an ANCOVA model (terms: baseline score, treatment, and investigator). At baseline, there were no significant treatment group differences in the percentage of patients with BRIEF-A composite or index T-scores ≥60 (p>.5), with over 92% of patients having composite scores ≥60 (≥60 deemed clinically meaningful for these analyses). At endpoint, statistically significantly greater mean reductions were seen in the atomoxetine versus placebo group for the BRIEF-A Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognitive Index (MI) scores, as well as the Inhibit, Self-Monitor, Working Memory, Plan/Organize and Task Monitor subscale scores (p<.05), with decreases in scores signifying improvements in executive functioning. Changes in the BRIEF-A Initiate (p = .051), Organization of Materials (p = .051), Shift (p = .090), and Emotional Control (p = .219) subscale scores were not statistically significant. In addition, the validity scales: Inconsistency (p = .644), Infrequency (p = .097), and Negativity (p = .456) were not statistically significant, showing scale validity. Statistically significantly greater improvement in executive function was observed in young adults with ADHD in the atomoxetine versus placebo group as measured by changes in the BRIEF-A scales. ClinicalTrials.gov NCT00510276.

Atomoxetine Effects on Executive Function as Measured by the BRIEF-A in Young Adults with ADHD: A Randomized, Double-Blind, Placebo-Controlled Study

PubMed Central

Adler, Lenard A.; Clemow, David B.; Williams, David W.; Durell, Todd M.

2014-01-01

Objective To evaluate the effect of atomoxetine treatment on executive functions in young adults with attention-deficit/hyperactivity disorder (ADHD). Methods In this Phase 4, multi-center, double-blind, placebo-controlled trial, young adults (18–30 years) with ADHD were randomized to receive atomoxetine (20–50 mg BID, N = 220) or placebo (N = 225) for 12 weeks. The Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) consists of 75 self-report items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning. Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using an ANCOVA model (terms: baseline score, treatment, and investigator). Results At baseline, there were no significant treatment group differences in the percentage of patients with BRIEF-A composite or index T-scores ≥60 (p>.5), with over 92% of patients having composite scores ≥60 (≥60 deemed clinically meaningful for these analyses). At endpoint, statistically significantly greater mean reductions were seen in the atomoxetine versus placebo group for the BRIEF-A Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognitive Index (MI) scores, as well as the Inhibit, Self-Monitor, Working Memory, Plan/Organize and Task Monitor subscale scores (p<.05), with decreases in scores signifying improvements in executive functioning. Changes in the BRIEF-A Initiate (p = .051), Organization of Materials (p = .051), Shift (p = .090), and Emotional Control (p = .219) subscale scores were not statistically significant. In addition, the validity scales: Inconsistency (p = .644), Infrequency (p = .097), and Negativity (p = .456) were not statistically significant, showing scale validity. Conclusion Statistically significantly greater improvement in executive function was observed in young adults with ADHD in the atomoxetine versus placebo group as measured by changes in the BRIEF-A scales. Trial Registration ClinicalTrials.gov NCT00510276 PMID:25148243

Initial Assessment of β3-Adrenoceptor-Activated Brown Adipose Tissue in Streptozotocin-Induced Type 1 Diabetes Rodent Model Using [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

PubMed

Baranwal, Aparna; Mirbolooki, M Reza; Mukherjee, Jogeshwar

2015-01-01

Metabolic activity of brown adipose tissue (BAT) is activated by β3-adrenoceptor agonists and norepinephrine transporter (NET) blockers and is measurable using [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography/computed tomography (PET/CT) in rats. Using the streptozotocin (STZ)-treated rat model of type 1 diabetes mellitus (T1DM), we investigated BAT activity in this rat model under fasting and nonfasting conditions using [(18)F]FDG PET/CT. Drugs that enhance BAT activity may have a potential for therapeutic development in lowering blood sugar in insulin-resistant diabetes. Rats were rendered diabetic by administration of STZ and confirmed by glucose measures. [(18)F]FDG was injected in the rats (fasted or nonfasted) pretreated with either saline or β3-adrenoceptor agonist CL316,243 or the NET blocker atomoxetine for PET/CT scans. [(18)F]FDG metabolic activity was computed as standard uptake values (SUVs) in interscapular brown adipose tissue (IBAT) and compared across the different drug treatment conditions. Blood glucose levels > 500 mg/dL were established for the STZ-treated diabetic rats. Under fasting conditions, average uptake of [(18)F]FDG in the IBAT of STZ-treated diabetic rats was approximately 70% lower compared to that of normal rats. Both CL316,243 and atomoxetine activated IBAT in normal rats had an SUV > 5, whereas activation in STZ-treated rats was significantly lower. The agonist CL316,243 activated IBAT up to threefold compared to saline in the fasted STZ-treated rat. In the nonfasted rat, the IBAT activation was up by twofold by CL316243. Atomoxetine had a greater effect on lowering blood sugar levels compared to CL316,243 in the nonfasted rats. A significant reduction in metabolic activity was observed in the STZ-treated diabetic rodent model. Increased IBAT activity in the STZ-treated diabetic rat under nonfasted conditions using the β3-adrenoceptor agonist CL316,243 suggests a potential role of BAT in modulating blood sugar levels. Further studies are needed to evaluate the therapeutic role of β3-adrenoceptor agonists in insulin-resistant T1DM.

Chronic atomoxetine treatment during adolescence does not influence decision-making on a rodent gambling task, but does modulate amphetamine's effect on impulsive action in adulthood.

PubMed

Silveira, Mason M; Murch, W Spencer; Clark, Luke; Winstanley, Catharine A

2016-06-01

In addition to the symptoms of inattention, hyperactivity, and impulsivity, individuals with attention deficit hyperactivity disorder exhibit impaired performance on tests of real-world cost/benefit decision-making. Atomoxetine, a nonstimulant drug approved for the treatment of attention deficit hyperactivity disorder, is a selective norepinephrine reuptake inhibitor administered chronically during adolescence, a time during which the frontal brain regions necessary for executive function undergo extensive maturation. This treatment protocol can affect behavior well into adulthood, but whether it produces long-term changes in complex decision-making has not been investigated. Twenty-four Long-Evans rats were administered saline or 1.0 mg/kg atomoxetine daily from postnatal day 40 to 54. Two weeks after treatment, the adult rats were trained and assessed on the rodent gambling task, in which the animals chose from four options varying in reward, punishment, and uncertainty. Impulsive action was also measured by recording the number of premature responses made. Regardless of the treatment administered during adolescence, rats learned to favor the advantageous options characterized by small, low-penalty rewards in lieu of the larger, higher-penalty reward options. Rodent gambling task performance was then assessed following acute treatment with atomoxetine (0.1-1.0 mg/kg) and amphetamine (0.3-1.5 mg/kg). Across groups, the highest dose of atomoxetine impaired decision-making and decreased premature responding at all doses tested. Amphetamine also impaired choice performance, but selectively increased impulsive action in rats that had previously received atomoxetine treatment during adolescence. These findings contribute to our understanding of the long-term effects associated with chronic adolescent atomoxetine exposure and suggest that this treatment does not alter decision-making under conditions of risk and uncertainty in adulthood.

Targeting Presynaptic Norepinephrine Transporter in Brown Adipose Tissue: A Novel Imaging Approach and Potential Treatment for Diabetes and Obesity

PubMed Central

MIRBOLOOKI, M. REZA; CONSTANTINESCU, CRISTIAN C.; PAN, MIN-LIANG; MUKHERJEE, JOGESHWAR

2013-01-01

Brown adipose tissue (BAT) plays a significant role in metabolism. In this study, we report the use of atomoxetine (a clinically applicable norepinephrine reuptake inhibitor) for 18F-FDG PET imaging of BAT and its effects on heat production and blood glucose concentration. Fasted-male Sprague-Dawley rats were administered with intravenous 18F-FDG. The same rats were treated with atomoxetine (0.1 mg/kg, i.v.) 30 min before 18F-FDG administration. To confirm the β-adrenergic effects, propranolol (β-adrenergic inhibitor) 5 mg/kg was given intraperitoneally 30 min prior to atomoxetine administration. The effect of atomoxetine on BAT metabolism was assessed in fasted and non-fasted rats and on BAT temperature and blood glucose in fasted rats. In 18F-FDG PET/CT images, interscapular BAT (IBAT) and other areas of BAT were clearly visualized. When rats were fasted, atomoxetine (0.1 mg/kg) increased the 18F-FDG uptake of IBAT by factor of 24 within 30 min. Propranolol reduced the average 18F-FDG uptake of IBAT significantly. Autoradiography of IBAT and white adipose tissue confirmed the data obtained by PET. When rats were not fasted, atomoxetine-induced increase of 18F-FDG uptake in IBAT was delayed and occurred in 120 min. For comparison, direct stimulation of β3-adrenreceptors in non-fasted rats with CL-316, 243 occurred within 30 min. Atomoxetine-induced IBAT activation was associated with higher IBAT temperature and lower blood glucose. This was mediated by inhibition of norepinephrine reuptake transporters in IBAT leading to increased norepinephrine concentration in the synapse. Increased synaptic norepinephrine activates β3-adrenreceptors resulting in BAT hypermetabolism that is visible and quantifiable by 18F-FDG PET/CT. PMID:23080264

Atomoxetine effects on attentional bias to drug-related cues in cocaine dependent individuals.

PubMed

Passamonti, Luca; Luijten, M; Ziauddeen, H; Coyle-Gilchrist, I T S; Rittman, T; Brain, S A E; Regenthal, R; Franken, I H A; Sahakian, B J; Bullmore, E T; Robbins, T W; Ersche, K D

2017-08-01

Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by drugs such as cocaine. We examined the potentially beneficial effects of the noradrenaline reuptake inhibitor atomoxetine in improving cognitive control during two tasks that used cocaine- and non-cocaine-related stimuli. A double-blind, placebo-controlled, and cross-over psycho-pharmacological design was employed. A single oral dose of atomoxetine (40 mg) was administered to 28 cocaine-dependent individuals (CDIs) and 28 healthy controls. All participants performed a pictorial attentional bias task involving both cocaine- and non-cocaine-related pictures as well as a verbal go/no-go task composed of cocaine- and food-related words. As expected, CDIs showed attentional bias to cocaine-related cues whilst controls did not. More importantly, however, atomoxetine, relative to placebo, significantly attenuated attentional bias in CDIs (F 26  = 6.73, P = 0.01). During the go/no-go task, there was a treatment × trial × group interaction, although this finding only showed a trend towards statistical significance (F 26  = 3.38, P = 0.07). Our findings suggest that atomoxetine reduces attentional bias to drug-related cues in CDIs. This may result from atomoxetine's modulation of the balance between tonic/phasic activity in the locus coeruleus and the possibly parallel enhancement of noradrenergic neurotransmission within the prefrontal cortex. Studying how cognitive enhancers such as atomoxetine influence key neurocognitive indices in cocaine addiction may help to develop reliable biomarkers for patient stratification in future clinical trials.

Dihydroxyphenylglycol as a Biomarker of Norepinephrine Transporter Inhibition by Atomoxetine: Human Model to Assess Central and Peripheral Effects of Dosing.

PubMed

Bieck, Peter R; Leibowitz, Mark; Lachno, D Richard; Ledent, Edouard; Padich, Robert; Jhee, Stan

2016-12-01

To assess the primary metabolite of norepinephrine, 3,4-dihydroxyphenylglycol (DHPG), as a sensitive biomarker for norepinephrine transporter (NET) function and the relationship of DHPG measured peripherally and centrally, NET was antagonized with 80 mg/d atomoxetine for 18 days. Twelve healthy subjects were treated with atomoxetine in an open-label, multiple-dose exploratory study. Plasma atomoxetine reached steady state by day 6, and the pharmacokinetic results demonstrated availability of atomoxetine to the central nervous system. The cerebrospinal fluid (CSF)/plasma ratios of atomoxetine based on area under concentration-time curve from 0 to 12 hours postdose (AUC0-12), maximum concentration (Cmax), and predose were 0.3%, 0.2%, and 11%, respectively. Plasma from atomoxetine-treated subjects (ex vivo) significantly inhibited radioligand binding to human NET (P < 0.001) only 1 hour after dosing. Plasma DHPG and DHPG/norepinephrine (ratio) during repeated posture tests were reduced significantly (P < 0.001) on day 5 and stayed significantly reduced up to 1 day after treatment. In CSF, both DHPG and the ratio were significantly reduced (P < 0.001) on day 18. Urine results showed significant decreases for both DHPG and the ratio (P = 0.010 to P < 0.001). Brain-derived neurotrophic factor in CSF was lesser than the limits of detection. The findings suggest that NET blockade can be assessed with DHPG concentration or with the ratio in plasma, CSF, and urine. The data suggest that DHPG is a useful biomarker to proactively assess the pharmacological activity of compounds intended to inhibit NET activity within the brain. The study shows that CSF is a medium for early identification and quantification of biomarkers useful in assessing novel neuroscience targets.

Adolescent Atomoxetine Treatment in a Rodent Model of ADHD: Effects on Cocaine Self-Administration and Dopamine Transporters in Frontostriatal Regions

PubMed Central

Somkuwar, Sucharita S; Jordan, Chloe J; Kantak, Kathleen M; Dwoskin, Linda P

2013-01-01

Cocaine abuse and attention deficit/hyperactivity disorder (ADHD) are often comorbid. Preclinical research indicates that medial prefrontal (mPFC) and orbitofrontal (OFC) cortices are important neural substrates for both disorders. Using the spontaneously hypertensive rat (SHR) model of ADHD, we reported that adolescent treatment with the stimulant methylphenidate, a dopamine (DAT) and norepinephrine (NET) transporter inhibitor, enhanced cocaine self-administration during adulthood, and was associated with increased DAT function in mPFC. This study investigates the effects of atomoxetine ((R)-N-methyl-γ-(2-methylphenoxy)-benzenepropanamine hydrochloride) treatment, a selective NET inhibitor, during adolescence on cocaine self-administration and on DAT function and cell-surface expression in mPFC and OFC during adulthood. SHR acquired cocaine self-administration faster than Wistar–Kyoto and Wistar. Across cocaine doses, SHR earned more cocaine infusions and had higher progressive-ratio breakpoints than Wistar–Kyoto and Wistar, demonstrating that the SHR phenotype models comorbid ADHD and cocaine abuse. Prior atomoxetine treatment did not augment cocaine self-administration in SHR, but acquisition was enhanced in Wistar–Kyoto. No strain differences were found for DAT kinetic parameters or cellular localization in the vehicle controls. Atomoxetine did not alter DAT kinetic parameters or localization in SHR mPFC. Rather, atomoxetine decreased Vmax and DAT cell surface expression in SHR OFC, indicating that inhibition of NET by atomoxetine treatment during adolescence indirectly reduced DAT function and trafficking to the cell surface in OFC, specifically in the ADHD model. Thus, atomoxetine, unlike methylphenidate, does not enhance vulnerability to cocaine abuse in SHR and may represent an important alternative for teens with ADHD when drug addiction is a concern. PMID:23822950

Patterns of long-term and short-term responses in adult patients with attention-deficit/hyperactivity disorder in a completer cohort of 12 weeks or more with atomoxetine.

PubMed

Sobanski, E; Leppämäki, S; Bushe, C; Berggren, L; Casillas, M; Deberdt, W

2015-11-01

Atomoxetine is a well-established pharmacotherapy for adult ADHD. Long-term studies show incremental reductions in symptoms over time. However, clinical experience suggests that patients differ in their response patterns. From 13 Eli Lilly-sponsored studies, we pooled and analyzed data for adults with ADHD who completed atomoxetine treatment at long-term (24 weeks; n=1443) and/or short-term (12 weeks; n=2830) time-points, and had CAARS-Inv:SV total and CGI-S data up to or after these time-points and at Week 0 (i.e. at baseline, when patients first received atomoxetine). The goal was to identify and describe distinct trajectories of response to atomoxetine using hierarchical clustering methods and linear mixed modelling. Based on the homogeneity of changes in CAARS-Inv:SV total scores, 5 response clusters were identified for patients who completed long-term (24 weeks) treatment with atomoxetine, and 4 clusters were identified for patients who completed short-term (12 weeks) treatment. Four of the 5 long-term clusters (comprising 95% of completer patients) showed positive trajectories: 2 faster responding clusters (L1 and L2), and 2 more gradually responding clusters (L3 and L4). Responses (i.e.≥30% reduction in CAARS-Inv:SV total score, and CGI-S score≤3) were observed at 8 and 24 weeks in 80% and 95% of completers in Cluster L1, versus 5% and 48% in Cluster L4. While many adults with ADHD responded relatively rapidly to atomoxetine, others responded more gradually without a clear plateau at 24 weeks. Longer-term treatment may be associated with greater numbers of responders. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Atomoxetine Use in Attention-Deficit/Hyperactivity Disorder and Comorbid Tic Disorder in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections.

PubMed

Demirkaya, Sevcan Karakoç; Demirkaya, Mithat; Yusufoğlu, Canan; Akın, Elif

2017-02-01

Attention-deficit/hyperactivity disorder (ADHD) is a common comorbid disease in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), in which tic-like involuntary movements are frequently seen clinical conditions. In contrast to psychostimulants, atomoxetine is considered as having minimal effects on tics. Here we report two cases with ADHD and PANDAS who were treated with atomoxetine for their ADHD and comorbid tics.

Serotonin enhances the impact of health information on food choice.

PubMed

Vlaev, Ivo; Crockett, Molly J; Clark, Luke; Müller, Ulrich; Robbins, Trevor W

2017-06-01

Serotonin has been implicated in promoting self-control, regulation of hunger and physiological homeostasis, and regulation of caloric intake. However, it remains unclear whether the effects of serotonin on caloric intake reflect purely homeostatic mechanisms, or whether serotonin also modulates cognitive processes involved in dietary decision making. We investigated the effects of an acute dose of the serotonin reuptake inhibitor citalopram on choices between food items that differed along taste and health attributes, compared with placebo and the noradrenaline reuptake inhibitor atomoxetine. Twenty-seven participants attended three sessions and received single doses of atomoxetine, citalopram, and placebo in a double-blind randomised cross-over design. Relative to placebo, citalopram increased choices of more healthy foods over less healthy foods. Citalopram also increased the emphasis on health considerations in decisions. Atomoxetine did not affect decision making relative to placebo. The results support the hypothesis that serotonin may influence food choice by enhancing a focus on long-term goals. The findings are relevant for understanding decisions about food consumption and also for treating health conditions such as eating disorders and obesity.

Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder.

PubMed

Schulz, Kurt P; Fan, Jin; Bédard, Anne-Claude V; Clerkin, Suzanne M; Ivanov, Iliyan; Tang, Cheuk Y; Halperin, Jeffrey M; Newcorn, Jeffrey H

2012-09-01

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD.

Increased Frequency of Encopresis in a Child Diagnosed With Attention Deficit/Hyperactivity Disorder and Encopresis After Atomoxetine Use: A Case Report.

PubMed

Yektaş, Çiğdem; Cansiz, Mehmet Akif; Tufan, Ali Evren

2016-01-01

Attention deficit hyperactivity disorder (ADHD) is among the most frequently reported coexisting psychiatric conditions in children with encopresis. Some case reports state that atomoxetine-a selective presynaptic norepinephrine reuptake inhibitor-approved for treatment of ADHD is also effective in the treatment of coexisting encopresis. Contrasting those reports, here we present a case diagnosed with ADHD and secondary encopresis without constipation whose encopretic symptoms increased after atomoxetine treatment and discuss possible mechanisms.

Relationships Between Functional Outcomes and Symptomatic Improvement in Atomoxetine-Treated Adult Patients with Attention-Deficit/Hyperactivity Disorder: Post Hoc Analysis of an Integrated Database.

PubMed

De Bruyckere, Katrien; Bushe, Chris; Bartel, Christoph; Berggren, Lovisa; Kan, Cornelis C; Dittmann, Ralf W

2016-06-01

Atomoxetine treatment is associated with improvements in functional outcomes in patients with attention-deficit/hyperactivity disorder (ADHD), although relationships between improvements in these outcomes and reductions in ADHD symptoms have not been comprehensively investigated in adults. The aim of this study was to assess relationships between functional outcomes and ADHD symptoms (primary objective), and to assess time courses of changes in functional outcomes from baseline to weeks 10 and 24 (secondary objective). We analyzed data pooled from seven Eli Lilly-sponsored placebo-controlled trials of atomoxetine in adults with ADHD that had Conners' Adult ADHD Rating Scales-Investigator Rated: Screening Version (CAARS-Inv:SV) total scores and functional outcome data at baseline and at week 10. Two trials also had these data at week 24. Patients were included in these pooled analyses if they had a CAARS-Inv:SV total score at baseline and at one or more post-baseline visits at weeks 10 or 24, or had post-baseline scores that would allow missing scores at weeks 10 or 24 to be imputed. To address the primary objective, changes in functional outcomes during treatment with atomoxetine versus placebo were assessed using last observation carried forward (LOCF) analysis of covariance (ANCOVA) and mixed-effects model repeated measures (MMRM) analysis, and correlations between score changes in CAARS-Inv:SV total and functional outcomes were assessed using Spearman's rank correlation coefficient (r) at weeks 10 and 24. The secondary objective was addressed using MMRM. At baseline, patients generally had moderately severe or worse ADHD symptoms (based on CAARS-Inv:SV total scores) and impaired functional outcomes (based on Adult ADHD Quality-of-Life [AAQoL], Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A], Sheehan Disability Scale [SDS], and 36-item Short-Form Health Survey [SF-36] scores). These baseline characteristics were comparable in the atomoxetine and placebo groups. For atomoxetine versus placebo, statistically significant improvements were detected in AAQoL total and subscores at weeks 10 and 24, and in BRIEF-A Self-Report scores at week 10, but not in BRIEF-A Informant Report or SDS scores at week 10 (no BRIEF-A or SDS data were available at week 24), and not in SF-36 at weeks 10 or 24. All functional improvements were gradual. During treatment with atomoxetine, there were moderate correlations between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range -0.58 to -0.39; n = 394-545), and also with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 256). With placebo, moderate correlations were also found between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range -0.56 to -0.28; n = 321-542), and with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 271). However, correlations between changes in CAARS-Inv:SV and BRIEF-A Informant at week 10 were low for atomoxetine-treated patients (r = 0.25; n = 65), moderate with placebo (r = 0.42; n = 72), and there were low/no correlations between changes in CAARS-Inv:SV and functional outcome rating scales that are not specific to ADHD; that is, for atomoxetine-treated patients, SDS total r = 0.19 (n = 32 at week 10) and SF-36 r range - 0.20 to -0.01 (n = 51 at week 10, n = 183 at week 24). Atomoxetine-treated adult patients experienced improvements in functional outcomes (AAQoL and BRIEF-A Self-Report) that correlated with reductions in ADHD symptoms. Although atomoxetine improved both the ADHD symptoms and functional outcomes, the correlation between symptoms and functional outcomes was low to moderate, suggesting that they measure overlapping but different aspects of the disorder. Hence, clinicians should assess not just ADHD symptoms, but also the functional impairments.

Long-Term Pharmacotherapy of Adults With Attention Deficit Hyperactivity Disorder: A Literature Review and Clinical Study.

PubMed

Fredriksen, Mats; Peleikis, Dawn E

2016-01-01

This MiniReview reports and discusses the main findings of the author's thesis including a literature study of long-term pharmacological treatment of adults with attention deficit hyperactivity disorder (ADHD), and a clinical study of 1-year medication. Electronic databases were systematically reviewed for original studies on pharmacotherapy of the defined duration, 24 weeks or more. Although few trials were found with limitations such as excluding comorbidities, treatment with stimulants and atomoxetine was reported tolerated and effective compared to non-treatment. The clinical study of the thesis was conducted on 250 medication-naïve patients with ADHD referred to a specialized outpatient clinic. Comorbid psychiatric disorders were diagnosed among 75% of the patients. About 56% had not completed secondary school, and 51% had been unable to work the preceding year. Persisting inattentive symptoms and comorbid mental disorders in adulthood were related to long-term work disability. In the prospective observational study of the thesis, patients were treated with methylphenidate as first-line drug and atomoxetine or dexamphetamine as second-line drugs, according to current treatment guidelines. At 12-month follow-up, 232 patients completed evaluation and 70% persisted on medication. About 80% of these used methylphenidate. Sustained improvement of symptoms and functioning was related to continued medication. Comorbid mental disorders and side effects were related to lower effectiveness and adherence, and 12% stopped medication due to side effects. Summing up the MiniReview, treatment with stimulants and atomoxetine of adults with ADHD has long-term beneficial effects and is tolerated but more longitudinal studies should be performed. With stated limitations, the findings of the thesis should contribute to a relevant guidance for clinical practice. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Atomoxetine ameliorates nocturnal enuresis with subclinical attention-deficit/hyperactivity disorder.

PubMed

Ohtomo, Yoshiyuki

2017-02-01

Recent studies have shown that incontinence and attention-deficit/hyperactivity disorder (ADHD) coexist and there is an interaction between them. The treatment for nocturnal enuresis (NE) and ADHD, however, has not been established. At the first visit to the outpatient clinic, physical examination and history taking were carried out in 265 new patients with NE. After excluding the possibility of comorbid ADHD and related disorders, patients with monosymptomatic NE (MNE) were treated with desmopressin and/or alarm, and those with non-monosymptomatic NE (NMNE) were treated with anti-cholinergics and/or alarm. This 12 week treatment did not work in 65 patients, and they were re-assessed for comorbid ADHD. A total of 24 were diagnosed with ADHD, and they were treated with atomoxetine (1.8 mg/kg/day) in addition to ongoing therapy for NE. After 8 weeks of atomoxetine, the average wet nights per months was significantly decreased: 18.5-4.6 in the MNE group (P = 0.001), and 22.1-12.4 in the NMNE group (P = 0.0251). Overall, atomoxetine was beneficial in 19 of 24 patients. Atomoxetine may be a suitable option for refractory NE with comorbid ADHD. © 2016 Japan Pediatric Society.

Atomoxetine Augmentation in a Case of Treatment Resistant Panic Disorder with Multiple Augments Failure: A Case Report

PubMed Central

Ram, Dushad; Patil, Shwetha; Gowdappa, Basavana; Rajalakshmi, Iyshwarya

2015-01-01

Atomoxetine, a selective norepinephrine inhibitor, is effective in comorbid anxiety and attention deficit hyperactivity disorder, however its role in panic disorder is unknown. We are presenting a case of panic disorder, who initially partially responded to clonazepam. When clonazepam was added with sertraline, escitalopram, desvenlafaxin, she did not improve significantly until paroxetine was added. When clonazepam-paroxetine combination was added with propranolol, etizolam, olanzepine, risperidone and amisulpride the symptom remission did not occur until a trial of Atomoxetine was done. PMID:26598594

[Atomoxetine for treatment of children and adolescents with ADHD].

PubMed

Resen, Katarina; Pagsberg, Anne Katrine; Jörgens, Gesche

2014-03-03

Atomoxetine reduces ADHD symptoms in children and adolescents significantly and is indicated for ADHD with co-morbid anxiety, depression and tics or with an increased risk of abuse. Number needed to treat is 3.4-5. Common adverse effects are stomach pain, decreased appetite and somnolence. Serious adverse effects include increased vascular tone, decreased growth rate and increased suicidal behaviour. In most cases adverse effects are mild to moderate and transient. Since atomoxetine was launched in 2006, 117 cases of toxic exposures have been reported in Denmark.

Open-label trial of atomoxetine hydrochloride in adults with ADHD.

PubMed

Johnson, Mats; Cederlund, Mats; Råstam, Maria; Areskoug, Björn; Gillberg, Christopher

2010-03-01

While atomoxetine is an established treatment for attention-deficit/hyperactivity disorder in children, few studies have examined its efficacy for adults. Open-label trial of atomoxetine in 20 individuals with ADHD, aged 19-47 years, for 10 weeks, and a total of one year for responders. Ten patients met primary efficacy criteria at 10 weeks. Only one patient completed the whole study. Six patients discontinued before 10 weeks and thirteen at 10 weeks or later, mainly because of side-effects (aggression, depressed mood, raised liver enzymes, thyroid hormones, diastolic blood pressure), decreasing efficacy or non-compliance. Fifty percent responded to treatment, but only one patient (5%) felt sufficient improvement to continue for one year. Dosage may have been too low, and baseline impairment too high, for atomoxetine to have sufficient effect on ADHD symptoms in our group of adults. The majority had few side-effects, but several terminated treatment because of adverse effects.

Post Hoc Analysis of Potential Predictors of Response to Atomoxetine for the Treatment of Adults with Attention-Deficit/Hyperactivity Disorder using an Integrated Database.

PubMed

Bushe, Chris; Sobanski, Esther; Coghill, David; Berggren, Lovisa; De Bruyckere, Katrien; Leppämäki, Sami

2016-04-01

Responses to atomoxetine vary for individual patients with attention-deficit/hyperactivity disorder (ADHD). However, we do not know whether any factors can be used to reliably predict how individuals with ADHD will respond to treatment. Our objective was to evaluate background variables that facilitate early identification of those adults with ADHD who are likely to respond to treatment with atomoxetine. We pooled data for atomoxetine-treated adults with ADHD from 12 clinical trials for a short-term (10-week) analysis, and from 11 clinical trials for a long-term (24-week) analysis. Patients not meeting a response definition [≥30 % reduction in Conners' Adult ADHD Rating Scales-Investigator Rated: Screening Version (CAARS-Inv:SV) total score and Clinical Global Impressions of ADHD Severity Scale (CGI-S) score ≤3 at endpoint], or who discontinued, were defined as non-responders. Another definition of response (≥30 % reduction in CAARS-Inv:SV total score at endpoint) was also used in these analyses; only the results with the former definition are shown in this abstract, as the same conclusions were gained with both definitions. A treatment-specified subgroup detection tool (a resampling-based ensemble tree method) was used to identify predictors of response. Of 1945 adults in the long-term analysis, 548 (28.2 %) were responders to atomoxetine at week 24; 65.2 % of 1397 non-responders had discontinued. Of 4524 adults in the short-term analysis, 1490 (32.9 %) were responders at week 10; 33.2 % of 1006 non-responders had discontinued. No analyzed baseline parameters (age, sex, prior stimulant use, ADHD subtype, CAARS-Inv:SV, CGI-S) were statistically significant predictors of response. Reductions in CAARS-Inv:SV total, CAARS-Inv:SV subscores, and CGI-S at week 4 in the short-term analysis, and at weeks 4 or 10 in the long-term analysis, were statistically significant predictors of response, i.e., patients with versus without these reductions early in treatment were more likely to be clinical responders at later time points. Sensitivity ranged from 28.6 to 85.9 %, and specificity ranged from 23.8 to 86.7 %. Predictors with higher sensitivity had lower specificity, and vice versa. Reductions in CAARS-Inv:SV and CGI-S scores at weeks 4 and 10 are statistically significant predictors of response to atomoxetine at later time points in adults with ADHD. However, the predictors identified by these analyses are not reliable enough for use in clinical practice. The only currently available method to judge whether individuals with ADHD will respond to atomoxetine is to start treatment and assess the response over an extended period, sometimes longer than 10 weeks.

Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease

PubMed Central

Borchert, Robin J; Rittman, Timothy; Passamonti, Luca; Ye, Zheng; Sami, Saber; Jones, Simon P; Nombela, Cristina; Vázquez Rodríguez, Patricia; Vatansever, Deniz; Rae, Charlotte L; Hughes, Laura E; Robbins, Trevor W; Rowe, James B

2016-01-01

Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest (‘task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems. PMID:26837463

Beta-adrenoreceptor blockade abolishes atomoxetine-induced risk taking.

PubMed

Yang, Fan Nils; Pan, Jing Samantha; Li, Xinwang

2016-01-01

Clinical studies have shown that patients with exaggerated risk-taking tendencies have high baseline levels of norepinephrine. In this work, we systemically manipulated norepinephrine levels in rats and studied their behavioral changes in a probabilistic discounting task, which is a paradigm for gauging risk taking. This study aims to explore the effects of the selective norepinephrine reuptake inhibitor (atomoxetine at doses of 0.6, 1.0 and 1.8 mg/kg), and receptor selective antagonists (propranolol at a single dose of 1.0/kg, and prazosin at a single dose of 0.1 mg/kg), on risk taking using a probabilistic discounting task. In this task, there were two levers available to rats: pressing the 'small/certain' lever guaranteed a single food pellet, and pressing the 'large/risky' lever yielded either four pellets or none. The probability of receiving four food pellets decreased across the four experimental blocks from 100% to 12.5%. Atomoxetine increased the tendency to choose the large/risky lever. It significantly reduced the lose-shift effect (i.e. pressing a different lever after losing a trial), but did not affect the win-stay effect (i.e. pressing the same lever after winning a trial). Furthermore, co-administration of beta-adrenoreceptor antagonist, propranolol, eliminated the effects of atomoxetine on risk taking and the lose-shift effect; but co-administration of alpha1-adrenoreceptor antagonist, prazosin, did not. Atomoxetine boosted NE levels and increased risk taking. This was because atomoxetine decreased rats' sensitivity to losses. These effects were likely mediated by beta-adrenoreceptor. Copyright © 2015 Elsevier Inc. All rights reserved.

Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease.

PubMed

Borchert, Robin J; Rittman, Timothy; Passamonti, Luca; Ye, Zheng; Sami, Saber; Jones, Simon P; Nombela, Cristina; Vázquez Rodríguez, Patricia; Vatansever, Deniz; Rae, Charlotte L; Hughes, Laura E; Robbins, Trevor W; Rowe, James B

2016-07-01

Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest ('task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems.

Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid-induced autism.

PubMed

Hara, Yuta; Ago, Yukio; Taruta, Atsuki; Katashiba, Keisuke; Hasebe, Shigeru; Takano, Erika; Onaka, Yusuke; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

2016-09-01

Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the α2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2016, 9: 926-939. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

The effects of atomoxetine on emotional control in adults with ADHD: An integrated analysis of multicenter studies.

PubMed

Asherson, P; Stes, S; Nilsson Markhed, M; Berggren, L; Svanborg, P; Kutzelnigg, A; Deberdt, W

2015-06-01

To investigate the effects of atomoxetine on emotional control in adults with ADHD. We performed an integrated analysis using individual patient data pooled from three Eli Lilly-sponsored studies. An integrated analysis can be viewed as a meta-analysis of individual patient-level data, rather than study-level summary data. Two populations were identified: a large sample of patients with pre-treatment baseline data (the "overall population"; n=2846); and a subset of these patients with placebo-controlled efficacy data from baseline to 10 or 12 weeks after initiating treatment (the "placebo-controlled population"; n=829). At baseline, in the overall population, ∼50% of ADHD patients had BRIEF-AS (Behavior Rating Inventory of Executive Function-Adult Version Self-Report) Emotional control subscores between 21 and 30, compared with ∼10% of normative subjects in the BRIEF-A manual. At endpoint, in the placebo-controlled population, atomoxetine led to a small (effect size 0.19) but significant (P=0.013) treatment effect for emotional control. The effect size was 0.32 in patients with BRIEF-AS Emotional control scores>20 at baseline. Improvements in emotional control correlated with improvements in the core ADHD symptoms and quality-of-life. As deficient emotional control is associated with impaired social, educational and occupational functioning over and above that explained by core ADHD symptoms alone, improvements in emotional control may be clinically relevant. At baseline, adults with ADHD were more likely to have impaired emotional control than normative subjects. In the adult ADHD patients, atomoxetine treatment was associated with improvements in emotional control, as well as in core ADHD symptoms and quality-of-life. Copyright © 2015. Published by Elsevier Masson SAS.

One-year prospective follow-up of pharmacological treatment in children with attention-deficit/hyperactivity disorder.

PubMed

Didoni, Anna; Sequi, Marco; Panei, Pietro; Bonati, Maurizio

2011-10-01

To delineate the safety and tolerability profile of methylphenidate and atomoxetine in children and adolescents with attention deficit hyperactivity disorder (ADHD) monitored for more than 1 year. A cohort study analyzing data from the national ADHD register on patients from the Lombardy Region treated with MPH or atomoxetine. A total of 229 children (median age 11 years, range 6-17), enrolled in 15 regional centers between June 2007 and May 2010. The prevalence rate of pharmacological treatment for ADHD was 0.23%, whereas the estimated ADHD prevalence in the population was 0.95%. In total, 73.8% of patients had been treated with atomoxetine (10-90 mg daily) or MPH (10-75 mg daily); 22% of patients also received an additional psychotropic drug. Of the treated children, 26.9% discontinued the drug prior to 1 year of treatment, mostly because of adverse effects (28.6%). No new or unexpected adverse events (rate 39.2%) were encountered. Decreased appetite, headache, and unstable mood were the leading events. The most severe events occurred in two boys: one experienced absence seizures for the first time with MPH, the other experienced hallucinations with atomoxetine. Therapy was discontinued in ten male patients (7.7%) because of adverse events. All patients with adverse effects recovered well. A very low rate of ADHD prevalence was estimated in Italian children compared to that reported in other countries. Although the medications for ADHD are generally well tolerated, with only mild or minor adverse effects in most cases, their rational use can only be guaranteed by disseminating and monitoring evidence-based practices and by monitoring the safety and efficacy of treatments in both the short and long terms with appropriate tools and approaches.

A randomized controlled trial investigation of a non-stimulant in attention deficit hyperactivity disorder (ACTION): rationale and design.

PubMed

Tsang, Tracey W; Kohn, Michael R; Hermens, Daniel F; Clarke, Simon D; Clark, C Richard; Efron, Daryl; Cranswick, Noel; Lamb, Chris; Williams, Leanne M

2011-03-13

The ACTION study (Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non-stimulant) is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD). The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD. This manuscript will describe the methodology and rationale for the ACTION study. Children and adolescents aged 6 - 17 y with ADHD will be enrolled. Clinical interview and validated scales will be used to confirm diagnosis and screen for exclusion criteria, which include concurrent stimulant use, and comorbid psychiatric or neurological conditions other than anxiety. Three assessment sessions will be conducted over the 13-week study period: Session 1 (Baseline, pre-treatment), Session 2 (six weeks, atomoxetine or placebo), and Session 3 (13 weeks, cross-over after one-week washout period). The standardized touch-screen battery, "IntegNeuro™", will be used to assess cognitive and emotional function. The primary measure of response will be symptom ratings, while quality of life will be a secondary outcome. Logistic regression will be used to determine predictors of treatment response, while repeated measures of analysis will determine any differences in effect of atomoxetine and placebo. The methodology for the ACTION study has been detailed. The ACTION study is the first controlled trial to investigate the efficacy of atomoxetine using objective cognitive and emotional function markers, and whether these objective measures predict outcomes with atomoxetine in ADHD with and without comorbid anxiety. First enrollment was in March 2008. The outcomes of this study will be a significant step towards a 'personalized medicine' (and therefore a more efficient) approach to ADHD treatment. Australian and New Zealand Clinical Trials Registry ANZCTRN12607000535471.

Combination use of atomoxetine hydrochloride and olanzapine in the treatment of attention-deficit/hyperactivity disorder with comorbid disruptive behavior disorder in children and adolescents 10-18 years of age.

PubMed

Holzer, Barry; Lopes, Vasco; Lehman, Robert

2013-08-01

The aim of this study was to assess the use of atomoxetine and olanzapine in combination to treat attention-deficit/hyperactivity disorder (ADHD) and comorbid disruptive behaviors in children and adolescents 10-18 years of age. Eleven subjects ages 10-18 received open-label atomoxetine and olanzapine for a 10 week treatment period. Patients were assessed at baseline, 2 weeks, 4 weeks, 6 weeks, and 10 weeks (posttreatment). ADHD improvement was measured through the ADHD Rating Scale (ADHD-RS) (Investigator and Parent ratings). Aggression was measured through the Modified Overt Aggression Scale (MOAS). The combined use of atomoxetine and olanzapine resulted in statistically significant improvement in ADHD symptoms and overt aggression from baseline to posttreatment. As evidenced by a 33% reduction in symptoms on the ADHD-RS-I and the MOAS, 73% of patients were considered responders to ADHD treatment, whereas 55% responded to treatment for aggression. Both medications were generally well tolerated. Olanzapine treatment was associated with significant weight gain. Patients gained, on average, 3.9 kg. throughout the treatment period. These data provide initial evidence that combination use of atomoxetine and olanzapine for the treatment of ADHD and comorbid disruptive behaviors was effective in reducing ADHD symptoms and aggressive behavior in a 10 week treatment period.

Atomoxetine, a norepinephrine reuptake inhibitor, reduces seizure-induced respiratory arrest.

PubMed

Zhang, Honghai; Zhao, Haiting; Feng, Hua-Jun

2017-08-01

Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication, and no effective preventive strategies are currently available for this fatal disorder. Clinical and animal studies of SUDEP demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized seizures in many cases. Enhancing brain levels of serotonin reduces S-IRA in animal models relevant to SUDEP, including the DBA/1 mouse. Given that serotonin in the brain plays an important role in modulating respiration and arousal, these findings suggest that deficits in respiration and/or arousal may contribute to S-IRA. It is well known that norepinephrine is an important neurotransmitter that modulates respiration and arousal in the brain as well. Therefore, we hypothesized that enhancing noradrenergic neurotransmission suppresses S-IRA. To test this hypothesis, we examined the effect of atomoxetine, a norepinephrine reuptake inhibitor (NRI), on S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice. We report the original observation that atomoxetine specifically suppresses S-IRA without altering the susceptibility to seizures evoked by acoustic stimulation, and atomoxetine also reduces S-IRA evoked by pentylenetetrazole in DBA/1 mice. Our data suggest that the noradrenergic signaling is importantly involved in S-IRA, and that atomoxetine, a medication widely used to treat attention deficit hyperactivity disorder (ADHD), is potentially useful to prevent SUDEP. Copyright © 2017 Elsevier Inc. All rights reserved.

Advanced Test of Attention in Children with Attention-Deficit/Hyperactivity Disorder in Japan for Evaluation of Methylphenidate and Atomoxetine Effects

PubMed Central

Fujioka, Toru; Takiguchi, Shinichiro; Yatsuga, Chiho; Hiratani, Michio; Hong, Kang-E M; Shin, Min-Sup; Cho, Sungzoon; Kosaka, Hirotaka; Tomoda, Akemi

2016-01-01

Objective This study was conducted to validate the Advanced Test of Attention (ATA) of the visual attention version of Japanese children with attention deficit/hyperactivity disorder (ADHD) and to evaluate the efficacy of methylphenidate (OROS-MPH) and atomoxetine medications. Methods To assess pharmacotherapy efficacy, the visual version of ATA was administered to 42 children with ADHD. Results were assessed using discriminant analysis, ANOVA for indices of ATA before and after medication treatment, and correlation analysis between the improvement of indices of ATA and clinical symptoms during medication treatment. Results Discriminant analysis showed that 69.0% of ADHD children were assigned correctly. The T score of commission errors increased as the trial progressed on the medication-off condition. T scores of commission errors and standard deviation of response times on medication-on condition were low compared to the medication-off condition. A few significant correlations were found between the improvements of indices of ATA and ADHD-Rating Scale (RS) during treatment. Conclusion The performance of the visual version of ATA on medication-off condition reflected the features of ADHD. Furthermore, the medication treatment effects were confirmed sufficiently. In addition, results suggest that indices of ATA reflected aspects of ADHD symptoms that are difficult to elucidate for ADHD-RS. For assessing symptoms and effects of medical treatment in children with ADHD, ATA might be a useful assessment tool. PMID:26792044

Atomoxetine Treatment of ADHD in Children with Comorbid Tourette Syndrome

ERIC Educational Resources Information Center

Spencer, Thomas J.; Sallee, F. Randy; Gilbert, Donald L.; Dunn, David W.; McCracken, James T.; Coffey, Barbara J.; Budman, Cathy L.; Ricardi, Randall K.; Leonard, Henrietta L.; Allen, Albert J.; Milton, Denai R.; Feldman, Peter D.; Kelsey, Douglas K.; Geller, Daniel A.; Linder, Steven L.; Lewis, Donald W.; Winner, Paul K.; Kurlan, Roger M.; Mintz, Mark

2008-01-01

Objective: This study examines changes in severity of tics and ADHD during atomoxetine treatment in ADHD patients with Tourette syndrome (TS). Method: Subjects (7-17 years old) with ADHD ("Diagnostic and Statistical Manual of Mental Disorders, DSM-IV") and TS were randomly assigned to double-blind treatment with placebo (n = 56) or atomoxetine…

Methylphenidate and Atomoxetine Enhance Prefrontal Function through alpha[subscript 2]-Adrenergic and Dopamine D[subscript 1] Receptors

ERIC Educational Resources Information Center

Gamo, Nao J.; Wang, Min; Arnsten, Amy F. T.

2010-01-01

Objective: This study examined the effects of the attention-deficit/hyperactivity disorder treatments, methylphenidate (MPH) and atomoxetine (ATM), on prefrontal cortex (PFC) function in monkeys and explored the receptor mechanisms underlying enhancement of PFC function at the behavioral and cellular levels. Method: Monkeys performed a working…

Functional Outcomes in the Treatment of Adults with ADHD

ERIC Educational Resources Information Center

Adler, Lenard A.; Spencer, Thomas J.; Levine, Louise R.; Ramsey, Janet L.; Tamura, Roy; Kelsey, Douglas; Ball, Susan G.; Allen, Albert J.; Biederman, Joseph

2008-01-01

Objective: ADHD is associated with significant functional impairment in adults. The present study examined functional outcomes following 6-month double-blind treatment with either atomoxetine or placebo. Method: Patients were 410 adults (58.5% male) with "DSM-IV"--defined ADHD. They were randomly assigned to receive either atomoxetine 40 mg/day to…

How Oppositionality, Inattention, and Hyperactivity Affect Response to Atomoxetine versus Methylphenidate: A Pooled Meta-Analysis

ERIC Educational Resources Information Center

van Wyk, Gregory W.; Hazell, Philip L.; Kohn, Michael R.; Granger, Renee E.; Walton, Richard J.

2012-01-01

Objective: To assess how threshold oppositional defiant disorder (ODD), inattention, and hyperactivity-impulsivity affect the response to atomoxetine versus methylphenidate. Method: Systematic review of randomized controlled trials (RCTs; greater than or equal to 6 weeks follow-up). The primary measure was core symptom response--greater than or…

Studying the association complex formation of atomoxetine and fluvoxamine with eosin Y and its application in their fluorimetric determination

NASA Astrophysics Data System (ADS)

Derayea, Sayed M.; Omar, Mahmoud A.; Abu-hassan, Ahmed A.

2018-03-01

A simple, sensitive and non-extractive spectrofluorimetric method has been developed and validated for the determination of two psychoanaleptic drugs, atomoxetine and fluvoxamine, in pure forms and pharmaceutical dosage forms. The proposed method is based on the formation of binary complexes between eosin Y and the studied drugs in the presence of a Teorell-Stenhagen buffer. The quenching of the native fluorescence of eosin Y due to complex formation with the studied drugs was measured spectrofluorimetrically at 545 nm after excitation at 302 nm. At the optimum reaction conditions, the fluorescence quenching values (ΔF) and concentrations were rectilinear over the concentration ranges of 0.2-2.2 and 0.3-2.2 µg ml-1 for atomoxetine and fluvoxamine, respectively. The developed method was successfully applied for the determination of the studied drugs in their pharmaceutical formulations with average percentage recoveries of 100.13 ± 0.66 and 99.69 ± 0.44 for atomoxetine and fluvoxamine, respectively (n = 5), without interference from common excipients.

Studying the association complex formation of atomoxetine and fluvoxamine with eosin Y and its application in their fluorimetric determination

PubMed Central

Omar, Mahmoud A.; Abu-hassan, Ahmed A.

2018-01-01

A simple, sensitive and non-extractive spectrofluorimetric method has been developed and validated for the determination of two psychoanaleptic drugs, atomoxetine and fluvoxamine, in pure forms and pharmaceutical dosage forms. The proposed method is based on the formation of binary complexes between eosin Y and the studied drugs in the presence of a Teorell–Stenhagen buffer. The quenching of the native fluorescence of eosin Y due to complex formation with the studied drugs was measured spectrofluorimetrically at 545 nm after excitation at 302 nm. At the optimum reaction conditions, the fluorescence quenching values (ΔF) and concentrations were rectilinear over the concentration ranges of 0.2–2.2 and 0.3–2.2 µg ml−1 for atomoxetine and fluvoxamine, respectively. The developed method was successfully applied for the determination of the studied drugs in their pharmaceutical formulations with average percentage recoveries of 100.13 ± 0.66 and 99.69 ± 0.44 for atomoxetine and fluvoxamine, respectively (n = 5), without interference from common excipients. PMID:29657744

Is emotion recognition the only problem in ADHD? effects of pharmacotherapy on face and emotion recognition in children with ADHD.

PubMed

Demirci, Esra; Erdogan, Ayten

2016-12-01

The objectives of this study were to evaluate both face and emotion recognition, to detect differences among attention deficit and hyperactivity disorder (ADHD) subgroups, to identify effects of the gender and to assess the effects of methylphenidate and atomoxetine treatment on both face and emotion recognition in patients with ADHD. The study sample consisted of 41 male, 29 female patients, 8-15 years of age, who were diagnosed as having combined type ADHD (N = 26), hyperactive/impulsive type ADHD (N = 21) or inattentive type ADHD (N = 23) but had not previously used any medication for ADHD and 35 male, 25 female healthy individuals. Long-acting methylphenidate (OROS-MPH) was prescribed to 38 patients, whereas atomoxetine was prescribed to 32 patients. The reading the mind in the eyes test (RMET) and Benton face recognition test (BFRT) were applied to all participants before and after treatment. The patients with ADHD had a significantly lower number of correct answers in child and adolescent RMET and in BFRT than the healthy controls. Among the ADHD subtypes, the hyperactive/impulsive subtype had a lower number of correct answers in the RMET than the inattentive subtypes, and the hyperactive/impulsive subtype had a lower number of correct answers in short and long form of BFRT than the combined and inattentive subtypes. Male and female patients with ADHD did not differ significantly with respect to the number of correct answers on the RMET and BFRT. The patients showed significant improvement in RMET and BFRT after treatment with OROS-MPH or atomoxetine. Patients with ADHD have difficulties in face recognition as well as emotion recognition. Both OROS-MPH and atomoxetine affect emotion recognition. However, further studies on the face and emotion recognition are needed in ADHD.

Effect of Atomoxetine on Executive Function Impairments in Adults with ADHD

ERIC Educational Resources Information Center

Brown, Thomas E.; Holdnack, James; Saylor, Keith; Adler, Lenard; Spencer, Thomas; Williams, David W.; Padival, Anoop K.; Schuh, Kory; Trzepacz, Paula T.; Kelsey, Douglas

2011-01-01

Objective: To assess the effect of atomoxetine on ADHD-related executive functions over a 6-month period using the Brown Attention-Deficit Disorder Scale (BADDS) for Adults, a normed, 40-item, self-report scale in a randomized, double-blind, placebo-controlled clinical trial. Method: In a randomized, double-blind clinical trial, adults with ADHD…

Relapse Prevention in Pediatric Patients with ADHD Treated with Atomoxetine: A Randomized, Double-Blind, Placebo-Controlled Study

ERIC Educational Resources Information Center

Michelson, David; Buitelaar, Jan K.; Danckaerts, Marina; Gillberg, Christopher; Spencer, Thomas J.; Zuddas, Alessandro; Faries, Douglas E.; Zhang, Shuyu; Biederman, Joseph

2004-01-01

Objective: Attention-deficit/hyperactivity disorder (ADHD) is typically treated over extended periods; however, few placebo-controlled, long-term studies of efficacy have been reported. Method: In a global multicenter study, children and adolescents who responded to an initial 12-week, open-label period of treatment with atomoxetine, a…

Atomoxetine for Hyperactivity in Autism Spectrum Disorders: Placebo-Controlled Crossover Pilot Trial

ERIC Educational Resources Information Center

Arnold, L. Eugene; Aman, Michael G.; Cook, Amelia M.; Witwer, Andrea N.; Hall, Kristy L.; Thompson, Susan; Ramadan, Yaser

2006-01-01

Objective: To explore placebo-controlled efficacy and safety of atomoxetine (ATX) for attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorders (ASD). Method: Children ages 5 to 15 with ASD and prominent ADHD symptoms were randomly assigned to order in a crossover of clinically titrated ATX and placebo, 6…

[Drugs for attention deficit hyperactivity disorder].

PubMed

Montañés-Rada, F; Gangoso-Fermoso, A B; Martíínez-Granero, M A

Quantitative studies have highlighted differences in several drugs approved for use in Spain in the treatment of attention deficit hyperactivity disorder. No clear differences are observed, however, in the case of qualitative studies. The number of patients needed to be treated in order for one to reach complete remission (NNT) of methylphenidate (MTF) is from 2.2 to 5, and the effect size (ES) is 0.9. Atomoxetine has an NNT of 4 and an ES of 0.7. The advantages of immediate-release MTF (IR-MTF) over the extended-release version (ER-MTF) lie in its low cost, its flexibility and the better results obtained in quantitative studies. In contrast, ER-MTF offers a lower risk of abuse, needs to be taken fewer times with less need for third parties to control administration, and there is a lower risk of stigmatisation. Combination or changes of IR-MTF and ER-MTF and the combination of MTF with atomoxetine are sometimes necessary to adjust the weekday or weekend doses. Starting treatment with IR-MTF and then maintaining or changing to ER-MTF offers certain advantages as regards safety, dose adjustments and dosage. Atomoxetine is the best alternative if there is a background of adverse events with low or moderate doses of stimulants, or lack of response to high doses of stimulants. In cases of notable comorbid anxiety, both MTF and atomoxetine have the same level of indication. If there is a risk of substance abuse, both atomoxetine and ER-MTF are the preferred treatment. For the other indications, MTF is the preferred treatment.

Comparison of Symptomatic versus Functional Changes in Children and Adolescents with ADHD during Randomized, Double-Blind Treatment with Psychostimulants, Atomoxetine, or Placebo

ERIC Educational Resources Information Center

Buitelaar, Jan K.; Wilens, Timothy E.; Zhang, Shuyu; Ning, Yu; Feldman, Peter D.

2009-01-01

Background: This meta-analysis was designed to determine the relationship between reduction of attention-deficit/hyperactivity disorder (ADHD) symptoms and improvement in functioning by examining short-term changes in functional and symptomatic scores in children and adolescents with ADHD. Methods: Search of atomoxetine's clinical trial database…

Efficacy of Atomoxetine for the Treatment of ADHD Symptoms in Patients with Pervasive Developmental Disorders: A Prospective, Open-Label Study

ERIC Educational Resources Information Center

Fernandez-Jaen, Alberto; Fernandez-Mayoralas, Daniel Martin; Calleja-Perez, Beatriz; Munoz-Jareno, Nuria; Campos Diaz, Maria del Rosario; Lopez-Arribas, Sonia

2013-01-01

Objective: Atomoxetine's tolerance and efficacy were studied in 24 patients with pervasive developmental disorder and symptoms of ADHD. Method: Prospective, open-label, 16-week study was performed, using the variables of the Clinical Global Impression Scale and the Conners' Scale, among others. Results: A significant difference was found between…

Effects of Long-Term Atomoxetine Treatment for Young Children with Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Kratochvil, Christopher J.; Wilens, Timothy E.; Greenhill, Laurence L.; Gao, Haitao; Baker, Kurt D.; Feldman, Peter D.; Gelowitz, Douglas L.

2006-01-01

Objective: The purpose of this 13-study (seven double-blind/placebo-controlled, six open-label) meta-analysis is to determine the effectiveness and tolerability of long-term atomoxetine treatment among young children with attention-deficit/hyperactivity disorder (ADHD). Method: Data were pooled from 6- and 7-year-olds (N = 272) who met DSM-IV…

The Treatment of Primary Orthostatic Hypotension.

PubMed

Hale, Genevieve M; Valdes, Jose; Brenner, Michael

2017-05-01

To review the efficacy and safety of pharmacological and nonpharmacological strategies used to treat primary orthostatic hypotension (OH). A literature review using PubMed and MEDLINE databases searching hypotension, non-pharmacological therapy, midodrine, droxidopa, pyridostigmine, fludrocortisone, atomoxetine, pseudoephedrine, and octreotide was performed. Randomized or observational studies, cohorts, case series, or case reports written in English between January 1970 and November 2016 that assessed primary OH treatment in adult patients were evaluated. Based on the chosen criteria, it was found that OH patients make up approximately 15% of all syncope patients, predominantly as a result of cardiovascular or neurological insults, or offending medication. Nonpharmacological strategies are the primary treatment, such as discontinuing offending medications, switching medication administration to bedtime, avoiding large carbohydrate-rich meals, limiting alcohol, maintaining adequate hydration, adding salt to diet, and so on. If these fail, pharmacotherapy can help ameliorate symptoms, including midodrine, droxidopa, fludrocortisone, pyridostigmine, atomoxetine, sympathomimetic agents, and octreotide. Midodrine and droxidopa possess the most evidence with respect to increasing blood pressure and alleviating symptoms. Pyridostigmine and fludrocortisone can be used in patients who fail to respond to these agents. Emerging evidence with low-dose atomoxetine is promising, especially in those with central autonomic failure, and may prove to be a viable alternative treatment option. Data surrounding other therapies such as sympathomimetic agents or octreotide are minimal. Medication management of primary OH should be guided by patient-specific factors, such as tolerability, adverse effects, and drug-drug and drug-disease interactions.

Long-Term, Open-Label Safety and Efficacy of Atomoxetine in Adults with ADHD: Final Report of a 4-Year Study

ERIC Educational Resources Information Center

Adler, Lenard A.; Spencer, Thomas J.; Williams, David W.; Moore, Rodney J.; Michelson, David

2008-01-01

Objective: Previously, data from 97 weeks of open-label atomoxetine treatment of adults with attention-deficit/hyperactivity disorder (ADHD) were reported. This final report of that study presents results from over 4 years of treatment. Method: Results were derived from the study of 384 patients (125 patients remaining in the open-label trial…

Parent Stress in a Randomized Clinical Trial of Atomoxetine and Parent Training for Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Lecavalier, Luc; Pan, Xueliang; Smith, Tristram; Handen, Benjamin L.; Arnold, L. Eugene; Silverman, Laura; Tumuluru, Rameshwari V.; Hollway, Jill; Aman, Michael G.

2018-01-01

We previously reported a 2 × 2 randomized clinical trial of atomoxetine (ATX) and parent training (PT) for attention deficit hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 children with autism spectrum disorder, ages 5-14 years. Children were randomized to one of four conditions: ATX alone, placebo alone, ATX + PT, or…

Clinical Responses to Atomoxetine in Attention-Deficit/Hyperactivity Disorder: The Integrated Data Exploratory Analysis (IDEA) Study

ERIC Educational Resources Information Center

Newcorn, Jeffrey H.; Sutton, Virginia K.; Weiss, Margaret D.; Sumner, Calvin R.

2009-01-01

Data from six randomized controlled trials in the U.S. reveal that 47 percent of patients aged six to 18 years showed a much improved clinical response to atomoxetine as a treatment for attention deficit hyperactivity disorder while 40 percent did not have a response. Augmenting or switching treatment in non-responders by week 4 is suggested.

The quantified EEG characteristics of responders and non-responders to long-term treatment with atomoxetine in children with attention deficit hyperactivity disorders.

PubMed

Chiarenza, Giuseppe Augusto; Chabot, Robert; Isenhart, Robert; Montaldi, Luciano; Chiarenza, Marco Paolo; Torto, Maria Grazia Lo; Prichep, Leslie S

2016-06-01

The aim of our study is to examine quantitative Electroencephalogram (QEEG) differences between ADHD patients that are responders and non-responders to long-term treatment with Atomoxetine at baseline and after 6 and 12months of treatment. Patients with attention deficit hyperactivity disorder (ADHD) received atomoxetine titrated, over 7days, from 0.5 to 1.2mg/kg/day. QEEG and Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) scores were recorded before treatment and after therapy. Twenty minutes of eyes closed resting EEG was recorded from 19 electrodes referenced to linked earlobes. Full frequency and narrow band spectra of two minutes of artifact-free EEG were computed as well as source localization using Variable Resolution Electrical Tomography (VARETA). Abnormalities were identified using Z-spectra relative to normative values. Patients were classified as responders, non-responders and partial responders based upon the SNAP-IV findings. At baseline, the responders showed increased absolute power in alpha and delta in frontal and temporal regions, whereas, non-responders showed increased absolute power in all frequency bands that was widely distributed. With treatment responders' absolute power values moved toward normal values, whereas, non-responders remained at baseline values. Patients with increased power in the alpha band with no evidence of alterations in the beta or theta range, might be responders to treatment with atomoxetine. Increased power in the beta band coupled with increased alpha seems to be related to non-responders and one should consider atomoxetine withdrawal, especially if there is persistence of increased alpha and beta accompanied by an increase of theta. Copyright © 2016 Elsevier B.V. All rights reserved.

Noradrenaline transporter blockade increases fronto-parietal functional connectivity relevant for working memory.

PubMed

Hernaus, Dennis; Casales Santa, Marta Ma; Offermann, Jan Stefan; Van Amelsvoort, Thérèse

2017-04-01

Experimental animal work has demonstrated that dopamine and noradrenaline play an essential role in modulating prefrontal cortex-mediated networks underlying working memory performance. Studies of functional connectivity have been instrumental in extending such notions to humans but, so far, have almost exclusively focussed on pharmacological agents with a predominant dopaminergic mechanism of action. Here, we investigate the effect of a single dose of atomoxetine 60mg, a noradrenaline transporter inhibitor, on working memory performance and associated functional connectivity during an n-back task in 19 healthy male volunteers. Atomoxetine increased functional connectivity between right anterior insula and dorsolateral prefrontal cortex, precentral gyrus, posterior parietal cortex and precuneus during the high-working memory load condition of the n-back task. Increased atomoxetine-induced insula-dorsolateral prefrontal cortex functional connectivity during this condition correlated with decreased reaction time variability and was furthermore predicted by working memory capacity. These results show for the first time that noradrenaline transporter blockade-induced increases in cortical catecholamines accentuate fronto-parietal working memory-related network integrity. The observation of significant inter-subject variability in response to atomoxetine has implications for inverted-U frameworks of dopamine and noradrenaline function, which could be useful to predict drug effects in clinical disorders with variable treatment response. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Atomoxetine Treatment of ADHD in Tourette Syndrome: Reduction in Motor Cortex Inhibition Correlates with Clinical Improvement

PubMed Central

Gilbert, Donald L.; Zhang, Jie; Lipps, Tara D.; Natarajan, Nina; Brandyberry, Jared; Wang, Zhewu; Sallee, F. Randy; Wassermann, Eric M.

2007-01-01

Objective: In children with Attention Deficit Hyperactivity Disorder (ADHD), clinical responses to the selective norepinephrine reuptake inhibitor atomoxetine (ATX) vary. We sought to determine in children with Tourette Syndrome (TS) whether clinical responses correlate with changes in short interval cortical inhibition (SICI). Methods: Fourteen children, ages 8 to 16, with ADHD and TS were treated open-label with ATX for one month. ADHD rating scale scores and SICI, measured with paired-pulse Transcranial Magnetic Stimulation (pTMS), were assessed blindly and independently at treatment onset and one month later. Results: Eleven children, mean ADHD Rating Scale scores 31.8 (SD 8.2) at onset completed the study. After one month, ADHDRS changes ranged from an increase of 4 points to a decrease (improvement) of 24 points (mean change -9.6, SD 9.1). The changes in ADHDRS scores correlated with reduction in SICI (r = .74, p = .010). Conclusions: In children with TS, one month of atomoxetine treatment appears to induce correlated improvements in ADHD and, paradoxically, further reductions in cortical inhibition. Significance: PTMS-evoked SICI in ADHD with TS may be a biomarker of both deficiency and compensatory changes within cortical interneuronal systems. Effective atomoxetine treatment may augment compensatory processes and thereby reduce SICI. PMID:17588810

Psychotropic Medication Use among Insured Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Madden, Jeanne M.; Lakoma, Matthew D.; Lynch, Frances L.; Rusinak, Donna; Owen-Smith, Ashli A.; Coleman, Karen J.; Quinn, Virginia P.; Yau, Vincent M.; Qian, Yinge X.; Croen, Lisa A.

2017-01-01

This study examined psychotropic medication use among 7901 children aged 1-17 with autism spectrum disorder (ASD) in five health systems, comparing to matched cohorts with no ASD. Nearly half (48.5%) of children with ASD received psychotropics in the year observed; the most common classes were stimulants, alpha-agonists, or atomoxetine (30.2%),…

Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): an open-label prospective study of time in treatment, dose, side-effects and comorbidity.

PubMed

Fredriksen, Mats; Dahl, Alv A; Martinsen, Egil W; Klungsøyr, Ole; Haavik, Jan; Peleikis, Dawn E

2014-12-01

How to generalize from randomized placebo controlled trials of ADHD drug treatment in adults to 'real-world' clinical practice is intriguing. This open-labeled prospective observational study examined the effectiveness of long-term stimulant and non-stimulant medication in adult ADHD including dose, side-effects and comorbidity in a clinical setting. A specialized ADHD outpatient clinic gave previously non-medicated adults (n=250) with ADHD methylphenidate as first-line drug according to current guidelines. Patients who were non-tolerant or experiencing low efficacy were switched to amphetamine or atomoxetine. Primary outcomes were changes of ADHD-symptoms evaluated with the Adult ADHD Self-Report Scale (ASRS) and overall severity by the Global Assessment of Functioning (GAF). Secondary outcomes were measures of mental distress, and response on the Clinical-Global-Impressions-Improvement Scale. Data at baseline and follow-ups were compared in longitudinal mixed model analyses for time on-medication, dosage, comorbidity, and side-effects. As results, 232 patients (93%) completed examination at the 12 month endpoint, and 163 (70%) remained on medication. Compared with the patients who discontinued medication, those still on medication had greater percentage reduction in ASRS-scores (median 39%, versus 13%, P<0.001) and greater improvement of GAF (median 20% versus 4%, P<0.001) and secondary outcomes. Continued medication and higher cumulated doses showed significant associations to sustained improvement. Conversely, psychiatric comorbidity and side-effects were related to lower effectiveness and more frequent termination of medication. Taken together, one-year treatment with stimulants or atomoxetine was associated with a clinically significant reduction in ADHD symptoms and mental distress, and improvement of measured function. No serious adverse events were observed. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Impact of psychostimulants and atomoxetine on the expression of 8-hydroxyguanine glycosylase 1 in human cells.

PubMed

Schmidt, Andreas Johannes; Clement, Hans-Willi; Gebhardt, Stefan; Hemmeter, Ulrich Michael; Schulz, Eberhard; Krieg, Jürgen-Christian; Kircher, Tilo; Heiser, Philip

2010-06-01

Oxidative DNA damage as one sign of reactive oxygen species induced oxidative stress is an important factor in the pathogenesis of various psychiatric disorders. Altered levels of DNA base damage products as well as the expression of the main repair enzyme 8-hydroxyguanine glycosylase 1 have been described. The aim of the present study was to examine the effects of drugs (amphetamine, methylphenidate and atomoxetine) used in the treatment of attention deficit-hyperactivity disorder on the expression of this enzyme via reverse transcriptase-polymerase chain reaction in human neuroblastoma SH-SY5Y and human monocytic U-937 cells at concentrations of 50, 500 and 5,000 ng/ml. We observed decreased expression of this enzyme for all applied substances. In U-937 cells, the significance level was reached after treatment with 5,000 ng/ml amphetamine as well as after treatment with 50, 500 and 5,000 ng/ml atomoxetine. Incubation of SH-SY5Y cells with 50 and 5,000 ng/ml amphetamine and 5,000 ng/ml methylphenidate led to significant decreases of 8-hydroxyguanine glycosylase 1. As a positive correlation between the expression of 8-hydroxyguanine glycosylase 1 and the level of oxidative DNA damage products has been described, we accordingly consider these substances (amphetamine, methylphenidate and atomoxetine) to possibly play a protective role in this process.

A Systematic Review of Combination Therapy with Stimulants and Atomoxetine for Attention-Deficit/Hyperactivity Disorder, Including Patient Characteristics, Treatment Strategies, Effectiveness, and Tolerability

PubMed Central

Gau, Susan Shur-Fen; Méndez, Luis; Montgomery, William; Monk, Julie A.; Altin, Murat; Wu, Shenghu; Lin, Chaucer C.H.; Dueñas, Héctor J.

2013-01-01

Abstract Objective The purpose of this article was to systematically review the literature on stimulant and atomoxetine combination therapy, in particular: 1) Characteristics of patients with attention-deficit/hyperactivity disorder (ADHD) given combination therapy, 2) treatment strategies used, 3) efficacy and effectiveness, and 4) safety and tolerability. Methods Literature databases (MEDLINE®, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, and SciVerse Scopus) were systematically searched using prespecified criteria. Publications describing stimulant and atomoxetine combination therapy in patients with ADHD or healthy volunteers were selected for review. Exclusion criteria were comorbid psychosis, bipolar disorder, epilepsy, or other psychiatric/neurologic diseases that could confound ADHD symptom assessment, or other concomitant medication(s) to treat ADHD symptoms. Results Of the 16 publications included for review, 14 reported findings from 3 prospective studies (4 publications), 7 retrospective studies, and 3 narrative reviews/medication algorithms of patients with ADHD. The other two publications reported findings from two prospective studies of healthy volunteers. The main reason for prescribing combination therapy was inadequate response to previous treatment. In the studies of patients with ADHD, if reported, 1) most patients were children/adolescents and male, and had a combined ADHD subtype; 2) methylphenidate was most often used in combination with atomoxetine for treatment augmentation or switch; 3) ADHD symptom control was improved in some, but not all, patients; and 4) there were no serious adverse events. Conclusions Published evidence of the off-label use of stimulant and atomoxetine combination therapy is limited because of the small number of publications, heterogeneous study designs (there was only one prospective, randomized controlled trial), small sample sizes, and geographic bias. Existing evidence suggests, but does not confirm, that this drug combination may benefit some, but not all, patients who have tried several ADHD medications without success. PMID:23560600

Combined methylphenidate and atomoxetine pharmacotherapy in attention deficit hyperactivity disorder.

PubMed

Ozbaran, Burcu; Kose, Sezen; Yuzuguldu, Onur; Atar, Burcu; Aydin, Cahide

2015-01-01

Pharmacological treatment of attention deficit hyperactivity disorder (ADHD) includes stimulant and non-stimulant medications. Our purpose in this study is to investigate efficacy, safety and tolerability of combined methylphenidate and atomoxetine pharmacotherapy. We included 12 patients of the 824 patients with ADHD using methylphenidate and atomoxetine combined therapy between the years 2010 and 2014. Kiddie-SADS, Turgay DSM-IV Based Child and Adolescent Behavior Disorders Screening and Rating Scale, Child Behavior Checklist, Clinic Global Impression Scale Severity and Impression (CGIS-S-I) scales were used. Patients were between the ages of 7 and 17 years. Before combined pharmacotherapy the CGIS-S score mean was 5.08. Mean CGIS-S score after the combined pharmacotherapy was 3.08 (P = 0.03; -2,980). The most common side effects were irritability (n = 5, 41.6%), appetite reduction (n = 3, 25%), palpitations (n = 2, 16.7%), headache (n = 1, 8.3%). Nine of these 12 patients showed significant improvement in their symptoms, combined therapy enhanced the effectiveness of monotherapy.

[Executive functioning and evoked potentials P300 pre- and post- treatment in attention deficit hyperactivity disorder].

PubMed

Roca, Patricia; Mulas, Fernando; Gandia, Rubén; Ortiz-Sánchez, Pedro; Abad, Luis

2013-02-22

Evoked potentials P300 and the analysis of executive functions have shown their utility in the monitoring of patients with symptoms of attention deficit hyperactivity disorder (ADHD). Neuropsychological profiles and evoked potentials P300 have been analysed for two groups of children with an ADHD treatment with atomoxetine and methylphenidate respectively. Correlations between P300 and the selected neuropsychological parameters are studied, and the differences between basal values and 1 year follow-up are analysed. Two groups were performed: a group of 22 children ADHD in the atomoxetine condition, and a group of 24 children ADHD in the methylphenidate condition. The results show a global improvement of all the parameters, in terms of executive function and P300 values in both, the atomoxetine and the methylphenidate group. Executive functions and evoked potentials P300 reflect an underlying processing and they are very useful in the clinical practice. This exploratory study shows the importance of designing personalized objective variables-based treatments.

Norepinephrine transporter blocker atomoxetine increases salivary alpha amylase.

PubMed

Warren, Christopher M; van den Brink, Ruud L; Nieuwenhuis, Sander; Bosch, Jos A

2017-04-01

It has been suggested that central norepinephrine (NE) activity may be inferred from increases in salivary alpha-amylase (SAA), but data in favor of this proposition are limited. We administered 40mg of atomoxetine, a selective NE transporter blocker that increases central NE levels, to 24 healthy adult participants in a double-blind, placebo-controlled cross-over design. Atomoxetine administration significantly increased SAA secretion and concentrations at 75-180min after treatment (more than doubling baseline levels). Consistent with evidence that elevation in central NE is a co-determinant of hypothalamic-pituitary-adrenal axis activity, salivary cortisol also approximately doubled at the same time points. Moreover, changes in salivary cortisol positively correlated with SAA (0.44

Effects of FDA Advisories on the Pharmacologic Treatment of ADHD, 2004–2008

PubMed Central

Kornfield, Rachel; Watson, Sydeaka; Higashi, Ashley S.; Conti, Rena M.; Dusetzina, Stacie B.; Garfield, Craig F.; Dorsey, E. Ray; Huskamp, Haiden A.; Alexander, G. Caleb

2014-01-01

Objective This study assessed the effect of public health advisories issued between 2005 and 2007 by the U.S. Food and Drug Administration (FDA) on treatments of attention-deficit hyperactivity disorder (ADHD) and physician prescribing practices. Methods Data obtained from the IMS Health National Disease and Therapeutic Index, a nationally representative audit of ambulatory physicians, were used to examine trends in office visits by children and adolescents (under age 18) during which ADHD was treated with Adderall, other psychostimulants, or atomoxetine. Segmented time series regressions were conducted to determine changes in use associated with three advisories issued between 2005 and 2007. Results In 2004, before the first FDA advisory, Adderall accounted for 36% of ADHD pharmacotherapy treatment visits. Other stimulants accounted for 46%, and atomoxetine accounted for 19%. Overall pharmacotherapy treatment rates were stable over the study period, but by 2008 the treatment visits accounted for by Adderall (that is, market share) declined to 24%, and the market share for atomoxetine declined to 8%. The market share for substitute therapies—clonidine, guanfacine, and bupropion—was stable over this period, ranging from 5% to 7%. Despite the declines in the use of Adderall and atomoxetine over the study period, results from the regression models suggest that the advisories did not have a statistically significant effect on ADHD medication prescribing. Conclusions FDA advisories regarding potential cardiovascular and other risks of ADHD medications had little discernible incremental effect on the use of these medicines in this nationally representative ambulatory audit. PMID:23318985

Attention-deficit/hyperactivity disorder Under Treatment Outcomes Research (AUTOR): a European observational study in pediatric subjects.

PubMed

Haynes, Virginia; Lopez-Romero, Pedro; Anand, Ernie

2015-12-01

The ADHD Under Treatment Observational Research (AUTOR) study was a European prospective, observational study that assessed factors associated with changes in ADHD severity, estimated change from baseline in quality of life (QoL), and characterized changes in ADHD symptoms over a 2-year period as a function of baseline treatment. The primary objective was to identify factors associated with worsening in ADHD severity during a 2-year follow-up period for subjects aged 6-17 years, who were receiving the same pharmacotherapy for 3-8 months before enrollment and had a Clinical Global Impression (CGI)-ADHD-Severity score of mild/lower and a CGI-ADHD-Improvement score of improved/very much improved. Multivariate logistic regression examined the association of factors with worsening in ADHD. Mixed-model repeated measures regression analyzed QoL in terms of change from baseline in CHIP-CE PRF scores. There were 704 subjects analyzed. Variables associated with worsening ADHD severity were parental occupation, poorer school outcomes, and use of psychoeducation; baseline treatment was not significant. Among the secondary objectives, initial use of atomoxetine (vs. stimulants) was associated with a significant improvement on the CHIP-CE PRF total score, with an adjusted treatment difference of -6.0 (95 % CI -7.9, -4.1) at 24 months. Additionally, the odds of stability (CGI-ADHD-S ≤ 3 over the 2-year period) were significantly lower for subjects initially responding to stimulants compared with atomoxetine (OR 0.5; 95 % CI 0.3, 0.8). ADHD symptom worsening was associated with initial use of psychoeducation, parental occupation, and poorer school outcomes. Response to initial treatment with atomoxetine was associated with improved QoL over 2 years.

Noradrenergic stimulation modulates activation of extinction-related brain regions and enhances contextual extinction learning without affecting renewal

PubMed Central

Lissek, Silke; Glaubitz, Benjamin; Güntürkün, Onur; Tegenthoff, Martin

2015-01-01

Renewal in extinction learning describes the recovery of an extinguished response if the extinction context differs from the context present during acquisition and recall. Attention may have a role in contextual modulation of behavior and contribute to the renewal effect, while noradrenaline (NA) is involved in attentional processing. In this functional magnetic resonance imaging (fMRI) study we investigated the role of the noradrenergic system for behavioral and brain activation correlates of contextual extinction and renewal, with a particular focus upon hippocampus and ventromedial prefrontal cortex (PFC), which have crucial roles in processing of renewal. Healthy human volunteers received a single dose of the NA reuptake inhibitor atomoxetine prior to extinction learning. During extinction of previously acquired cue-outcome associations, cues were presented in a novel context (ABA) or in the acquisition context (AAA). In recall, all cues were again presented in the acquisition context. Atomoxetine participants (ATO) showed significantly faster extinction compared to placebo (PLAC). However, atomoxetine did not affect renewal. Hippocampal activation was higher in ATO during extinction and recall, as was ventromedial PFC activation, except for ABA recall. Moreover, ATO showed stronger recruitment of insula, anterior cingulate, and dorsolateral/orbitofrontal PFC. Across groups, cingulate, hippocampus and vmPFC activity during ABA extinction correlated with recall performance, suggesting high relevance of these regions for processing the renewal effect. In summary, the noradrenergic system appears to be involved in the modification of established associations during extinction learning and thus has a role in behavioral flexibility. The assignment of an association to a context and the subsequent decision on an adequate response, however, presumably operate largely independently of noradrenergic mechanisms. PMID:25745389

Methylphenidate and Atomoxetine-Responsive Prefrontal Cortical Genetic Overlaps in "Impulsive" SHR/NCrl and Wistar Rats.

PubMed

Dela Peña, Ike; Dela Peña, Irene Joy; de la Peña, June Bryan; Kim, Hee Jin; Shin, Chan Young; Han, Doug Hyun; Kim, Bung-Nyun; Ryu, Jong Hoon; Cheong, Jae Hoon

2017-09-01

Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of "impulsive" SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.

Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

PubMed Central

Udvardi, Patrick T; Föhr, Karl J; Henes, Carolin; Liebau, Stefan; Dreyhaupt, Jens; Boeckers, Tobias M; Ludolph, Andrea G

2013-01-01

Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound’s effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip]) or saline (0.9%, ip) for 21 consecutive days on postnatal days (PND) 21–41. In humans, atomoxetine’s earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound’s long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine’s effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound’s impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of synaptic composition. These alterations might contribute to atomoxetine’s clinical effects in the treatment of ADHD, a neurodevelopmental disorder in which synaptic processes and especially a dysregulated glutamatergic metabolism seem to be involved. PMID:24348020

Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and Subcortical Limbic Mechanisms in Rats

PubMed Central

Achterberg, E.J. Marijke; van Kerkhof, Linda W.M.; Damsteegt, Ruth; Trezza, Viviana

2015-01-01

Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111

Age-related changes in prefrontal norepinephrine transporter density: The basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats

PubMed Central

Bradshaw, Sarah E.; Agster, Kara L.; Waterhouse, Barry D.; McGaughy, Jill A.

2016-01-01

Adolescence is a period of major behavioral and brain reorganization. As diagnoses and treatment of disorders like attention deficit hyperactivity disorder (ADHD) often occur during adolescence, it is important to understand how the prefrontal cortices change and how these changes may influence the response to drugs during development. The current study uses an adolescent rat model to study the effect of standard ADHD treatments, atomoxetine and methylphenidate on attentional set shifting and reversal learning. While both of these drugs act as norepinephrine reuptake inhibitors, higher doses of atomoxetine and all doses of methylphenidate also block dopamine transporters (DAT). Low doses of atomoxetine, were effective at remediating cognitive rigidity found in adolescents. In contrast, methylphenidate improved performance in rats unable to form an attentional set due to distractibility but was without effect in normal subjects. We also assessed the effects of GBR 12909, a selective DAT inhibitor, but found no effect of any dose on behavior. A second study in adolescent rats investigated changes in norepinephrine transporter (NET) and dopamine beta hydroxylase (DBH) density in five functionally distinct subregions of the prefrontal cortex: infralimbic, prelimbic, anterior cingulate, medial and lateral orbitofrontal cortices. These regions are implicated in impulsivity and distractibility. We found that NET, but not DBH, changed across adolescence in a regionally selective manner. The prelimbic cortex, which is critical to cognitive rigidity, and the lateral orbitofrontal cortex, critical to reversal learning and some forms of response inhibition, showed higher levels of NET at early than mid- to late adolescence. PMID:26774596

Capillary electrophoresis coupled with electrochemiluminescence for determination of atomoxetine hydrochloride and the study on its interactions with three proteins.

PubMed

Zeng, Hua-jin; Yang, Ran; Zhang, Ying; Li, Jian-jun; Qu, Ling-bo

2015-03-01

A simple, rapid and sensitive method for the determination of atomoxetine hydrochloride (AH) by capillary electrophoresis with electrochemiluminescence detection (CE-ECL) using tris(2,2'-bipyridyl) ruthenium (II) was developed. Under optimized conditions, the determinations of AH in capsules and rat plasmas and the study on its interactions with three plasma proteins, including bovine serum albumin, cytochrome c and myoglobin were performed successfully. Relative to some previous studies, in this paper the methodologies for the determination of AH in aqueous solution and spiked plasma systems were established, respectively. By comparing the difference between the two work curves of two systems, the matrix effect in plasma samples on the determination of AH by the CE-ECL method was discussed in detail. The results indicated that the effect of the matrix in plasma samples should not be ignored even if no obvious interference was found in the electropherograms and the establishment of method validation in complex samples by the CE-ECL method was necessary. Copyright © 2014 John Wiley & Sons, Ltd.

Driving performance in adults with ADHD: results from a randomized, waiting list controlled trial with atomoxetine.

PubMed

Sobanski, E; Sabljic, D; Alm, B; Dittmann, R W; Wehmeier, P M; Skopp, G; Strohbeck-Kühner, P

2013-08-01

To investigate effects of a 12-week treatment with atomoxetine (ATX) on driving performance in real traffic, driving-related neuropsychological performance tests and self-evaluation of driving in adult patients with ADHD compared to an untreated control group with ADHD. Parallel group design with an ATX and a waiting list group. At baseline and endpoint patients were evaluated with a standardized on-road driving test (SDBO), a driving-related neuropsychological test battery (Act and React Test System [ART2020]), and subjective measures of driving performance (one-week driving diary, Driver Coping Questionnaire). Forty-three of the 64 included patients completed the study (n=22 ATX, n=21 controls). Mean intervention period was 11.9±3.0 weeks, mean daily ATX dosage was 71.6±14.9mg. At endpoint, 60.1% of patients treated with ATX and 0% of waiting list group had reduced ADHD symptoms by greater or equal to 30%. In SDBO, ATX group reduced driving errors in three of four driving performance categories (attention, P<0.05; risk-related self-control, P<0.005; driver skills, P<0.001), number of driving errors remained stable in control group. At endpoint, 47.6% of control group and 18.2% of ATX group (P<0.05) did not fulfil the driving fitness criteria according to German Guidelines (percentile rank less or equal to 16 in one or more subtests in ART2020). Total number of self-reported critical traffic situations decreased from 12.0 to 6.8 per week in ATX group (P<0.05) and remained stable in controls by 9.3 and 9.9 at baseline and endpoint (ns). Coping strategies with stressful traffic situations did not change within both groups. Our study provides first evidence that treatment with ATX improves driving performance in real traffic in adults with ADHD. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Self-esteem in adolescent patients with attention-deficit/hyperactivity disorder during open-label atomoxetine treatment: psychometric evaluation of the Rosenberg Self-Esteem Scale and clinical findings.

PubMed

Dittmann, Ralf W; Wehmeier, Peter M; Schacht, Alexander; Lehmann, Martin; Lehmkuhl, Gerd

2009-12-01

To report on (1) psychometric properties of the Rosenberg Self-Esteem Scale (SES) studied in adolescents with ADHD, (2) correlations of SES with ADHD scale scores, and (3) change in patient-reported self-esteem with atomoxetine treatment. ADHD patients (12-17 years), treated in an open-label study for 24 weeks. Secondary analyses on ADHD symptoms (assessed with ADHD-RS, CGI, GIPD scales) and self-esteem (SES) were performed. One hundred and fifty-nine patients were treated. A dichotomous structure of the SES could be confirmed. Reliability and internal consistency were moderate to excellent. Highest coefficients were found for the correlation between SES and GIPD scores. Self-esteem significantly increased over time, accompanied by an improvement of ADHD symptoms and related perceived difficulties. The Rosenberg SES was shown to be internally consistent, reliable, and sensitive to treatment-related changes of self-esteem. According to these findings, self-esteem may be an important individual patient outcome beyond the core symptoms of ADHD. © The Author(s) 2009. This article is published with open access at Springerlink.com

Extinction of alcohol seeking is enhanced by compound extinction and the noradrenaline reuptake inhibitor atomoxetine.

PubMed

Leung, Hiu T; Corbit, Laura H

2017-01-01

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli provides a means for reducing their impact on relapse. However, the expression of extinction can be disrupted by exposure to the previous reinforcer as well as the simple passage of time. We investigated whether augmentation of prediction error or of noradrenaline neurotransmission by the reuptake inhibitor atomoxetine would enhance long-term extinction of alcohol-seeking behavior. Rats received Pavlovian conditioning of multiple stimuli signaling the delivery of an alcohol reward before individual extinction was given to each of these stimuli. Further extinction was then given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg/kg; Experiment 2). Experiment 3 examined whether the compound stimulus effect relied on noradrenergic activity by testing the effects of the β-adrenergic antagonist propranolol, given prior to compound stimulus trials. Long-term retention of extinction learning was assessed a week later. Compound stimulus presentations enhanced long-term extinction as the stimulus extinguished in compound elicited less responding than a stimulus receiving equal extinction alone when tested a week later. This effect was mimicked by atomoxetine and blocked by propranolol given during extinction training. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Both behavioral and neurobiological processes could be exploited to enhance the outcome of extinction-based treatments for alcohol use disorders. © 2015 Society for the Study of Addiction.

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

PubMed Central

Ye, Zheng; Rae, Charlotte L.; Nombela, Cristina; Ham, Timothy; Rittman, Timothy; Jones, Peter Simon; Rodríguez, Patricia Vázquez; Coyle‐Gilchrist, Ian; Regenthal, Ralf; Altena, Ellemarije; Housden, Charlotte R.; Maxwell, Helen; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2016-01-01

Abstract Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037, 2016. © 2016 Wiley Periodicals, Inc. PMID:26757216

Comparative treatment patterns, healthcare resource utilization and costs of atomoxetine and long-acting methylphenidate among children and adolescents with attention-deficit/hyperactivity disorder in Germany.

PubMed

Greven, Peter; Sikirica, Vanja; Chen, Yaozhu J; Curtice, Tammy G; Makin, Charles

2017-09-01

Attention-deficit/hyperactivity disorder (ADHD) imposes a substantial burden on patients and their families. A retrospective, propensity score-matched cohort study compared treatment patterns, healthcare resource utilization (HRU) and costs among children/adolescents with ADHD aged 6-17 years at treatment initiation (index) in Germany who received atomoxetine (ATX) or long-acting methylphenidate (LA-MPH) monotherapy. Patients received at least one prescription for their index medication (ATX/LA-MPH) during 2006-2010; the first prescription marked the index date. ATX- and LA-MPH-indexed cohorts were matched 1:1 (n = 737); a patient subset was identified that had not received ADHD-indicated medications in 12 months prior to index (novel initiators: ATX, n = 486; LA-MPH, n = 488). Treatment patterns were evaluated among novel initiators, and HRU and costs among the matched cohorts in the 12 months after index. No significant differences in baseline characteristics were found between the novel initiator patient subsets. ATX-indexed novel initiators had significantly longer persistence to index medication [mean (standard deviation; SD) days: 222.0 (133.9) vs 203.2 (135.0), P = 0.029) but higher switching rates (8.8 vs 5.5 %, P = 0.045) than LA-MPH-indexed novel initiators. The total ATX-indexed cohort required more prescriptions [any medication; mean (SD): 20.9 (11.5) vs 15.7 (9.0), P < 0.001] and outpatient visits [mean (SD): 10.1 (6.3) vs 8.3 (5.3), P < 0.001], and incurred significantly higher total median healthcare costs (€1144 vs €541, P < 0.001) versus matched LA-MPH patients. These real-world data indicate that, among children/adolescents with ADHD in Germany, ATX-indexed patients may require more prescriptions and physician visits, and incur higher total healthcare costs, than matched LA-MPH patients.

[Clinical effect of atomoxetine hydrochloride in 66 children with narcolepsy].

PubMed

Zhang, Shen; Ding, Changhong; Wu, Husheng; Fang, Fang; Wang, Xiaohui; Ren, Xiaotun

2015-10-01

To observe the efficacy and safety of atomoxetine hydrochloride in children with narcolepsy. Totally 66 patients with narcolepsy who were conformed international classification of sleep disturbances (ICSD-2) diagnostic criteria treated with atomoxetine hydrochloride seen from November 2010 to December 2014 were enrolled into this study, 42 of them were male and 24 female, mean age of onset was 7.5 years (3.75-13.00 years), mean duration before diagnosis was 1.75 years (0.25-5.00 years). Complete blood count, liver and kidney function, multiple sleep latency test (MSLT), polysomnography (PGS), neuroimaging and electroencephalography (EEG) were performed for each patient. For some of the children HLA-DR2 gene and serum markers of infection were tested. The 66 cases were followed up from 2 to 49 months (average 18 months) to observe the clinical efficacy and adverse reactions. In 62 cases excessive daytime sleepiness was improved, in 11 cases (16.7%) it was controlled (16.7%), in 29 cases (43.9%) the treatment was obviously effective and in 22 (33.3%) it was effective; cataplexy occurred in 54 cases, in 18 (33.3%) it was controlled, in 19 (35.2%) the treatment was obviously effective and in 10 (18.5%) effective; night sleep disorders existed in 55 cases, in 47 cases it was improved, in 14 (25.5%) it was controlled, in 20 (36.4%) the treatment was obviously effective and in 13 (23.6%) effective; hypnagogic or hypnopompic hallucination was present in 13 cases, in only 4 these symptoms were controlled. Sleep paralysis existed in 4 cases, it was controlled in only 1 case. In 18 cases attention and learning efficiency improved.Anorexia occurred in 18 cases, mood disorder in 5 cases, depression in 2 cases, nocturia, muscle tremors, involuntary tongue movement each occurred in 1 case. P-R interval prolongation and atrial premature contraction were found in 1 case. Atomoxetine hydrochloride showed good effects in patients with narcolepsy on excessive daytime sleepiness, cataplexy and night sleep disorders, the effects on hallucinations and sleep paralysis were not significant. Adverse reactions were slight, anorexia and mood disorder were common. As a non-central nervous system stimulant, atomoxetine hydrochloride does not induce drug dependence and has no prescription limits; it has good tolerability, safety and effectiveness, it can be a good alternative in treatment of children with narcolepsy.

Comparative efficacy and safety of methylphenidate and atomoxetine for attention-deficit hyperactivity disorder in children and adolescents: Meta-analysis based on head-to-head trials.

PubMed

Liu, Qiang; Zhang, Hong; Fang, Qingqing; Qin, Lili

2017-11-01

Comparative efficacy and safety are important issues for appropriate drug selection for attention-deficit hyperactivity disorder (ADHD) treatment. Therefore we conducted a meta-analysis, where we compared atomoxetine (ATX) and methylphenidate (MPH) for ADHD treatment in children and adolescents. Literature retrieval was conducted in relevant databases from their inception to April 2016 to select head-to-head trials that compared ATX and MPH in children and adolescents. Outcomes like response rate, ADHD Rating Scale (ADHD-RS) score, and adverse events were compared between ATX and MPH treatments. The standardized mean difference (SMD) and risk ratio (RR) with their corresponding 95% confidence intervals (CIs) were used as the effect size for continuous data or dichotomous data, respectively. Eleven eligible randomized-controlled trials were included, and two of them were double-blind, while the remaining were open-label. Compared to ATX, MPH showed a higher response rate (RR = 1.14, 95% CI [1. 09, 1.20]), decreased inattention (SMD = -0.13, 95% CI [-0.25, -0.01]) and lower risk of adverse events (drowsiness: RR = 0.17, 95% CI [0.11, 0.26; nausea: RR = 0.49; 95% CI [0.29, 0.85; vomiting: RR = 0.41, 95% CI [0.27, 0.63]). However, MPH presented a higher risk of insomnia than ATX (RR = 2.27, 95% CI [1.63, 3.15], p < .01). Results of the meta-analysis add additional evidence of the effectiveness of both ATX and MPH and suggest that MPH should be a first treatment option in most patients with ADHD.

Atomoxetine reverses locomotor hyperactivity, impaired novel object recognition, and prepulse inhibition impairment in mice lacking pituitary adenylate cyclase-activating polypeptide.

PubMed

Shibasaki, Y; Hayata-Takano, A; Hazama, K; Nakazawa, T; Shintani, N; Kasai, A; Nagayasu, K; Hashimoto, R; Tanida, M; Katayama, T; Matsuzaki, S; Yamada, K; Taniike, M; Onaka, Y; Ago, Y; Waschek, J A; Köves, K; Reglődi, D; Tamas, A; Matsuda, T; Baba, A; Hashimoto, H

2015-06-25

Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is characterized by attention difficulties, impulsivity, and hyperactivity. A non-stimulant drug, atomoxetine (ATX), which is a selective noradrenaline reuptake inhibitor, is widely used for ADHD because it exhibits fewer adverse effects compared to conventional psychostimulants. However, little is known about the therapeutic mechanisms of ATX. ATX treatment significantly alleviated hyperactivity of pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP(-/-)) mice with C57BL/6J and 129S6/SvEvTac hybrid background. ATX also improved impaired novel object recognition memory and prepulse inhibition in PACAP(-/-) mice with CD1 background. The ATX-induced increases in extracellular noradrenaline and dopamine levels were significantly higher in the prefrontal cortex of PACAP(-/-) mice compared to wild-type mice with C57BL/6J and 129S6/SvEvTac hybrid background. These results suggest that ATX treatment-induced increases in central monoamine metabolism may be involved in the rescue of ADHD-related abnormalities in PACAP(-/-) mice. Our current study suggests that PACAP(-/-) mice are an ideal rodent model with predictive validity for the study of ADHD etiology and drug development. Additionally, the potential effects of differences in genetic background of PACAP(-/-) mice on behaviors are discussed. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Pilot study of atomoxetine in patients with Parkinson's disease and dopa-unresponsive Freezing of Gait.

PubMed

Revuelta, Gonzalo J; Embry, Aaron; Elm, Jordan J; Gregory, Chris; Delambo, Amy; Kautz, Steve; Hinson, Vanessa K

2015-01-01

Freezing of gait (FoG) is a common and debilitating condition in Parkinson's disease (PD) associated with executive dysfunction. A subtype of FoG does not respond to dopaminergic therapy and may be related to noradrenergic deficiency. This pilot study explores the effects of atomoxetine on gait in PD patients with dopa-unresponsive FoG using a novel paradigm for objective gait assessment. Ten patients with PD and dopa-unresponsive FoG were enrolled in this eight-week open label pilot study. Assessments included an exploratory gait analysis protocol that quantified spatiotemporal parameters during straight-away walking and turning, while performing a dual task. Clinical, and subjective assessments of gait, quality of life, and safety were also administered. The primary outcome was a validated subjective assessment for FoG (FOG-Q). Atomoxetine was well tolerated, however, no significant change was observed in the primary outcome. The gait analysis protocol correlated well with clinical scales, but not with subjective assessments. DBS patients were more likely to increase gait velocity (p = 0.033), and improved in other clinical assessments. Objective gait analysis protocols assessing gait while dual tasking are feasible and useful for this patient population, and may be superior correlates of FoG severity than subjective measures. These findings can inform future trials in this population.

Daily methylphenidate and atomoxetine treatment impacts on clock gene protein expression in the mouse brain.

PubMed

Baird, Alison L; Coogan, Andrew N; Kaufling, Jennifer; Barrot, Michel; Thome, Johannes

2013-06-04

Circadian rhythms are repeating patterns of physiological and other parameters that recur with periods of approximately 24h, and are generated by an endogenous circadian timekeeping mechanism. Such circadian rhythms, and their underlying molecular mechanisms, are known to be altered by a number of central nervous system acting pharmacological compounds, as well as becoming perturbed in a number of common psychiatric and neurological conditions. The psychostimulant methylphenidate and the non-stimulant atomoxetine are used in the pharmacotherapy of attention deficit hyperactivity disorder, a common condition in which circadian rhythms have been reported to be altered. In the present study we have examined the effects of daily methylphenidate or atomoxetine treatment across 7 days on circadian clock gene product expression across numerous brain regions in the male mouse to test the potential impact of such compounds on circadian timing. We report drug, brain region and molecular specific effects of such treatments, including alterations in expression profiles in the suprachiasmatic nucleus, the master circadian pacemaker. These results indicate that drugs used in the clinical management of attention deficit hyperactivity disorder can alter molecular factors that are believed to underpin circadian timekeeping, and such effects may be of importance in both the therapeutic and side effect profiles of such drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Targeting impulsivity in Parkinson’s disease using atomoxetine

PubMed Central

Housden, Charlotte R.; Regenthal, Ralf; Barker, Roger A.; Müller, Ulrich; Rowe, James; Sahakian, Barbara J.; Robbins, Trevor W.

2014-01-01

Noradrenergic dysfunction may play a significant role in cognition in Parkinson’s disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson’s disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R2 = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R2 = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson’s disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder. PMID:24893708

Pharmacology and pharmacogenetics of pediatric ADHD with associated aggression: a review.

PubMed

Patel, Bianca D; Barzman, Drew H

2013-12-01

Attention deficit hyperactivity disorder (ADHD) is often associated with symptoms of aggression in children and adolescents. Clinically, this is complex because aggression can be from hyperactivity and impulsivity, or could be a distinct symptom from a comorbid diagnosis. Past research has recommended first treating the primary disorder of ADHD. Stimulants are the most common treatment for pediatric ADHD, which can be helpful in decreasing aggressive behaviors. Alpha-adrenergic agonists and atomoxetine (ATX) are non-stimulant medications for ADHD and aggression, but more research is necessary to compare these drugs to stimulants. If aggressive symptoms do not improve from treating the primary disorder, aggression can be treated separately. Risperidone, lithium, valproic acid, clonidine, and guanfacine have shown positive results in reducing aggression, but studies including children with aggression and ADHD are limited. The variability in treatment tolerability in patients has stimulated research in pharmacogenetics for ADHD. Although this field is still emerging, research has found evidence supporting a link between the response rate of methylphenidate and the dopamine transporter (DAT1) and a link between the metabolism rate of atomoxetine and hepatic cytochrome 450 isozymes. Pharmacogenetics may be relevant to ADHD and associated aggression. Further research in pharmacogenetics will strive to identify patterns of genetic variations that can tailor individual treatments.

Effectiveness of atomoxetine and methylphenidate for problematic online gaming in adolescents with attention deficit hyperactivity disorder.

PubMed

Park, Jeong Ha; Lee, Young Sik; Sohn, Ji Hyun; Han, Doug Hyun

2016-11-01

There is a high prevalence of problematic online gaming in adolescents with attention deficit hyperactivity disorder (ADHD). In the current study, we compared the effectiveness of atomoxetine (ATM) and methylphenidate (MPH) on problematic online gaming in adolescents with ADHD. We recruited 86 adolescents diagnosed with ADHD together with Internet gaming disorder. These participants were divided into two treatment groups: 44 participants were treated with MPH for 12 weeks, and 42 participants were treated with ATM for 12 weeks. During the 3-month study period, the MPH group showed greater improvement in Korean ADHD rating scale scores than the ATM group. The ATM group showed greater improvement in Child Depression Inventory scores than the MPH group. However, Young Internet Addiction Scale and Behavioral Inhibition & Activation Scales score changes did not differ significantly between the MPH and ATM groups. In both groups, changes in Young Internet Addiction Scale scores were positively correlated with the changes in Behavioral Inhibition & Activation Scales scores. Both MPH and ATM reduced the severity of Internet gaming disorder symptoms, and this reduction was correlated with impulsivity reduction, which also resulted from both ADHD medications. These findings suggest impulsivity plays a critical role in the development of problematic online gaming. Copyright © 2016 John Wiley & Sons, Ltd.

Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD.

PubMed

Brown, J T; Abdel-Rahman, S M; van Haandel, L; Gaedigk, A; Lin, Y S; Leeder, J S

2016-06-01

The effect of CYP2D6 genotype on the dose-exposure relationship for atomoxetine has not been well characterized in children. Children 6-17 years of age diagnosed with attention-deficit hyperactivity disorder (ADHD) were stratified by CYP2D6 genotype into groups with 0 (poor metabolizers [PMs], n = 4), 0.5 (intermediate metabolizers [IMs], n = 3), one (extensive metabolizer [EM]1, n = 8) or two (EM2, n = 8) functional alleles and administered a single 0.5 mg/kg oral dose of atomoxetine (ATX). Plasma and urine samples were collected for 24 (IM, EM1, and EM2) or 72 hours (PMs). Dose-corrected ATX systemic exposure (area under the curve [AUC]0-∞ ) varied 29.6-fold across the study cohort, ranging from 4.4 ± 2.7 μM*h in EM2s to 5.8 ± 1.7 μM*h, 16.3 ± 2.9 μM*h, and 50.2 ± 7.3 μM*h in EM1s, IMs, and PMs, respectively (P < 0.0001). Simulated steady state profiles at the maximum US Food and Drug Administration (FDA)-recommended dose suggest that most patients are unlikely to attain adequate ATX exposures. These data support the need for individualized dosing strategies for more effective use of the medication. © 2015 American Society for Clinical Pharmacology and Therapeutics.

A Review of Atomoxetine Effects in Young People with Developmental Disabilities

PubMed Central

Aman, Michael G.; Smith, Tristram; Arnold, L. Eugene; Corbett-Dick, Patricia; Rameshwari.Tumuluru; Hollway, Jill A.; Hyman, Susan L.; Mendoza-Burchamm, Marissa; Pan, Xueliang; Mruzek, Daniel W.; Lecavalier, Luc; Levato, Lynne; Silverman, Laura B.; Handen, Benjamin

2014-01-01

This review summarizes the pharmacokinetic characteristics, pharmacodynamic properties, common side effects, and clinical advantages and disadvantages associated with atomoxetine (ATX) treatment in typically developing children and adults with ADHD. Then the clinical research to date in developmental disabilities (DD), including autism spectrum disorders (ASD), is summarized and reviewed. Of the 11 relevant reports available, only two were placebo-controlled randomized clinical trials, and both focused on a single DD population (ASD). All trials but one indicated clinical improvement in ADHD symptoms with ATX, although it was difficult to judge the magnitude and validity of reported improvement in the absence of placebo controls. Effects of ATX on co-occurring behavioral and cognitive symptoms were much less consistent. Appetite decrease, nausea, and irritability were the most common adverse events reported among children with DD; clinicians should be aware that, as with stimulants, irritability appears to occur much more commonly in persons with DD than in typically developing individuals. Splitting the dose initially, starting below the recommended starting dose, and titrating slowly may prevent or ameliorate side effects. Patience is needed for the slow build-up of benefit. Conclusions: ATX holds promise for managing ADHD symptoms in DD, but properly controlled, randomized clinical trials of atomoxetine in intellectual disability and ASD are sorely needed. Clinicians and researchers should be vigilant for emergence of irritability with ATX treatment. Effects of ATX on cognition in DD are virtually unstudied. PMID:24732041

Atomoxetine

MedlinePlus

... works by increasing the levels of norepinephrine, a natural substance in the brain that is needed to ... loss of appetite weight loss constipation stomach pain gas dry mouth excessive tiredness dizziness headache mood swings ...

[The health economics of attention deficit hyperactivity disorder in Germany. Part 2: Therapeutic options and their cost-effectiveness].

PubMed

Schlander, M; Trott, G-E; Schwarz, O

2010-03-01

Attention deficit hyperactivity disorder (ADHD) has been associated with a continuous increase of health care utilization and thus expenditures. This raises the issue of cost-effectiveness of health care provided for patients with ADHD. Comparative health economic evaluations generate relevant insights and typically report incremental cost-effectiveness ratios (ICERs) of alternatives versus an established standard. Typically, results of cost-effectiveness analyses (CEAs) are reported in terms of incremental cost-effectiveness ratios (ICERs). International evaluations, as well specific adaptations to Germany, indicate an acceptable to attractive cost-effectiveness--according to currently used international benchmarks--of an intense medication management strategy based on stimulants, primarily methylphenidate, with ICERs ranging from 20,000 EUR to 37,000 EUR per quality-adjusted life year (QALY) gained. Economic modeling studies also suggest cost-effectiveness of long-acting modified-release preparations of methylphenidate, owing to improved treatment compliance associated with simplified once daily administration schemes. Atomoxetine, in contrast, appears economically inferior compared to long-acting stimulants, given its higher acquisition costs and at best equal clinical effectiveness. There are currently no data supporting the cost-effectiveness of psychotherapeutic or behavioral interventions. Economic evaluations, which have been published to date, are generally limited by time horizons of up to 1 year and by their prevailing focus on ADHD core symptom improvement only. Therefore, further research into the cost-effectiveness of ADHD treatment strategies seems warranted.

Priapism: Prolonged Erection

MedlinePlus

... as atomoxetine (Strattera) Alcohol and drug use Alcohol, marijuana, cocaine and other illicit drug abuse can cause ... Clinic logo are trademarks of Mayo Foundation for Medical Education and Research. © 1998-2018 Mayo Foundation for ...

Current issues around the pharmacotherapy of ADHD in children and adults.

PubMed

Meijer, Willemijn M; Faber, Adrianne; van den Ban, Els; Tobi, Hilde

2009-10-01

New drugs and new formulations enter the growing market for ADHD medication. The growing awareness of possible persistence of ADHD impairment beyond childhood and adolescence resulting in increased pharmacotherapy of ADHD in adults, is also a good reason for making an inventory of the what is generally known about pharmacotherapy in ADHD. To discuss current issues in the possible pharmacotherapy treatment of ADHD in children, adolescents and adults with respect to the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used. A search of the literature with an emphasis on the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used in pharmacotherapy. According to the guidelines, the treatment of ADHD in children consists of psychosocial interventions in combination with pharmacotherapy when needed. Stimulants are the first-choice drugs in the pharmacological treatment of ADHD in children despite a number of well known and frequently reported side effects like sleep disorders and loss of appetite. With regard to the treatment of adults, stimulant treatment was recommended as the first-choice pharmacotherapy in the single guideline available. Both in children and adults, there appears to be an additional though limited role for the nonadrenergic drug atomoxetine. The increase of ADHD medication use, in children, adolescents and in adults, can not only be interpreted as a sign of overdiagnosis of ADHD. Despite the frequent use of stimulants, there is still a lack of clarity on the effects of long-term use on growth and nutritional status of children. Cardiovascular effects of both stimulants and atomoxetine are rare but can be severe. The literature suggests that atomoxetine may be associated with suicidal ideation in children. Although pharmacotherapy is increasing common in the treatment of ADHD in both children and adults, there are still a lot of questions about side effects and how best to counter them. This suggests an important role for close monitoring of children and adults treated with stimulants or atomoxetine.

Review of ADHD Pharmacotherapies: Advantages, Disadvantages, and Clinical Pearls

ERIC Educational Resources Information Center

Daughton, Joan M.; Kratochvil, Christopher J.

2009-01-01

The advantages, disadvantages, as well as helpful hints on when to use several drug therapies against attention deficit hyperactivity disorder are discussed. The drugs discussed are methylphenidate, atomoxetine, clonidine, and bupropion.

Evaluation of the Potential Pharmacokinetic Interaction between Atomoxetine and Fluvoxamine in Healthy Volunteers.

PubMed

Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Briciu, Corina

2017-01-01

Attention deficit hyperactivity disorder (ADHD) is frequently associated with other psychiatric pathologies. Therefore, the present study investigated a possible pharmacokinetic interaction between atomoxetine (ATX), a treatment option for ADHD, and an antidepressant, namely, fluvoxamine (FVX). Designed as an open-label, non-randomized clinical trial, the study included 2 periods. In period 1 (reference), each subject received ATX 25 mg (single-dose), whereas in period 2 (test), all subjects were given a combination of ATX 25 mg + FVX 100 mg, following a 6-day pretreatment regimen with the enzymatic inhibitor. Non-compartmental methods were employed to determine the pharmacokinetic parameters of ATX and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide. The results revealed significant differences between the study periods for Cmax, AUC0-t and AUC0-∞ values corresponding to ATX and its metabolite. Small, but statistically significant increases in AUC values were reported for both parent drug (1,583.05 ± 1,040.29 vs. 2,111.55 ± 1,411.59 ng*h/ml) and 4-hydroxyatomoxetine-O-glucuronide (5,754.71 ± 1,235.5 vs. 6,293.17 ± 1,219.34 ng*h/ml) after combined treatment of ATX and the enzymatic inhibitor. FVX had a modest effect on the pharmacokinetics of ATX and 4-hydroxyatomoxetine-O-glucuronide. The presence or absence of any clinical consequences associated with this pharmacokinetic drug-drug interaction needs to be established in future studies. © 2016 S. Karger AG, Basel.

Alternative pharmacological strategies for adult ADHD treatment: a systematic review.

PubMed

Buoli, Massimiliano; Serati, Marta; Cahn, Wiepke

2016-01-01

Adult Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition associated with high disability and frequent comorbidity. Current standard pharmacotherapy (methylphenidate and atomoxetine) improves ADHD symptoms in the short-term, but poor data were published about long-term treatment. In addition a number of patients present partial or no response to methylphenidate and atomoxetine. Research into the main database sources has been conducted to obtain an overview of alternative pharmacological approaches in adult ADHD patients. Among alternative compounds, amphetamines (mixed amphetamine salts and lisdexamfetamine) have the most robust evidence of efficacy, but they may be associated with serious side effects (e.g. psychotic symptoms or hypertension). Antidepressants, particularly those acting as noradrenaline or dopamine enhancers, have evidence of efficacy, but they should be avoided in patients with comorbid bipolar disorder. Finally metadoxine and lithium may be particularly suitable in case of comorbid alcohol misuse or bipolar disorder.

Psychopharmacology of Attention-Deficit Hyperactivity Disorder: Effects and Side Effects.

PubMed

Golmirzaei, Javad; Mahboobi, Hamidreza; Yazdanparast, Maryam; Mushtaq, Gohar; Kamal, Mohammad A; Hamzei, Enayatollah

2016-01-01

Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in children which manifests with hyperactivity, impulsivity, and/or inattention. Several drugs are used in treatment of ADHD. Stimulants, atomoxetine, anti-depressants, and bupropion are common medications used in the treatment of ADHD. Stimulants are widely used as the first line treatment in children with ADHD. Their mechanism of action is the release of dopamine and norepinephrine in central nervous system. Methylphenidate is the most common stimulant used for the treatment of ADHD. Methylphenidate significantly reduces ADHD symptoms in children both at home and school and improves their social skills. Methylphenidate is safe in healthy children and has shown to have no cardiac side effects in these patients. Other medications include: Atomoxetine, Amphetamines, Clonidine, Melatonin, and anti-depressants. Effects, side effects, and mechanism of action these drugs have been discussed in this paper.

Quantification of Methylphenidate, Dexamphetamine, and Atomoxetine in Human Serum and Oral Fluid by HPLC With Fluorescence Detection.

PubMed

Stegmann, Benedikt; Dörfelt, Anett; Haen, Ekkehard

2016-02-01

For psychostimulants, a marked individual variability in the dose-response relationship and large differences in plasma concentrations after similar doses are known. Therefore, optimizing the efficacy of these drugs is at present the most promising way to exploit their full pharmacological potential. Moreover, it seems important to examine oral fluid as less invasive biological matrix for its benefit in therapeutic drug monitoring for patients with hyperkinetic disorder. A high-performance liquid chromatography method for quantification of methylphenidate (MPH), dexamphetamine (DXA), and atomoxetine in serum and oral fluid has been developed and validated. The analytical procedure involves liquid-liquid extraction, derivatization with 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride as a label and chromatographic separation on a Phenomenex Gemini-NX C18 analytical column using gradient elution with water-acetonitrile. The derivatized analytes were detected at 330 nm (excitation wavelength) and 440 nm (emission wavelength). To examine the oral fluid/serum ratios, oral fluid samples were collected simultaneously to blood samples from patients with hyperkinetic disorder. The method allows quantification of all analytes in serum and oral fluid within 16 minutes under the same or similar conditions. Oral fluid/serum ratios for MPH and DXA were highly variable and showed an accumulation of these drugs in oral fluid. The developed method covers the determination of MPH, DXA, and atomoxetine concentrations in serum and oral fluid after the intake of therapeutic doses. Oral fluid samples are useful for the qualitative detection of MPH and DXA.

Event-related potentials reflect the efficacy of pharmaceutical treatments in children and adolescents with attention deficit/hyperactivity disorder.

PubMed

Yamamuro, Kazuhiko; Ota, Toyosaku; Iida, Junzo; Nakanishi, Yoko; Matsuura, Hiroki; Uratani, Mitsuhiro; Okazaki, Kosuke; Kishimoto, Naoko; Tanaka, Shohei; Kishimoto, Toshifumi

2016-08-30

Few objective biological measures of pharmacological treatment efficacy exist for attention deficit/hyperactivity disorder (ADHD). Although we have previously demonstrated that event-related potentials (ERPs) reflect the effects of osmotic-release methylphenidate in treatment of naïve pediatric patients with ADHD, whether this is true for the therapeutic effects of atomoxetine (ATX) is unknown. Here, we used the Japanese version of the ADHD rating-scale IV to evaluate 14 patients with ADHD, and compared their ERP data with 14 age- and sex-matched controls. We measured P300 and mismatch negativity (MMN) components during an auditory oddball task before treatment (treatment naïve) and after 2 months of ATX treatment. Compared with controls, P300 components at baseline were attenuated and prolonged in the ADHD group at Fz (fronto-central), Cz (centro-parietal), Pz (parietal regions), C3 and C4 electrodes. ATX treatment reduced ADHD symptomology, and after 2 months of treatment, P300 latencies at Fz, Cz, Pz, C3, and C4 electrodes were significantly shorter than those at baseline. Moreover, MMN amplitudes at Cz and C3 electrodes were significantly greater than those at baseline. Thus, ERPs may be useful for evaluating the pharmacological effects of ATX in pediatric and adolescent patients with ADHD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Osmotic Release Oral System Methylphenidate Versus Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder in Chinese Youth: 8-Week Comparative Efficacy and 1-Year Follow-Up.

PubMed

Su, Yi; Yang, Li; Stein, Mark A; Cao, Qingjiu; Wang, Yufeng

2016-05-01

The purpose of this study was to compare the short-term efficacy, tolerability, and 1-year adherence in Chinese children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with either osmotic release oral system methylphenidate (OROS MPH) or atomoxetine (ATX). Children and adolescents meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for ADHD were randomly assigned to receive either OROS MPH (n = 119) or ATX (n = 118). Participants underwent a 1-4 week dose titration period to determine optimal dose, and then were maintained on that dose for 4 weeks (maintenance period). Assessment for efficacy was conducted every week over the titration period and at the end of the maintenance period. The primary efficacy measure was the investigator-rated total ADHD Rating Scale-IV (ADHD-RS-IV) score. Response was further classified as remission (ADHD-RS-IV [18 or 9 items] average score ≤1), robust improvement (ADHD-RS-IV ≥40% decrease in total score), or improvement (≥ 25% decrease in total score) at the end of maintenance period. Medication adherence (taking medication at least 5 days in 1 week) and reasons for nonadherence were evaluated every week over the titration period, at the end of maintenance period, and then at 3, 6, and 12 months. At the end of maintenance period, both OROS MPH and ATX were associated with significant and similar reductions from baseline in ADHD symptoms. Percentages achieving remission, robust improvement, and improvement were comparable for OROS MPH and ATX treatment (35.3% vs. 37.1%, 45.4% vs. 44.8%, 65.5% vs. 66.4%). Medication use decreased over time for both treatments; however, at end of maintenance period, 3 month, 6 month, and 1 year follow-ups, subjects in the OROS MPH group were more likely to be compliant with treatment (74.8%, 50.4%, 38.7%, and 21.8% for OROS MPH vs. 52.5%, 33.9%, 12.7%, and 3.4% for ATX) ( p < 0.05). The most common reasons for nonadherence were adverse events and lack of efficacy. Both OROS MPH and ATX resulted in similar reductions in ADHD symptoms in Chinese children and adolescents with ADHD. Long-term adherence with medication was poor in general, although somewhat better with OROS MPH than with ATX. ClinicalTrials.gov , Identifier: NCT01065259.

Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.

PubMed

Handen, Benjamin L; Aman, Michael G; Arnold, L Eugene; Hyman, Susan L; Tumuluru, Rameshwari V; Lecavalier, Luc; Corbett-Dick, Patricia; Pan, Xueliang; Hollway, Jill A; Buchan-Page, Kristin A; Silverman, Laura B; Brown, Nicole V; Rice, Robert R; Hellings, Jessica; Mruzek, Daniel W; McAuliffe-Bellin, Sarah; Hurt, Elizabeth A; Ryan, Melissa M; Levato, Lynne; Smith, Tristram

2015-11-01

Impairments associated with attention-deficit/hyperactivity disorder (ADHD) and noncompliance are prevalent in children with autism spectrum disorder (ASD). However, ADHD response to stimulants is well below rates in typically developing children, with frequent side effects. Group studies of treatments for noncompliance are rare in ASD. We examined individual and combined-effectiveness of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance. In a 3-site, 10-week, double-blind, 2 × 2 trial of ATX and PT, 128 children (ages 5-14 years) with ASD and ADHD symptoms were randomized to ATX, ATX+PT, placebo+PT, or placebo. ATX was adjusted to optimal dose (capped at 1.8 mg/kg/day) over 6 weeks and maintained for 4 additional weeks. Nine PT sessions were provided. Primary outcome measures were the parent-rated DSM ADHD symptoms on the Swanson, Nolan and Pelham (SNAP) scale and Home Situations Questionnaire (HSQ). On the SNAP, ATX, ATX+PT and placebo+PT were each superior to placebo (effect sizes 0.57-0.98; p values of .0005, .0004, and .025, respectively). For noncompliance, ATX and ATX+PT were superior to placebo (effect sizes 0.47-0.64; p values .03 and .0028, respectively). ATX was associated with decreased appetite but was otherwise well tolerated. Both ATX and PT resulted in significant improvement on ADHD symptoms, whereas ATX (both alone and combined with PT) was associated with significant decreases on measures of noncompliance. ATX appears to have a better side effects profile than psychostimulants in the population with ASD. Atomoxetine, Placebo and Parent Management Training in Autism; http://clinicaltrials.gov/; NCT00844753. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Pay attention to impulsivity: modelling low attentive and high impulsive subtypes of adult ADHD in the 5-choice continuous performance task (5C-CPT) in female rats.

PubMed

Tomlinson, Anneka; Grayson, Ben; Marsh, Samuel; Harte, Michael K; Barnes, Samuel A; Marshall, Kay M; Neill, Joanna C

2014-08-01

Varying levels of attention and impulsivity deficits are core features of the three subtypes of adult attention deficit-hyperactivity disorder (ADHD). To date, little is known about the neurobiological correlates of these subtypes. Development of a translational animal model is essential to improve our understanding and improve therapeutic strategies. The 5-choice continuous performance task (5C-CPT) in rats can be used to examine different forms of attention and impulsivity. Adult rats were trained to pre-set 5C-CPT criterion and subsequently separated into subgroups according to baseline levels of sustained attention, vigilance, premature responding and response disinhibition in the 5C-CPT. The behavioural subgroups were selected to represent the different subtypes of adult ADHD. Consequently, effects of the clinically used pharmacotherapies (methylphenidate and atomoxetine) were assessed in the different subgroups. Four subgroups were identified: low-attentive (LA), high-attentive (HA), high-impulsive (HI) and low-impulsive (LI). Methylphenidate and atomoxetine produced differential effects in the subgroups. Methylphenidate increased sustained attention and vigilance in LA animals, and reduced premature responding in HI animals. Atomoxetine also improved sustained attention and vigilance in LA animals, and reduced response disinhibition and premature responding in HI animals. This is the first study using adult rats to demonstrate the translational value of the 5C-CPT to select subgroups of rats, which may be used to model the subtypes observed in adult ADHD. Our findings suggest that this as an important paradigm to increase our understanding of the neurobiological underpinnings of adult ADHD-subtypes and their response to pharmacotherapy. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

The effects of compound stimulus extinction and inhibition of noradrenaline reuptake on the renewal of alcohol seeking

PubMed Central

Furlong, T M; Pan, M J; Corbit, L H

2015-01-01

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli can reduce their impact on relapse; however, the expression of extinction can be disrupted when testing occurs outside the context where extinction learning took place, an effect termed renewal. Behavioral and pharmacological methods have recently been shown to augment extinction learning; yet, it is not known whether the improved expression of extinction following these treatments remains context-dependent. Here we examined whether two methods, compound–stimulus extinction and treatment with the noradrenaline reuptake inhibitor atomoxetine, would reduce the vulnerability of extinction to a change in context. Following alcohol self-administration, responding was extinguished in a distinct context. After initial extinction, further extinction was given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg kg−1; Experiment 2). A stimulus extinguished as part of a compound elicited less responding than a stimulus receiving equal extinction alone regardless of whether animals were tested in the training or extinction context; however, reliable renewal was not observed in this paradigm. Importantly, atomoxetine enhanced extinction relative to controls even in the presence of a reliable renewal effect. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Importantly, both methods improve extinction even when the context is changed between extinction training and test, and thus could be utilized to enhance the outcome of extinction-based treatments for alcohol-use disorders. PMID:26327688

Reduced Short Interval Cortical Inhibition Correlates with Atomoxetine Response in Children with ADHD

PubMed Central

Chen, Tina H.; Wu, Steve W.; Welge, Jeffrey A.; Dixon, Stephan; Shahana, Nasrin; Huddleston, David A.; Sarvis, Adam R.; Sallee, Floyd R.; Gilbert, Donald L.

2014-01-01

Clinical trials in children with Attention Deficit Hyperactivity Disorder (ADHD) show variability in behavioral responses to the selective norepinephrine reuptake inhibitor atomoxetine (ATX). The objective of this study was to determine whether Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (SICI) might be a biomarker predicting, or correlating with, clinical ATX response. At baseline and after 4 weeks of ATX treatment in 7–12 year old children with ADHD, TMS-SICI was measured, blinded to clinical improvement. Primary analysis was by multivariate ANCOVA. Baseline SICI did not predict clinical responses. However, paradoxically, after 4 weeks of ATX, mean SICI was reduced 31.9% in responders and increased 6.1% in non-responders (ANCOVA t41=2.88; p = .0063). Percent reductions in SICI correlated with reductions in ADHD-Rating Scale (ADHDRS) (r = .50; p = .0005). In children ages 7–12 years with ADHD treated with ATX, improvements in clinical symptoms are correlated with reductions in motor cortex SICI. PMID:24413361

Sex differences in the reduction of impulsive choice (delay discounting) for cocaine in rats with atomoxetine and progesterone

PubMed Central

Smethells, John R.; Swalve, Natashia L.; Eberly, Lynn E.; Carroll, Marilyn E.

2016-01-01

Rationale Impulsive choice, or an inability to delay immediate gratification, has been strongly linked to the development and persistence of drug abuse. Indeed, delaying drug use itself may underlie drug addiction and relapse. Thus, employing treatments that are efficacious in reducing impulsive choice (atomoxetine; ATO) or drug-seeking behavior (progesterone; PRO) may be an effective means of treating drug addiction. Objective The current study assessed sex differences in the effects of PRO, ATO and their combination in a delay discounting paradigm for cocaine and for sucrose pellets. Method Male and female rats chose between a small-immediate or a large-delayed (0, 7.5, 15, 30, 60 sec) outcome in an impulsive choice procedure for sucrose pellets (1 vs 3 pellets) or for iv cocaine infusions (0.3 vs 0.9 mg/kg). Following baseline assessment of impulsive choice, rats received daily treatment of vehicle (VEH), PRO (0.5 mg/kg), ATO (1.5 mg/kg) or a combination (PRO + ATO) until a second assessment of impulsive choice was determined. Results Compared to the VEH group, females were less impulsive for cocaine following PRO or the PRO + ATO combined treatment, whereas males were less impulsive for cocaine following ATO. No treatment effects were observed on impulsive choice for sucrose pellets. Conclusions The present results indicate that impulsive choice for cocaine is reduced by PRO in females and by ATO in males. These findings suggest both treatments may be an effective intervention in treating cocaine abuse, but that their effectiveness differs by sex. PMID:27325394

Methylphenidate, Atomoxetine, and Caffeine: A Primer for School Psychologists

ERIC Educational Resources Information Center

Carlson, John S.; Kruer, Jessica L.; Ogg, Julia A.; Mathiason, Jacob B.; Magen, Jed

2007-01-01

Knowledge of evidence-based pharmacological and psychosocial treatments is essential to carrying out roles and responsibilities within school-based practice. The purpose of this paper is to review the level of support for three psychotropic drugs reported in the literature to treat symptoms of Attention-Deficit Hyperactivity Disorder (ADHD).…

Characteristics of Placebo Responders in Pediatric Clinical Trials of Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Newcorn, Jeffrey H.; Sutton, Virginia K.; Zhang, Shuyu; Wilens, Timothy; Kratochvil, Christopher; Emslie, Graham J.; D'Souza, Deborah N.; Schuh, Leslie M.; Allen, Albert J.

2009-01-01

Objective: Understanding placebo response is a prerequisite to improving clinical trial methodology. Data from placebo-controlled trials of atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) were analyzed to identify demographic and clinical characteristics that might predict placebo…

Switch in Therapy from Methylphenidate to Atomoxetine in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: An Analysis of Patient Records.

PubMed

Warrer, Pernille; Thomsen, Per Hove; Dalsgaard, Søren; Hansen, Ebba Holme; Aagaard, Lise; Wallach Kildemoes, Helle; Rasmussen, Henrik Berg

2016-05-01

The purpose of this study was to investigate therapy switching from methylphenidate (MPH) to atomoxetine (ATX) in a clinical sample of Danish children and adolescents with attention-deficit/hyperactivity disorder (ADHD); specifically, to determine the duration of MPH treatment before switching to ATX, and the reasons leading to a switch in therapy. We included 55 patients with ADHD who switched from first-line MPH to second-line ATX during January 01, 2012 and May 15, 2014. Patient and treatment characteristics along with clinical reasons for switching therapy were extracted from individual patients' records. Mean duration of MPH treatment until switch to ATX was 11.2 months (range = 0.3-28.5 months); 36% of the patients switched within the first 6 months, 56% within the first year, and 76% within 1.5 years of initiating MPH; 24% continued MPH treatment for up to 2.5 years prior to switching. Most common reasons for switching were "adverse events" (AEs) (78%), "wish for more optimal day coverage" (24%), and "lack of efficacy" (16%). Other reasons for switching included "patient/parental request" (13%) and "noncompliance" (2%). Most common AEs leading to switch were psychiatric disorders (insomnia, aggression, tic, depression, anxiety) and decreased appetite. Our findings highlight the importance of continuous evaluation of the need for prescription switch to ATX in children and adolescents treated with MPH, taking into consideration various factors including potential AEs, non-optimal day coverage, lack of efficacy, patient/parental preferences, and noncompliance. These factors should be considered, not only at the initial stage of MPH treatment but throughout the whole treatment course.

Sweat testing for the detection of atomoxetine from paediatric patients with attention deficit/ hyperactivity disorder: application to clinical practice.

PubMed

Marchei, Emilia; Papaseit, Esther; Garcia-Algar, Oscar; Bilbao, Amaia; Farré, Magí; Pacifici, Roberta; Pichini, Simona

2013-03-01

Atomoxetine (ATX) is a selective norepinephrine reuptake inhibitor approved since 2002 for the treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults as an alternative treatment to methylphenidate. Within the framework of a project evaluating the use of alternative biological matrices for therapeutic monitoring of psychoactive drugs in paediatric and non-paediatric individuals, the excretion of ATX and its principal metabolites has been recently studied in oral fluid and hair. The aim of this study was to describe the excretion profile of ATX and its metabolites 4-hydroxyatomoxetine (4-OH-ATX) and N-desmethylatomoxetine (N-des-ATX) in sweat following the administration of different dosage regimens (60, 40, 35, and 18 mg/day) of ATX to six paediatric patients. Sweat patches were applied to the back of each participant and removed at timed intervals. ATX and its metabolites were measured in patches using a previously validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Independently from the administered dose, ATX appeared in the sweat patches 1 h post administration and reached its maximum concentration generally at 24 h. Peak ATX concentrations ranged between 2.31 and 40.4 ng/patch and did not correlate with the administered drug dose, or with body surface area. Total ATX excreted in sweat ranged between 0.008 and 0.121 mg, corresponding to 0.02 and 0.3% of the administered drug. Neither 4-OH-ATX, nor N-des-ATX was detected in either of the collected sweat patches. Measuring ATX in sweat patches can provide information on cumulative drug use from patch application until removal. Copyright © 2012 John Wiley & Sons, Ltd.

Training Raters to Assess Adult ADHD: Reliability of Ratings

ERIC Educational Resources Information Center

Adler, Lenard A.; Spencer, Thomas; Faraone, Stephen V.; Reimherr, Fred W.; Kelsey, Douglas; Michelson, David; Biederman, Joseph

2005-01-01

The standardization of ADHD ratings in adults is important given their differing symptom presentation. The authors investigated the agreement and reliability of rater standardization in a large-scale trial of atomoxetine in adults with ADHD. Training of 91 raters for the investigator-administered ADHD Rating Scale (ADHDRS-IV-Inv) occurred prior to…

The effectiveness of methylphenidate in the treatment of encopresis independent from attention-deficit hyperactivity disorder symptoms.

PubMed

Akça, Ömer Faruk; Yılmaz, Savaş

2015-01-01

Several medications are reported to be effective in treatment of encopresis. However, mechanisms of action related to these drugs are not known. We report a patient with ADHD and encopresis whose encopretic signs have disappeared with long acting methylphenidate while they have not changed with atomoxetine.

Simulated Driving Changes in Young Adults with ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine

ERIC Educational Resources Information Center

Kay, Gary G.; Michaels, M. Alex; Pakull, Barton

2009-01-01

Background: Psychostimulant treatment may improve simulated driving performance in young adults with attention-deficit/hyperactivity disorder (ADHD). Method: This was a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with mixed amphetamine salts--extended release (MAS XR) 50 mg/day (Cohort 1) and…

Examination of antimicrobial activity of selected non-antibiotic medicinal preparations.

PubMed

Kruszewska, Hanna; Zareba, Tomasz; Tyski, Stefan

2012-01-01

The aim of this study was to detect and characterize the antimicrobial activity of non-antibiotic drugs, selected from the pharmaceutical products analyzed during the state control performed in National Medicines Institute, Warszawa, Poland. In 2010, over 90 pharmaceutical preparations have been randomly chosen from different groups of drugs. The surveillance study was performed on standard ATCC microbial strains used for drug control: S. aureus, E. coli, P. aeruginosa and C. albicans. It was shown that the drugs listed below inhibited growth of at least one of the examined strains: Arketis 20 mg tab. (paroxetine), Buvasodil 150 mg tab. (buflomedile), Halidor 100 mg tab. (bencyclane), Hydroxyzinum espefa 25 mg tab. (hydroxyzine), Norifaz 35 mg tab. (risedronate), Strattera 60 mg cap. (atomoxetine), Tamiflu 75 mg tab. (oseltamivir), Valpro-ratiopharm Chrono 300 mg tab. with longer dissolution (valproate), Vetminth oral paste 24 g+3 g/100 mL (niclozamide, oxybendazol). Strattera cap. showed broad activity spectrum. It inhibited growth of all examined strains (MIC of active substance -- atomoxetine ranged between 2.6-13 mg/mL).

Academic outcomes in Asian children aged 8-11 years with attention-deficit/hyperactivity disorder treated with atomoxetine hydrochloride.

PubMed

Mendez, Luis; Singh, Pritibha; Harrison, Gavan; Huang, Yu-Shu; Jin, Xingming; Cho, Soo Churl

2011-06-01

To investigate the relationship between changes in attention-deficit/hyperactivity disorder (ADHD) core symptoms and changes in academic outcome of Asian children treated with atomoxetine. This open-label study enrolled patients aged 8-11 years with DSM-IV-TR-defined ADHD, who were naïve to ADHD medications and met the symptomatic severity threshold of 1.5 standard deviations above the age and gender norm for the ADHDRS-IV-Parent:Inv (ADHDRS) total score. Data collection occurred for 24 weeks and included academic outcome, measured by the school grade average (SGA). Of 228 patients enrolled from China (n = 82), Taiwan (n = 76), and Korea (n = 70), 77.2% completed the study. Statistically significant (P < 0.001) baseline to last observation improvements in ADHDRS and SGA scores were observed. However, no linear correlation between change in ADHDRS total score and SGA (-0.083, P = 0.293) was observed. Despite significant independent improvements in core ADHD symptoms and academic grades over 24 weeks, the mean improvements observed in these measures did not appear to be correlated.

Atomoxetine and Parent Training for Children With Autism and Attention-Deficit/Hyperactivity Disorder: A 24-Week Extension Study.

PubMed

Smith, Tristram; Aman, Michael G; Arnold, L Eugene; Silverman, Laura B; Lecavalier, Luc; Hollway, Jill; Tumuluru, Rameshwari; Hyman, Susan L; Buchan-Page, Kristin A; Hellings, Jessica; Rice, Robert R; Brown, Nicole V; Pan, Xueliang; Handen, Benjamin L

2016-10-01

The authors previously reported on a 2-by-2 randomized clinical trial of individual and combined treatment with atomoxetine (ATX) and parent training (PT) for attention-deficit/hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 5- to 14-year-old children with autism spectrum disorder. In the present report, they describe a 24-week extension of treatment responders and nonresponders. One-hundred seventeen participants from the acute trial (91%) entered the extension; 84 of these were in 2 subgroups: "treatment responders" (n = 43) from all 4 groups in the acute trial, seen monthly for 24 weeks, and "placebo nonresponders" (n = 41), treated with open-label ATX for 10 weeks. Participants originally assigned to PT continued PT during the extension; the remainder served as controls. Primary outcome measurements were the parent-rated Swanson, Nolan and Pelham ADHD scale and the Home Situations Questionnaire. Sixty percent (26 of 43) of treatment responders in the acute trial, including 68% of responders originally assigned to ATX, still met the response criteria at the end of the extension. The response rate of placebo nonresponders treated with 10-week open-label ATX was 37% (15 of 41), similar to the acute trial. Children receiving open-label ATX + PT were significantly more likely to be ADHD responders (53% versus 23%) and noncompliance responders (58% versus 14%) than those receiving open-label ATX alone. Most ATX responders maintained their responses during the extension. PT combined with ATX in the open-label trial appeared to improve ADHD and noncompliance outcomes more than ATX alone. Clinical trial registration information-Atomoxetine, Placebo and Parent Management Training in Autism (Strattera); http://clinicaltrials.gov; NCT00844753. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity.

PubMed

Zlebnik, Natalie E; Carroll, Marilyn E

2015-03-01

Aerobic exercise and the attention-deficit/hyperactivity disorder medication, atomoxetine (ATO), are two monotherapies that have been shown to suppress reinstatement of cocaine-seeking in an animal model of relapse. The present study investigated the effects of combining wheel running and ATO versus each treatment alone on cocaine-seeking precipitated by cocaine and cocaine-paired cues in rats with differing susceptibility to drug abuse (i.e., high vs. low impulsive). Rats were screened for high (HiI) or low impulsivity (LoI) based on their performance on a delay-discounting task and then trained to self-administer cocaine (0.4 mg/kg/inf) for 10 days. Following 14 days of extinction, both groups were tested for reinstatement of cocaine-seeking precipitated by cocaine or cocaine-paired cues in the presence of concurrent running wheel access (W), pretreatment with ATO, or both (W+ATO). HiI rats acquired cocaine self-administration more quickly than LoI rats. While both individual treatments and W+ATO significantly attenuated cue-induced cocaine seeking in HiI and LoI rats, only W+ATO was effective in reducing cocaine-induced reinstatement compared with vehicle treatment. There were dose-dependent and phenotype-specific effects of ATO with HiI rats responsive to the low but not high ATO dose. Floor effects of ATO and W on cue-induced reinstatement prevented the assessment of combined treatment effects. These findings demonstrated greater attenuation of cue- versus cocaine-induced reinstatement by ATO and W alone and recapitulate impulsivity phenotype differences in both acquisition of cocaine self-administration and receptivity to treatment.

The Effectiveness of Methylphenidate in the Treatment of Encopresis Independent from Attention-Deficit Hyperactivity Disorder Symptoms

PubMed Central

Yılmaz, Savaş

2015-01-01

Several medications are reported to be effective in treatment of encopresis. However, mechanisms of action related to these drugs are not known. We report a patient with ADHD and encopresis whose encopretic signs have disappeared with long acting methylphenidate while they have not changed with atomoxetine. PMID:25670959

Adrenergic pathway activation enhances brown adipose tissue metabolism: A [18F]FDG PET/CT study in mice

PubMed Central

Mirbolooki, M. Reza; Upadhyay, Sanjeev Kumar; Constantinescu, Cristian C.; Pan, Min-Liang; Mukherjee, Jogeshwar

2013-01-01

Objective Pharmacologic approaches to study brown adipocyte activation in vivo with a potential of being translational to humans are desired. The aim of this study was to examine pre- and postsynaptic targeting of adrenergic system for enhancing brown adipose tissue (BAT) metabolism quantifiable by [18F]fluoro-2-deoxyglucose ([18F]FDG) positron emission tomography (PET)/ computed tomography (CT) in mice. Methods A β3-adrenoreceptor selective agonist (CL 316243), an adenylyl cyclase enzyme activator (forskolin) and a potent blocker of presynaptic norepinephrine transporter (atomoxetine) were injected through the tail vein of Swiss Webster mice 30 minutes before intravenous (iv) administration of [18F]FDG. The mice were placed on the PET/CT bed for 30 min PET acquisition followed by 10 min CT acquisition for attenuation correction and anatomical delineation of PET images. Results Activated interscapular (IBAT), cervical, periaortic and intercostal BAT were observed in 3-dimentional analysis of [18F]FDG PET images. CL 316243 increased the total [18F]FDG standard uptake value (SUV) of IBAT 5-fold greater compared to that in placebo-treated mice. It also increased the [18F]FDG SUV of white adipose tissue (2.4-fold), and muscle (2.7-fold), as compared to the control. There was no significant difference in heart, brain, spleen and liver uptakes between groups. Forskolin increased [18F]FDG SUV of IBAT 1.9-fold greater than that in placebo-treated mice. It also increased the [18F]FDG SUV of white adipose tissue (2.2-fold) and heart (5.4-fold) compared to control. There was no significant difference in muscle, brain, spleen, and liver uptakes between groups. Atomoxetine increased [18F]FDG SUV of IBAT 1.7-fold greater than that in placebo-treated mice. There were no significant differences in all other organs compared to placebo-treated mice except liver (1.6 fold increase). A positive correlation between SUV levels of IBAT and CT hounsfiled unit (HU) (R2=0.55, p<0.001) and between CT HU levels of IBAT and liver (R2=0.69, p<0.006) was observed. Conclusions The three pharmacologic approaches reported here enhanced BAT metabolism by targeting different sites in adrenergic system as measured by [18F]FDG PET/CT. PMID:24090673

Pharmacological treatment for attention deficit hyperactivity disorder: functional outcomes in children and adolescents from non-Western countries.

PubMed

Altin, Murat; El-Shafei, Ahmed A; Yu, Maria; Desaiah, Durisala; Treuer, Tamas; Zavadenko, Nikolay; Gao, Hong Yun

2013-09-13

Functional outcomes were measured over a 12-month period in children and adolescents with attention deficit hyperactivity disorder (ADHD) after they received monotherapy. Prospective, observational, noninterventional study. Conducted in six non-Western countries. Outpatients 6 to 17 years of age with a verified diagnosis of ADHD in accordance with the Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR), together with their physicians, decided to initiate or switch treatment for ADHD. Patients were prescribed pharmacological monotherapy: methylphenidate (n=221), nootropic agents (n=91), or atomoxetine (n=234). Patients were followed for changes in their functional status and quality of life, which were assessed with the Child Health and Illness Profile-Child Edition (CHIP-CE) Achievement domain. At the end of the study, a mean improvement on the CHIP-CE Achievement domain score was observed for all countries and therapies except in Taiwan, where patients received atomoxetine, and in Lebanon, where patients received methylphenidate. No patient experienced a serious adverse event during the study. Four patients discontinued due to a treatment-emergent adverse event. After 12 months of treatment, clinical and functional outcomes were improved in children and adolescents from non-Western countries who initiated and remained on their prescribed pharmacological monotherapy.

Tic Symptoms Induced by Atomoxetine in Treatment of ADHD: A Case Report and Literature Review.

PubMed

Yang, Rongwang; Li, Rong; Gao, Weijia; Zhao, Zhengyan

Patients with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for tic disorders. Atomoxetine (ATX) has been accepted as an alternative medication for patients with ADHD and a comorbid tic disorder. It is rarely reported that tic symptoms are induced by ATX. This present report described a boy with ADHD who developed tic symptoms during ATX initiation. We used an ABAB trial to confirm the tics were related to ATX administration. In addition, we reviewed the published literature of patients whose tic symptoms were confirmed or suspected of relating to ATX usage. This present case with an ABAB design showed on-off control of tics with or without ATX, which allowed us to make a strong conclusion that the tics were related to ATX administration. Literature review also indicated that ATX might induce tic symptoms in children with ADHD, especially in those being boys and having a history of tics. The time from starting ATX to tics symptoms appearing was approximately 19 days. The most common tic symptoms were eye blinking, vocal tics, or throat clearing, and neck movements. These tics symptoms in most cases could be resolved after discontinuing ATX without further pharmacotherapy. Pediatricians and child psychiatrists should be well aware of this potential adverse effect in children with ADHD receiving ATX.

Neurochemical enhancement of conscious error awareness.

PubMed

Hester, Robert; Nandam, L Sanjay; O'Connell, Redmond G; Wagner, Joe; Strudwick, Mark; Nathan, Pradeep J; Mattingley, Jason B; Bellgrove, Mark A

2012-02-22

How the brain monitors ongoing behavior for performance errors is a central question of cognitive neuroscience. Diminished awareness of performance errors limits the extent to which humans engage in corrective behavior and has been linked to loss of insight in a number of psychiatric syndromes (e.g., attention deficit hyperactivity disorder, drug addiction). These conditions share alterations in monoamine signaling that may influence the neural mechanisms underlying error processing, but our understanding of the neurochemical drivers of these processes is limited. We conducted a randomized, double-blind, placebo-controlled, cross-over design of the influence of methylphenidate, atomoxetine, and citalopram on error awareness in 27 healthy participants. The error awareness task, a go/no-go response inhibition paradigm, was administered to assess the influence of monoaminergic agents on performance errors during fMRI data acquisition. A single dose of methylphenidate, but not atomoxetine or citalopram, significantly improved the ability of healthy volunteers to consciously detect performance errors. Furthermore, this behavioral effect was associated with a strengthening of activation differences in the dorsal anterior cingulate cortex and inferior parietal lobe during the methylphenidate condition for errors made with versus without awareness. Our results have implications for the understanding of the neurochemical underpinnings of performance monitoring and for the pharmacological treatment of a range of disparate clinical conditions that are marked by poor awareness of errors.

Development and validation of a stability-indicating RP-HPLC method for determination of atomoxetine hydrochloride in tablets.

PubMed

Patel, Sejal K; Patel, Natvarlal J

2010-01-01

This paper describes the development of a stability-indicating RP-HPLC method for the determination of atomoxetine hydrochloride (ATX) in the presence of its degradation products generated from forced decomposition studies. The drug substance was subjected to stress conditions of acid, base, oxidation, wet heat, dry heat, and photodegradation. In stability tests, the drug was susceptible to acid, base, oxidation, and dry and wet heat degradation. It was found to be stable under the photolytic conditions tested. The drug was successfully separated from the degradation products formed under stress conditions on a Phenomenex C18 column (250 x 4.6 mm id, 5 microm particle size) by using acetonitrile-methanol-0.032 M ammonium acetate (55 + 05 + 40, v/v/v) as the mobile phase at 1.0 mL/min and 40 degrees C. Photodiode array detection at 275 nm was used for quantitation after RP-HPLC over the concentration range of 0.5-5 microg/mL with a mean recovery of 100.8 +/- 0.4% for ATX. Statistical analysis demonstrated that the method is repeatable, specific, and accurate for the estimation of ATX. Because the method effectively separates the drug from its degradation products, it can be used as a stability-indicating method.

Functional outcomes from a head-to-head, randomized, double-blind trial of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder and an inadequate response to methylphenidate.

PubMed

Nagy, Peter; Häge, Alexander; Coghill, David R; Caballero, Beatriz; Adeyi, Ben; Anderson, Colleen S; Sikirica, Vanja; Cardo, Esther

2016-02-01

Attention-deficit/hyperactivity disorder (ADHD) is associated with functional impairments in multiple domains of patients' lives. A secondary objective of this randomized, active-controlled, head-to-head, double-blind, dose-optimized clinical trial was to compare the effects of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) on functional impairment in children and adolescents with ADHD. Patients aged 6-17 years with an ADHD Rating Scale IV total score ≥ 28 and an inadequate response to methylphenidate treatment (judged by investigators) were randomized (1:1) to once-daily LDX or ATX for 9 weeks. Parents/guardians completed the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at baseline and at week 9 or early termination. p values were nominal and not corrected for multiple comparisons. Of 267 randomized patients, 200 completed the study (LDX 99, ATX 101). At baseline, mean WFIRS-P total score in the LDX group was 0.95 [standard deviation (SD) 0.474; 95% confidence interval (CI) 0.87, 1.03] and in the ATX group was 0.91 (0.513; 0.82, 1.00). Scores in all WFIRS-P domains improved from baseline to endpoint in both groups, with least-squares mean changes in total score of -0.35 (95% CI -0.42, -0.29) for LDX and -0.27 (-0.33, -0.20) for ATX. The difference between LDX and ATX was statistically significant (p < 0.05) for the Learning and School (effect size of LDX vs ATX, 0.43) and Social Activities (0.34) domains and for total score (0.27). Both treatments reduced functional impairment in children and adolescents with ADHD; LDX was statistically significantly more effective than ATX in two of six domains and in total score.

Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder.

PubMed

Walker, Daniel J; Mason, Oren; Clemow, David B; Day, Kathleen A

2015-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a CNS disorder that has its onset in childhood, but often persists into adulthood. There is growing recognition that adult ADHD can result in multiple negative consequences for individuals. ADHD is also often associated with a number of comorbid psychiatric disorders. Atomoxetine (ATX), a nonstimulant, selective noradrenergic reuptake inhibitor, was approved in the United States in 2002 for the treatment of ADHD in children and adolescents, as well as adults. We review here the safety and efficacy of ATX in adults with ADHD, including data in special populations, functional outcomes, as well as provider and patient real-world perceptions. We searched the databases Embase, MEDLINE and PsycINFO using the terms 'ADHD' and 'adult' and 'ATX' capturing publications from January 1, 1998, to March 27, 2014. Only publications in English were considered. ATX demonstrated significantly greater improvement than placebo (PBO) on the Conners Adult ADHD Rating Scale-Investigator rated:Screening Version (CAARS-Inv:SV) in all trials (N = 6; total score difference ranged from -3.5 to -5.5). For long-term trials using the CAARS-Inv:SV, ATX demonstrated significantly greater improvement than PBO in three of four trials (total score differences ranged from -0.1 to -6.0). In short-term studies, ATX showed significantly greater improvement than PBO on the Adult ADHD Quality-of-Life scale total score in three of three studies, but results were mixed on the Sheehan Disability Scale. Three studies of ATX have reported statistically significant improvement (compared with PBO) on the Behavior Rating Inventory of Executive Function-Adult Version Self Report scale. The most common adverse events (occurring in ≥ 10% of patients taking ATX) were nausea, dry mouth, decreased appetite, insomnia and fatigue. ATX is an important treatment option for the right patient. ATX can provide long-term, consistent symptom relief and functional improvement for adults with ADHD.

The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials

PubMed Central

Hutton, Brian; Núñez-Beltrán, Amparo; Page, Matthew J.; Ridao, Manuel; Macías Saint-Gerons, Diego; Catalá, Miguel A.; Tabarés-Seisdedos, Rafael; Moher, David

2017-01-01

Background Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents. Methods and findings We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016). Interventions of interest were pharmacological (stimulants, non-stimulants, antidepressants, antipsychotics, and other unlicensed drugs), psychological (behavioural, cognitive training and neurofeedback) and complementary and alternative medicine (dietary therapy, fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity). The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation). Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy (alone or in combination with stimulants), stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms (anorexia, weight loss and insomnia), but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution. Conclusions Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008. PMID:28700715

The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials.

PubMed

Catalá-López, Ferrán; Hutton, Brian; Núñez-Beltrán, Amparo; Page, Matthew J; Ridao, Manuel; Macías Saint-Gerons, Diego; Catalá, Miguel A; Tabarés-Seisdedos, Rafael; Moher, David

2017-01-01

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents. We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016). Interventions of interest were pharmacological (stimulants, non-stimulants, antidepressants, antipsychotics, and other unlicensed drugs), psychological (behavioural, cognitive training and neurofeedback) and complementary and alternative medicine (dietary therapy, fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity). The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation). Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy (alone or in combination with stimulants), stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms (anorexia, weight loss and insomnia), but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution. Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008.

Comorbidity of personality disorders and attention-deficit hyperactivity disorder in adults.

PubMed

Irastorza Eguskiza, Luis Javier; Bellón, Jose M; Mora, María

2016-03-08

A high comorbidity has been observed among attention-deficit hyperactivity disorder (ADHD) and categorical personality disorders (PD). A study is conducted on the dimensional traits associated with ADHD and PD, in order to determine whether there are any differences. A cross-sectional study was conducted on 78 outpatients attending a Mental Health Clinic in Arganda (Madrid) from January 2013 to June 2015. ADHD diagnosis was evaluated with the CAARS, the CAADID, and the WURS scales, and the PD with the SCID-II-DSM-IV questionnaire. None of the patients were receiving any stimulant or atomoxetine before the study, and all patients signed the informed consent before the study. A high comorbidity was found with all PD clusters, especially with hyperactive and combined type ADHD. Depressive PD was associated with inattentive ADHD. In spite of using a questionnaire to evaluate PD, some differences can be observed between specific ADHD types and PD. More studies are needed to investigate dimensional personality traits in order to improve the diagnosis and therapeutics goals. Copyright © 2016 SEP y SEPB. Published by Elsevier España. All rights reserved.

[Evaluation and treatment of sleep problems in children diagnosed with attention deficit hyperactivity disorder: an update of the evidence].

PubMed

Chamorro, M; Lara, J P; Insa, I; Espadas, M; Alda-Diez, J A

2017-05-01

Attention deficit hyperactivity disorder (ADHD) affects approximately 5% of all children and adolescents, and these patients frequently suffer from sleep problems. The association between sleep disorders and ADHD, however, is multifaceted and complex. To explore the relationship between sleep disorders and ADHD. Sleep problems in children with ADHD include altered sleep and specific disorders per se or that may be due to comorbid psychiatric disorders or to the stimulants they receive as treatment for their ADHD. Today, an evaluation of the sleep conditions in children with ADHD is recommended before starting pharmacological treatment. The first step in managing their sleep problems is good sleep hygiene and cognitive-behavioural psychotherapy. Another option is to consider modifying the dosage and formulation of the stimulants. Atomoxetine and melatonin are therapeutic alternatives for children with ADHD and more severe sleep problems. Specific treatments exist for respiratory and movement disorders during sleep. It is important to evaluate sleep in children who present symptoms suggestive of ADHD, since problems during sleep can play a causal role or exacerbate the clinical features of ADHD. Correct evaluation and treatment of sleep disorders increase the family's and the child's quality of life and can lessen the severity of the symptoms of ADHD.

Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan

PubMed Central

Doyle, Carolyn A.; McDougle, Christopher J.

2012-01-01

This review outlines pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders (ASDs) in children, adolescents, and adults. Symptom domains include repetitive and stereotyped behaviors, irritability and aggression, hyperactivity and inattention, and social impairment. Medications covered include serotonin reuptake inhibitors (SRIs), mirtazapine, antipsychotics, psychostimulants, atomoxetine, α-2 agonists, D-cycloserine, and memantine. Overall, SRIs are less efficacious and more poorly tolerated in children with ASDs than in adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in ASDs, and may be useful in the treatment of other symptoms. Psychostimulants demonstrate some benefit for the treatment of hyperactivity and inattention in individuals with ASDs, but are less efficacious and associated with more adverse effects compared with individuals with ADHD. D-cycloserine and memantine appear helpful in the treatment of social impairment, although further research is needed. PMID:23226952

A 1.5-Year Follow-Up of Parent Training and Atomoxetine for Attention-Deficit/Hyperactivity Disorder Symptoms and Noncompliant/Disruptive Behavior in Autism.

PubMed

Arnold, L Eugene; Ober, Nicole; Aman, Michael G; Handen, Benjamin; Smith, Tristram; Pan, Xueliang; Hyman, Susan L; Hollway, Jill; Lecavalier, Luc; Page, Kristin; Rice, Robert

2018-06-01

To examine status of children with autism spectrum disorder (ASD) 10 months after a 34-week clinical trial of atomoxetine (ATX) and parent training (PT). In a 2 × 2 design, 128 children with ASD and attention-deficit/hyperactivity disorder (ADHD) were randomly assigned ATX, PT+placebo, PT+ATX, or placebo alone. PT was weekly for 10 weeks, and then monthly. ATX/placebo was titrated over 6 weeks [≤1.8 mg/kg/d], and then maintained until week 10. Responders continued to week 34 or nonresponse. Placebo nonresponders had a 10-week ATX open trial; ATX nonresponders were treated clinically. All continued to week 34. With no further treatment from the study, all were invited to follow-up (FU) at 1.5 years postbaseline; 94 (73%) participated. Changes from Week 34 to FU and from baseline to FU were tested by one-way analysis of variance or chi-squared test. PT versus no PT was tested by chi-squared test, Fisher's exact test, Welch's t-test, Student's t-test, and Mann-Whitney's U test. For the whole sample, the primary outcomes (parent-rated ADHD on the Swanson, Nolan, and Pelham [SNAP] scale and noncompliance on the Home Situations Questionnaire [HSQ]) deteriorated mildly from week 34 to FU, but were still substantially better than baseline (SNAP: t = 12.177, df = 93, p < 0.001; HSQ: t = 8.999, df = 93, p < 0.001). On the SNAP, 61% improved ≥30% from baseline (67% did at week 34); on noncompliance, 56% improved ≥30% from baseline (77% did at week 34). Outcomes with PT were not significantly better than without PT (SNAP p = 0.30; HSQ p = 0.27). Originally assigned treatment groups did not differ significantly. Only 34% still took ATX; 27% were taking stimulants; and 25% took no medication. The majority retained their 34-week end-of-study improvement 10 months later, even though most participants stopped ATX. For some children, ATX continuation may not be necessary for continued benefit or other drugs may be necessary. Cautious individual clinical experimentation may be justified. Twelve sessions of PT made little long-term difference. ClinicalTrials.gov Identifier: Atomoxetine, Placebo and Parent Management Training in Autism (Strattera) (NCT00844753).

Design of Monoamine Reuptake Inhibitors: SSRIs, SNRIs and NRIs

NASA Astrophysics Data System (ADS)

Whitlock, Gavin A.; Andrews, Mark D.; Brown, Alan D.; Fish, Paul V.; Stobie, Alan; Wakenhut, Florian

This review will detail the medicinal chemistry involved in the design, synthesis and discovery of selective serotonin, noradrenaline reuptake inhibitors and dual serotonin/noradrenaline reuptake inhibitors. In particular, this review will focus exclusively on series and compounds which have been disclosed within the medicinal chemistry literature between January 2000 and June 2008. Background information on previously disclosed clinical agents, such as atomoxetine, milnacipran and reboxetine, is included for comparison purposes with more recently disclosed agents.

Are there any potentially dangerous pharmacological effects of combining ADHD medication with alcohol and drugs of abuse? A systematic review of the literature.

PubMed

Barkla, Xanthe M; McArdle, Paul A; Newbury-Birch, Dorothy

2015-10-30

Among young people up to 18 years of age, approximately 5% have attention deficit hyperactivity disorder (ADHD), many of whom have symptoms persisting into adulthood. ADHD is associated with increased risk of co-morbid psychiatric disorders, including substance misuse. Many will be prescribed medication, namely methylphenidate, atomoxetine, dexamphetamine and lisdexamfetamine. If so, it is important to know if interactions exist and if they are potentially toxic. Three databases (Medline, EMBASE and PsychINFO) from a 22 year period (1992 - June 2014) were searched systematically. Key search terms included alcohol, substance related disorders, methylphenidate, atomoxetine, dexamphetamine, lisdexamfetamine, and death, which identified 493 citations (344 after removal of duplicates). The eligibility of each study was assessed jointly by two investigators, leaving 20 relevant articles. We identified only a minimal increase in side-effects when ADHD medication (therapeutic doses) was taken with alcohol. None of the reviewed studies showed severe sequelae among those who had overdosed on ADHD medication and other coingestants, including alcohol. The numbers across all the papers studied remain too low to exclude uncommon effects. Also, studies of combined effects with novel psychoactive substances have not yet appeared in the literature. Nevertheless, no serious sequelae were identified from combining ADHD medication with alcohol/illicit substances from the pre-novel psychoactive substance era.

Compound stimulus presentation and the norepinephrine reuptake inhibitor atomoxetine enhance long-term extinction of cocaine-seeking behavior.

PubMed

Janak, Patricia H; Bowers, M Scott; Corbit, Laura H

2012-03-01

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

Adverse Events of Atomoxetine in a Double-Blind Placebo-Controlled Study in Children with Autism.

PubMed

Tumuluru, Rameshwari V; Corbett-Dick, Patricia; Aman, Michael G; Smith, Tristram; Arnold, L Eugene; Pan, Xueliang; Buchan-Page, Kristin A; Brown, Nicole V; Ryan, Melissa M; Hyman, Susan L; Hellings, Jessica; Williams, Craig; Hollway, Jill A; Lecavalier, Luc; Rice, Robert R; McAuliffe-Bellin, Sarah; Handen, Benjamin L

2017-10-01

Attention-deficit/hyperactivity disorder (ADHD) symptoms, including inattention and over activity, occur in approximately one-third of children with autism spectrum disorder (ASD). We describe the rate and duration of adverse events in a randomized controlled trial of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance in children with ASD. We conducted a 10-week, double-blind, 2 × 2 trial of ATX and PT with 128 children (ages 5-14) randomized to ATX alone, ATX+PT, placebo+PT, or placebo alone. For 6 weeks, ATX (or placebo) doses were clinically adjusted to a maximum of 1.8 mg/(kg·day) and maintained for an additional 4 weeks. An average of seven PT sessions were conducted in the two PT arms. Adverse events (AEs) were assessed through parent ratings of common symptoms on a seven-point Likert severity scale and through direct interviews with study medical staff. ATX was associated with decreased appetite and fatigue, but was otherwise well tolerated. Most reported AEs lasted 4 weeks or less. Unlike reports with typically developing (TD) children, there were no concerns with QTc changes or suicidal ideation. This study extends the findings of previous studies of ATX in ASD by documenting that the type of AEs was similar to that of TD children, with no significant safety concerns.

Systemic administration of guanfacine improves food-motivated impulsive choice behavior primarily via direct stimulation of postsynaptic α2A-adrenergic receptors in rats.

PubMed

Nishitomi, Kouhei; Yano, Koji; Kobayashi, Mika; Jino, Kohei; Kano, Takuya; Horiguchi, Naotaka; Shinohara, Shunji; Hasegawa, Minoru

2018-06-01

Impulsive choice behavior, which can be assessed using the delay discounting task, is a characteristic of various psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Guanfacine is a selective α 2A -adrenergic receptor agonist that is clinically effective in treating ADHD. However, there is no clear evidence that systemic guanfacine administration reduces impulsive choice behavior in the delay discounting task in rats. In the present study, we examined the effect of systemic guanfacine administration on food-motivated impulsive choice behavior in rats and the neuronal mechanism underlying this effect. Repeated administration of either guanfacine, methylphenidate, or atomoxetine significantly enhanced impulse control, increasing the number of times the rats chose a large but delayed reward in a dose-dependent manner. The effect of guanfacine was significantly blocked by pretreatment with an α 2A -adrenergic receptor antagonist. Furthermore, the effect of guanfacine remained unaffected in rats pretreated with a selective noradrenergic neurotoxin, consistent with a post-synaptic action. In contrast, the effect of atomoxetine on impulsive choice behavior was attenuated by pretreatment with the noradrenergic neurotoxin. These results provide the first evidence that systemically administered guanfacine reduces impulsive choice behavior in rats and that direct stimulation of postsynaptic, rather than presynaptic, α 2A -adrenergic receptors is involved in this effect. Copyright © 2018 Elsevier B.V. All rights reserved.

Investigation into the plasma concentration of ω3 polyunsaturated fatty acids in Japanese attention-deficit hyperactivity disorder patients.

PubMed

Yonezawa, Ken; Nonaka, Shunsuke; Iwakura, Yuka; Kusano, Yuka; Funamoto, Yuko; Kanchi, Nobukazu; Yamaguchi, Naohiro; Kusumoto, Yuko; Imamura, Akira; Ozawa, Hiroki

2018-06-20

Several studies report that patients with attention-deficit hyperactivity disorder (ADHD) have a low plasma concentration of polyunsaturated fatty acids (PUFAs). Since fish intake varies among countries and is high in Japan, those results may not apply to Japanese patients with ADHD. However, there is currently not enough evidence to support this. We compared the plasma PUFAs levels of patients with ADHD with the standard reference levels for healthy subjects, and examined the relationship between those PUFAs levels and the subject's psychological evaluation. The subjects were 24 patients (age < 20 years) previously diagnosed with ADHD (according to the DSM-IV-TR criteria) at the psychiatric department of the Nagasaki University Hospital, between November 2010 and November 2015. The plasma concentrations of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) were measured using gas chromatography. Data pertaining to global assessment of functioning (GAF), clinical global impressions, ADHD Rating Scale-IV, and the drug used for treatment (atomoxetine or methylphenidate) were obtained from the medical records. The plasma concentrations of DHA, EPA, and EPA/AA were significantly lower than the normal reference range, indicating that ADHD patients present an imbalance in PUFAs levels. This trend is similar to ADHD patients in other countries and replacement therapy in Japanese ADHD patients may be useful.

Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management.

PubMed

Spiller, Henry A; Hays, Hannah L; Aleguas, Alfred

2013-07-01

The prevalence of attention-deficit hyperactivity disorder (ADHD) in the USA is estimated at approximately 4-9% in children and 4% in adults. It is estimated that prescriptions for ADHD medications are written for more than 2.7 million children per year. In 2010, US poison centers reported 17,000 human exposures to ADHD medications, with 80% occurring in children <19 years old and 20% in adults. The drugs used for the treatment of ADHD are diverse but can be roughly separated into two groups: the stimulants such as amphetamine, methylphenidate, and modafinil; and the non-stimulants such as atomoxetine, guanfacine, and clonidine. This review focuses on mechanisms of toxicity after overdose with ADHD medications, clinical effects from overdose, and management. Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin. The primary clinical syndrome involves prominent neurological and cardiovascular effects, but secondary complications can involve renal, muscle, pulmonary, and gastrointestinal (GI) effects. In overdose, the patient may present with mydriasis, tremor, agitation, hyperreflexia, combative behavior, confusion, hallucinations, delirium, anxiety, paranoia, movement disorders, and seizures. The management of amphetamine, dextroamphetamine, and methylphenidate overdose is largely supportive, with a focus on interruption of the sympathomimetic syndrome with judicious use of benzodiazepines. In cases where agitation, delirium, and movement disorders are unresponsive to benzodiazepines, second-line therapies include antipsychotics such as ziprasidone or haloperidol, central alpha-adrenoreceptor agonists such as dexmedetomidine, or propofol. Modafinil is not US FDA approved for treatment of ADHD; however, it has been shown to improve ADHD signs and symptoms and has been used as an off-label pharmaceutical for this diagnosis in both adults and children. The mechanism of action of modafinil is complex and not fully understood. It is known to cause an increase in extracellular concentrations of dopamine, norepinephrine, and serotonin in the neocortex. Overdose with modafinil is generally of moderate severity, with reported ingestions of doses up to 8 g. The most common neurological effects include increased anxiety, agitation, headache, dizziness, insomnia, tremors, and dystonia. The management of modafinil overdose is largely supportive, with a focus on sedation, and control of dyskinesias and blood pressure. Atomoxetine is a selective presynaptic norepinephrine transporter inhibitor. The clinical presentation after overdose with atomoxetine has generally been mild. The primary effects have been drowsiness, agitation, hyperactivity, GI upset, tremor, hyperreflexia, tachycardia hypertension, and seizure. The management of atomoxetine overdose is largely supportive, with a focus on sedation, and control of dyskinesias and seizures. Clonidine is a synthetic imidazole derivative with both central and peripheral alpha-adrenergic agonist actions. The primary clinical syndrome involves prominent neurological and cardiovascular effects, with the most commonly reported features of depressed sensorium, bradycardia, and hypotension. While clonidine is an anti-hypertensive medication, a paradoxical hypertension may occur early with overdose. The clinical syndrome after overdose of guanfacine may be mixed depending on central or peripheral alpha-adrenoreceptor effects. Initial clinical effects may be drowsiness, lethargy, dry mouth, and diaphoresis. Cardiovascular effects may depend on time post-ingestion and may present as hypotension or hypertension. The management of guanfacine overdose is largely supportive, with a focus on support of blood pressure. Overdose with ADHD medications can produce major morbidity, with many cases requiring intensive care medicine and prolonged hospital stays. However, fatalities are rare with appropriate care.

Pharmacotherapy of conduct disorder: Challenges, options and future directions.

PubMed

Hambly, Jessica L; Khan, Sohil; McDermott, Brett; Bor, William; Haywood, Alison

2016-10-01

There is a critical need for evaluation of the pharmacotherapies used in conduct disorder (CD), due to the high incidence of off-label prescribing. The aim of this review was to identify concerns associated with the safety, efficacy and impact on quality of life (QOL) that pharmacotherapy has in children and adolescents with CD. A systematic review was undertaken using pre-defined search criteria and four databases, including reference searches. We assessed these studies using the Strength of Recommendation Taxonomy, Grading of Recommendations Assessment, Development and Evaluation, and Review Manager Risk of Bias (RevMan®) tools. There were 12 randomised controlled trials that met our inclusion criteria. antipsychotics, atomoxetine, lithium, clonidine, divalproex sodium and psychostimulants. The antipsychotics demonstrated efficacy, but were associated with adverse effects. Other agents demonstrated mixed responses, highlighting the lack of clinical significance and increased incidence of adverse effects. The management of related adverse effects was addressed to assist with clinical gaps. Overall, there is limited evidence regarding the role of pharmacotherapy in CD. More research is needed that takes into account the heterogeneity of CD and analysis of pharmacotherapy in pure CD. © The Author(s) 2016.

Injury prevention by medication among children with attention-deficit/hyperactivity disorder: a case-only study.

PubMed

Mikolajczyk, Rafael; Horn, Johannes; Schmedt, Niklas; Langner, Ingo; Lindemann, Christina; Garbe, Edeltraut

2015-04-01

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have an increased risk of injuries. Attention-deficit/hyperactivity disorder is often treated with medication, but the evidence regarding prevention of injuries is inconclusive. To determine via a case-only design whether the use of methylphenidate hydrochloride or atomoxetine hydrochloride reduces the risk of injuries among children and adolescents with ADHD. We used the German Pharmacoepidemiological Research Database, which includes records from about 17 million insurees (approximately 20% of the population) from 4 statutory health insurance providers in Germany to identify children aged 3 to 17 years with new diagnoses of ADHD in 2005 and 2006. We identified 37,650 children with ADHD based on inpatient and outpatientdiagnostic codes (F90.0, F90.1, and F90.9) from the German modification of the International Statistical Classification of Diseases and Related Health Problems, 10th Revision. Among them, we identified those with an inpatient injury diagnosis during follow-up until 2009. A total of 2128 children with any injury diagnosis at hospitalization, 821 of whom had a brain injury diagnosis, were included in the analysis. We applied the self-controlled case series design to control for time-invariant characteristics of the patients and time trends in the exposure. Treatment with methylphenidate or atomoxetine based on prescription data. Hospitalization because of any injury or brain injury according to the injury mortality diagnosis matrix. Incidence rate ratios for the periods with medication compared with nonmedicated periods were 0.87 (95% CI, 0.74-1.02) for hospitalization with any injuries and 0.66 (95% CI, 0.48-0.91) for brain injuries only in the full sample. These estimates remained stable in sensitivity analyses restricting the sample to a narrower age range or to patients with a single hospitalization. There was no indication that medication prescriptions are increased after hospitalizations. No significant risk reduction for hospitalizations with injury diagnoses was observed during periods of ADHD medication, but there was a preventive effect on the risk of brain injuries (34% risk reduction). The effects were controlled for time-invariant characteristics of the patients by the study design.

Adverse drug events related to mood and emotion in paediatric patients treated for ADHD: A meta-analysis.

PubMed

Pozzi, Marco; Carnovale, Carla; Peeters, Gabriëlla G A M; Gentili, Marta; Antoniazzi, Stefania; Radice, Sonia; Clementi, Emilio; Nobile, Maria

2018-05-22

ADHD is frequently comorbid with anxiety and mood disorders, which may increase the severity of inattention and hyperactivity symptoms. Emotional symptoms (anxiety, irritability, mood lability) also affect patients without comorbidity or emerge as adverse drug events. The influence of ADHD drugs on emotional symptoms demands investigation to improve therapies. Systematic review of trials reporting adverse events in patients pharmacologically treated for ADHD. Meta-analysis of the occurrence of irritability, anxiety, apathy, reduced talk, sadness, crying, emotional lability, biting nails, staring, perseveration, euphoria. Meta-regression analysis. Forty-five trials were meta-analysed. The most frequently reported outcomes were irritability, anxiety, sadness, and apathy. Methylphenidates, especially immediate-release formulations, were most studied; amphetamines were half as studied and were predominantly mixed amphetamine salts. Reports on atomoxetine were scant. Meta-analysis showed that methylphenidates reduced the risk of irritability, anxiety, euphoria, whereas they worsened the risk of apathy and reduced talk; amphetamines worsened the risk of emotional lability. Factors influencing risks were study year and design, patients' sex and age, drug dose and release formulation. Possible discrepancy between adverse events as indicated in clinical trials and as summarised herein. Confounding due to the aggregation of drugs into groups; uninvestigated sources of bias; incomplete lists of adverse events; lack of observations on self-injury. Methylphenidates appeared safer than amphetamines, although younger patients and females may incur higher risks, especially with high-dose, immediate-release methylphenidates. Only atomoxetine holds a black-box warning, but amphetamines and methylphenidates also did not show a safe profile regarding mood and emotional symptoms. Copyright © 2018. Published by Elsevier B.V.

Frontal Traumatic Brain Injury in Rats Causes Long-Lasting Impairments in Impulse Control That Are Differentially Sensitive to Pharmacotherapeutics and Associated with Chronic Neuroinflammation.

PubMed

Vonder Haar, Cole; Lam, Frederick C W; Adams, Wendy K; Riparip, Lara-Kirstie; Kaur, Sukhbir; Muthukrishna, Michael; Rosi, Susanna; Winstanley, Catharine A

2016-11-16

Traumatic brain injury (TBI) affects millions yearly, and is increasingly associated with chronic neuropsychiatric symptoms. We assessed the long-term effects of different bilateral frontal controlled cortical impact injury severities (mild, moderate, and severe) on the five-choice serial reaction time task, a paradigm with relatively independent measurements of attention, motor impulsivity, and motivation. Moderately- and severely injured animals exhibited impairments across all cognitive domains that were still evident 14 weeks postinjury, while mild-injured animals only demonstrated persistent deficits in impulse control. However, recovery of function varied considerably between subjects such that some showed no impairment ("TBI-resilient"), some demonstrated initial deficits that recovered ("TBI-vulnerable"), and some never recovered ("chronically-impaired"). Three clinically relevant treatments for impulse-control or TBI, amphetamine, atomoxetine, and amantadine, were assessed for efficacy in treating injury-induced deficits. Susceptibility to TBI affected the response to pharmacological challenge with amphetamine. Whereas sham and TBI-resilient animals showed characteristic impairments in impulse control at higher doses, amphetamine had the opposite effect in chronically impaired rats, improving task performance. In contrast, atomoxetine and amantadine reduced premature responding but increased omissions, suggesting psychomotor slowing. Analysis of brain tissue revealed that generalized neuroinflammation was associated with impulsivity even when accounting for the degree of brain damage. This is one of the first studies to characterize psychiatric-like symptoms in experimental TBI. Our data highlight the importance of testing pharmacotherapies in TBI models in order to predict efficacy, and suggest that neuroinflammation may represent a treatment target for impulse control problems following injury.

Noradrenergic modulation of risk/reward decision making.

PubMed

Montes, David R; Stopper, Colin M; Floresco, Stan B

2015-08-01

Catecholamine transmission modulates numerous cognitive and reward-related processes that can subserve more complex functions such as cost/benefit decision making. Dopamine has been shown to play an integral role in decisions involving reward uncertainty, yet there is a paucity of research investigating the contributions of noradrenaline (NA) transmission to these functions. The present study was designed to elucidate the contribution of NA to risk/reward decision making in rats, assessed with a probabilistic discounting task. We examined the effects of reducing noradrenergic transmission with the α2 agonist clonidine (10-100 μg/kg), and increasing activity at α2A receptor sites with the agonist guanfacine (0.1-1 mg/kg), the α2 antagonist yohimbine (1-3 mg/kg), and the noradrenaline transporter (NET) inhibitor atomoxetine (0.3-3 mg/kg) on probabilistic discounting. Rats chose between a small/certain reward and a larger/risky reward, wherein the probability of obtaining the larger reward either decreased (100-12.5 %) or increased (12.5-100 %) over a session. In well-trained rats, clonidine reduced risky choice by decreasing reward sensitivity, whereas guanfacine did not affect choice behavior. Yohimbine impaired adjustments in decision biases as reward probability changed within a session by altering negative feedback sensitivity. In a subset of rats that displayed prominent discounting of probabilistic rewards, the lowest dose of atomoxetine increased preference for the large/risky reward when this option had greater long-term utility. These data highlight an important and previously uncharacterized role for noradrenergic transmission in mediating different aspects of risk/reward decision making and mediating reward and negative feedback sensitivity.

An LC-MS/MS method for the simultaneous determination of 15 antipsychotics and two metabolites in hair and its application to rat hair.

PubMed

Sim, Juhyun; Kim, Eunmi; Yang, Wonkyung; Woo, Sanghee; In, Sangwhan

2017-05-01

In recent years, the inappropriate use of antipsychotics by young Korean men has become a social problem. As military service exemptions are given for mental illness, some men pose as mental health patients to avoid military service. In order to verify the authenticity of mental illnesses, we developed simultaneous analytical methods for the detection of 15 antipsychotics and 2 of their metabolites in hair using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The target drugs were modafinil, atomoxetine, aripiprazole, benztropine, buspirone, duloxetine, gabapentin, oxcarbazepine, topiramate, escitalopram, paliperidone, ziprasidone, lamotrigine, clonazepam, levetiracetam, and metabolites of oxcarbazepine and clonazepam. To remove possible contaminants on the hair surface, hair samples were washed twice with methanol and distilled water, and then were extracted with methanol overnight at 38°C. Desipramine-d 3 was used as an internal standard. LC-MS/MS analysis was performed on an Agilent 1290 Infinity UHPLC coupled to an AB Sciex Qtrap ® 5500 MS/MS. The total chromatographic run time was 14min. The following validation parameters were evaluated: selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy, matrix effect, and recovery. The LOD and LOQ values for all analytes, except modafinil, ranged from 0.2 to 10pg/mg hair and from 0.2 to 20pg/mg hair, respectively. Good linearity was achieved for most of the analytes in the range of 20-200pg/mg hair. The method showed acceptable precision and accuracy, which were less than 15%, as well as satisfactory matrix effects and recoveries. Furthermore, this method was also applied to the analysis of rat hair samples. The study in rats showed that the concentrations of atomoxetine and aripiprazole in pigmented hair were significantly higher than those in non-pigmented hair. However, no significant difference was observed in the concentration of topiramate between pigmented and non-pigmented hair. This method will be useful in monitoring the inappropriate use of antipsychotics in suspects posing as mental health patients. However, further research is necessary before applying this method to authentic hair samples from mental health patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Norepinephrine and Stimulant Addiction

PubMed Central

Sofuoglu, Mehmet; Sewell, R. Andrew

2008-01-01

No pharmacotherapies are approved for stimulant use disorders, which are an important public health problem. Stimulants increase synaptic levels of the monoamines dopamine (DA), serotonin (5-HT), and norepinephrine (NE). Stimulant reward is attributable mostly to increased DA in the reward circuitry, although DA stimulation alone cannot explain the rewarding effects of stimulants. The noradrenergic system, which uses NE as the main chemical messenger, serves multiple brain functions including arousal, attention, mood, learning, memory, and stress response. In preclinical models of addiction, NE is critically involved in mediating stimulant effects including sensitization, drug discrimination, and reinstatement of drug seeking. In clinical studies, adrenergic blockers have shown promise as treatments for cocaine abuse and dependence, especially in patients experiencing severe withdrawal symptoms. Disulfiram, which blocks NE synthesis, increased the number of cocaine-negative urines in five randomized clinical trials. Lofexidine, an α2-adrenergic agonist, reduces the craving induced by stress and drug cues in drug users. In addition, the norepinephrine transporter (NET) inhibitor atomoxetine attenuates some of d-amphetamine’s subjective and physiological effects in humans. These findings warrant further studies evaluating noradrenergic medications as treatments for stimulant addiction. PMID:18811678

[Multimodal treatment of attention-deficit hyperactivity disorder in children].

PubMed

Jans, T; Kreiker, S; Warnke, A

2008-07-01

Evidence-based treatments for attention-deficit hyperactivity disorder (ADHD) in children include primarily medication (stimulants and atomoxetine) and psychosocial interventions (parent training and behavioural classroom interventions). Results of treatment studies suggest that ADHD without significant coexisting disorders can be treated effectively by pharmacotherapy and expert counselling, while additional behaviour therapy demonstrates no significant improvement. Incremental benefits of combined pharmacological and behavioural interventions emerge if a comorbid condition is present. Behaviour therapy alone may be useful for treating less pronounced ADHD symptoms. Therapeutic strategies also account for the specific treatment of comorbid disorders and the need for support by youth welfare services.

Methylphenidate Disrupts Social Play Behavior in Adolescent Rats

PubMed Central

Vanderschuren, Louk JMJ; Trezza, Viviana; Griffioen-Roose, Sanne; Schiepers, Olga JG; Van Leeuwen, Natascha; De Vries, Taco J; Schoffelmeer, Anton NM

2008-01-01

Methylphenidate is the first-choice treatment for attention-deficit/hyperactivity disorder (ADHD), but its mechanism of action is incompletely understood. The cognitive effects of methylphenidate have been extensively studied, but little is known about its effects on spontaneous social behavior. During adolescence, rats display a characteristic, highly vigorous form of social behavior, termed social play behavior, which is of critical importance for social and cognitive development. We investigated the neurobehavioral mechanisms by which methylphenidate affects social play behavior in rats. Methylphenidate (0.3-3.0 mg/kg, s.c. or p.o.) abolished social play behavior, without altering general social interest. This effect of methylphenidate did not depend upon the baseline level of social play and was not secondary to changes in locomotion. Furthermore, the play-suppressant effect of methylphenidate was not subject to tolerance or sensitization. Methylphenidate blocked both the initiation to play and the responsivity to play initiation. The effect of methylphenidate was mimicked by the noradrenaline reuptake inhibitor atomoxetine, which is also used for the treatment of ADHD, and was blocked by an α-2 adrenoceptor antagonist. In addition, combined administration of subeffective doses of methylphenidate and atomoxetine suppressed social play. However, blockade of α-1 adrenoceptors, β-adrenoceptors, or dopamine receptors did not alter the effect of methylphenidate. These data show that methylphenidate selectively blocks the most vigorous part of the behavioral repertoire of adolescent rats through a noradrenergic mechanism. We suggest that the effect of methylphenidate on social play is a reflection of its therapeutic effect in ADHD, that is, improved behavioral inhibition. However, given the importance of social play for development, these findings may also indicate an adverse side effect of methylphenidate. PMID:18305462

Methylphenidate disrupts social play behavior in adolescent rats.

PubMed

Vanderschuren, Louk J M J; Trezza, Viviana; Griffioen-Roose, Sanne; Schiepers, Olga J G; Van Leeuwen, Natascha; De Vries, Taco J; Schoffelmeer, Anton N M

2008-11-01

Methylphenidate is the first-choice treatment for attention-deficit/hyperactivity disorder (ADHD), but its mechanism of action is incompletely understood. The cognitive effects of methylphenidate have been extensively studied, but little is known about its effects on spontaneous social behavior. During adolescence, rats display a characteristic, highly vigorous form of social behavior, termed social play behavior, which is of critical importance for social and cognitive development. We investigated the neurobehavioral mechanisms by which methylphenidate affects social play behavior in rats. Methylphenidate (0.3-3.0 mg/kg, s.c. or p.o.) abolished social play behavior, without altering general social interest. This effect of methylphenidate did not depend upon the baseline level of social play and was not secondary to changes in locomotion. Furthermore, the play-suppressant effect of methylphenidate was not subject to tolerance or sensitization. Methylphenidate blocked both the initiation to play and the responsivity to play initiation. The effect of methylphenidate was mimicked by the noradrenaline reuptake inhibitor atomoxetine, which is also used for the treatment of ADHD, and was blocked by an alpha-2 adrenoceptor antagonist. In addition, combined administration of subeffective doses of methylphenidate and atomoxetine suppressed social play. However, blockade of alpha-1 adrenoceptors, beta-adrenoceptors, or dopamine receptors did not alter the effect of methylphenidate. These data show that methylphenidate selectively blocks the most vigorous part of the behavioral repertoire of adolescent rats through a noradrenergic mechanism. We suggest that the effect of methylphenidate on social play is a reflection of its therapeutic effect in ADHD, that is, improved behavioral inhibition. However, given the importance of social play for development, these findings may also indicate an adverse side effect of methylphenidate.

Caregiver Satisfaction with a Multisite Trial of Atomoxetine and Parent Training for Attention-Deficit/Hyperactivity Disorder and Behavioral Noncompliance in Children with Autism Spectrum Disorder

PubMed Central

Aman, Michael G.; Mendoza-Burcham, Marissa I.; Silverman, Laura; Arnold, L. Eugene; Tumuluru, Rameshwari; Handen, Benjamin L.; Lecavalier, Luc; Page, Kristin; Sayre, Pamela; Smith, Tristram

2016-01-01

Abstract Objective: The purpose of this study was to examine caregiver satisfaction with the research experience in a randomized clinical trial of atomoxetine (ATX) and parent training (PT) for attention-deficit/hyperactivity disorder (ADHD) and behavioral noncompliance co-occurring with autism. Methods: The Children with Hyperactivity and Autism Research Treatment Study (CHARTS) randomly assigned 128 children 5.00–14.11 years of age to four treatment groups (ATX + PT, ATX alone, PT + placebo[PBO], and PBO). Caregivers completed an 18 item questionnaire about their satisfaction with the research experience. We summarized caregiver responses with descriptive statistics and examined whether the responses were associated with demographic variables, treatment assignment, or the child's response to treatment (positive or negative). Results: Ninety-three percent of caregivers (119) completed the questionnaire. When asked if they would join the study again if given the chance, 87% (103) responded “yes,” 13% (15) responded “maybe,” and 1% (1) responded “no.” When asked if they would recommend the study to other caregivers of children with similar problems, 92% (109) responded “yes” and 8% responded (10) “maybe.” Of the 59 Parent Satisfaction Questionnaire (PSQ) respondents who received PT, 75% (44) felt more confident in managing current child behaviors, 24% (14) felt that their level of confidence was unchanged, and 2% (1) felt less confident. Most caregivers expressed satisfaction with the study procedures, including the number of visits and the safety monitoring protocols. Conclusions: In general, caregivers were highly satisfied with their research experience. These findings may be useful for informing human subject committees and for designing study protocols that are appealing to families. PMID:26797318

A critical appraisal of atomoxetine in the management of ADHD

PubMed Central

Childress, Ann C

2016-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder beginning in childhood and often continuing into adulthood. A wealth of data shows that ADHD symptoms respond well to pharmacological treatment. Stimulant medications, including amphetamine and methylphenidate, are most commonly used to treat ADHD. However, with the approval of atomoxetine (Strattera®, [ATX]) by the US Food and Drug Administration in late 2002, an effective non-stimulant option became available. The US Food and Drug Administration approved ATX for the treatment of ADHD in children, adolescents, and adults. Although the effect size of ATX is generally lower than that of stimulants, the American Academy of Child and Adolescent Psychiatry Practice Parameter for the treatment of ADHD lists ATX as a first-line treatment option. ATX is widely prescribed and accounted for 6% of the prescriptions of ADHD visits in the US in 2010. Numerous trials have found that ATX improves quality of life and emotional lability in addition to core ADHD symptoms. Although some improvement may be seen in a patient as early as one week after the initiation of treatment, ATX generally takes longer to have a full effect. The median time to response using 25% improvement in ADHD symptoms in pooled trials was 3.7 weeks. Data from these trials indicate that the probability of symptom improvement may continue to increase up to 52 weeks after treatment is initiated. ATX has been shown to be safe and effective in combination with stimulants. It has also been studied systematically in subjects with ADHD and comorbid oppositional defiant disorder, anxiety, depression, and substance use disorders. The mechanism of action of ATX, its efficacy, and adverse events reported in trials is reviewed. PMID:26730199

Effects of Atomoxetine in Individuals with Attention-Deficit/Hyperactivity Disorder and Low-Functioning Autism Spectrum Disorder.

PubMed

Kilincaslan, Ayse; Mutluer, Tuba Duzman; Pasabeyoglu, Basak; Tutkunkardas, Mustafa Deniz; Mukaddes, Nahit Motavalli

2016-11-01

This naturalistic, retrospective study investigated the effects of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with autism spectrum disorders (ASDs) and intellectual disability (ID). Participants (n = 37, age range 6-17 years, mean: 10.16 ± 3.60) were assessed at baseline, 4th and 12th weeks using Clinical Global Impressions (CGI) scales, DSM-IV-based ADHD-rating scale (ADHD-RS), and amended Turkish version of Aberrant Behavior Checklist (ABC). The primary outcome measure was a treatment response defined by a CGI-improvement score of 1 or 2 together with a decrease of at least 25% in the parent-rated ADHD-RS total score at the end of 12th week. Five patients (13.5%) stopped medication at 4 weeks due to ineffectivity (2) and intolerable side effects (increased motor activity and talkativeness [n = 1], irritability [n = 2], temper outbursts [n = 2], and increased blood pressure [n = 1]). Sixteen patients (43.2%) were judged to be responders according to primary outcome measure. Improvement rate on CGI scale was 48.8%. On ADHD-RS, there were significant reductions between baseline and 4th week and between baseline and 12th week in both hyperactivity and inattention, and between baseline and 12th week in impulsivity scores. Decrease was significant in hyperactivity and social withdrawal subscales of the parent-reported ABC. Responders based on primary outcome measure were not significantly different from nonresponders in terms of sociodemographic features or clinical parameters, including intellectual, language, autism symptom, and ADHD symptom levels. In this chart review, ATX appears to be safe and effective for social withdrawal and ADHD symptoms in children with ASD and ID.

A pharmacokinetic/pharmacodynamic investigation: assessment of edivoxetine and atomoxetine on systemic and central 3,4-dihydroxyphenylglycol, a biochemical marker for norepinephrine transporter inhibition.

PubMed

Kielbasa, William; Pan, Alan; Pereira, Alvaro

2015-03-01

Inhibition of norepinephrine (NE) reuptake into noradrenergic nerves is a common therapeutic target in the central nervous system (CNS). In noradrenergic nerves, NE is oxidized by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). In this study, 40 healthy male subjects received the NE transporter (NET) inhibitor edivoxetine (EDX) or atomoxetine (ATX), or placebo. The pharmacokinetic and pharmacodynamic profile of these drugs in plasma and cerebrospinal fluid (CSF) was assessed. In Part A, subjects received EDX once daily (QD) for 14 or 15 days at targeted doses of 6mg or 9mg. In Part B, subjects received 80mg ATX QD for 14 or 15 days. Each subject received a lumbar puncture before receiving drug and after 14 or 15 days of dosing. Plasma and urine were collected at baseline and after 14 days of dosing. Edivoxetine plasma and CSF concentrations increased dose dependently. The time to maximum plasma concentration of EDX was 2h, and the half-life was 9h. At the highest EDX dose of 9mg, DHPG concentrations were reduced from baseline by 51% at 8h postdose in CSF, and steady-state plasma and urine DHPG concentrations decreased by 38% and 26%, respectively. For 80mg ATX, the decrease of plasma, CSF, or urine DHPG was similar to EDX. Herein we provide clinical evidence that EDX and ATX decrease DHPG concentrations in the periphery and CNS, presumably via NET inhibition. EDX and ATX concentrations measured in the CSF confirmed the availability of those drugs in the CNS. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine.

PubMed

Swalve, Natashia; Smethells, John R; Zlebnik, Natalie E; Carroll, Marilyn E

2016-06-01

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e., relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5mg/kg) alone (PRO+SAL), ATO (1.5mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes. Copyright © 2016 Elsevier Inc. All rights reserved.

Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder

PubMed Central

Handen, Benjamin L.; Aman, Michael G.; Arnold, L. Eugene; Hyman, Susan L.; Tumuluru, Rameshwari V.; Lecavalier, Luc; Corbett-Dick, Patricia; Pan, Xueliang; Hollway, Jill A.; Buchan-Page, Kristin A.; Silverman, Laura B.; Brown, Nicole V.; Rice, Robert R.; Hellings, Jessica; Mruzek, Daniel W.; McAuliffe-Bellin, Sarah; Hurt, Elizabeth A.; Ryan, Melissa M.; Levato, Lynne; Smith, Tristram

2015-01-01

Objective Impairments associated with attention-deficit/hyperactivity disorder (ADHD) and noncompliance are prevalent in children with autism spectrum disorder (ASD). However, ADHD response to stimulants is well below rates in typically developing children, with frequent side effects. Group studies of treatments for noncompliance are rare in ASD. We examined individual and combined-effectiveness of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance. Method In a 3-site, 10-week, double-blind, 2×2 trial of ATX and PT, 128 children (ages 5–14) with ASD and ADHD symptoms were randomized to ATX, ATX+PT, placebo+PT, or placebo. ATX was adjusted to optimal dose (capped at 1.8 mg/kg/day) over 6 weeks and maintained for 4 additional weeks. Nine PT sessions were provided. Primary outcome measures were the parent-rated DSM ADHD symptoms on the Swanson, Nolan and Pelham (SNAP) scale and Home Situations Questionnaire (HSQ). Results On the SNAP, ATX, ATX+PT and placebo+PT were each superior to placebo (effect sizes 0.57–0.98), with p-values of 0.0005, 0.0004 and 0.025, respectively. For noncompliance, ATX and ATX+PT were superior to placebo (effect sizes 0.47–0.64; p values of .03 and .0028, respectively). ATX was associated with decreased appetite but otherwise well-tolerated. Conclusion Both ATX and PT resulted in significant improvement on ADHD symptoms while ATX (both alone and combined with PT) was associated with significant decreases on measures of noncompliance. ATX appears to have a better side effects profile than psychostimulants in the population with ASD. PMID:26506581

Clinical and neurobiological factors in the management of treatment refractory attention-deficit hyperactivity disorder.

PubMed

Shim, Se-Hoon; Yoon, Hee-Jung; Bak, Jeongjae; Hahn, Sang-Woo; Kim, Yong-Ku

2016-10-03

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent mental disorder of childhood, which often continues into adolescence and adulthood. Stimulants such as methylphenidate (MPH) and non-stimulants such as atomoxetine are effective medications for the treatment of ADHD. However, about 30% of patients do not respond to these medications. Pharmacological treatment for ADHD, although highly effective, is associated with marked variabilities in clinical response, optimal dosage needed and tolerability. This article provides an overview of up-to-date knowledge regarding the clinical and neurobiological factors which contribute to and help predict treatment-refractory ADHD. Pharmacogenetic, pharmacogenomics and neuroimaging studies are still controversial with respect to determining the associations between response to medication and genetic factors, thereby resulting in hypotheses that differences in the genetic factors and neuroimaging findings contribute to treatment outcome. Much research on the potential role of genotype in pharmacological effects has focused on the catecholaminergic gene related to executive functions. Many neuroimaging studies have also reported a relationship between treatment response and common patterns of brain structure or activity according to various genetic polymorphisms. When children, adolescents and adults with ADHD do not respond to MPH, we should consider additional pharmacological options, including other classes of psychostimulants, the nonstimulant atomoxetine, bupropion, tricyclic antidepressant, clonidine, guanfacine and lisdexamphetamine. Prudent choice of an appropriate medication and active engagement of children, parents, and teachers in daily management may help to ensure long-term adherence. Therefore, additional research might help to optimize the treatment of children, adolescents and adults with ADHD and to find new options for the treatment of patients who do not respond to stimulants and the other medications. Because these findings should be interpreted cautiously, further studies are needed to elucidate these issues more clearly. Copyright © 2016 Elsevier Inc. All rights reserved.

Attention-deficit hyperactivity disorder, its treatment with medication and the probability of developing a depressive disorder: A nationwide population-based study in Taiwan.

PubMed

Lee, Min-Jing; Yang, Kang-Chung; Shyu, Yu-Chiau; Yuan, Shin-Sheng; Yang, Chun-Ju; Lee, Sheng-Yu; Lee, Tung-Liang; Wang, Liang-Jen

2016-01-01

The purpose of this study is to determine the risk of developing depressive disorders by evaluating children with attention-deficit/hyperactivity disorder (ADHD) in comparison to controls that do not have ADHD, as well as to analyze whether the medications used to treat ADHD, methylphenidate (MPH) and atomoxetine (ATX), influence the risk of depression. A group of patients newly diagnosed with ADHD (n=71,080) and age- and gender-matching controls (n=71,080) were chosen from Taiwan's National Health Insurance database during the period of January 2000 to December 2011. Both the patients and controls were monitored through December 31, 2011. We also explore the potential influence of the length of MPH and ATX treatment on developing depressive disorders. The ADHD patients showed a significantly increased probability of developing a depressive disorder when compared to the control group (ADHD: 5.3% vs. 0.7%; aHR, 7.16, 99% CI: 6.28-8.16). Regarding treatment with MPH, a longer MPH use demonstrates significant protective effects against developing a depressive disorder (aOR, 0.91, 99%CI: 0.88-0.94). However, the duration of ATX treatment could not be significantly correlated with the probability of developing a depressive disorder. The database employed in this study lacks of comprehensive clinical information for the patients with ADHD. Potential moderating factors between ADHD and depression were not considered in-depth in this study. The results of this study reveal that youths diagnosed with ADHD have a greater risk of developing depressive disorders. Long-term treatment with MPH correlated to the reduced probability of developing a depressive disorder among youths with ADHD. Copyright © 2015 Elsevier B.V. All rights reserved.

Comparative efficacy and tolerability of pharmacological interventions for attention-deficit/hyperactivity disorder in children, adolescents and adults: protocol for a systematic review and network meta-analysis.

PubMed

Cortese, Samuele; Adamo, Nicoletta; Mohr-Jensen, Christina; Hayes, Adrian J; Bhatti, Sahar; Carucci, Sara; Del Giovane, Cinzia; Atkinson, Lauren Z; Banaschewski, Tobias; Simonoff, Emily; Zuddas, Alessandro; Barbui, Corrado; Purgato, Marianna; Steinhausen, Hans-Christoph; Shokraneh, Farhad; Xia, Jun; Cipriani, Andrea; Coghill, David

2017-01-10

Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles. We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences. CRD42014008976. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Comparative efficacy and tolerability of pharmacological interventions for attention-deficit/hyperactivity disorder in children, adolescents and adults: protocol for a systematic review and network meta-analysis

PubMed Central

Cortese, Samuele; Adamo, Nicoletta; Mohr-Jensen, Christina; Hayes, Adrian J; Bhatti, Sahar; Carucci, Sara; Del Giovane, Cinzia; Atkinson, Lauren Z; Banaschewski, Tobias; Simonoff, Emily; Zuddas, Alessandro; Barbui, Corrado; Purgato, Marianna; Steinhausen, Hans-Christoph; Shokraneh, Farhad; Xia, Jun; Coghill, David

2017-01-01

Introduction Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles. Methods and analysis We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. Ethics and dissemination No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences. Trial registration number CRD42014008976. PMID:28073796

Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

NASA Astrophysics Data System (ADS)

Zheng, Guoxun; Xue, Weiwei; Wang, Panpan; Yang, Fengyuan; Li, Bo; Li, Xiaofeng; Li, Yinghong; Yao, Xiaojun; Zhu, Feng

2016-05-01

Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine’s enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.

New drugs of 2003.

PubMed

Hussar, Daniel A

2004-01-01

To provide information regarding the most important properties of the new therapeutic agents marketed in 2003. Product labeling supplemented selectively with published studies and drug information reference sources. By the author. By the author. The 28 new therapeutic agents marketed in the United States during 2003 are reviewed in this article: adalimumab, agalsidase beta, alefacept, alfuzosin hydrochloride, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, bortezomib, daptomycin, efalizumab, eletriptan hydrobromide, emtricitabine, enfuvirtide, eplerenone, gefitinib, icodextrin, laronidase, memantine hydrochloride, mequinol/tretinoin, miglustat, nitazoxanide, omalizumab, palonosetron hydrochloride, pegvisomant, rosuvastatin calcium, tadalafil, tositumomab and iodine I 131 tositumomab, and vardenafil hydrochloride. Indications and information on dosage and administration for these agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. When possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. A number of the new therapeutic agents marketed in 2003 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.

Differential impact of methylphenidate and atomoxetine on sustained attention in youth with attention-deficit/hyperactivity disorder.

PubMed

Bédard, Anne-Claude V; Stein, Mark A; Halperin, Jeffrey M; Krone, Beth; Rajwan, Estrella; Newcorn, Jeffrey H

2015-01-01

This study examined the effects of atomoxetine (ATX) and OROS methylphenidate (MPH) on laboratory measures of inhibitory control and attention in youth with attention-deficit/hyperactivity disorder (ADHD). It was hypothesized that performance would be improved by both treatments, but response profiles would differ because the medications work via different mechanisms. One hundred and two youth (77 male; mean age = 10.5 ± 2.7 years) with ADHD received ATX (1.4 ± 0.5 mg/kg) and MPH (52.4 ± 16.6 mg) in a randomized, double-blind, crossover design. Medication was titrated in 4-6-week blocks separated by a 2-week placebo washout. Inhibitory control and attention measures were obtained at baseline, following washout, and at the end of each treatment using Conners' Continuous Performance Test II (CPT-II), which provided age-adjusted T-scores for reaction time (RT), reaction time variability (RT variability), and errors. Repeated-measures analyses of variance were performed, with Time (premedication, postmedication) and Treatment type (ATX, MPH) entered as within-subject factors. Data from the two treatment blocks were checked for order effects and combined if order effects were not present. Clinicaltrials.gov: NCT00183391. Main effects for Time on RT (p = .03), RTSD (p = .001), and omission errors (p = .01) were significant. A significant Drug × Time interaction indicated that MPH improved RT, RTSD, and omission errors more than ATX (p < .05). Changes in performance with treatment did not correlate with changes in ADHD symptoms. MPH has greater effects than ATX on CPT measures of sustained attention in youth with ADHD. However, the dissociation of cognitive and behavioral change with treatment indicates that CPT measures cannot be considered proxies for symptomatic improvement. Further research on the dissociation of cognitive and behavioral endpoints for ADHD is indicated. © 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.

Autism Spectrum Disorder: consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology

PubMed Central

Howes, Oliver D; Charman, Tony; King, Bryan H.; Loth, Eva; McAlonan, Gráinne M.; McCracken, James T.; Parr, Jeremy R; Santosh, Paramala; Wallace, Simon; Murphy, Declan G.

2018-01-01

An expert review of the aetiology, assessment, and treatment of autism spectrum disorder (ASD), and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of ASD involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid (GABA), serotonergic and glutamatergic systems. The presentation of ASD varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder (ADHD), and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of ASD. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for ADHD. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without ASD. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials. PMID:29237331

Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology.

PubMed

Howes, Oliver D; Rogdaki, Maria; Findon, James L; Wichers, Robert H; Charman, Tony; King, Bryan H; Loth, Eva; McAlonan, Gráinne M; McCracken, James T; Parr, Jeremy R; Povey, Carol; Santosh, Paramala; Wallace, Simon; Simonoff, Emily; Murphy, Declan G

2018-01-01

An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of autism spectrum disorder involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid, serotonergic and glutamatergic systems. The presentation of autism spectrum disorder varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of autism spectrum disorder. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for attention deficit/hyperactivity disorder. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without autism spectrum disorder. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials.

Has NICE got it right? An international perspective considering the case of Technology Appraisal No. 98 by the National Institute for Health and Clinical Excellence (NICE).

PubMed

Schlander, Michael

2008-04-01

The National Institute for Health and Clinical Excellence (NICE) has been widely recognised as setting an international standard for high-quality health technology assessments (HTAs) including economic evaluation. A previous critical analysis of NICE Technology Appraisal No. 98 (TA98), evaluating methylphenidate, dexamphetamine and atomoxetine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, revealed a number of issues, which must cast doubt on the robustness of the NICE approach when addressing a complex clinical decision problem. The exploration of potential underlying problems will be followed by a discussion of lessons for international healthcare policy-makers, and is intended to be an invitation to further debate and inquiry, not a presentation of definitive conclusions. Pertaining to the technology assessment report, potential problems were identified relating to an unnecessarily narrow scope, data search and selection strategy, the distinction between efficacy and effectiveness, data synthesis across studies and clinical effect measures, and limitations of the economic model. The appraisal process moderated the asserted 'clear conclusions' of the assessment but could not compensate for some of its gaps. It is suggested that key issues contributing to these problems may have included a separation of clinical and economic perspectives, a highly standardised reference case analysis that was followed schematically, the absence of an effective system for quality assurance of technology assessments, and transparency deficits of the economic evaluation. Further considerations for international policy-makers looking at NICE as a potential role model for HTAs are discussed, such as institutional context, the objectives of collectively financed healthcare and related value judgments, the reliance on QALYs as a universal and comprehensive measure of health benefits, the appropriate perspective for analysis, and process-related implications.

Extended-release Methylphenidate Treatment and Outcomes in Comorbid Social Anxiety Disorder and Attention-deficit/Hyperactivity Disorder: 2 Case Reports.

PubMed

Koyuncu, Ahmet; Çelebi, Fahri; Ertekin, Erhan; Kahn, David A

2015-05-01

Social anxiety disorder is frequently comorbid with attention-deficit/hyperactivity disorder (ADHD). However, treatment recommendations are not clear in the presence of such comorbidity. A few studies in the literature have reported improvement in symptoms of both disorders with treatment specific for ADHD (ie, stimulants and atomoxetine). In this report, we present cases of 2 adults with social anxiety disorder and ADHD who were treated with methylphenidate monotherapy. Both cases responded well in terms of not only their ADHD symptoms but also the social anxiety disorder symptoms. Methylphenidate was well tolerated with no significant side effects. More studies are needed to better establish the potential of ADHD medications to be effective for comorbid social anxiety disorder symptoms.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-10-01

[Methoxy-11c]PD-153035; Afamelanotide, Agalsidase beta, Alemtuzumab, Alkaline phosphatase, Amlodipine, Anecortave acetate, Apixaban, Aripiprazole, Atomoxetine hydrochloride; Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brimonidine tartrate/timolol maleate, Brivudine; Canakinumab, Cetuximab, Chlorotoxin, Cinaciguat; Dapagliflozin, Decitabine, Duloxetine hydrochloride; Elagolix sodium, Eplerenone, Eritoran tetrasodium, Escitalopram oxalate, Etoricoxib, Ezetimibe; Fospropofol disodium; G-207, Gabapentin enacarbil, Gefitinib, Golimumab; Human plasmin; Inotuzumab ozogamicin, Insulin glargine, Insulin glulisine, Istaroxime, Ixabepilone; KLH; Levodopa/carbidopa/entacapone; Miglustat, Mitumprotimut-T, MP-470; Oblimersen sodium, Olmesartan medoxomil; P53-SLP, PAN-811, Patupilone, Pazopanib hydrochloride, PC-515, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Pemetrexed disodium, Plitidepsin, Pregabalin; Rasagiline mesilate, Rotigotine; SCH-697243, Sirolimus-eluting stent, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, TMC-207; V-211, Valganciclovir hydrochloride; Zolpidem tartrate. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Copper-catalyzed selective hydroamination reactions of alkynes

PubMed Central

Shi, Shi-Liang; Buchwald, Stephen L.

2014-01-01

The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a longstanding goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective, and step-efficient synthesis of amines is still needed. In this work we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines, and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio-, and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine, and tolterodine. PMID:25515888

Copper-catalysed selective hydroamination reactions of alkynes

NASA Astrophysics Data System (ADS)

Shi, Shi-Liang; Buchwald, Stephen L.

2015-01-01

The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine and tolterodine.

Medicines and the media: news reports of medicines recommended for government reimbursement in Australia.

PubMed

Robertson, Jane; Walkom, Emily J; Bevan, Marc D; Newby, David A

2013-05-21

Previous analyses of the listings of trastuzumab on the Australian Pharmaceutical Benefits Scheme (PBS) and HPV vaccine on the National Immunisation Program (NIP) suggest a media influence on policy makers. We examined the timing and content of Australian newspaper reports of medicines in relation to Pharmaceutical Benefits Advisory Committee (PBAC) decisions. We identified newspaper reports (2005-2008) of medicines recommended for PBS listing in 2006-2007, analysing the content for mentions of the medicine, PBS and medicine costs to the patient and the government and counting the numbers of articles published in the six months before, the month of, and the six months after the relevant PBAC meeting. Case studies examined reporting for infliximab for Crohn's Disease, pemetrexed for mesothelioma, and ADHD (Attention Deficit Hyperactivity Disorder) medicines atomoxetine and methylphenidate. Of 79 eligible medicines, 62 had news reports. Most often reported were HPV vaccine (1230 stories), trastuzumab (410), pemetrexed (83), botulinum toxin (71), lapatinib (65), methylphenidate (57), atomoxetine (54), infliximab (49), rotavirus vaccine (45). Eighteen medicines had ≥20 news reports (total 2350 stories); nine of these cost more than AU$10,000 per course or year of treatment. For these 18 medicines, 31% of stories appeared in the six months prior to the PBAC meeting, 14% in the meeting month and 33% in the six months post-meeting. 38% of the stories had ≥3 medicine mentions, 37% referred to the PBS, 24% to cost to the patient, and 9% cost to Government.There was active patient lobby group campaigning in support of listing of infliximab and pemetrexed; the stories for ADHD were often more negative, referring to the dangers of the medicines and sometimes questioning the appropriateness of treatment and public subsidy. There was little discussion of the PBAC's evidence-based decision-making processes. While there was no general trend to increased news reporting associated with PBAC meetings, some drugs did attract media attention. With more new and expensive drugs, decisions on public funding will become increasingly difficult. The media have an important role in enhancing public understanding of the issues around resource allocation. Specialist journalists, guidelines and checklists may help reporting.

Long-Term Tolerability and Safety of Pharmacological Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A 6-Year Prospective Naturalistic Study.

PubMed

Edvinsson, Dan; Ekselius, Lisa

2018-06-20

Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder typically treated with stimulants and atomoxetine. Data on long-term tolerability and safety of such pharmacological treatment in subjects diagnosed in adulthood are limited. A cohort of adults diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria was followed-up on an average of 6 years after first evaluation. Of 168 adults, 112 (67%) who initiated medication were available for follow-up. Data were obtained from patient record data, self-report forms, and a telephone interview. Of the 112 participants assessed, 57 (51%) were still on treatment with methylphenidate (MPH) at follow-up and 55 (49%) had discontinued. The 3 leading reasons for discontinuing treatment with MPH were lack of effect (29%), elevated mood or hypomania (11%), and losing contact with the prescribing physician (9%). The most common adverse effects in subjects still on treatment with MPH were decreased appetite (28%), dry mouth (24%), anxiousness/restlessness and increased pulse frequency (19% each), decreased sexual desire (17%), and perspiration (15%). Subjects still on treatment reported increased quality of life, a higher level of functioning, and a greater understanding of their way of functioning from those being close compared with nonmedicated subjects. The high attrition rate underscores the need for further research to identify possible modes to increase retention to treatment. Those diagnosed with ADHD and on long-term treatment with stimulants experience mild and tolerable adverse effects.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Attention Deficit Hyperactivity Disorder Medication Use Among Teens and Young Adults.

PubMed

Johansen, Michael E; Matic, Kathleen; McAlearney, Ann Scheck

2015-08-01

The purpose of this study was to determine rates of stimulant/atomoxetine use among teens (aged 12-17 years) and young adults (aged 18-23 years) and to investigate associations in medication use before and after the transition from teen to young adult. Repeated cross-sectional analyses using the nationally representative Medical Expenditure Panel Survey. The sample included all teens and young adults between 2003 and 2012. Within this group, a staggered sample of individuals between 2006 and 2012 born during a 5-year range was used to minimize false positive findings due to temporal trends. The primary outcome was attention deficit hyperactivity disorder (ADHD) medication use (two or more prescriptions and ≥60 tablets). A multivariable logistic regression was utilized to determine associations between ADHD medication use and race/ethnicity and other sociodemographic factors. A total of 62,699 individuals were included between 2003 and 2012. Rates of ADHD medication use increased for both teens (4.2%-6.0%) and young adults (1.2%-2.6%) between 2003-2004 and 2011-2012. In adjusted analysis, blacks, Hispanics, and Asians had lower rates of use compared with whites. The decrease in use among young adults was more pronounced among blacks compared with whites. A usual source of care and health insurance were less common among young adults, and both were associated with ADHD medication use. Although there has been an increase in the use of ADHD medications in both teens and young adults, we found a drop-off in levels of ADHD treatment among young adults when compared with teens. A portion of this decrease appears to be related to race/ethnicity, usual source of care, and health insurance status. Copyright © 2015 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Update on therapy for narcolepsy.

PubMed

Thorpy, Michael J

2015-05-01

Narcolepsy is a severe, incurable, neurological disorder that is treated by pharmacological management of its symptoms. The main symptoms are excessive daytime sleepiness (EDS) and cataplexy, although addition symptoms that may require treatment include sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. Sodium oxybate and modafinil/armodafinil are the first-line treatments for EDS, and sodium oxybate for cataplexy. Sodium oxybate treats all the symptoms of narcolepsy, whereas modafinil is effective for EDS only. Alternative medications for EDS include methylphenidate or amphetamines such as dextroamphetamine, lisdexamfetamine, methamphetamine, or combination amphetamine salts. Non-FDA approved medications for cataplexy include norepinephrine reuptake inhibitors such as venlafaxine or atomoxetine. Combination therapy can be more effective for sleepiness such as sodium oxybate and modafinil/armodafinil. Medication for narcolepsy is generally well tolerated and usually required life-long although does not eliminate all symptoms of narcolepsy.

Medical Treatment of Children and Youths with Attention-Deficit/Hyperactivity Disorder (ADHD): A Norwegian Prescription Registry Based Study

PubMed Central

Norum, Jan; Olsen, Aina Iren; Nohr, Frank Ivar; Heyd, Anca; Totth, Arpad

2014-01-01

Objectives: Attention-deficit/hyperactivity disorder (ADHD) is a lifelong neurological condition with a profound effect on quality of life. Prescription databases may document pattern of use. In this study we aimed to explore the use in Norway employing such a database. Methods: All prescriptions on drugs for the treatment of ADHD between 2004 and 2011, as registered in the Norwegian Prescription Database (NPD) were analyzed. The following drugs were included: Amphetamine, dexamphetamine, methylphenidate and atomoxetine. In-hospital drug administration was excluded. Numbers of users per 1,000 inhabitants were calculated according to gender, age and residence. A sub-analysis compared users born in January-June with those born in July-December. Drug costs were calculated and converted into Euros (€ 1 = N.kr 7.4540). Results: Drugs for the treatment of ADHD was significantly more often prescribed in northern Norway than in any other Norwegian health region (P < 0.001). Within the northern region, Nordland County was the “culprit” (P < 0.02). Compared to Norwegian figures, significantly more females (aged 10-19 years) were treated in northern Norway [male/female ratios 3:1 and 2.2:1 (P < 0.01)] and especially in Nordland County (ratio 2.1:1). The subanalysis did not indicate a northern overtreatment of those being a younger group in their grade. The annual drug cost per user in Norway was € 919. Conclusions: The prescription rate was significantly higher in northern Norway and Nordland County was the culprit. A prescription database may be a tool for monitoring the national use of these drugs. PMID:24999151

Animal model of methylphenidate's long-term memory-enhancing effects.

PubMed

Carmack, Stephanie A; Howell, Kristin K; Rasaei, Kleou; Reas, Emilie T; Anagnostaras, Stephan G

2014-01-16

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01-10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1-10 mg/kg, i.p.), bupropion (0.5-20 mg/kg, i.p.), and citalopram (0.01-10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development.

Animal model of methylphenidate's long-term memory-enhancing effects

PubMed Central

Carmack, Stephanie A.; Howell, Kristin K.; Rasaei, Kleou; Reas, Emilie T.; Anagnostaras, Stephan G.

2014-01-01

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01–10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1–10 mg/kg, i.p.), bupropion (0.5–20 mg/kg, i.p.), and citalopram (0.01–10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development. PMID:24434869

Care Provision and Prescribing Practices of Physicians Treating Children and Adolescents With ADHD.

PubMed

Patel, Ayush; Medhekar, Rohan; Ochoa-Perez, Melissa; Aparasu, Rajender R; Chan, Wenyaw; Sherer, Jeffrey T; Alonzo, Joy; Chen, Hua

2017-07-01

Care provision and prescribing practices of physicians treating children with attention-deficit hyperactivity disorder (ADHD) were compared. A retrospective cohort study was conducted with the 1995-2010 General Electric Centricity Electronic Medical Record database. The sample included children (≤18 years) with newly diagnosed ADHD (ICD-9-CM code 314.XX) who received a prescription for a stimulant or atomoxetine. Identification of comorbid psychiatric disorders, duration from initial ADHD diagnosis to treatment, prescription of other psychotropic medications, and follow-up care during the ten months after the ADHD treatment initiation were compared across provider type (primary care physicians [PCPs], child psychiatrists, and physicians with an unknown specialty). The associations between provider type and practice variations were further determined by multivariate logistic regression accounting for patient demographic characteristics, region, insurance type, and prior mental health care utilizations. Of the 66,719 children identified, 75.8% were diagnosed by PCPs, 2.6% by child psychiatrists, and 21.6% by physicians whose specialty was unknown. Child psychiatrists were less likely than PCPs to initiate ADHD medication immediately after the diagnosis. However, once the ADHD treatment was initiated, they were more likely to prescribe psychotropic polytherapy even after analyses accounted for the comorbid psychiatric disorders identified. Only one-third of ADHD cases identified by both PCPs and child psychiatrists have met the HEDIS quality measure for ADHD medication-related follow-up visits. Differences were found by physician type in care of children with ADHD. Additional studies are needed to understand clinical consequences of these differences and the implications for care coordination across provider specialties.

Genetic and Pharmacological Modulation of the Steroid Sulfatase Axis Improves Response Control; Comparison with Drugs Used in ADHD

PubMed Central

Davies, William; Humby, Trevor; Trent, Simon; Eddy, Jessica B; Ojarikre, Obah A; Wilkinson, Lawrence S

2014-01-01

Maladaptive response control is a feature of many neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase (STS) influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,XY*O mouse model, or pharmacological manipulation of the STS axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analog of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a prepotent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicates that the STS axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. While the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent. PMID:24842408

A Review of Pharmacological Management of Attention-Deficit/Hyperactivity Disorder

PubMed Central

Todd, Timothy

2016-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a common psychological diagnosis in children. This disorder impacts children and adolescents in all areas of life, including academic performance, extracurricular activities, and social interactions. ADHD can continue into adulthood where unemployment and substance abuse has been described. Although behavioral therapy is recommended for all patients with ADHD, medication management typically is initiated soon after diagnosis. Psychostimulants remain the primary medication of choice. This review focuses on the clinical use of psychostimulant medication in children and adolescents. The pharmacodynamic and pharmacokinetic differences between the newest long-acting formulations as well as commonly encountered adverse drug reactions, with suggested management strategies, will be highlighted. Non-stimulant therapy with atomoxetine or alpha2-adrenergic agonists is also reviewed. These agents may be warranted for patients who cannot tolerate psychostimulant therapy or have a comorbid condition. Finally, the 8-year multimodal treatment study results are also discussed. PMID:27453697

Evaluation of [11C]TAZA for amyloid β plaque imaging in postmortem human Alzheimer's disease brain region and whole body distribution in rodent PET/CT.

PubMed

Pan, Min-Liang; Mukherjee, Meenakshi T; Patel, Himika H; Patel, Bhavin; Constantinescu, Cristian C; Mirbolooki, M Reza; Liang, Christopher; Mukherjee, Jogeshwar

2016-04-01

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aβ plaques in the brain. The aim of this study was to evaluate the effectiveness of a novel radiotracer, 4-[(11) C]methylamino-4'-N,N-dimethylaminoazobenzene ([(11)C]TAZA), for binding to Aβ plaques in postmortem human brain (AD and normal control (NC)). Radiosyntheses of [(11)C]TAZA, related [(11)C]Dalene ((11)C-methylamino-4'-dimethylaminostyrylbenzene), and reference [(11)C]PIB were carried out using [(11)C]methyltriflate prepared from [(11) C]CO(2) and purified using HPLC. In vitro binding affinities were carried out in human AD brain homogenate with Aβ plaques labeled with [(3) H]PIB. In vitro autoradiography studies with the three radiotracers were performed on hippocampus of AD and NC brains. PET/CT studies were carried out in normal rats to study brain and whole body distribution. The three radiotracers were produced in high radiochemical yields (>40%) and had specific activities >37 GBq/μmol. TAZA had an affinity, K(i) = 0.84 nM and was five times more potent than PIB. [(11)C]TAZA bound specifically to Aβ plaques present in AD brains with gray matter to white matter ratios >20. [(11)C]TAZA was displaced by PIB (>90%), suggesting similar binding site for [(11)C]TAZA and [(11)C]PIB. [(11)C]TAZA exhibited slow kinetics of uptake in the rat brain and whole body images showed uptake in interscapular brown adipose tissue (IBAT). Binding in brain and IBAT were affected by preinjection of atomoxetine, a norepinephrine transporter blocker. [(11)C]TAZA exhibited high binding to Aβ plaques in human AD hippocampus. Rat brain kinetics was slow and peripheral binding to IBAT needs to be further evaluated. © 2016 Wiley Periodicals, Inc.

Medicines and the media: news reports of medicines recommended for government reimbursement in Australia

PubMed Central

2013-01-01

Background Previous analyses of the listings of trastuzumab on the Australian Pharmaceutical Benefits Scheme (PBS) and HPV vaccine on the National Immunisation Program (NIP) suggest a media influence on policy makers. We examined the timing and content of Australian newspaper reports of medicines in relation to Pharmaceutical Benefits Advisory Committee (PBAC) decisions. Methods We identified newspaper reports (2005-2008) of medicines recommended for PBS listing in 2006–2007, analysing the content for mentions of the medicine, PBS and medicine costs to the patient and the government and counting the numbers of articles published in the six months before, the month of, and the six months after the relevant PBAC meeting. Case studies examined reporting for infliximab for Crohn’s Disease, pemetrexed for mesothelioma, and ADHD (Attention Deficit Hyperactivity Disorder) medicines atomoxetine and methylphenidate. Results Of 79 eligible medicines, 62 had news reports. Most often reported were HPV vaccine (1230 stories), trastuzumab (410), pemetrexed (83), botulinum toxin (71), lapatinib (65), methylphenidate (57), atomoxetine (54), infliximab (49), rotavirus vaccine (45). Eighteen medicines had ≥20 news reports (total 2350 stories); nine of these cost more than AU$10,000 per course or year of treatment. For these 18 medicines, 31% of stories appeared in the six months prior to the PBAC meeting, 14% in the meeting month and 33% in the six months post-meeting. 38% of the stories had ≥3 medicine mentions, 37% referred to the PBS, 24% to cost to the patient, and 9% cost to Government. There was active patient lobby group campaigning in support of listing of infliximab and pemetrexed; the stories for ADHD were often more negative, referring to the dangers of the medicines and sometimes questioning the appropriateness of treatment and public subsidy. There was little discussion of the PBAC’s evidence-based decision-making processes. Conclusions While there was no general trend to increased news reporting associated with PBAC meetings, some drugs did attract media attention. With more new and expensive drugs, decisions on public funding will become increasingly difficult. The media have an important role in enhancing public understanding of the issues around resource allocation. Specialist journalists, guidelines and checklists may help reporting. PMID:23687910

Five-Fold Increase in National Prevalence Rates of Attention-Deficit/Hyperactivity Disorder Medications for Children and Adolescents with Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, and other Psychiatric Disorders: A Danish Register-Based Study

PubMed Central

Nielsen, Helena Skyt; Simonsen, Marianne

2013-01-01

Abstract Objective The purpose of this study was to estimate the prevalence and time trends in prescriptions of methylphenidate, dexamphetamine, and atomoxetine in children and adolescents, within three diagnostic groups: 1) autism spectrum disorder (ASD), 2) attention-deficit/hyperactivity disorder (ADHD), and 3) other psychiatric disorders. Methods Data from six different national registers were used and merged to identify a cohort of all children and adolescents born in Denmark between 1990 and 2001 (n=852,711). Sociodemographic covariates on cohort members and their parents and lifetime prescriptions of methylphenidate, dexamphetamine, and atomoxetine were extracted from the registers. Prescriptions were also stratified by duration (<6 months. vs.≥6 months). Results Sixteen percent of 9698 children and adolescents with ASD (n=1577), 61% of 11,553 children and adolescents with ADHD (n=7021) and 3% of 48,468 children and adolescents with other psychiatric disorders (n=1537) were treated with one or more ADHD medications. There was a significant increase in prescription rates of these medications for all three groups. From 2003 to 2010, youth 6–13 years of age with ASD, ADHD, and other psychiatric disorders had 4.7-fold (4.4–4.9), 6.3-fold (6.0–6.4), and 5.5-fold (5.0–5.9) increases, respectively, in prescription rates of ADHD medications. Conclusion This is the largest study to date assessing stimulant treatment in children and adolescents with ASD, and is the first prospective study quantifying the change over time in the prevalence of treatment with ADHD medications in a population-based national cohort of children and adolescents with ASD. The prevalence of stimulant treatment in youth with ASD of 16% is consistent with earlier studies. The past decade has witnessed a clear and progressive increase in the prescription rates of medications typically used to treat ADHD in children and adolescents in Denmark. This increase is not limited to only those with ADHD, but includes others with neuropsychiatric disorders, including ASD. The risks and benefits of this practice await further study. PMID:24015896

[Update on attention-deficit/hyperactive disorder treatment].

PubMed

Loro-López, M; Quintero, J; García-Campos, N; Jiménez-Gómez, B; Pando, F; Varela-Casal, P; Campos, J A; Correas-Lauffer, J

Attention-deficit/hyperactive disorder (ADHD) is one of the most common and investigated childhood neuropsychiatric disorder witch has an important repercussion in patient's every day life. AIM. To make an update on psychopharmacological and psychological treatment for ADHD and to asses his efficacy as a single drug treatment as well as a combined treatment. As a chronic disorder ADHD needs a carefully designed and complete treatment plan. That takes into account psychoeducation and the most recent medical evidences as well as preferences and worries of their families and patients. Psychostimulants are the most studied drugs and the gold-standard in the ADHD treatment with responses as high as 65 to 85%. Atomoxetine is another alternative for treating this patients with Food and Drug Administration and European Medicines Agency approval seal. The treatment plan for these patients must be chosen, not only by their treating doctor but should include patients and patient's family preferences and should be suited to each patient. Comorbidities are an important issue in the ADHD treatment planning, mainly in non responders' patients.

Tics in the Pediatric Population: Pragmatic Management.

PubMed

Ganos, Christos; Martino, Davide; Pringsheim, Tamara

2017-01-01

Primary tic disorders, notably Tourette syndrome, are very common movement disorders in childhood. However, the management of such patients still poses great therapeutic challenges to medical professionals. Based on a synthesis of the available guidelines published in Europe, Canada, and the United States, coupled with more recent therapeutic developments, the authors provide a pragmatic guide to aid clinicians in deciding when and how to treat patients who have primary tic disorders. After a systematic assessment of tics and common neuropsychiatric comorbidities (primarily attention-deficit hyperactivity disorder [ADHD] and obsessive-compulsive disorder [OCD]), the first step in treatment is a comprehensive psychoeducation of patients and families that addresses the protean phenomenology of tics and associated behaviors, coping mechanisms, prognosis, and treatment options. When more active intervention beyond watchful monitoring is indicated, hierarchical evaluation of treatment targets (i.e., tics vs. comorbid behavioral symptoms) is crucial. Behavioral treatments for tics are restricted to older children and are not readily available to all centers, mainly due to the paucity of well-trained therapists. Pharmacological treatments, such as antipsychotics for tics, stimulants and atomoxetine for ADHD, and α2A-agonists for children with tics plus ADHD, represent widely available and effective treatment options, but safety monitoring must be provided. Combined polypharmacological and behavioral/pharmacological approaches, as well as neuromodulation strategies, remain under-investigated in this population of patients. The treatment of children with tics and Tourette syndrome is multifaceted. Multidisciplinary teams with expertise in neurology, psychiatry, psychology, and pediatrics may be helpful to address the complex needs of these children.

Impact of negative media publicity on attention-deficit/hyperactivity disorder medication in Taiwan.

PubMed

Wang, Liang-Jen; Lee, Sheng-Yu; Yuan, Shin-Sheng; Yang, Chun-Ju; Yang, Kang-Chung; Lee, Tung-Liang; Shyu, Yu-Chiau

2016-01-01

This study explores trends in attention-deficit/hyperactivity disorder (ADHD) medications in Taiwan from 2000 to 2011 and whether negative media coverage of Ritalin in January 2010 impacted ADHD prescriptions throughout the country. Patients throughout Taiwan who had been newly diagnosed with ADHD (n = 145,269) between January 2000 and December 2011 were selected from Taiwan's National Health Insurance database as subjects for this study. We analyzed monthly and yearly data on person-days of treatment with immediate-release methylphenidate (IR-MPH), osmotic controlled-release formulation of methylphenidate (OROS-MPH), and atomoxetine (ATX) using linear models of curve estimation and the time series expert modeler. Of our sample, 57.8%, 28.9%, and 4.3% had been prescribed one or more doses of IR-MPH, OROS-MPH, or ATX, respectively. The annual person-days of IR-MPH use increased regularly from 2000 to 2009, dropped abruptly in 2010, and then increased again the next year. Furthermore, the person-days of OROS-MPH prescriptions did not reach their expected goal in 2010; however, the person-days of ATX prescriptions have increased constantly since entering the market in 2007. Compared with patients newly diagnosed with ADHD in 2009, those newly diagnosed in 2010 were less likely to be treated with medication. These findings suggest that negative publicity affected the writing of stimulant prescriptions for ADHD patients throughout Taiwan. Media reporting has a vital role in influencing children with ADHD, their parents, and their willingness to accept pharmacotherapy as treatment. Copyright © 2015 John Wiley & Sons, Ltd.

Validation of [(11) C]ORM-13070 as a PET tracer for alpha2c -adrenoceptors in the human brain.

PubMed

Lehto, Jussi; Hirvonen, Mika M; Johansson, Jarkko; Kemppainen, Jukka; Luoto, Pauliina; Naukkarinen, Tarja; Oikonen, Vesa; Arponen, Eveliina; Rouru, Juha; Sallinen, Jukka; Scheinin, Harry; Vuorilehto, Lauri; Finnema, Sjoerd J; Halldin, Christer; Rinne, Juha O; Scheinin, Mika

2015-03-01

This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies. © 2014 Wiley Periodicals, Inc.

Examining why patients with attention-deficit/hyperactivity disorder lack adherence to medication over the long term: a review and analysis.

PubMed

Frank, Elliot; Ozon, Cristina; Nair, Vinitha; Othee, Karandeep

2015-11-01

To investigate the reasons why patients with attention-deficit/hyperactivity disorder (ADHD) adhere poorly to medications over the long term (≥ 1 year). PubMed was reviewed for studies between 1997 and January 2015 citing the reasons for medication nonadherence using these main keywords: ADHD, amphetamine, methylphenidate, atomoxetine, guanfacine, clonidine, long term, and adverse effects. Non-English language articles were excluded as were those that had a follow-up of < 1 year. Of 1,137 entries, 41 published articles citing reasons for subject withdrawal from treatment were included. None were included for clonidine. Similar reasons for drug or study withdrawal were grouped together for analysis using a normalized numerical average, while unique reasons were analyzed individually. Reasons for discontinuing Food and Drug Administration (FDA)-approved medication after 1 year included "own wish/remission/don't need" (19.9%; 95% CI, 9.0-30.80), "withdrew consent" (16.2%; 95% CI, 10.0-22.5), "adverse effects" (15.1%; 95% CI, 10.4-19.8) and "suboptimal effect" (14.6%; 95% CI, 8.5-20.6), with the most common adverse event being "reduction in weight/appetite" (19.2%; 95% CI, 5.1-33.4). Other important factors included age, long- versus short-acting medication, psychosocial stressors, and "stop feeling like him/herself" on medication. The reasons why patients do not adhere to stimulant medication remain poorly studied and understood, especially over the long term. Standardizing the way studies evaluate patients who stop treatment and including more qualitative measures should lead to better treatment outcome and adherence to medication over the long term. © Copyright 2015 Physicians Postgraduate Press, Inc.

Melt-in-Mouth Multi-particulate System for the Treatment of ADHD: A Convenient Platform for Pediatric Use.

PubMed

Patadia, Jalashri; Tripathi, Rahul; Joshi, Amita

2016-08-01

Generally, pellets obtained from extrusion/spheronization, containing microcrystalline cellulose (MCC), do not disintegrate. An attempt has been made to develop melt-in-mouth pellets of taste-masked atomoxetine hydrochloride, using extrusion-spheronization, for pediatric patients. Melt-in-mouth pellets were prepared using extrusion-spheronization method and optimized using 3(3) FFD. MCC (X1, %), mannitol (X2, %) and Indion 414: Pharmaburst 500 ratio (X3, ratio) were the factors (independent variables) studied, whereas responses studied (dependent variables) were friability (Y1, %), yield (Y2, %) shape (Y3, roundness) in vitro disintegration time (Y4, seconds). The optimized formulation obtained from FFD was characterized for friability, shape and morphology, in vitro disintegration time, porosity, moisture uptake, in vitro release study and in vivo taste and disintegration time in healthy human volunteers. Randomized, two-treatment, two-sequence, two-period, single dose, crossover sensory evaluation study of taste-masked melt-in-mouth pellet was carried out in 10 healthy human subjects. A statistically significant polynomial mathematical relationship was generated between the factors and responses to obtain an optimized formulation. The optimized formulation was characterized (in vitro and in vivo) and exhibited a rapid drug release in vitro attributed to fast disintegration of pellets and high solubility of drug in 0.1 N HCl and buffer (pH 6.8). In vivo, 40% of volunteers ranked taste-masked optimized formulation as slightly bitter while 60% ranked it as no taste. The optimized pellets were conveniently administered in volunteers and exhibited rapid in-vivo disintegration in the oral cavity. Melt-in-mouth pellets can be a used as a platform technology for administering drugs to paediatric patients accurately and conveniently resulting in patient compliance.

Canadian Guidelines on Pharmacotherapy for Disruptive and Aggressive Behaviour in Children and Adolescents With Attention-Deficit Hyperactivity Disorder, Oppositional Defiant Disorder, or Conduct Disorder

PubMed Central

Gorman, Daniel A; Gardner, David M; Murphy, Andrea L; Feldman, Mark; Bélanger, Stacey A; Steele, Margaret M; Boylan, Khrista; Cochrane-Brink, Kate; Goldade, Roxanne; Soper, Paul R; Ustina, Judy; Pringsheim, Tamara

2015-01-01

Objective: To develop evidence-based guidelines on pharmacotherapy for severe disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), or conduct disorder (CD). The guidelines assume that psychosocial interventions have been pursued but did not achieve sufficient improvement. Method: A multidisciplinary consensus group used the Grading of Recommendations Assessment, Development and Evaluation approach for rating evidence quality and for grading recommendations. We conducted a systematic review of medications studied in placebo-controlled trials for treating disruptive and aggressive behaviour in children and adolescents with ADHD, ODD, or CD. We followed consensus procedures to make 1 of 4 recommendations for each medication: strong, in favour (↑↑); conditional, in favour (↑?); conditional, against (↓?); and strong, against (↓↓). Results: For children and adolescents with disruptive or aggressive behaviour associated with ADHD, psychostimulants received a strong recommendation in favour of use, while atomoxetine and alpha-2 agonists received a conditional recommendation in favour of use. If these patients do poorly with ADHD medications, the medication with the most evidence is risperidone. Risperidone also has the most evidence for treating disruptive or aggressive behaviour in the absence of ADHD. However, given risperidone’s major adverse effects, it received only a conditional recommendation in favour of use. We recommended against using quetiapine, haloperidol, lithium, or carbamazepine because of the poor quality of evidence and their major adverse effects. Conclusion: When severe disruptive or aggressive behaviour occurs with ADHD, medications for ADHD should be used first. Other medications have major adverse effects and, with the exception of risperidone, very limited evidence to support their use. PMID:25886657

Treatment of Tourette syndrome.

PubMed

Kurlan, Roger M

2014-01-01

Tourette's syndrome (TS) consists of chronic motor and phonic tics and characteristically begins in childhood. The tics can be disabling and commonly associated behavioral comorbities such as attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), can also cause problems in daily functioning. The underlying etiology and neurobiology of TS remain unknown although genetic factors appear to be important, cortical control of basal ganglia motor function appears to be disturbed and neurochemical abnormalities, particularly involving dopamine neurotransmission, are likely present. The treatment of TS involves appropriate education and support. Tics can be treated with habit reversal cognitive behavioral therapy, medications (most commonly alpha agonists and antipsychotics), local intramuscular injections of botulinum toxin and some severe, refractory cases have responded to deep brain stimulation surgery (DBS). It is important to appropriately diagnose and treat comorbid behavioral disorders that are disrupting function. OCD can be treated with cognitive behavioral therapy, selective serotonin reuptake inhibitors, and atypical antipsychotics. DBS has become a treatment option for patients with disabling OCD despite other therapies. ADHD is treated with appropriate classroom accommodations, behavioral therapy, alpha agonists, atomoxetine or methylphenidate-containing stimulant drugs.

Therapeutic drug monitoring of seven psychotropic drugs and four metabolites in human plasma by HPLC-MS.

PubMed

Choong, Eva; Rudaz, Serge; Kottelat, Astrid; Guillarme, Davy; Veuthey, Jean-Luc; Eap, Chin B

2009-12-05

A simple and sensitive LC-MS method was developed and validated for the simultaneous quantification of aripiprazole (ARI), atomoxetine (ATO), duloxetine (DUL), clozapine (CLO), olanzapine (OLA), sertindole (STN), venlafaxine (VEN) and their active metabolites dehydroaripiprazole (DARI), norclozapine (NCLO), dehydrosertindole (DSTN) and O-desmethylvenlafaxine (OVEN) in human plasma. The above mentioned compounds and the internal standard (remoxipride) were extracted from 0.5 mL plasma by solid-phase extraction (mix mode support). The analytical separation was carried out on a reverse phase liquid chromatography at basic pH (pH 8.1) in gradient mode. All analytes were monitored by MS detection in the single ion monitoring mode and the method was validated covering the corresponding therapeutic range: 2-200 ng/mL for DUL, OLA, and STN, 4-200 ng/mL for DSTN, 5-1000 ng/mL for ARI, DARI and finally 2-1000 ng/mL for ATO, CLO, NCLO, VEN, OVEN. For all investigated compounds, good performance in terms of recoveries, selectivity, stability, repeatability, intermediate precision, trueness and accuracy, was obtained. Real patient plasma samples were then successfully analysed.

Towards trans-diagnostic mechanisms in psychiatry: neurobehavioral profile of rats with a loss-of-function point mutation in the dopamine transporter gene

PubMed Central

Vengeliene, Valentina; Bespalov, Anton; Roßmanith, Martin; Horschitz, Sandra; Berger, Stefan; Relo, Ana L.; Noori, Hamid R.; Schneider, Peggy; Enkel, Thomas; Bartsch, Dusan; Schneider, Miriam; Behl, Berthold; Hansson, Anita C.; Schloss, Patrick

2017-01-01

ABSTRACT The research domain criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT) gene (Slc6a3_N157K) to systematically study the RDoC matrix. First, we examined the impact of the Slc6a3_N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity. PMID:28167616

Towards trans-diagnostic mechanisms in psychiatry: neurobehavioral profile of rats with a loss-of-function point mutation in the dopamine transporter gene.

PubMed

Vengeliene, Valentina; Bespalov, Anton; Roßmanith, Martin; Horschitz, Sandra; Berger, Stefan; Relo, Ana L; Noori, Hamid R; Schneider, Peggy; Enkel, Thomas; Bartsch, Dusan; Schneider, Miriam; Behl, Berthold; Hansson, Anita C; Schloss, Patrick; Spanagel, Rainer

2017-04-01

The research domain criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT) gene ( Slc6a3 _N157K) to systematically study the RDoC matrix. First, we examined the impact of the Slc6a3 _N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity. © 2017. Published by The Company of Biologists Ltd.

A cost-effectiveness analysis of lisdexamfetamine dimesylate in the treatment of adults with attention-deficit/hyperactivity disorder in the UK.

PubMed

Zimovetz, Evelina A; Joseph, Alain; Ayyagari, Rajeev; Mauskopf, Josephine A

2018-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder in children that may persist into adulthood. Lisdexamfetamine dimesylate (LDX) is approved in many countries for ADHD treatment in children, adolescents, and adults. Estimate the cost-effectiveness of LDX as a first- or second-line treatment for adults with ADHD from the United Kingdom (UK) National Health Service (NHS) perspective compared with methylphenidate extended release (MPH-ER) and atomoxetine (ATX). A 1-year decision-analytic model was developed. Health outcomes included response, non-response and inability to tolerate. Efficacy data were obtained from a mixed-treatment comparison (MTC). Response was a score of 1 or 2 on the Clinical Global Impression-Improvement scale. Tolerability was assessed by discontinuation rates due to adverse events. Utilities were identified via a systematic literature review. Health care resource use estimates were obtained via a survey of clinicians. Daily drug costs were estimated from mean doses reported in the trials used in the MTC. One-way and probabilistic sensitivity analyses (PSAs) were performed. LDX dominated MPH-ER and ATX; reducing mean per-patient annual cost by £5 and £200, and increasing mean quality-adjusted life years (QALYs) by 0.005 and 0.009, respectively. In the PSA, the probability of cost-effectiveness for LDX vs. MPH-ER and ATX at a threshold of £20,000 per QALY was 61% and 80%, respectively. From the perspective of the UK NHS, LDX is likely to provide a cost-effective treatment for adults with ADHD. This conclusion may be drawn with more certainty in comparison with ATX than with MPH-ER.

ADHD Medication and Substance-Related Problems.

PubMed

Quinn, Patrick D; Chang, Zheng; Hur, Kwan; Gibbons, Robert D; Lahey, Benjamin B; Rickert, Martin E; Sjölander, Arvid; Lichtenstein, Paul; Larsson, Henrik; D'Onofrio, Brian M

2017-09-01

Substance use disorders are major contributors to excess mortality among individuals with attention deficit hyperactivity disorder (ADHD), yet associations between pharmacological ADHD treatment and substance-related problems remain unclear. This study investigated concurrent and long-term associations between ADHD medication treatment and substance-related events. The authors analyzed 2005-2014 commercial health care claims from 2,993,887 (47.2% female) adolescent and adult ADHD patients. Within-individual analyses compared the risk of substance-related events (i.e., emergency department visits related to substance use disorders) during months in which patients received prescribed stimulant medication or atomoxetine relative to the risk during months in which they did not. In adjusted within-individual comparisons, relative to periods in which patients did not receive ADHD medication, male patients had 35% lower odds of concurrent substance-related events when receiving medication (odds ratio=0.65, 95% CI=0.64-0.67), and female patients had 31% lower odds of concurrent substance-related events (odds ratio=0.69, 95% CI=0.67-0.71). Moreover, male patients had 19% lower odds of substance-related events 2 years after medication periods (odds ratio=0.81, 95% CI=0.78-0.85), and female patients had 14% lower odds of substance-related events 2 years after medication periods (odds ratio=0.86, 95% CI= 0.82-0.91). Sensitivity analyses supported most findings but were less consistent for long-term associations among women. These results provide evidence that receiving ADHD medication is unlikely to be associated with greater risk of substance-related problems in adolescence or adulthood. Rather, medication was associated with lower concurrent risk of substance-related events and, at least among men, lower long-term risk of future substance-related events.

An update on pharmacotherapy of autism spectrum disorder in children and adolescents.

PubMed

Goel, Ritu; Hong, Ji Su; Findling, Robert L; Ji, Na Young

2018-02-01

To date, no medication is proven to be effective in treating core symptoms of autism spectrum disorder (ASD). Psychotropic medications are widely used to target emotional and behavioural symptoms in ASD. This article reviewed evidence for pharmacotherapy, novel therapeutic agents, and Complementary and Alternative Medicine (CAM) in children and adolescents with ASD. Currently, only risperidone and aripiprazole have been approved by the US Food and Drug Administration (FDA) for treatment of irritability associated with ASD in children and adolescents. However, associated metabolic side-effects are concerning. Evidence supports use of methylphenidate and atomoxetine for attention deficit hyperactivity disorder (ADHD) symptoms and clonidine and guanfacine ER appear to be helpful. SSRIs are poorly tolerated and lack evidence in reducing restricted repetitive behaviours (RRB), anxiety, and depression. Buspirone shows promise in the treatment of RRB. The evidence is inconsistent for the effectiveness of anti-epileptic medications. Recent studies of glutamatergic, Gamma-aminobutyric acid (GABA)ergic, and cholinergic agents and oxytocin show inconsistent results. Despite wide use of CAM agents, the evidence is inconclusive. Melatonin can be helpful in reducing sleep problems. Overall, the evidence is limited for pharmacotherapy in children with ASD, and side-effects with long-term use can be burdensome.

Attention-Deficit/Hyperactivity Disorder Drugs and Growth: An Italian Prospective Observational Study

PubMed Central

Germinario, Elena A.P.; Arcieri, Romano; Bonati, Maurizio; Zuddas, Alessandro; Masi, Gabriele; Vella, Stefano; Chiarotti, Flavia

2013-01-01

Abstract Objective This study was conducted to assess the long-term effect of methylphenidate (MPH) or atomoxetine (ATX) on growth in attention-deficit/hyperactivity disorder (ADHD) drug-naïve children. Design The study was an observational, post-marketing, fourth phase study. Methods Data on height and weight were collected at baseline and every 6 months up to 24 months. Results Both ATX and MPH lead to decreased height gain (assessed by means of z-scores); the effect was significantly higher for ATX than for MPH. At any time, height z-score decrease in the ATX group was higher than the corresponding decrease observed in the MPH group, but the difference was significantly relevant only during the first year of treatment. An increment of average weight was observed both in patients treated with MPH and in those treated with ATX. However, using Tanner's percentile, a subset of patients showed a degree of growth lower than expected. This negative effect was significantly higher for ATX than for MPH. Conclusions We conclude that ADHD drugs show a negative effect on linear growth in children in middle term. Such effect appears more evident for ATX than for MPH. PMID:24024538

Robustness of reliable change indices to variability in Parkinson's disease with mild cognitive impairment.

PubMed

Turner, T H; Renfroe, J B; Elm, J; Duppstadt-Delambo, A; Hinson, V K

2016-01-01

Ability to identify change is crucial for measuring response to interventions and tracking disease progression. Beyond psychometrics, investigations of Parkinson's disease with mild cognitive impairment (PD-MCI) must consider fluctuating medication, motor, and mental status. One solution is to employ 90% reliable change indices (RCIs) from test manuals to account for account measurement error and practice effects. The current study examined robustness of 90% RCIs for 19 commonly used executive function tests in 14 PD-MCI subjects assigned to the placebo arm of a 10-week randomized controlled trial of atomoxetine in PD-MCI. Using 90% RCIs, the typical participant showed spurious improvement on one measure, and spurious decline on another. Reliability estimates from healthy adults standardization samples and PD-MCI were similar. In contrast to healthy adult samples, practice effects were minimal in this PD-MCI group. Separate 90% RCIs based on the PD-MCI sample did not further reduce error rate. In the present study, application of 90% RCIs based on healthy adults in standardization samples effectively reduced misidentification of change in a sample of PD-MCI. Our findings support continued application of 90% RCIs when using executive function tests to assess change in neurological populations with fluctuating status.

Cognitive enhancement as a pharmacotherapy target for stimulant addiction.

PubMed

Sofuoglu, Mehmet

2010-01-01

No medications have been proven to be effective for cocaine and methamphetamine addiction. Attenuation of drug reward has been the main strategy for medications development, but this approach has not led to effective treatments. Thus, there is a need to identify novel treatment targets in addition to the brain reward system. To propose a novel treatment strategy for stimulant addiction that will focus on medications enhancing cognitive function and attenuating drug reward. Pre-clinical and clinical literature on potential use of cognitive enhancers for stimulant addiction pharmacotherapy was reviewed. Cocaine and methamphetamine users show significant cognitive impairments, especially in attention, working memory and response inhibition functions. The cognitive impairments seem to be predictive of poor treatment retention and outcome. Medications targeting acetylcholine and norepinephrine are particularly well suited for enhancing cognitive function in stimulant users. Many cholinergic and noradrenergic medications are on the market and have a good safety profile and low abuse potential. These include galantamine, donepezil and rivastigmine (cholinesterase inhibitors), varenicline (partial nicotine agonist), guanfacine (alpha(2)-adrenergic agonist) and atomoxetine (norepinephrine transporter inhibitor). Future clinical studies designed optimally to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these cognitive enhancers for stimulant addiction.

An open-label, randomized positron emission tomography (PET)study in healthy male volunteers consisiting of Part A and Part B.Part A: Clinical validation of norepinephrine transporter (NET) PET ligand, (S,S)-[11C]O-methylreboxetine ([11C]MRB) using different doses of oral atomoxetine as NET reuptake inhibitor.Part B: Evaluation of NET occupancy, as measured by [11C]MRB, with multiple dosing regimens of orally administered GSK372475.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, Joanna; Furey, Michael

Results from human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K(i)=2-5 nM). METHODS: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [(11)C](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volumemore » (DV). Images were normalized to a template, and average parametric images for each group were formed. RESULTS: [(11)C](S,S)-MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density approximately 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24+/-7%; 100 mg=31+/-11%), these differences were not significant. The different blocking between MBR (average decrease=28+/- 10%) and THL (average decrease=17+/-10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the average baseline DV image and the average blocked image showed the expected NET distribution with the MBR (LC) and hypothalamus>THL>CNG and CB, as well as a significant change in the supplementary motor area. DVR reproducibility for the different brain regions was approximately 10%, but intersubject variability was large. CONCLUSIONS: The highest density of NETs was found in the MBR where the LC is located, followed by THL, whereas the lowest density was found in basal ganglia (lowest in CDT), consistent with the regional localization of NETs in the nonhuman primate brain. While all three doses of ATX were found to block most regions, no significant differences between doses were found for any region, although the average percent change across subjects of the MBR did correlate with ATX dose. The lack of a dose effect could reflect a low signal-to-noise ratio coupled with the possibility that a sufficient number of transporters were blocked at the lowest dose and further differences could not be detected. However, since the lowest (25 mg) dose is less than the therapeutic doses used in children for the treatment of attention-deficit/hyperactivity disorder ( approximately 1.0 mg/kg/day), this would suggest that there may be additional targets for ATX's therapeutic actions.« less

Prevalence rates of youths diagnosed with and medicated for ADHD in a nationwide survey in Taiwan from 2000 to 2011.

PubMed

Wang, L-J; Lee, S-Y; Yuan, S-S; Yang, C-J; Yang, K-C; Huang, T-S; Chou, W-J; Chou, M-C; Lee, M-J; Lee, T-L; Shyu, Y-C

2017-12-01

Public controversy regarding the potential overdiagnosis and overmedication of children with attention-deficit/hyperactivity disorder (ADHD) has continued for decades. This study used the National Health Insurance Research Database of Taiwan (NHIRD-TW) to explore trends in ADHD diagnosis in youths and the proportion of those receiving medication, with the aim of determining whether ADHD is overdiagnosed and overmedicated in Taiwan. Youths (age ≤18 years) who had at least two NHIRD-TW claims records with ADHD diagnosis between January 2000 and December 2011 were selected as the subject cohort. In total, the study sample comprised 145 018 patients with ADHD (mean age at a diagnosis of ADHD: 7.7 ± 3.1 years; 21.4% females). The number of cases of ADHD were calculated annually for each year (from 2000 to 2011), and the number of cases per year who received medication was determined as those with at least one record of pharmacotherapy (immediate-release methylphenidate, osmotic controlled-release formulation of methylphenidate, and atomoxetine) in each year. The prevalence rates of a diagnosis of ADHD in the youths ranged from 0.11% in 2000 to 1.24% in 2011. Compared with children under 6 years of age, the ADHD diagnosis rates in children aged between 7 and 12 years (ratio of prevalence rates = 4.36) and in those aged between 13 and 18 years (ratio of prevalence rates = 1.42) were significantly higher during the study period. The prevalence in males was higher than that in females (ratio of prevalence rates = 4.09). Among the youths with ADHD, 50.2% received medications in 2000 compared with 61.0% in 2011. The probability of receiving ADHD medication increased with age. More male ADHD patients received medications that females patients (ratio of prevalence rates = 1.16). The rate of ADHD diagnosis was far lower than the prevalence rate (7.5%) identified in a previous community study using face-to-face interviews. Approximately 40-50% of the youths with ADHD did not receive any medications. These findings are not consistent with a systematic public opinion about overdiagnosis or overmedication of ADHD in Taiwan.

Understanding the treatment of attention deficit hyperactivity disorder in newly diagnosed adult patients in general practice: a UK database study

PubMed Central

Bushe, Christopher; Wilson, Bernard; Televantou, Foula; Belger, Mark; Watson, Louise

2015-01-01

Background Adult attention deficit hyperactivity disorder (ADHD) has been largely ignored in psychiatric and general practice guidance until recently. Adult ADHD has a high social and medical burden, but health care is not well described in the UK. The main study objective was to evaluate a primary care adult ADHD population in terms of prescribing and health care contact rates. Methods This was a retrospective observational study using data from the Clinical Practice Research Database from January 1, 2002 to July 31, 2011. Adult patients with an incident ADHD diagnosis or ADHD medication were identified as having been free of ADHD medication or diagnoses in the previous 2 years. Patients were followed for 12–24 months after diagnosis. Results Of the 663 patients with ADHD in the cohort, 54.1% were prescribed ADHD medication during the observation period. During the first 6 months, 34.2% of patients initiated methylphenidates and 14.0% atomoxetine. In total, 36.3% patients were referred to secondary care psychiatry during observation, with the remaining population (63.7%) never having a referral. Most of the referrals were before diagnosis in primary care. At the end of the observation period, 16.2% of patients were on antipsychotics, 17.3% hypnotics, and 34.8% antidepressants or anxiolytics; however, some patients appeared to be prescribed antipsychotic or antidepressant medications even if they did not have an observable diagnosis in their records. Health care contact rates (general practitioner or hospital) increased by 39.2% post-diagnosis (incidence rate ratio: 1.39; 95% confidence interval: 1.32, 1.47), which may be related to the need for medication monitoring and titration. Conclusion This study has shown in primary care that there is relatively low use of ADHD medication, low referrals into secondary care, high rates of usage of psychiatric non-ADHD medications for different indications, and an increasing burden in terms of health care contacts in adult ADHD patients post-diagnosis. PMID:27774030

Pharmacological treatment of comorbid PTSD and substance use disorder: recent progress.

PubMed

Sofuoglu, Mehmet; Rosenheck, Robert; Petrakis, Ismene

2014-02-01

Previous research has identified a strong association between posttraumatic stress disorder (PTSD) and substance use disorder (SUD), necessitating the development of treatments that address both conditions. Some pharmacotherapies are effective for the treatment of PTSD and SUD alone, however; no medications have been proven to be effective for the combination of these conditions. We review the recent advances in pharmacological treatment of comorbid PTSD and SUD. A randomized clinical trial of sertraline, a serotonin reuptake inhibitor (SSRI), did not show overall efficacy for comorbid PTSD and alcohol dependence (AD), although it may have efficacy among light drinkers. Another clinical trial demonstrated the efficacy of both disulfiram and naltrexone for the treatment of AD in individuals with PTSD. A more recent clinical trial suggested that norepinephrine uptake inhibitors may also have efficacy for the treatment of comorbid PTSD and AD. In animal and preliminary human studies, brain norepinephrine and glutamate/GABA have emerged as potential treatment targets for comorbid PTSD and SUD. Noradrenergic medications that are promising for comorbid PTSD and SUD include prazosin, guanfacine, and atomoxetine. Promising glutamate/GABA medications include topiramate, memantine, acamprosate, N-acetylcysteine (NAC), and ketamine. The safety and efficacy of these medications for the treatment of PTSD and SUD need to be tested in controlled clinical trials. Published by Elsevier Ltd.

Antidepressants in Parkinson's disease. Recommendations by the movement disorder study group of the Neurological Association of Madrid.

PubMed

Peña, E; Mata, M; López-Manzanares, L; Kurtis, M; Eimil, M; Martínez-Castrillo, J C; Navas, I; Posada, I J; Prieto, C; Ruíz-Huete, C; Vela, L; Venegas, B

2016-03-19

Although antidepressants are widely used in Parkinson's disease (PD), few well-designed studies to support their efficacy have been conducted. These clinical guidelines are based on a review of the literature and the results of an AMN movement disorder study group survey. Evidence suggests that nortriptyline, venlafaxine, paroxetine, and citalopram may be useful in treating depression in PD, although studies on paroxetine and citalopram yield conflicting results. In clinical practice, however, selective serotonin reuptake inhibitors are usually considered the treatment of choice. Duloxetine may be an alternative to venlafaxine, although the evidence for this is less, and venlafaxine plus mirtazapine may be useful in drug-resistant cases. Furthermore, citalopram may be indicated for the treatment of anxiety, atomoxetine for hypersomnia, trazodone and mirtazapine for insomnia and psychosis, and bupropion for apathy. In general, antidepressants are well tolerated in PD. However, clinicians should consider the anticholinergic effect of tricyclic antidepressants, the impact of serotonin-norepinephrine reuptake inhibitors on blood pressure, the extrapyramidal effects of antidepressants, and any potential interactions between monoamine oxidase B inhibitors and other antidepressants. Copyright © 2016 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Evolution of the treatment of attention-deficit/hyperactivity disorder in children: a review.

PubMed

Findling, Robert L

2008-05-01

Efficacious and well-tolerated medications are available for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants such as methylphenidate (MPH) and amphetamines are the most widely used medications approved by the US Food and Drug Administration for the treatment of ADHDin children. This article reviews the literature on the development and use of medications for the treatment of ADHD in children. A search of MEDLINE was conducted toidentify relevant studies and critical reviews on the treatment of ADHD in children. The main criteria for inclusion of a study were that it have a controlled design, enroll >100 subjects if a clinical trial and >20 subjects if a classroom study, assess symptoms with the most widely used scales and tests,and be published from 2000 to 2008.A few older pivotal studies were also included. Many studies have reported the long-term efficacy and tolerability of immediate-release formulations of MPH. The disadvantages of such formulations include the need for multiple daily dosing and a potential for abuse. Various extended-release formulations of MPH have been found effective in controlled studies enrolling large numbers of children with ADHD. The efficacy and tolerability of dexmethylphenidate, the active D-isomer of MPH, in an extended-release formulation have also been reported. An extended-release formulation of mixed amphetamine salts (MMAS-XR) that is dosed once daily has been found to be efficacious and well tolerated. The non-stimulant atomoxetine has been reported to be well tolerated and efficacious, although it may not be as effective as stimulants; this formulation is, however, less likely than stimulants to be associated with abuse and diversion. A recently approved prodrug stimulant, lisdexamfetamine dimesylate (LDX), was developed to provide a long duration of effect that is consistent throughout the day, with a reduced potential for abuse. In a placebo-controlled study in children with ADHD, less intersubject variability in T(max), C(max), and AUC from time zero to the last quantifiable concentration was seen in the 8 subjects who received LDX (percent coefficient of variation, 15.3, 20.3, and 21.6, respectively) compared with the 9 subjects who received MAS-XR (52.8, 44.0, and 42.8).In 2 clinical trials, significantly greater improvements in teacher and parent ratings of ADHD symptoms were seen with LDX compared with placebo (P<0.001).A study of the abuse potential of LDX evaluated subjective responses to the effects of oral LDX and immediate-release d-amphetamine in adults with a history of stimulant abuse. LDX was associated with a significantly lower abuse-related liking effect than d-aamphetamine (P = 0.039). Currently available treatments for ADHD in children are efficacious and well tolerated, but many of them are limited by the requirement for multiple daily dosing and abuse potential. LDX, a long-acting prodrug of d-amphetamine, has been reported to be effective and appears to overcome some of these limitations.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2003-05-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 2F5, 2G12, abetimus sodium, ABI-007, adalimumab, adefovir dipivoxil, AE-941, alefacept, altropane, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminopterin, anakinra, aprinocarsen sodium, atazanavir, atlizumab, atomoxetine hydrochloride; B7-1 vaccine, bevacizumab, biricodar dicitrate, BMS-188667, brasofensine sulfate, bryostatin 1; cantuzumab mertansine, CHS-828, cinacalcet hydrochloride, cipamfylline, creatine, CVT-3146; darbepoetin alfa, DITPA, drotrecogin alfa (activated), duloxetine hydrochloride; edatrexate, efalizumab, ENMD-0997, epoetin, erlosamide, esomeprazole magnesium, etiprednol dicloacetate, etoricoxib, everolimus, ezetimibe; fampridine, fenretinide, FTY-720; IGF-I/IGFBP-3, IL-1 cytokine trap, ilodecakin, interferon beta, ISIS-104838, ISIS-2503, ISIS-5132, ivabradine hydrochloride; lafutidine, lanthanum carbonate, l-Arginine hydrochloride, LEA29Y, lerdelimumab, levetiracetam, levobupivacaine hydrochloride, levosimendan, lopinavir; melagatran, mibefradil hydrochloride, miglustat, morphine-6-glucuronide; nesiritide; omalizumab, omapatrilat; p24-VLP, parecoxib sodium, peginterferon alfa-2a, peginterferon alfa-2b, pegsunercept, pitavastatin calcium, plevitrexed, prasterone, pregabalin, PRO-2000, prucalopride; rapacuronium bromide, rebimastat, RGA-0853, rubitecan, ruboxistaurin mesilate hydrate, RWJ-67657; S-16020-2, sarizotan, SLV-306, stiripentol; TA-CIN, tenecteplase, teriparatide, tezacitabine, tipifarnib, trabectedin, troglitazone; valdecoxib, vardenafil; Z-338, ziconotide.

Pharmacological Treatment of Cannabis-Related Disorders: A Narrative Review.

PubMed

Gorelick, David A

2016-01-01

Cannabis is the most widely used illicit psychoactive substance world-wide, yet no medication is approved for the treatment of intoxication, withdrawal, or cannabis use disorder (CUD). To comprehensively review the current state of knowledge. Search of the PubMed electronic data base and review of reference lists of relevant articles to identify controlled clinical trials of pharmacological treatment. The search identified 4 trials for specific intoxication symptoms (none for global intoxication), 7 trials for withdrawal, and 12 phase II trials for CUD. One or two trials each suggest that propranolol is effective for some intoxication symptoms, antipsychotics for cannabis-induced psychosis, and dronabinol (synthetic THC) and gabapentin for cannabis withdrawal. Of 10 medications and one medication combination studied in 12 trials for CUD, only two medications were effective (in single trials): gabapentin and Nacetylcysteine (in adolescents). Not effective were dronabinol and several antidepressants, anticonvulsants, and antianxiety medications. Three trials of antidepressants for CUD with comorbid depression gave inconsistent results. A trial of atomoxetine for CUD with comorbid ADHD showed no efficacy. Five trials of second-generation antipsychotics for CUD with comorbid schizophrenia showed none better than any other. Further research is needed to confirm the efficacy of gabapentin for withdrawal and gabapentin and N-acetylcysteine for CUD and to develop new medications for all 3 cannabis-related disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD).

PubMed

de la Peña, June Bryan; Dela Peña, Irene Joy; Custodio, Raly James; Botanas, Chrislean Jun; Kim, Hee Jin; Cheong, Jae Hoon

2018-05-01

Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-05-01

O(6)-Benzylguanine; (-)-Gossypol; Abatacept, AC-2592, Adalimumab, AIDSVAX gp120 B/E, Alemtuzumab, Aliskiren fumarate, ALVAC E120TMG, Ambrisentan, Amlodipine, Anakinra, Aripiprazole, Armodafinil, Atomoxetine hydrochloride, Avotermin; Bevacizumab, BIBW-2992, Bortezomib, Bosentan, Botulinum toxin type B; Canakinumab, CAT-354, Ciclesonide, CMV gB vaccine, Corifollitropin alfa, Daptomycin, Darbepoetin alfa, Dasatinib, Denosumab; EndoTAG-1, Eplerenone, Esomeprazole sodium, Eszopiclone, Etoricoxib, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; F-50040, Fesoterodine fumavate, Fondaparinux sodium, Fulvestrant; Gabapentin enacarbil, Golimumab; Imatinib mesylate, Inhalable human insulin, Insulin glargine, Ivabradine hydrochloride; Lercanidipine hydrochloride/enalapril maleate, Levosimendan, Liposomal vincristine sulfate, Liraglutide; MDV-3100, Mometasone furoate/formoterol fumavate, Multiepitope CTL peptide vaccine, Mycophenolic acid sodium salt, Nabiximols, Natalizumab, Nesiritide; Obeticholic acid, Olmesartan medoxomil, Omalizumab, Omecamtiv mecarbil; Paclitaxel-eluting stent, Paliperidone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, Polymyxin B nonapeptide, PORxin-302, Prasugrel, Pregabalin, Pridopidine; Ranelic acid distrontium salt, Rasagiline mesilate, rDEN4delta30-4995, Recombinant human relaxin H2, rhFSH, Rilonacept, Rolofylline, Rosiglitazone maleate/metformin hydrochloride, Rosuvastatin calcium, Rotigotine; Salcaprozic acid sodium salt, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, Temsirolimus, Tenofovir, Tenofovir disoproxil fumarate, Teriparatide, Tiotropium bromide, Tocilizumab, Tolvaptan, Tozasertib, Treprostinil sodium; Ustekinumab; Vardenafil hydrochloride hydrate, Varenicline tartrate, Vatalanib succinate, Voriconazole, Vorinostat; Zotarolimus-eluting stent. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Current pharmacotherapy of attention deficit hyperactivity disorder.

PubMed

Reddy, D S

2013-10-01

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral developmental disorder in children and adults characterized by a persistent pattern of impulsiveness, inattention and hyperactivity. It affects about 3-10% of children and 2-5% of adolescents and adults and occurs about four times more commonly in boys than girls. The cause of ADHD is unknown, but it has strong genetic and environment components. The first-line treatment options for ADHD include behavioral therapy, pharmacotherapy with stimulants or both. Methylphenidate and amphetamine salts are the stimulant drugs of choice for ADHD treatment. Amphetamines act by increasing presynaptic release of dopamine and other biogenic amines in the brain. Methylphenidate inhibits the reuptake of dopamine and norepinephrine and therefore its pharmacology is identical to that of amphetamines. Lisdex-amfetamine is a prodrug of dextroamphetamine with low feasibility for abuse. Atomoxetine, a selective norepinephrine reuptake inhibitor, is an alternative, non-stimulant drug for ADHD but it is less efficacious than stimulants. Stimulants are generally safe but are associated with adverse effects including headache, insomnia, anorexia and weight loss. There is increased awareness about serious cardiovascular and psychiatric adverse events with ADHD drugs including concern for growth suppression in children. Stimulants have a high potential for abuse and dependence, and should be handled safely to prevent misuse and abuse. Copyright 2013 Prous Science, S.A.U. or its licensors. All rights reserved.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-12-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: 131I-chTNT; Abatacept, adalimumab, alemtuzumab, APC-8015, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, azimilide hydrochloride; Bevacizumab, bortezomib, bosentan, buserelin; Caspofungin acetate, CC-4047, ChAGCD3, ciclesonide, clopidogrel, curcumin, Cypher; Dabigatran etexilate, dapoxetine hydrochloride, darbepoetin alfa, darusentan, denosumab, DMXB-Anabaseine, drospirenone, drospirenone/estradiol, duloxetine hydrochloride, dutasteride; Edodekin alfa, efaproxiral sodium, elaidic acid-cytarabine, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, eszopiclone, etonogestrel/testosterone decanoate, exenatide; Fulvestrant; Gefitinib, glycine, GVS-111; Homoharringtonine; ICC-1132, imatinib mesylate, iodine (I131) tositumomab, i.v. gamma-globulin; Levetiracetam, levocetirizine, lintuzumab, liposomal nystatin, lumiracoxib, lurtotecan; Manitimus, mapatumumab, melatonin, micafungin sodium, mycophenolic acid sodium salt; Oblimersen sodium, OGX-011, olmesartan medoxomil, omalizumab, omapatrilat, oral insulin; Parathyroid hormone (human recombinant), pasireotide, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, phVEGF-A165, pimecrolimus, pitavastatin calcium, plerixafor hydrochloride, posaconazole, pramlintide acetate, prasterone, pregabalin, PT-141; Quercetin; Ranolazine, rosuvastatin calcium, rubitecan, rupatadine fumarate; Sardomozide, sunitinib malate; Tadalafil, talactoferrin alfa, tegaserod maleate, telithromycin, testosterone transdermal patch, TH-9507, tigecycline, tiotropium bromide, tipifarnib, tocilizumab, treprostinil sodium; Valdecoxib, vandetanib, vardenafil hydrochloride hydrate, voriconazole. Copyright 2005 Prous Science. All rights reserved.

[Proposals for social policies to improve the quality of life in attention deficit/hyperactivity disorder [ADHD

PubMed

Cid Foix, Ana

2011-01-01

This article describes the effects of pre and postnatal stress on the cerebral morphological findings described as attention deficit/hyperactivity disorder. [ADHD]. The consequences of ADHD cause social problems because these children have difficulties with family, school and social integration. Previous treatments are reviewed up to the present day. The drug that has been used most frequently is Metilphenidate, a psychostimulant, and recently, a new drug, Atomoxetine, a non psychostimulant was introduced. The therapy is combined with physiological training. These drugs give relief to the symptoms but their long term side-effects are unknown. Recent investigations have shown that children with ADHD who are receiving either cognitive or control training have increased cerebral activity without previous medication. With these facts in mind the European ADHD Guidelines group suggests a new focus of attention on the children and adults with this problem with the aim of modifying the treatment followed until now. The ethical motives for this review are: a) to make society more aware of the problems of ADHD with the aim of taking measures to avoid the possible causes of the illness; b) to take into account that the effects of long term psychostimulant drugs on the developing mind are unknown; c) to gather information that supports the view that diagnosis of ADHD has increased.

The Changing Drug Culture: Use and Misuse of Cognition-Enhancing Drugs.

PubMed

Albertson, Timothy E; Chenoweth, James A; Colby, Daniel K; Sutter, Mark E

2016-02-01

There has been an increase in diagnoses of attention-deficit/hyperactivity disorder (ADHD), with approximately 9% of American children now diagnosed, and a concomitant increase in the use of stimulants (eg, amphetamines, methylphenidate) to manage ADHD. Nonstimulant drugs (eg, atomoxetine, guanfacine, clonidine) also are used, but most patients are treated with stimulants. All of these drugs are effective for management of ADHD, and, overall, use in childhood does not seem to increase the risk of substance abuse later in life. However, widespread use has resulted in prescription stimulants being diverted for nonmedical uses, particularly by high school and college students seeking cognitive enhancement for improved academic performance. Studies of ADHD drugs for improving cognition in patients without ADHD have mixed results, and any improvements appear to be modest and short-term. Other substances also are used for cognitive enhancement. Drugs for Alzheimer disease are being used for mild cognitive impairment, though there is no evidence that they are effective. Creatine may have mild cognition-enhancing properties, but study results often are confounded by the addition of exercise, which by itself is thought to improve cognition. There is no evidence that other supplements, such as vitamins and omega-3 fatty acids, improve cognitive function. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Variability and trends in the consumption of drugs for treating attention-deficit/hyperactivity disorder in Castile-La Mancha, Spain (1992-2015).

PubMed

Criado-Álvarez, J J; González González, J; Romo Barrientos, C; Mohedano Moriano, A; Montero Rubio, J C; Pérez Veiga, J P

2016-09-16

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common behavioural disorders of childhood; its prevalence in Spain is estimated at 5-9%. Available treatments for this condition include methylphenidate, atomoxetine, and lisdexamfetamine, whose consumption increases each year. The prevalence of ADHD was estimated by calculating the defined daily dose per 1,000 population per day of each drug and the total doses (therapeutic group N06BA) between 1992 and 2015 in each of the provinces of Castile-La Mancha (Spain). Trends, joinpoints, and annual percentages of change were analysed using joinpoint regression models. The minimum prevalence of ADHD in the population of Castile-La Mancha aged 5 to 19 was estimated at 13.22 cases per 1,000 population per day; prevalence varied across provinces (p<.05). Overall consumption has increased from 1992 to 2015, with an annual percentages of change of 10.3% and several joinpoints (2000, 2009, and 2012). methylphenidate represents 89.6% of total drug consumption, followed by lisdexamfetamine at 8%. Analysing drug consumption enables us to estimate the distribution of ADHD patients in Castile-La Mancha. Our data show an increase in the consumption of these drugs as well as differences in drug consumption between provinces, which reflect differences in ADHD management in clinical practice. Copyright © 2016. Publicado por Elsevier España, S.L.U.

Deepened extinction following compound stimulus presentation: Noradrenergic modulation

PubMed Central

Janak, Patricia H.; Corbit, Laura H.

2011-01-01

Behavioral extinction is an active form of new learning involving the prediction of nonreward where reward has previously been present. The expression of extinction learning can be disrupted by the presentation of reward itself or reward-predictive stimuli (reinstatement) as well as the passage of time (spontaneous recovery) or contextual changes (renewal). The following experiments replicated the demonstration that presenting multiple previously rewarded stimuli in compound during extinction enhances extinction learning. To explore the pharmacological basis for this we next examined the effects of pharmacological treatments that either facilitated or blocked noradrenergic activity to test the hypothesis that increased noradrenergic activity at the time of extinction training would improve, whereas blockade of noradrenergic activity would impair the extinction of appetitive stimulus–reward memories. Different groups of rats were trained in a discriminative stimulus paradigm to lever-press for food reward. Once stable responding was achieved, responding was extinguished for 2 d. Prior to a third extinction session, rats received systemic administration of either saline, yohimbine (α2 antagonist), atomoxetine (norepinephrine reuptake inhibitor), or propranolol (β-receptor antagonist). Spontaneous recovery of responding to the stimuli was tested 4 wk later. Our results indicate that increasing noradrenergic activity during extinction augments extinction learning resulting in less recovery of responding at test. These results have important implications for models of relapse to drug seeking and the development of extinction-based therapies. PMID:21224211

Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction.

PubMed

Arnsten, Amy F T

2009-01-01

Recent advances in neurobiology have aided our understanding of attention-deficit hyperactivity disorder (ADHD). The higher-order association cortices in the temporal and parietal lobes and prefrontal cortex (PFC) interconnect to mediate aspects of attention. The parietal association cortices are important for orienting attentional resources in time/space, while the temporal association cortices analyse visual features critical for identifying objects/places. These posterior cortices are engaged by the salience of a stimulus (its physical characteristics such as movement and colour). Conversely, the PFC is critical for regulating attention based on relevance (i.e. its meaning). The PFC is important for screening distractions, sustaining attention and shifting/dividing attention in a task-appropriate manner. The PFC is critical for regulating behaviour/emotion, especially for inhibiting inappropriate emotions, impulses and habits. The PFC is needed for allocating/planning to achieve goals and organizing behaviour/thought. These regulatory abilities are often referred to as executive functions. In humans, the right hemisphere of the PFC is important for regulating distractions, inappropriate behaviour and emotional responses. Imaging studies of patients with ADHD indicate that these regions are underactive with weakened connections to other parts of the brain. The PFC regulates attention and behaviour through networks of interconnected pyramidal cells. These networks excite each other to store goals/rules to guide actions and are highly dependent on their neurochemical environment, as small changes in the catecholamines noradrenaline (NA) or dopamine (DA) can have marked effects on PFC function. NA and DA are released in the PFC according to our arousal state; too little (during fatigue or boredom) or too much (during stress) impairs PFC function. Optimal amounts are released when we are alert/interested. The beneficial effects of NA occur at postsynaptic alpha(2A)-receptors on the dendritic spines of PFC pyramidal cells. Stimulation of these receptors initiates a series of chemical events inside the cell. These chemical signals lead to the closing of special ion channels, thus strengthening the connectivity of network inputs to the cell. Conversely, the beneficial effects of moderate amounts of DA occur at D(1) receptors, which act by weakening irrelevant inputs to the cells on another set of spines. Genetic linkage studies of ADHD suggest that these catecholamine pathways may be altered in some families with ADHD, e.g. alterations in the enzyme that synthesizes NA (DA beta-hydroxylase) are associated with weakened PFC abilities. Pharmacological studies in animals indicate catecholamine actions in the PFC are highly relevant to ADHD. Blocking NA alpha(2A)-receptors in the PFC with yohimbine produces a profile similar to ADHD: locomotor hyperactivity, impulsivity and poor working memory. Conversely, drugs that enhance alpha(2)-receptor stimulation improve PFC function. Guanfacine directly stimulates postsynaptic alpha(2A)-receptors in the PFC and improves functioning, while methylphenidate and atomoxetine increase endogenous NA and DA levels and indirectly improve PFC function via alpha(2A)- and D(1) receptor actions. Methylphenidate and atomoxetine have more potent actions in the PFC than in subcortical structures, which may explain why proper administration of stimulant medications does not lead to abuse. Further understanding of the neurobiology of attention and impulse control will allow us to better tailor treatments for specific patient needs.

Cannabis Withdrawal in Adults With Attention-Deficit/Hyperactivity Disorder.

PubMed

Chauchard, Emeline; Hartwell, Karen J; McRae-Clark, Aimee L; Sherman, Brian J; Gorelick, David A

2018-02-22

Cannabis withdrawal has not been studied in adults with attention-deficit/hyperactivity disorder (ADHD) who have high rates of cannabis use. We aimed to describe cannabis withdrawal, motivations to quit, and strategies to quit cannabis use in cannabis-dependent adults with ADHD. Twenty-three adults with ADHD enrolled in a controlled clinical trial of pharmacotherapy (atomoxetine) for cannabis dependence (DSM-IV criteria) completed the Marijuana Quit Questionnaire (MJQQ) to provide information on their "most serious" quit attempt made without formal treatment. The study was conducted between November 2005 and June 2008. Participants were predominantly male (82.6%, n = 19), with a mean (SD) age of 27.4 (8.5) years (range, 18-53) at the start of their index quit attempt. The most common motive for quitting cannabis was "to save money" (87%, n = 20); the most common strategy to maintain abstinence was "stopped associating with people who smoke marijuana" (43%, n = 10). Almost all (96%, n = 22) subjects reported ≥ 1 cannabis withdrawal symptom; 7 (30%) met DSM-5 diagnostic criteria for cannabis withdrawal syndrome. Participants with comorbid ADHD and cannabis dependence reported withdrawal symptoms similar to other samples of non-treatment-seeking cannabis-dependent adults with no psychiatric comorbidity. These findings suggest that ADHD does not influence cannabis withdrawal in the way that it does tobacco (nicotine) withdrawal. Data used in this secondary analysis came from ClinicalTrials.gov identifier: NCT00360269. © Copyright 2018 Physicians Postgraduate Press, Inc.

Adult Attention-Deficit/Hyperactivity Disorder (ADHD) and Insomnia: an Update of the Literature.

PubMed

Wynchank, Dora; Bijlenga, Denise; Beekman, Aartjan T; Kooij, J J Sandra; Penninx, Brenda W

2017-10-30

Insomnia is diagnosed when there is dissatisfaction with sleep quantity or quality. It has a prevalence in the general population ranging from 31 to 56%. Insomnia has previously been associated with adult attention-deficit/hyperactivity disorder (ADHD). In this review, we address three topics: (1) the cross-sectional relationship between ADHD and insomnia in adulthood, (2) the longitudinal relationship between ADHD and insomnia, and (3) insomnia as a side effect of pharmacological treatments for adult ADHD. Three cross-sectional, clinical, and population studies report a prevalence of insomnia in ADHD adults ranging from 43 to 80%. Longitudinal evidence for a link between childhood-onset ADHD and insomnia at later age is mixed, with one study confirming and another study not supporting such a longitudinal association. In randomized, placebo-controlled trials, insomnia is reported significantly more often in the treatment arm than in the placebo arm. In varying percentages of trial participants, insomnia is a treatment-emergent adverse effect in triple-bead mixed amphetamine salts (40-45%), dasotraline (35-45%), lisdexamfetamine (10-19%), and extended-release methylphenidate (11%). Ten to seventeen percent of subjects in placebo-controlled trials of atomoxetine report insomnia, possibly related to poor metabolizer status. The mechanisms explaining the relationship between ADHD and sleep problems are incompletely understood, but both genetic and non-shared environmental influences may be involved. Adults with ADHD should be assessed for insomnia, which is frequently comorbid, and both conditions should be treated.

Pharmacological and clinical dilemmas of prescribing in co-morbid adult attention-deficit/hyperactivity disorder and addiction

PubMed Central

Pérez de los Cobos, José; Siñol, Núria; Pérez, Víctor; Trujols, Joan

2014-01-01

The present article reviews whether available efficacy and safety data support the pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD) in patients with concurrent substance use disorders (SUD). Arguments for and against treating adult ADHD with active SUD are discussed. Findings from 19 large open studies and controlled clinical trials show that the use of atomoxetine or extended-release methylphenidate formulations, together with psychological therapy, yield promising though inconclusive results about short term efficacy of these drugs in the treatment of adult ADHD in patients with SUD and no other severe mental disorders. However, the efficacy of these drugs is scant or lacking for treating concurrent SUD. No serious safety issues have been associated with these drugs in patients with co-morbid SUD-ADHD, given their low risk of abuse and favourable side effect and drug–drug interaction profile. The decision to treat adult ADHD in the context of active SUD depends on various factors, some directly related to SUD-ADHD co-morbidity (e.g. degree of diagnostic uncertainty for ADHD) and other factors related to the clinical expertise of the medical staff and availability of adequate resources (e.g. the means to monitor compliance with pharmacological treatment). Our recommendation is that clinical decisions be individualized and based on a careful analysis of the advantages and disadvantages of pharmacological treatment for ADHD on a case-by-case basis in the context of active SUD. PMID:23216449

Predicted effect size of lisdexamfetamine treatment of attention deficit/hyperactivity disorder (ADHD) in European adults: Estimates based on indirect analysis using a systematic review and meta-regression analysis.

PubMed

Fridman, M; Hodgkins, P S; Kahle, J S; Erder, M H

2015-06-01

There are few approved therapies for adults with attention-deficit/hyperactivity disorder (ADHD) in Europe. Lisdexamfetamine (LDX) is an effective treatment for ADHD; however, no clinical trials examining the efficacy of LDX specifically in European adults have been conducted. Therefore, to estimate the efficacy of LDX in European adults we performed a meta-regression of existing clinical data. A systematic review identified US- and Europe-based randomized efficacy trials of LDX, atomoxetine (ATX), or osmotic-release oral system methylphenidate (OROS-MPH) in children/adolescents and adults. A meta-regression model was then fitted to the published/calculated effect sizes (Cohen's d) using medication, geographical location, and age group as predictors. The LDX effect size in European adults was extrapolated from the fitted model. Sensitivity analyses performed included using adult-only studies and adding studies with placebo designs other than a standard pill-placebo design. Twenty-two of 2832 identified articles met inclusion criteria. The model-estimated effect size of LDX for European adults was 1.070 (95% confidence interval: 0.738, 1.401), larger than the 0.8 threshold for large effect sizes. The overall model fit was adequate (80%) and stable in the sensitivity analyses. This model predicts that LDX may have a large treatment effect size in European adults with ADHD. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

[Children's relative age in class and medication for attention-deficit/hyperactivity disorder. A population-based study in a health department in Spain].

PubMed

Librero, Julián; Izquierdo-María, Roberto; García-Gil, María; Peiró, Salvador

2015-12-07

Previous studies in various countries have shown that the youngest school children in the same class-grade are more likely to be treated for attention-deficit/hyperactivity disorder (ADHD) than their older classmates. The aim of this study is to determine in the Spanish setting whether younger relative age children in each grade have a higher prevalence of treatment for ADHD. Population, observational, cross-sectional study in a health department, using prevalence data (November 2013) of treatment for ADHD in children aged 6-12 years. Data was obtained from the information systems of the Valencia Ministry of Health and multivariate models were used to estimate the prevalence ratio of treatment according to the month of birth of children in each grade. Twenty thousand two hundred and thirty-seven children were included of whom 1.73% were treated for ADHD (boys: 2.70%; girls: 0.71%) in October 2013. The prevalence of treatment increased with age, in males, and in youngest children (born in the last months of each year). In the multivariate analysis, the prevalence of treatment in the youngest children (born in the months of August to December) was 2.5 to 3 times higher than in their older classmates (born in January). The younger children relative to their classmates are more likely to be treated pharmacologically with methylphenidate and/or atomoxetine. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD).

PubMed

Sharma, Alok; Couture, Justin

2014-02-01

To review the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). A literature search was conducted in PubMed and EMBASE using the terms attention deficit hyperactive disorder, ADHD, pathophysiology, etiology, and neurobiology. Limits applied were the following: published in the past 10 years (January 2003 to August 2013), humans, review, meta-analysis, and English language. These yielded 63 articles in PubMed and 74 in EMBASE. After removing duplicate/irrelevant articles, 86 articles and their relevant reference citations were reviewed. ADHD is a neurological disorder that affects children, but symptoms may persist into adulthood. Individuals suffering from this disorder exhibit hyperactivity, inattention, impulsivity, and problems in social interaction and academic performance. Medications used to treat ADHD such as methylphenidate, amphetamine, and atomoxetine indicate a dopamine/norepinephrine deficit as the neurochemical basis of ADHD, but the etiology is more complex. Moreover, these agents have poor adverse effect profiles and a multitude of drug interactions. Because these drugs are also dispensed to adults who may have concomitant conditions or medications, a pharmacist needs to be aware of these adverse events and drug interactions. This review, therefore, focuses on the pathophysiology, etiology, and treatment of ADHD and details the adverse effects and drug interaction profiles of the drugs used to treat it. Published research shows the benefit of drug therapy for ADHD in children, but given the poor adverse effect and drug interaction profiles, these must be dispensed with caution.

Reappraisal of abnormal EEG findings in children with ADHD: on the relationship between ADHD and epileptiform discharges.

PubMed

Kanazawa, Osamu

2014-12-01

Attention-deficit hyperactivity disorder is suggested to be closely related to epilepsy. A recent large-scale study revealed that ADHD in children is often accompanied by epilepsy. In Japan, methylphenidate (MPH) as a sustained-action tablet and atomoxetine (ATX) became commercially available as medications for children recently. Since then, the number of prescriptions of both medicines has increased rapidly. Methylphenidate, as a psychostimulant, has been a source of concern because of the perceived lowered threshold for convulsions in children. Based on this background, reappraisal of EEG findings in children with ADHD is important in order to detect indications of potential comorbid epilepsy and to investigate the developmental mechanisms of the neurophysiological manifestations in patients with ADHD. EEG findings in children newly diagnosed with ADHD and their relationship with clinical findings were investigated. The author evaluated 208 patients with ADHD newly diagnosed between 2008 and 2013. Of these, there were 145 patients for whom EEG findings were obtained along with a clinical follow-up for at least three months. Patients with IQ<70 were excluded in order to obtain a homogenous group of patients with ADHD. The male-to-female ratio was 130:15, and the age range was between 5 years, 9 months and 19 years, 9 months, with mean age of 11 years, 4 months. The results revealed that about half (48.3%) of the children with ADHD had abnormal EEG findings and that 22.1% of them had epileptiform discharges. Patients without comorbidity of autism spectrum disorder (ore homogenous group with ADHD) were especially likely to show abnormal EEG findings (51.0%) including epileptiform discharges (24.5%). Afebrile seizures, that is, epileptic seizures, occurred in a boy three days after commencement of administration with MPH as a sustained-action tablet. In four patients with a past history of epilepsy, neither relapse of EEG abnormality nor epileptic seizures were observed during the follow-up period. There was to be a significantly close relationship between ADHD and epileptiform discharges. Therefore, in patients with ADHD, it is important to obtain more precise information about seizures and presence of epilepsy from the personal and family histories, as well as to undertake a thorough EEG examination. Copyright © 2014 Elsevier Inc. All rights reserved.

Attention-deficit hyperactivity disorder medication use: factors involved in prescribing, safety aspects and outcomes.

PubMed

Martinez-Raga, Jose; Ferreros, Amparo; Knecht, Carlos; de Alvaro, Raquel; Carabal, Eloisa

2017-03-01

While treatment of patients with attention-deficit hyperactivity disorder (ADHD) is based on a multimodal approach that combines medication with specific psychological interventions, pharmacotherapy alone is generally considered an essential and cost-effective element. This paper aims to comprehensively and critically review factors involved in prescribing and medication use in individuals diagnosed with ADHD, focusing on the difficulties facing patients with ADHD seeking treatment, as well as the safety and tolerability aspects of ADHD pharmacotherapies, with particular attention on the cardiovascular adverse events and the potential risk of misuse or diversion of ADHD medications. A comprehensive and systematic literature search of PubMed/MEDLINE database was conducted to identify studies published in peer-reviewed journals until 1 August 2016. Children, adolescents and adults often encounter significant difficulties in the process of accessing specialist assessment and treatment for ADHD as a consequence of disparities in service organization and available treatment provision. Despite the well-established efficacy and overall safety profile, ADHD medications are not exempt from adverse events. The cardiovascular safety of pharmacotherapies used for treating individuals with ADHD has raised particular concerns; however there is little evidence of serious cardiovascular adverse events, including no serious corrected QT (QTc) abnormalities associated with stimulants, atomoxetine or α2-adrenergic receptor agonists. Although the abuse of prescription stimulant drugs, particularly, short-acting stimulants is a prevalent and growing problem, nonmedical use of prescription stimulants within the clinical context is very limited. In addition, nonstimulant ADHD medications lack any reinforcing effects and consequently any abuse potential.

[Attention deficit hyperactivity disorder: pharmacological options that are not "Ritalin"].

PubMed

Shmueli, Dorit; Gross-Tsur, Varda

2005-08-01

Methylphenidate (Ritalin) is the drug of choice for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Methylphenidate has been rigorously studied and found to be a safe and effective drug. However, there is a need for pharmacological alternatives since there are patients and therapists who are reluctant to use the drug. In some cases it is ineffective, others suffer from intolerable side effects and still others need treatment extended for the entire day. Recently, new pharmacological agents have been introduced for use in Israel. This article discusses the use of these new psychostimulants as well as other non-psychostimulant options. One of the new psychostimulants is Concerta, a very long acting methylphenidate preparation, that has been shown to be very effective. Adderall, a mixture of amphetamine salts, and Dexedrine (dexamphetamine) are also widely used. This article also presents data on an older psychostimulant, Cylert, Nitan (pemoline), prescribed until recently as a major alternative for Ritalin but, at present, it is rarely used because of its hepatotoxicity. Strattera (atomoxetine), a new non-stimulant drug, is a selective noradrenaline reuptake inhibitor that is a promising therapeutic option for children with ADHD. In summary, it is encouraging that there are multiple pharmacological options for treating children with ADHD. There is no one drug for all children and this is particularly important for children with do not respond to methylphenidate. Last, but not least, the mere fact that the new drugs are not called Ritalin, may play an important role in reducing the irrational opposition to the pharmacological treatment of ADHD.

The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety.

PubMed

Heal, D J; Cheetham, S C; Smith, S L

2009-12-01

Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.

Responding for a conditioned reinforcer or unconditioned sensory reinforcer in mice: interactions with environmental enrichment, social isolation, and monoamine reuptake inhibitors.

PubMed

Browne, Caleb J; Fletcher, Paul J; Zeeb, Fiona D

2016-03-01

Environmental factors influence the etiology of many psychiatric disorders. Likewise, environmental factors can alter processes central to motivation. Therefore, motivational deficits present in many disorders may be influenced by early life environmental conditions. We examined whether housing animals in different environmental conditions influenced the ability of sensory stimuli to acquire incentive value and whether elevated monoamine activity altered responsing for these stimuli. Isolation-housed (IH), pair-housed (PH), and environmentally enriched (EE) male C57BL/6N mice were examined in tests of responding for a conditioned reinforcer (CRf) or an unconditioned sensory reinforcer (USRf). The CRf was previously paired with saccharin delivery through Pavlovian conditioning, while the USRf was not conditioned with a reward. Following baseline tests of responding for the CRf or USRf, the effects of elevated monoamine activity were examined. At baseline, PH and EE mice responded similarly for the CRf or USRf. IH mice responded more for the CRf but exhibited slower acquisition of responding for the USRf. Administration of citalopram, a serotonin transporter blocker, or atomoxetine, a norepinephrine transporter blocker, decreased responding for the CRf and USRf in all groups. The dopamine transporter blocker GBR 12909 generally increased responding for the CRf and USRf, but further analysis revealed enhanced responding for both reinforcers only in EE mice. Baseline incentive motivation is strongly influenced by the social component of housing conditions. Furthermore, environmental enrichment increased the sensitivity to elevated dopamine activity, while acute elevations in serotonin and norepinephrine inhibit incentive motivation irrespective of housing condition.

The Quality of Life of Adults with Attention Deficit Hyperactivity Disorder

PubMed Central

Goldenberg, Matthew; Perry, Robert; Ishak, Waguih William

2012-01-01

Objective: Across all medical specialties, quality of life has become an important measure of outcomes in both research and clinical settings. However, to date, there has not been a systematic review of the research relevant to quality of life in populations with adult attention deficit hyperactivity disorder. We approach quality of life in adult attention deficit hyperactivity disorder by answering the following questions: 1) What specific metrics are used to assess quality of life in adult attention deficit hyperactivity disorder? 2) What is the impact of adult attention deficit hyperactivity disorder on quality of life? 3) What effects do attention deficit hyperactivity disorder treatments have on quality of life? Searches of major electronic databases were conducted, and reference lists from the identified articles were searched for additional studies, with a focus on studies that utilized quality of life measures. Design: Thirty-six relevant studies are included in our review. Results: There are multiple unique measures currently used to measure quality of life in adult attention deficit hyperactivity disorder, ranging from general quality of life scales to those specifically designed for use in attention deficit hyperactivity disorder. Attention deficit hyperactivity disorder was found to significantly worsen the quality of life in adults. Treatment with atomoxetine and mixed amphetamine salts has shown beneficial effects on quality of life even in cases without symptomatology improvement. Conclusion: Pharmacological treatment and early diagnosis have a positive impact on outcomes, longterm prognosis, and quality of life in adults with attention deficit hyperactivity disorder. Having multiple unique measures of quality of life have limited the direct comparison of different classes of attention deficit hyperactivity disorder medication treatments and future research should be aimed to address this. PMID:22808445

Review of the evidence for the management of co-morbid Tic disorders in children and adolescents with attention deficit hyperactivity disorder

PubMed Central

Ogundele, Michael O; Ayyash, Hani F

2018-01-01

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children and adolescents, with prevalence ranging between 5% and 12% in the developed countries. Tic disorders (TD) are common co-morbidities in paediatric ADHD patients with or without pharmacotherapy treatment. There has been conflicting evidence of the role of psychostimulants in either precipitating or exacerbating TDs in ADHD patients. We carried out a literature review relating to the management of TDs in children and adolescents with ADHD through a comprehensive search of MEDLINE, EMBASE, CINAHL and Cochrane databases. No quantitative synthesis (meta-analysis) was deemed appropriate. Meta-analysis of controlled trials does not support an association between new onset or worsening of tics and normal doses of psychostimulant use. Supratherapeutic doses of dextroamphetamine have been shown to exacerbate TD. Most tics are mild or moderate and respond to psychoeducation and behavioural management. Level A evidence support the use of alpha adrenergic agonists, including Clonidine and Guanfacine, reuptake noradrenenaline inhibitors (Atomoxetine) and stimulants (Methylphenidate and Dexamphetamines) for the treatment of Tics and comorbid ADHD. Priority should be given to the management of co-morbid Tourette’s syndrome (TS) or severely disabling tics in children and adolescents with ADHD. Severe TDs may require antipsychotic treatment. Antipsychotics, especially Aripiprazole, are safe and effective treatment for TS or severe Tics, but they only moderately control the co-occurring ADHD symptomatology. Short vignettes of different common clinical scenarios are presented to help clinicians determine the most appropriate treatment to consider in each patient presenting with ADHD and co-morbid TDs. PMID:29456930

Contrasting Roles of Dopamine and Noradrenaline in the Motivational Properties of Social Play Behavior in Rats.

PubMed

Achterberg, E J Marijke; van Kerkhof, Linda W M; Servadio, Michela; van Swieten, Maaike M H; Houwing, Danielle J; Aalderink, Mandy; Driel, Nina V; Trezza, Viviana; Vanderschuren, Louk J M J

2016-02-01

Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-04-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: ABX-IL-8, Acclaim, adalimumab, AGI-1067, alagebrium chloride, alemtuzumab, Alequel, Androgel, anti-IL-12 MAb, AOD-9604, aripiprazole, atomoxetine hydrochloride; Biphasic insulin aspart, bosentan, botulinum toxin type B, bovine lactoferrin, brivudine; Cantuzumab mertansine, CB-1954, CDB-4124, CEA-TRICOM, choriogonadotropin alfa, cilansetron, CpG-10101, CpG-7909, CTL-102, CTL-102/CB-1954; DAC:GRF, darbepoetin alfa, davanat-1, decitabine, del-1 Genemedicine, dexanabinol, dextofisopam, dnaJP1, dronedarone hydrochloride, dutasteride; Ecogramostim, eletriptan, emtricitabine, EPI-hNE-4, eplerenone, eplivanserin fumarate, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, etoricoxib, ezetimibe; Falecalcitriol, fingolimod hydrochloride; Gepirone hydrochloride; HBV-ISS, HSV-2 theracine, human insulin; Imatinib mesylate, Indiplon, insulin glargine, ISAtx-247; L612 HuMAb, levodopa/carbidopa/entacapone, lidocaine/prilocaine, LL-2113AD, lucinactant, LY-156735; Meclinertant, metelimumab, morphine hydrochloride, morphine-6-glucuronide; Natalizumab, nimotuzumab, NX-1207, NYVAC-HIV C; Omalizumab, onercept, osanetant; PABA, palosuran sulfate, parathyroid hormone (human recombinant), parecoxib sodium, PBI-1402, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, PINC, pregabalin; Ramelteon, rasagiline mesilate, rasburicase, rimonabant hydrochloride, RO-0098557, rofecoxib, rosiglitazone maleate/metformin hydrochloride; Safinamide mesilate, SHL-749, sitaxsentan sodium, sparfosic acid, SprayGel, squalamine, St. John's Wort extract, synthetic human secretin; Taxus, telavancin hydrochloride, telithromycin, temoporfin, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate/emtricitabine, teriparatide, testosterone gel, TG-1024, tirapazamine, travoprost, travoprost/timolol; Valdecoxib, valganciclovir hydrochloride, voriconazole; Ximelagatran.

The noradrenergic paradox: implications in the management of depression and anxiety

PubMed Central

Montoya, Alonso; Bruins, Robert; Katzman, Martin A; Blier, Pierre

2016-01-01

Both major depressive disorder and the anxiety disorders are major causes of disability and markedly contribute to a significant global burden of the disease worldwide. In part because of the significant socioeconomic burden associated with these disorders, theories have been developed to specifically build clinical treatment approaches. One such theory, the monoaminergic hypothesis, has led to the development of several generations of selective and nonselective inhibitors of transporters of serotonin and norepinephrine, with the goal of augmenting monoaminergic transmission. These efforts have led to considerable success in the development of antidepressant therapeutics. However, there is a strong correlation between enhanced noradrenergic activity and fear and anxiety. Consequently, some physicians have expressed concerns that the same enhanced noradrenergic activity that alleviates depression could also promote anxiety. The fact that the serotonergic and noradrenergic reuptake inhibitors are successfully used in the treatment of anxiety and panic disorders seems paradoxical. This review was undertaken to determine if any clinical evidence exists to show that serotonergic and noradrenergic reuptake inhibitors can cause anxiety. The PubMed, EMBASE, and Cochrane Library databases were searched, and the results limited to randomized, double-blind, placebo-controlled studies performed in nongeriatric adults and with clear outcome measures were reported. Based on these criteria, a total of 52 studies were examined. Patients in these studies suffered from depression or anxiety disorders (generalized and social anxiety disorders, panic disorder, and posttraumatic stress disorder). The large majority of these studies employed venlafaxine or duloxetine, and the remainder used tri-cyclic antidepressants, atomoxetine, or reboxetine. All the studies reported clinically significant alleviation of depressive and/or anxious symptoms by these therapeutics. In none of these studies was anxiety a treatment-emergent adverse effect. This review argues against the impression that enhanced generalized noradrenergic activity promotes the emergence of anxiety. PMID:27042068

In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude.

PubMed

Venkatakrishnan, Karthik; Obach, R Scott

2005-06-01

Attempts at predicting drug-drug interactions perpetrated by paroxetine from in vitro data have utilized reversible enzyme inhibition models and have been unsuccessful to date, grossly underpredicting interaction magnitude. Recent data have provided evidence for mechanism-based inactivation of CYP2D6 by paroxetine. We have predicted the pharmacokinetic consequences of CYP2D6 inactivation by paroxetine from in vitro inactivation kinetics (kinact 0.17 min(-1), unbound KI 0.315 microM), in vivo inhibitor concentrations, and an estimated CYP2D6 degradation half-life of 51 h, using a mathematical model of mechanism-based inhibition. The model-predicted accumulation ratio of paroxetine was 5 times that expected from single-dose kinetics and in excellent agreement with the observed 5- to 6-fold greater accumulation. Magnitudes of interactions produced by paroxetine (20-30 mg/day) with desipramine, risperidone, perphenazine, atomoxetine, (S)-metoprolol, and (R)-metoprolol were predicted, considering the contribution of CYP2D6 to their oral clearance. Predicted fold-increases in victim drug AUC were 5-, 6-, 5-, 6-, 4-, and 6-fold, respectively, and are in reasonable agreement with observed values of 5-, 6-, >7-, 7-, 5-, and 8-fold, respectively. Failure to consider microsomal binding in vitro adversely affected predictive accuracy. Simulation of the sensitivities of these predictions to model inputs suggests a 2-fold underprediction of interaction magnitude when a CYP2D6 degradation half-life of 14 h (reported for rat CYP3A) is used. In summary, the scaling model for mechanism-based inactivation successfully predicted the pharmacokinetic consequences of CYP2D6 inactivation by paroxetine from in vitro data.

Use of drugs for ADHD among adults-a multinational study among 15.8 million adults in the Nordic countries.

PubMed

Karlstad, Øystein; Zoëga, Helga; Furu, Kari; Bahmanyar, Shahram; Martikainen, Jaana E; Kieler, Helle; Pottegård, Anton

2016-12-01

The use of ADHD drugs among adults is controversial and has until recently not been approved for use in adults in most countries. The aim was to investigate use of ADHD drugs (stimulants and atomoxetine) among the entire adult population in the Nordic countries. We conducted a multinational population-based prescription register study based on the entire adult population in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). All users of ADHD drugs aged 18-64 years during 2008-2012 were included, which for 2012 comprised 76,896 drug users among 15.8 million adult inhabitants. Annual prevalence of drug use increased during the study period for both genders and all age groups. The overall prevalence increased from 2.4 to 5.3 per 1000 men and 1.8 to 4.4 per 1000 women. Incidence also increased, but to a lesser extent in the last part of the study period. Methylphenidate was used by 88 % of drug users. Treatment was discontinued within the first year by 21 % of new drug users. Among all users of ADHD drugs, 53 % of men and 64 % of women concurrently used other psychotropic drugs, most frequently antidepressants and hypnotics. Psychotropic co-medication increased with age and was more pronounced among women than men. Use of ADHD drug among adults more than doubled over a 5-year period, and a majority were concurrently treated with other psychotropics. Adults constitute a substantial proportion of persons treated with ADHD drugs. Thus, evidence for long-term efficacy and safety in adults is urgently needed.

ADHD Medications and Risk of Serious Cardiovascular Events In Young and Middle-Aged Adults

PubMed Central

Habel, Laurel A.; Cooper, William O.; Sox, Colin M.; Chan, K. Arnold; Fireman, Bruce H.; Arbogast, Patrick G.; Cheetham, T. Craig; Quinn, Virginia P.; Dublin, Sascha; Boudreau, Denise M.; Andrade, Susan E.; Pawloski, Pamala A.; Raebel, Marsha A.; Smith, David H.; Achacoso, Ninah; Uratsu, Connie; Go, Alan S.; Sidney, Steve; Nguyen-Huynh, Mai N; Ray, Wayne A.; Selby, Joe V.

2012-01-01

Context More than 1.5 million US adults use stimulants and other medications labeled for treatment of attention deficit hyperactivity disorder (ADHD). These agents can increase heart rate and blood pressure, raising concerns about their cardiovascular safety. Objective Examine whether current use of medications used primarily to treat ADHD is associated with increased risk of serious cardiovascular events in young and middle-aged adults. Design Retrospective, population-based cohort study Setting Computerized health records from 4 study sites (OptumInsight Epidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network), starting in 1986 at one site and ending in 2005 at all sites, with additional covariate assessment using 2007 survey data. Participants Adults aged 25–64 years with dispensed prescriptions for methylphenidate, amphetamine, or atomoxetine at baseline. Each medication user (n=150,359) was matched to two non-users on study site, birth year, sex, and calendar year (total users and non-users=443,198). Main Outcome Serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death (SCD), or stroke. Comparison between current or new users and remote users to account for potential healthy user bias. Results During 806,182 person-years of follow-up (median 1.3 years per person), 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred. There were 107,322 person-years of current use (median 0.33 years), with a crude incidence per 1000 person-years of 1.34 (95% CI, 1.14–1.57) for MI, 0.30 (95% CI, 0.20–0.42) for SCD, and 0.56 (95% CI, 0.43–0.72) for stroke. The multivariable adjusted rate ratio (RR) of serious cardiovascular events for current use vs non-use of ADHD medications was 0.83 (95% CI 0.72–0.96). Among new users of ADHD medications, the adjusted RR was 0.77 (95% CI 0.63–0.94). The adjusted RR was 1.03 (95% CI, 0.86–1.24) for current use vs remote use, and was 1.02 (95% CI, 0.82–1.28) for new use vs remote use. Conclusion Among young and middle-aged adults, current or new use of ADHD medications, compared with non-use or remote use, was not associated with an increased risk of serious cardiovascular events. Apparent protective associations likely represent healthy user bias. PMID:22161946

Correlates of incident bipolar disorder in children and adolescents diagnosed with attention-deficit/hyperactivity disorder.

PubMed

Jerrell, Jeanette M; McIntyre, Roger S; Park, Yong-Moon Mark

2014-11-01

The greater severity and chronicity of illness in youths with co-occurring attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder deserve further investigation as to the risk imparted by comorbid conditions and the pharmacotherapies employed. A retrospective cohort design was employed, using South Carolina's Medicaid claims dataset covering outpatient and inpatient medical and psychiatric service claims with International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses and medication prescriptions between January 1996 and December 2006 for patients ≤ 17 years of age. The cohort included 22,797 cases diagnosed with ADHD at a mean age of 7.8 years; 1,604 (7.0%) were diagnosed with bipolar disorder at a mean age of 12.2 years. The bipolar disorder group developed conduct disorder (CD)/oppositional defiant disorder (ODD), anxiety disorder, and a substance use disorder later than the ADHD-only group. The odds of a child with ADHD developing bipolar disorder were significantly and positively associated with a comorbid diagnosis of CD/ODD (adjusted odds ratio [aOR] = 4.01), anxiety disorder (aOR = 2.39), or substance use disorder (aOR = 1.88); longer treatment with methylphenidate, mixed amphetamine salts, or atomoxetine (aOR = 1.01); not being African American (aOR = 1.61); and being treated with certain antidepressant medications, most notably fluoxetine (aOR = 2.00), sertraline (aOR = 2.29), bupropion (aOR = 2.22), trazodone (aOR = 2.15), or venlafaxine (aOR = 2.37) prior to the first diagnosis of mania. Controlling for pharmacotherapy differences, incident bipolar disorder was more likely in individuals clustering specific patterns of comorbid psychiatric disorders, suggesting that there are different pathways to bipolarity and providing a clinical impetus for prioritizing prevention and preemptive strategies to reduce their hazardous influence. © Copyright 2014 Physicians Postgraduate Press, Inc.

Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model.

PubMed

Tomlinson, Anneka; Grayson, Ben; Marsh, Samuel; Hayward, Andrew; Marshall, Kay M; Neill, Joanna C

2015-04-01

Prefrontal cortical dopamine plays an important role in cognitive control, specifically in attention and response inhibition; the core deficits in ADHD. We have previously shown that methylphenidate and atomoxetine differentially improve these deficits dependent on baseline performance. The present study extends this work to investigate the effects of putative therapeutic targets in our model. A selective dopamine D4 receptor agonist (A-412997) and the catechol-O-methyl-transferase (COMT) inhibitor; tolcapone, were investigated in the combined subtype of adult ADHD (ADHD-C). Adult female rats were trained to criterion in the 5C-CPT (5-Choice Continuous Performance Task) and then separated into subgroups according to baseline levels of sustained attention, vigilance, and response disinhibition. The subgroups included: high-attentive (HA) and low-attentive with high response disinhibition (ADHD-C). The ADHD-C subgroup was selected to represent the combined subtype of adult ADHD. Effects of tolcapone (3.0, 10.0, 15.0mg/kg) and A-412997 (0.1, 0.3, 1.0µmol/kg) were tested by increasing the variable inter-trial-interval (ITI) duration in the 5C-CPT. Tolcapone (15mg/kg) significantly increased sustained attention, vigilance and response inhibition in ADHD-C animals, and impaired attention in HA animals. A-412997 (1.0µmol/kg) significantly increased vigilance and response inhibition in ADHD-C animals only, with no effect in HA animals. This is the first study to use the translational 5C-CPT to model the adult ADHD-C subtype in rats and to study new targets in this model. Both tolcapone and A-412997 increased vigilance and response inhibition in the ADHD-C subgroup. D4 and COMT are emerging as important potential therapeutic targets in adult ADHD that warrant further investigation. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

78 FR 59729 - Final Comparative Environmental Evaluation of Alternatives for Handling Low-Level Radioactive...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-27

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0218] Final Comparative Environmental Evaluation of... Regulatory Commission (NRC) is issuing the Final Comparative Environmental Evaluation of Alternatives for... commercial nuclear power plants (NPPs). This comparative environmental evaluation has been conducted...

10 CFR 960.3-2-2-3 - Comparative evaluation of all sites proposed for nomination.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Comparative evaluation of all sites proposed for...-3 Comparative evaluation of all sites proposed for nomination. Sixth, for those potentially... reasonable comparative evaluation of each such site with all other such sites shall be made. For each site...

10 CFR 960.3-2-2-3 - Comparative evaluation of all sites proposed for nomination.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Comparative evaluation of all sites proposed for...-3 Comparative evaluation of all sites proposed for nomination. Sixth, for those potentially... reasonable comparative evaluation of each such site with all other such sites shall be made. For each site...

10 CFR 960.3-2-2-3 - Comparative evaluation of all sites proposed for nomination.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 4 2013-01-01 2013-01-01 false Comparative evaluation of all sites proposed for...-3 Comparative evaluation of all sites proposed for nomination. Sixth, for those potentially... reasonable comparative evaluation of each such site with all other such sites shall be made. For each site...

10 CFR 960.3-2-2-3 - Comparative evaluation of all sites proposed for nomination.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 4 2012-01-01 2012-01-01 false Comparative evaluation of all sites proposed for...-3 Comparative evaluation of all sites proposed for nomination. Sixth, for those potentially... reasonable comparative evaluation of each such site with all other such sites shall be made. For each site...

10 CFR 960.3-2-2-3 - Comparative evaluation of all sites proposed for nomination.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 4 2014-01-01 2014-01-01 false Comparative evaluation of all sites proposed for...-3 Comparative evaluation of all sites proposed for nomination. Sixth, for those potentially... reasonable comparative evaluation of each such site with all other such sites shall be made. For each site...

77 FR 58416 - Comparative Environmental Evaluation of Alternatives for Handling Low-Level Radioactive Waste...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-20

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0218] Comparative Environmental Evaluation of Alternatives... public comment the Draft Comparative Environmental Evaluation of Alternatives for Handling Low-Level.... Availability of Documents ADAMS Accession No. Document title ML12256A965 Draft Comparative Environmental...

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 5 2010-10-01 2010-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 5 2013-10-01 2013-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 5 2014-10-01 2014-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 5 2012-10-01 2012-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

47 CFR 101.51 - Comparative evaluation of mutually exclusive applications.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 5 2011-10-01 2011-10-01 false Comparative evaluation of mutually exclusive....51 Comparative evaluation of mutually exclusive applications. (a) In order to expedite action on... this section if: (1) The applications are entitled to comparative consideration pursuant to § 101.45...

10 CFR 960.3-1-5 - Basis for site evaluations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... comparative evaluations of sites in terms of the capabilities of the natural barriers for waste isolation and.... Comparative site evaluations shall place primary importance on the natural barriers of the site. In such... only to the extent necessary to obtain realistic source terms for comparative site evaluations based on...

10 CFR 960.3-1-5 - Basis for site evaluations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... comparative evaluations of sites in terms of the capabilities of the natural barriers for waste isolation and.... Comparative site evaluations shall place primary importance on the natural barriers of the site. In such... only to the extent necessary to obtain realistic source terms for comparative site evaluations based on...

10 CFR 960.3-1-5 - Basis for site evaluations.

Code of Federal Regulations, 2011 CFR

2011-01-01

... comparative evaluations of sites in terms of the capabilities of the natural barriers for waste isolation and.... Comparative site evaluations shall place primary importance on the natural barriers of the site. In such... only to the extent necessary to obtain realistic source terms for comparative site evaluations based on...

10 CFR 960.3-1-5 - Basis for site evaluations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... comparative evaluations of sites in terms of the capabilities of the natural barriers for waste isolation and.... Comparative site evaluations shall place primary importance on the natural barriers of the site. In such... only to the extent necessary to obtain realistic source terms for comparative site evaluations based on...

10 CFR 960.3-1-5 - Basis for site evaluations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... comparative evaluations of sites in terms of the capabilities of the natural barriers for waste isolation and.... Comparative site evaluations shall place primary importance on the natural barriers of the site. In such... only to the extent necessary to obtain realistic source terms for comparative site evaluations based on...

Procedures for Comparing Instructional Programs.

ERIC Educational Resources Information Center

Klein, Stephen

This paper examines comparative educational program evaluation. Suggested evaluative criteria and evaluation techniques and their weaknesses are discussed. An evaluation formula is proposed, and an example of its operation is provided. (DG)

Drug Treatment Patterns of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents in Germany: Results from a Large Population-Based Cohort Study

PubMed Central

Mikolajczyk, Rafael T.; Banaschewski, Tobias; Petermann, Ulrike; Petermann, Franz; Kraut, Angela A.; Langner, Ingo

2012-01-01

Abstract Objective Despite a substantial increase in total methylphenidate (MPH) prescriptions in Germany over the last 20 years, and the introduction of modified release MPH (MR MPH) and atomoxetine (ATX), remarkably little is known about treatment patterns of attention- deficit/hyperactivity disorder (ADHD) in individual patients. Methods Usage patterns of ADHD drugs in children and adolescents in Germany were analyzed using data from one large German health insurance including >7,200,000 members. Of those, 6210 ADHD patients newly diagnosed in 2005 were followed for a maximum of 4 years. Kaplan–Meier estimates were calculated for onset and discontinuation of ADHD drug treatment. Predictors of time until drug treatment initiation were assessed by Cox regression. Results During follow-up, 52.0% of ADHD subjects (53.4% of boys, 47.5% of girls) received ADHD drug treatment. The majority of them (91.6%) were started on MPH, with immediate release MPH (IR MPH) being the initial treatment choice in 75.3%. In these subjects, change to drug treatment with MR MPH in the first year occurred in 48% by switch or addition. Significant predictors of drug treatment were behavioral and emotional disorders (HR=1.13; 95% CI 1.03–1.24) and a diagnosis of ADHD with conduct disorder (HR=1.21, 95% CI 1.12–1.32), whereas young age showed a protective effect. After 6, 12, and 24 months of treatment initiation, 22.4%, 43.4%, and 66.3% of treated girls, and 17.8%, 36.1%, and 54.1% of treated boys had discontinued ADHD treatment. Conclusion Drug treatment of ADHD was relatively common in Germany and more frequent in boys than in girls. IR MPH was the predominant treatment choice at treatment initiation. Approximately 20% of treated subjects discontinued drug treatment within the first 6 months, with girls stopping drug treatment earlier than boys. The reasons for early drug discontinuation need to be further explored. PMID:23234588

Depressive symptoms as a side effect of the sustained release form of methylphenidate in a 7-year-old boy with attention-deficit hyperactivity disorder.

PubMed

Lakić, Aneta

2012-02-01

Hyperkinetic disorder or attention-deficit hyperactivity disorder (ADHD) is a clinical entity consisting of a cluster of symptoms including hyperactivity, attention disorder and impulse control disorder group. In the context of ADHD etiology we may say that genetic, clinical and imaging studies point out a disruption of the brain dopamine system, which is corroborated by the clinical effectiveness of stimulant drugs, which increase extracellular dopamine in the brain. Basically, it is a biological and not psychological disorder, which is important both for the comprehension and therapeutical approach to this problem. Today, the best recommended approach regarding children with ADHD is a combination of two therapeutic modalities: pharmacotherapy and behavioral treatment. The first-choice drugs for this disorder belong to the group of sympathomimetics--psychostimulants and atomoxetine (more recently). As the first-choice therapy, methylphenydate in sustained release form has numerous advantages. Like all drugs, methylphenidate has its unwanted side effects. Most common are: loss of appetite, weight loss, sleeping disorders, irritability, headache. These side effects are well-known and documented in the literature. By analysing the available literature we have found cases of psychiatric side effects such as: psychosis, mania, visual hallucinations, agitation, suicidal ideas. We have not found examples of ADHD in children who use increased dosage of sustained release of methylphenidate leading to depressive symptomatology. On the other side, methylphenidate may be prescribed for off-label use in treatment-resistant cases of depression. The case of a 7-year-old boy diagnosed with ADHD was on a minimal dose of sustained release form of methylphenidate. After initial titration of the drug, i.e. after raising the dose to the next level the boy developed clinical signs of depression. The treatment was ceased and depressive symptoms were withdrawed. Manifestation of depressive symptomatology after dose increasement of sustained release form of methylphenidate in a 7-year-old boy with ADHD represents an uncommon side effect. Precise drug activity mechanisms responsible for the appearance of these symptoms remains to be explained.

The cannabis withdrawal syndrome: current insights

PubMed Central

Bonnet, Udo; Preuss, Ulrich W

2017-01-01

The cannabis withdrawal syndrome (CWS) is a criterion of cannabis use disorders (CUDs) (Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition) and cannabis dependence (International Classification of Diseases [ICD]-10). Several lines of evidence from animal and human studies indicate that cessation from long-term and regular cannabis use precipitates a specific withdrawal syndrome with mainly mood and behavioral symptoms of light to moderate intensity, which can usually be treated in an outpatient setting. Regular cannabis intake is related to a desensitization and downregulation of human brain cannabinoid 1 (CB1) receptors. This starts to reverse within the first 2 days of abstinence and the receptors return to normal functioning within 4 weeks of abstinence, which could constitute a neurobiological time frame for the duration of CWS, not taking into account cellular and synaptic long-term neuroplasticity elicited by long-term cannabis use before cessation, for example, being possibly responsible for cannabis craving. The CWS severity is dependent on the amount of cannabis used pre-cessation, gender, and heritable and several environmental factors. Therefore, naturalistic severity of CWS highly varies. Women reported a stronger CWS than men including physical symptoms, such as nausea and stomach pain. Comorbidity with mental or somatic disorders, severe CUD, and low social functioning may require an inpatient treatment (preferably qualified detox) and post-acute rehabilitation. There are promising results with gabapentin and delta-9-tetrahydrocannabinol analogs in the treatment of CWS. Mirtazapine can be beneficial to treat CWS insomnia. According to small studies, venlafaxine can worsen the CWS, whereas other antidepressants, atomoxetine, lithium, buspirone, and divalproex had no relevant effect. Certainly, further research is required with respect to the impact of the CWS treatment setting on long-term CUD prognosis and with respect to psychopharmacological or behavioral approaches, such as aerobic exercise therapy or psychoeducation, in the treatment of CWS. The up-to-date ICD-11 Beta Draft is recommended to be expanded by physical CWS symptoms, the specification of CWS intensity and duration as well as gender effects. PMID:28490916

Research Governance and the Role of Evaluation: A Comparative Study

ERIC Educational Resources Information Center

Molas-Gallart, Jordi

2012-01-01

Through a comparative study of the United Kingdom and Spain, this article addresses the effect of different research governance structures on the functioning and uses of research evaluation. It distinguishes three main evaluation uses: distributive, improvement, and controlling. Research evaluation in the United Kingdom plays important…

A Synthetic Comparator Approach to Local Evaluation of School-Based Substance Use Prevention Programming.

PubMed

Hansen, William B; Derzon, James H; Reese, Eric L

2014-06-01

We propose a method for creating groups against which outcomes of local pretest-posttest evaluations of evidence-based programs can be judged. This involves assessing pretest markers for new and previously conducted evaluations to identify groups that have high pretest similarity. A database of 802 prior local evaluations provided six summary measures for analysis. The proximity of all groups using these variables is calculated as standardized proximities having values between 0 and 1. Five methods for creating standardized proximities are demonstrated. The approach allows proximity limits to be adjusted to find sufficient numbers of synthetic comparators. Several index cases are examined to assess the numbers of groups available to serve as comparators. Results show that most local evaluations would have sufficient numbers of comparators available for estimating program effects. This method holds promise as a tool for local evaluations to estimate relative effectiveness. © The Author(s) 2012.

76 FR 44929 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-27

... proposed information collection project: ``Evaluation of ARRA Comparative Effectiveness Research... INFORMATION: Proposed Project Evaluation of ARRA Comparative Effectiveness Research Dissemination Contractor... for reviewing and disseminating Comparative Effectiveness Research (CER) and findings to clinicians...

Comparative Evaluation of Quantitative Test Methods for Gases on a Hard Surface

DTIC Science & Technology

2017-02-01

COMPARATIVE EVALUATION OF QUANTITATIVE TEST METHODS FOR GASES ON A HARD SURFACE ECBC-TR-1426 Vipin Rastogi...1 COMPARATIVE EVALUATION OF QUANTITATIVE TEST METHODS FOR GASES ON A HARD SURFACE 1. INTRODUCTION Members of the U.S. Environmental...Generator 4 2.4 Experimental Design Each quantitative method was performed three times on three consecutive days. For the CD runs, three

Evaluating the Evaluators: Comparative Study of High School Newspaper Critique Services.

ERIC Educational Resources Information Center

Davis, Nancy

High school publication staffs depend on national critique services as a major means of evaluation and recognition, but most have no measure of how one critique service compares to the others, because they can afford the entry fee for only one evaluation. Thus, a study was conducted to test the validity of three major national critique…

A Multimodal Evaluation of the Comparative Efficacy of Yoga versus a Patient Centered Support Group for Treating Chronic Pain in Gulf War Illness

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-14-1-0615 TITLE: A Multimodal Evaluation of the Comparative Efficacy of Yoga versus a Patient- Centered Support Group for...Annual 3. DATES COVERED 29 Sept 2015- 28 Sept 2016 4. TITLE AND SUBTITLE A Multimodal Evaluation of the Comparative Efficacy of Yoga versus a Patient...veterans as compared to a pain management (control) group. (In progress) 4. Determine if the health-related benefits of treatment persist after

Evaluating Comparability in the Scoring of Performance Assessments for Accountability Purposes

ERIC Educational Resources Information Center

Lyons, Susan; Evans, Carla

2017-01-01

This brief summarizes "Comparability in Balanced Assessment Systems for State Accountability," published in "Educational Measurement: Issues and Practice" (Evans & Lyons 2017). The study evaluated comparability claims in local scoring of performance assessments across districts participating in New Hampshire's Performance…

A Multi-Stage Longitudinal Comparative Design Stage II Evaluation of the Changing Lives Program: The Life Course Interview (RDA-LCI)

ERIC Educational Resources Information Center

Arango, Lisa Lewis; Kurtines, William M.; Montgomery, Marilyn J.; Ritchie, Rachel

2008-01-01

The study reported in this article, a Multi-Stage Longitudinal Comparative Design Stage II evaluation conducted as a planned preliminary efficacy evaluation (psychometric evaluation of measures, short-term controlled outcome studies, etc.) of the Changing Lives Program (CLP), provided evidence for the reliability and validity of the qualitative…

Mere exposure revisited: the influence of growth versus security cues on evaluations of novel and familiar stimuli.

PubMed

Gillebaart, Marleen; Förster, Jens; Rotteveel, Mark

2012-11-01

Combining regulatory focus theory (Higgins, 1997) and novelty categorization theory (Förster, Marguc, & Gillebaart, 2010), we predicted that novel stimuli would be more positively evaluated when focused on growth as compared with security and that familiar stimuli would be more negatively evaluated when focused on growth as compared with security. This would occur, at least in part, because of changes in category breadth. We tested effects of several variables linked to growth and security on evaluations of novel and familiar stimuli. Using a subliminal mere exposure paradigm, results showed novel stimuli were evaluated more positively in a promotion focus compared to a prevention focus (Experiments 1A-1C), with high power compared to low power (Experiment 2A), and with the color blue compared to red (Experiment 2B). For familiar stimuli, all effects were reversed. Additionally, as predicted by novelty categorization theory, novel stimuli were liked better after broad compared to narrow category priming, and familiar stimuli were liked better after narrow compared with broad category priming (Experiment 3). We suggest, therefore, that although familiarity glows warmly in security-related contexts, people prefer novelty when they are primarily focused on growth. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

A novel resident-as-teacher training program to improve and evaluate obstetrics and gynecology resident teaching skills.

PubMed

Ricciotti, Hope A; Dodge, Laura E; Head, Julia; Atkins, K Meredith; Hacker, Michele R

2012-01-01

Residents play a significant role in teaching, but formal training, feedback, and evaluation are needed. Our aims were to assess resident teaching skills in the resident-as-teacher program, quantify correlations of faculty evaluations with resident self-evaluations, compare resident-as-teacher evaluations with clinical evaluations, and evaluate the resident-as-teacher program. The resident-as-teacher training program is a simulated, videotaped teaching encounter with a trained medical student and standardized teaching evaluation tool. Evaluations from the resident-as-teacher training program were compared to evaluations of resident teaching done by faculty, residents, and medical students from the clinical setting. Faculty evaluation of resident teaching skills in the resident-as-teacher program showed a mean total score of 4.5 ± 0.5 with statistically significant correlations between faculty assessment and resident self-evaluations (r = 0.47; p < 0.001). However, resident self-evaluation of teaching skill was lower than faculty evaluation (mean difference: 0.4; 95% CI 0.3-0.6). When compared to the clinical setting, resident-as-teacher evaluations were significantly correlated with faculty and resident evaluations, but not medical student evaluations. Evaluations from both the resident-as-teacher program and the clinical setting improved with duration of residency. The resident-as-teacher program provides a method to train, give feedback, and evaluate resident teaching.

Are Some Countries More Prone to Pressure Evaluators than Others? Comparing Findings from the United States, United Kingdom, Germany, and Switzerland

ERIC Educational Resources Information Center

Pleger, Lyn; Sager, Fritz; Morris, Michael; Meyer, Wolfgang; Stockmann, Reinhard

2017-01-01

Pressure on evaluators has been investigated recently by surveys in the USA, the UK, Germany, and Switzerland. This study compares the results of those studies regarding pressure on evaluators in different countries. The findings suggest that independence of evaluations does not exist for many respondents. Moreover, the person who commissioned the…

Student Evaluation of Instruction: Comparison between In-Class and Online Methods

ERIC Educational Resources Information Center

Capa-Aydin, Yesim

2016-01-01

This study compares student evaluations of instruction that were collected in-class with those gathered through an online survey. The two modes of administration were compared with respect to response rate, psychometric characteristics and mean ratings through different statistical analyses. Findings indicated that in-class evaluations produced a…

Evaluation of drug interaction microcomputer software: comparative study.

PubMed

Poirier, T I; Giudici, R

1991-01-01

Twelve drug interaction microcomputer software programs were evaluated and compared using general and specific criteria. This article summarizes and compares the features, ratings, advantages, and disadvantages of each program. Features of an ideal drug interaction program are noted. Recommended programs based on three price ranges are suggested.

Methods for comparative evaluation of propulsion system designs for supersonic aircraft

NASA Technical Reports Server (NTRS)

Tyson, R. M.; Mairs, R. Y.; Halferty, F. D., Jr.; Moore, B. E.; Chaloff, D.; Knudsen, A. W.

1976-01-01

The propulsion system comparative evaluation study was conducted to define a rapid, approximate method for evaluating the effects of propulsion system changes for an advanced supersonic cruise airplane, and to verify the approximate method by comparing its mission performance results with those from a more detailed analysis. A table look up computer program was developed to determine nacelle drag increments for a range of parametric nacelle shapes and sizes. Aircraft sensitivities to propulsion parameters were defined. Nacelle shapes, installed weights, and installed performance was determined for four study engines selected from the NASA supersonic cruise aircraft research (SCAR) engine studies program. Both rapid evaluation method (using sensitivities) and traditional preliminary design methods were then used to assess the four engines. The method was found to compare well with the more detailed analyses.

Constructive Student Feedback: Online vs. Traditional Course Evaluations

ERIC Educational Resources Information Center

Donovan, Judy; Mader, Cynthia E.; Shinsky, John

2010-01-01

Substantial efforts have been made recently to compare the effectiveness of traditional course formats to alternative formats (most often, online delivery compared to traditional on-site delivery). This study examines, not the delivery format but rather the evaluation format. It compares traditional paper and pencil methods for course evaluation…

Evaluating Comparative Judgment as an Approach to Essay Scoring

ERIC Educational Resources Information Center

Steedle, Jeffrey T.; Ferrara, Steve

2016-01-01

As an alternative to rubric scoring, comparative judgment generates essay scores by aggregating decisions about the relative quality of the essays. Comparative judgment eliminates certain scorer biases and potentially reduces training requirements, thereby allowing a large number of judges, including teachers, to participate in essay evaluation.…

Evaluation of Database Coverage: A Comparison of Two Methodologies.

ERIC Educational Resources Information Center

Tenopir, Carol

1982-01-01

Describes experiment which compared two techniques used for evaluating and comparing database coverage of a subject area, e.g., "bibliography" and "subject profile." Differences in time, cost, and results achieved are compared by applying techniques to field of volcanology using two databases, Geological Reference File and GeoArchive. Twenty…

Osteopathic manipulative treatment: A systematic review and critical appraisal of comparative effectiveness and health economics research.

PubMed

Steel, Amie; Sundberg, Tobias; Reid, Rebecca; Ward, Lesley; Bishop, Felicity L; Leach, Matthew; Cramer, Holger; Wardle, Jon; Adams, Jon

2017-02-01

In recent years, evidence has emerged regarding the effectiveness of osteopathic manipulative treatments (OMT). Despite growing evidence in this field, there is need for appropriate research designs that effectively reflect the person-centred system of care promoted in osteopathy and provide data which can inform policy decisions within the healthcare system. The purpose of this systematic review is to identify, appraise and synthesise the evidence from comparative effectiveness and economic evaluation research involving OMT. A database search was conducted using CINAHL, PubMed, PEDro, AMED, SCOPUS and OSTMED.DR, from their inception to May 2015. Two separate searches were undertaken to identify original research articles encompassing the economic evaluation and comparative effectiveness of OMT. Identified comparative effectives studies were evaluated using the Cochrane risk of bias tool and appraised using the Good Reporting of Comparative Effectiveness (GRACE) principles. Identified economic studies were assessed with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guidelines. Sixteen studies reporting the findings of comparative effectiveness (n = 9) and economic evaluation (n = 7) research were included. The comparative effectiveness studies reported outcomes for varied health conditions and the majority (n = 6) demonstrated a high risk of bias. The economic evaluations included a range of analyses and considerable differences in the quality of reporting were evident. Despite some positive findings, published comparative effectiveness and health economic studies in OMT are of insufficient quality and quantity to inform policy and practice. High quality, well-designed, research that aligns with international best practice is greatly needed to build a pragmatic evidence base for OMT. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluating and Comparing Interventions Designed to Enhance Math Fact Accuracy and Fluency: Cover, Copy, and Compare versus Taped Problems

ERIC Educational Resources Information Center

Poncy, Brian C.; Skinner, Christopher H.; Jaspers, Kathryn E.

2007-01-01

An adapted alternating treatments design was used to evaluate and compare the effects of two procedures designed to enhance math fact accuracy and fluency in an elementary student with low cognitive functioning. Results showed that although the cover, copy, compare (CCC) and the taped problems (TP) procedures both increased the student's math fact…

Comparative study on the welded structure fatigue strength assessment method

NASA Astrophysics Data System (ADS)

Hu, Tao

2018-04-01

Due to the welding structure is widely applied in various industries, especially the pressure container, motorcycle, automobile, aviation, ship industry, such as large crane steel structure, so for welded structure fatigue strength evaluation is particularly important. For welded structure fatigue strength evaluation method mainly has four kinds of, the more from the use of two kinds of welded structure fatigue strength evaluation method, namely the nominal stress method and the hot spot stress evaluation method, comparing from its principle, calculation method for the process analysis and research, compare the similarities and the advantages and disadvantages, the analysis of practical engineering problems to provide the reference for every profession and trade, as well as the future welded structure fatigue strength and life evaluation method put forward outlook.

Mere Exposure Revisited: The Influence of Growth versus Security Cues on Evaluations of Novel and Familiar Stimuli

ERIC Educational Resources Information Center

Gillebaart, Marleen; Forster, Jens; Rotteveel, Mark

2012-01-01

Combining regulatory focus theory (Higgins, 1997) and novelty categorization theory (Forster, Marguc, & Gillebaart, 2010), we predicted that novel stimuli would be more positively evaluated when focused on growth as compared with security and that familiar stimuli would be more negatively evaluated when focused on growth as compared with security.…

Program Fair Evaluation--Summative Appraisal of Instructional Sequences with Dissimilar Objectives.

ERIC Educational Resources Information Center

Popham, W. James

A comparative evaluation involving two instructional programs is given, although the approach can easily serve to compare more than two programs. The steps involved in conducting a program fair evaluation of two instructional programs are: (1) Identify objectives (a) common to both programs, (b) unique to one program, and (c) unique to the other…

A Comparative Evaluation of the Thesaurus of Engineering and Scientific Terms and the DDC Retrieval and Indexing Terminology.

DTIC Science & Technology

1977-11-01

UNLIMITED!IBIR-4J1 * : . C)" A COMPARATIVE EVALUATION OF THE THESAURUS OF, SAENGINEERING AND SCIENTIFIC TERMS AND THE DDC RETRIEVAL AND INDEXING...f cce7,i on For TER1 AND THE DDC RETRIEVAL AND A--" o " INDEXING TERMINOLOGY NTIS - * ByD , 2 _jDitr" : i :/ _ _ . _Av: "jl r " 1 t v Codes...34 . (ii. ABSTRACT A comparative evaluation nas been undertaken or the DDC Retrieval and Indexing Terminology (DRIT) and the Thesaurus of Engineering and

Pharmacological and therapeutic directions in ADHD: Specificity in the PFC.

PubMed

Levy, Florence

2008-02-28

Recent directions in the treatment of ADHD have involved both a broadening of pharmacological perspectives to include nor-adrenergic as well as dopaminergic agents. A review of animal and human studies of pharmacological and therapeutic directions in ADHD suggests that the D1 receptor is a specific site for dopaminergic regulation of the PFC, but optimal levels of dopamine (DA) are required for beneficial effects on working memory. Animal and human studies indicate that the alpha-2A receptor is also important for prefrontal regulation, leaving open the question of the relative importance of these receptor sites. The therapeutic effects of ADHD medications in the prefrontal cortex have focused attention on the development of working memory capacity in ADHD. The actions of dopaminergic vs noradrenergic agents, currently available for the treatment of ADHD have overlapping, but different actions in the prefrontal cortex (PFC) and subcortical centers. While stimulants act on D1 receptors in the dorsolateral prefrontal cortex, they also have effects on D2 receptors in the corpus striatum and may also have serotonergic effects at orbitofrontal areas. At therapeutic levels, dopamine (DA) stimulation (through DAT transporter inhibition) decreases noise level acting on subcortical D2 receptors, while NE stimulation (through alpha-2A agonists) increases signal by acting preferentially in the PFC possibly on DAD1 receptors. On the other hand, alpha-2A noradrenergic transmission is more limited to the prefrontal cortex (PFC), and thus less likely to have motor or stereotypic side effects, while alpha-2B and alpha-2C agonists may have wider cortical effects. The data suggest a possible hierarchy of specificity in the current medications used in the treatment of ADHD, with guanfacine likely to be most specific for the treatment of prefrontal attentional and working memory deficits. Stimulants may have broader effects on both vigilance and motor impulsivity, depending on dose levels, while atomoxetine may have effects on attention, anxiety, social affect, and sedation via noradrenergic transmission. At a theoretical level, the advent of possible specific alpha-2A noradrenergic therapies has posed the question of the role of working memory in ADHD. Head to head comparisons of stimulant and noradrenergic alpha-2A, alpha-2B and alpha-2C agonists, utilizing vigilance and affective measures should help to clarify pharmacological and therapeutic differences.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2006-10-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issues focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (-)-gossypol, 2-deoxyglucose, 3,4-DAP, 7-monohydroxyethylrutoside; Ad5CMV-p53, adalimumab, adefovir dipivoxil, ADH-1, alemtuzumab, aliskiren fumarate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, amrubicin hydrochloride, AN-152, anakinra, anecortave acetate, antiasthma herbal medicine intervention, AP-12009, AP-23573, apaziquone, aprinocarsen sodium, AR-C126532, AR-H065522, aripiprazole, armodafinil, arzoxifene hydrochloride, atazanavir sulfate, atilmotin, atomoxetine hydrochloride, atorvastatin, avanafil, azimilide hydrochloride; Bevacizumab, biphasic insulin aspart, BMS-214662, BN-83495, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, cetuximab, chrysin, ciclesonide, clevudine, clofarabine, clopidogrel, CNF-1010, CNTO-328, CP-751871, CX-717, Cypher; Dapoxetine hydrochloride, darifenacin hydrobromide, dasatinib, deferasirox, dextofisopam, dextromethorphan/quinidine sulfate, diclofenac, dronedarone hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Edaravone, efaproxiral sodium, emtricitabine, entecavir, eplerenone, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, etoricoxib, ezetimibe, ezetimibe/simvastatin; Finrozole, fipamezole hydrochloride, fondaparinux sodium, fulvestrant; Gabapentin enacarbil, gaboxadol, gefitinib, gestodene, ghrelin (human); Human insulin, human papillomavirus vaccine; Imatinib mesylate, immunoglobulin intravenous (human), indiplon, insulin detemir, insulin glargine, insulin glulisine, intranasal insulin, istradefylline, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; LA-419, lacosamide, landiolol, lanthanum carbonate, lidocaine/prilocaine, liposomal cisplatin, lutropin alfa; Matuzumab, MBP(82-98), mecasermin, MGCD-0103, MMR-V, morphine hydrochloride, mycophenolic acid sodium salt; Natalizumab, NCX-4016, neridronic acid, nesiritide, nilotinib, NSC-330507; O6-benzylguanine, olanzapine/fluoxetine hydrochloride, omalizumab; Panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegvisomant, pemetrexed disodium, perospirone hydrochloride, pexelizumab, phorbol 12-myristate 13-acetate, pneumococcal 7-valent conjugate vaccine, posaconazole, pramiconazole, prasugrel, pregabalin, prilocaine; rAAV-GAD65, raclopride, rasagiline mesilate, retapamulin, rosuvastatin calcium, rotigotine, rufinamide; SarCNU, SB-743921, SHL-749, sirolimus-eluting stent, sitaxsentan sodium, sorafenib; TachoSil, tadalafil, talampanel, Taxus, tegaserod maleate, telithromycin, telmisartan/hydrochlorothiazide, temsirolimus, tenatoprazole, teriflunomide, tetrathiomolybdate, ticilimumab, timcodar dimesilate, tipifarnib, tirapazamine, TPI, tramiprosate, trifluridine/TPI, trimethoprim; Ularitide, Urocortin 2; Valdecoxib, valganciclovir hydrochloride, valproate magnesium, valspodar, vardenafil hydrochloride hydrate, vitespen, vofopitant hydrochloride, volociximab, vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan; Ziprasidone hydrochloride, zotarolimus, zotarolimus-eluting stent.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2005-01-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate; ACP-103, Ad.Egr.TNF.11 D, adalimumab, AF-IL 12, AIDSVAX gp120 B/B, alefacept, alemtuzumab, a-Galactosylceramide, ALVAC vCP 1452, alvimopan hydrate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, anakinra, anidulafungin, antarelix, aprepitant, aripiprazole, arsenic sulfide, asoprisnil, atazanavir sulfate, atomoxetine hydrochloride; Bevacizumab, bimatoprost, BMS-184476, bortezomib, bosentan, botulinum toxin type B, BrachySil, brivudine; Caffeine, calcipotriol/betamethasone dipropionate, cannabidiol, capsaicin for injection, caspofungin acetate, CC-4047, cetuximab, CGP-36742, clofazimine, CpG-7909, Cypher; Darbepoetin alfa, dextromethorphan/quinidine sulfate, dimethylfumarate, dronabinol/cannabidiol, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecogramostim, efalizumab, eletriptan, emtricitabine, enfuvirtide, eplerenone, esomeprazole magnesium, estradiol acetate, eszopiclone, etoricoxib, exenatide, ezetimibe, ezetimibe/simvastatin; Fampridine, fondaparinux sodium, fosamprenavir calcium; Gefitinib, GPI-0100; hA 20, HTU-PA, human insulin, HuOKT 3 gamma 1(Ala 234-Ala 235), hyaluronic acid; Icatibant, imatinib mesylate, Indiplon, INKP-100, INKP-102, iodine (I131) tositumomab, istradefylline, IV gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, landiolol, lanthanum carbonate, lasofoxifene tartrate, LB-80380, lenalidomide, lidocaine/tetracaine, linezolid, liposomal doxorubicin, liposomal vincristine sulfate, lopinavir, lopinavir/ritonavir, lumiracoxib, lurtotecan; Maribavir, morphine glucuronide, MVA-5 T 4; NBI-56418, NCX-4016, nesiritide, nicotine conjugate vaccine, NSC-330507; Oglufanide, omalizumab, oxipurinol; Palifermin, palonosetron hydrochloride, parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, PEGylated interferon alfacon-1, perospirone hydrochloride, pimecrolimus, pixantrone maleate, plerixafor hydrochloride, PowderJect lidocaine, pradefovir mesylate, prasterone, pregabalin, Prostvac VF, PT-141, PTC-124, pyridoxamine; QS-21, quercetin; R-126638, R-411, ralfinamide, rasagiline mesilate, rF-PSA, RG-2077, rhThrombin, rimonabant hydrochloride, rofecoxib, rosuvastatin calcium, rotigotine hydrochloride, rV-PSA; S-18886, S-303, seocalcitol, SGN-40, sitaxsentan sodium, SPP-301, St. John's Wort extract; Tadalafil, taxus, telithromycin, tenatoprazole, tenofovir disoproxil fumarate, testosterone MDTS, testosterone transdermal patch, tgAAC-09, TH-9507, thioacetazone, tipifarnib, TQ-1011, trabectedin, travoprost, trimethoprim; Valdecoxib, valganciclovir hydrochloride, valopicitabine, voriconazole; Xcellerated T cells. (c) 2005 Prous Science. All rights reserved.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-06-01

[¹¹C]RAC; (18)F-Fluoromisonidazole; 89-12; 9-[¹⁸F]Fluoropropyl-(+)-dihydrotetrabenazine; Adalimumab, Adecatumumab, ADMVA, ADXS-11-001, Aflibercept, Agatolimod sodium, AGS-004, Alglucosidase alfa, Aliskiren fumarate, Alvocidib hydrochloride, AMG-108, AMG-853, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride; Bevacizumab, BioMatrix Flex drug eluting stent, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, Cediranib, Cetuximab, ChimeriVax-Dengue, Choriogonadotropin alfa, Cinacalcet hydrochloride, Cizolirtine citrate, Clofarabine, Cocaine conjugate vaccine, CX-717; Darbepoetin alfa, Dasatinib, Decitabine, Denosumab, Desvenlafaxine succinate, Dexamethasone sodium phosphate, Dienogest, Diphencyprone, Doripenem, DTaP-HepB-IPV, Dutasteride; E-7010, Ecallantide, Ecstasy, Eicosapentaenoic acid/docosahexaenoic acid, Emtricitabine, Enfuvirtide, Erlotinib hydrochloride, Eszopiclone, Etonogestrel/ethinyl estradiol, Etoricoxib, Everolimus, Everolimus-eluting coronary stent EVT-201, Ezetimibe, Ezetimibe/simvastatin; Ferumoxytol, Fesoterodine fumavate, Figitumumab, Filgrastim, Fingolimod hydrochloride, Fluticasone furoate, Fluval P, Fluzone, Fondaparinux sodium, Fulvestrant, Fungichromin; Gamma-hydroxybutyrate sodium, Gefitinib, GHB-01L1, GLY-230, GSK-1349572; Hib-MenCY-TT, Hib-TT, HPV-6/11/16/18, Hydrocodone bitartrate; IC-51, Icatibant acetate, Imatinib mesylate, Immunoglobulin intravenous (human), Indetanib, Influenza A (H1N1) 2009 Monovalent Vaccine, Inhalable human insulin, Insulin glargine, Insulin glulisine, Interferon-beta, Ispinesib mesylate, Ixabepilone; Laromustine, Latanoprost/timolol maleate, L-Citrulline, Lenalidomide, Lexatumumab, Linezolid, Lopinavir/ritonavir, Lutropin alfa; Mapatumumab, MDX-066, MDX-1388, Mepolizumab, Methoxy polyethylene glycol-epoetin-beta, Metreleptin, Micafungin sodium, Mometasone furoate/oxymetazoline hydrochloride, Mx-dnG1, Mycophenolic acid sodium salt; Nabiximols, Natalizumab, Nemonoxacin, Norelgestromin/ethinyl estradiol; Oblimersen sodium, Ocriplasmin, Olmesartan medoxomil, Omacetaxine mepesuccinate; Paclitaxel-eluting stent, Pagoclone, Paliperidone, Panitumumab, Pazopanib hydrochloride, PCV7, Pegaptanib octasodium, Peginterferon alfa-2a, Peginterferon alfa-2b/ ribavirin, Pegvisomant, Pemetrexed disodium, Perifosine, Pimecrolimus, Pitavastatin calcium, Plerixafor hydrochloride, Plitidepsin, Posaconazole, Pregabalin, Progesterone capriate; Raltegravir potassium, Ramucirumab, Ranelic acid distrontium salt, Rasburicase, Recombinant Bet V1, Recombinant human insulin, rhFSH, Rolofylline, Romidepsin, Romiplostim, Rosuvastatin calcium; Sapacitabine, Sevelamer carbonate, Sinecatechins, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, SN-29244, Sorafenib, Sugammadex sodium, Sunitinib malate; Tadalafil, Tafenoquine, Talnetant, Tanezumab, Tapentadol hydrochloride, Tasocitinib citrate, Technosphere/Insulin, Telcagepant, Tenofovir disoproxil fumarate, Teriparatide, Ticagrelor, Tigecycline, Tiotropium bromide, Tipifarnib, Tocilizumab, TS-041; Ulipristal acetate, Urtoxazumab, Ustekinumab; Vandetanib, Varenicline tartrate, Vicriviroc, Voriconazole, Vorinostat, VRC-HIVADV014-00-VP, VRC-HIVDNA016-00-VP; Zoledronic acid monohydrate. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Comparing Student, Instructor, Classroom and Institutional Data to Evaluate a Seven-Year Department-Wide Science Education Initiative

ERIC Educational Resources Information Center

Jones, Francis

2018-01-01

We compared seven unrelated data-sets to evaluate a major education improvement initiative. Perceptions of students in 54 course sections were surveyed regarding the helpfulness of 39 specific teaching or learning strategies, and relative workloads and enthusiasm were compared to their other courses. Classes were observed using an established…

Economic evaluations of trastuzumab in HER2-positive metastatic breast cancer: a systematic review and critique.

PubMed

Parkinson, Bonny; Pearson, Sallie-Anne; Viney, Rosalie

2014-01-01

Published economic evaluations of trastuzumab for the treatment of HER2-positive metastatic breast cancer have arrived at different conclusions regarding the cost-effectiveness of trastuzumab, despite comparative efficacy being demonstrated by a small set of randomised controlled trials (RCTs). This article aims to provide insight into the quality of the evaluations and explore the possible drivers of the conflicting conclusions. A systematic literature review was conducted to identify all published economic evaluations that compared the incremental costs and outcomes of trastuzumab versus a comparator. Fifteen economic evaluations were identified. In the evaluations that estimated efficacy using an RCT, the key drivers of the conclusions regarding cost-effectiveness were: the approach used to estimate overall survival in the control group given crossover to trastuzumab following progression in the trials; the inclusion of treatment beyond progression; inclusion of wastage due to unused vial portions, adverse events, and the cost of HER2 testing. Four evaluations used non-randomised approaches to estimate efficacy, thus introducing the potential for confounding. As a result these evaluations reported relatively optimistic estimates of comparative effectiveness. Finally the evaluations used different thresholds to determine whether treatment with trastuzumab was cost-effective. There were numerous drivers of the different conclusions regarding the cost-effectiveness of trastuzumab, many of which are due to judgements made by the authors when translating data from RCTs. Many of the potential drivers were not identified by the published systematic reviews of economic evaluations and perhaps more remain unidentified because of inconsistent and limited reporting.

Gender Bias in Nurse Evaluations of Residents in Obstetrics and Gynecology.

PubMed

Galvin, Shelley L; Parlier, Anna Beth; Martino, Ellen; Scott, Kacey Ryan; Buys, Elizabeth

2015-10-01

We examined the evaluations given by nurses to obstetrics and gynecology residents to estimate whether gender bias was evident. Women receive more negative feedback and evaluations than men-from both sexes. Some suggest that, to be successful in traditionally male roles such as surgeon, women must manifest a warmth-related (communal) rather than competence-related (agentic) demeanor. Compared with male residents, female residents experience more interpersonal difficulties and less help from female nurses. We examined feedback provided to residents by female nurses. We examined Professional Associate Questionnaires (2006-2014) using a mixed-methods design. We compared scores per training year by gender using Mann-Whitney and linear regression adjusting for resident and nurse cohorts. Using grounded theory analysis, we developed a coding system for blinded comments based on principles of effective feedback, medical learners' evaluation, and impression management. χ examined the proportions of negative and positive and communal and agentic comments between genders. We examined 2,202 evaluations: 397 (18%) for 10 men and 1,805 (82%) for 34 women. Twenty-three compliments (eg, "Great resident!") were excluded. Evaluations per training year varied: men n=77-134; women n=384-482. Postgraduate year (PGY)-1, PGY-2, and PGY-4 women had lower mean ratings (P<.035); when adjusted, the difference remained significant in PGY-2 (MWomen=1.5±0.6 compared with MMen=1.7±0.5; P=.001). Postgraduate year-1 women received disproportionately fewer positive and more negative agentic comments than PGY-1 men (positive=17.3% compared with 40%, negative=17.3% compared with 3.3%, respectively; P=.041). Evidence of gender bias in evaluations emerged; albeit subtle, women received harsher feedback as lower-level residents than men. Training in effective evaluation and gender bias management is warranted.

Combining synthetic controls and interrupted time series analysis to improve causal inference in program evaluation.

PubMed

Linden, Ariel

2018-04-01

Interrupted time series analysis (ITSA) is an evaluation methodology in which a single treatment unit's outcome is studied over time and the intervention is expected to "interrupt" the level and/or trend of the outcome. The internal validity is strengthened considerably when the treated unit is contrasted with a comparable control group. In this paper, we introduce a robust evaluation framework that combines the synthetic controls method (SYNTH) to generate a comparable control group and ITSA regression to assess covariate balance and estimate treatment effects. We evaluate the effect of California's Proposition 99 for reducing cigarette sales, by comparing California to other states not exposed to smoking reduction initiatives. SYNTH is used to reweight nontreated units to make them comparable to the treated unit. These weights are then used in ITSA regression models to assess covariate balance and estimate treatment effects. Covariate balance was achieved for all but one covariate. While California experienced a significant decrease in the annual trend of cigarette sales after Proposition 99, there was no statistically significant treatment effect when compared to synthetic controls. The advantage of using this framework over regression alone is that it ensures that a comparable control group is generated. Additionally, it offers a common set of statistical measures familiar to investigators, the capability for assessing covariate balance, and enhancement of the evaluation with a comprehensive set of postestimation measures. Therefore, this robust framework should be considered as a primary approach for evaluating treatment effects in multiple group time series analysis. © 2018 John Wiley & Sons, Ltd.

Autonomous Dirigible Airships: A Comparative Analysis and Operational Efficiency Evaluation for Logistical Use in Complex Environments

DTIC Science & Technology

2012-06-01

NAVAL POSTGRADUATE SCHOOL MONTEREY, CALIFORNIA MBA PROFESSIONAL REPORT Autonomous Dirigible Airships: A Comparative Analysis...COVERED MBA Professional Report 4. TITLE AND SUBTITLE: Autonomous Dirigible Airships: A Comparative Analysis and Operational Efficiency Evaluation...NAME(S) AND ADDRESS(ES) N/ A 10. SPONSORING / MONITORING AGENCY REPORT NUMBER 11. SUPPLEMENTARY NOTES The views expressed in this report are

Conducting Configurational Comparative Research with Qualitative Comparative Analysis: A Hands-On Tutorial for Applied Evaluation Scholars and Practitioners

ERIC Educational Resources Information Center

Thiem, Alrik

2017-01-01

The search for necessary and sufficient causes of some outcome of interest, referred to as "configurational comparative research," has long been one of the main preoccupations of evaluation scholars and practitioners. However, only the last three decades have witnessed the evolution of a set of formal methods that are sufficiently…

A Comparative Study of Data Envelopment Analysis and Other Approaches to Efficiency Evaluation and Estimation.

DTIC Science & Technology

1982-11-01

ADA27 91 A COMPARATIVE STJDO DATAENVEOPMENT ANALYSISAND / HER APPROACHES TO A .i)TEXAS UN VAT AUSIN CENTER FOCAS RE CCYR 5 NO BERRETIC STADIES A... COMPARATIVE STUDY OF DATA ENVELOPMENT ANALYSIS AND OTHER APPROACHES TO EFFICIENCY EVALUATION AND ESTIMATIONt by A. Charnes W.W. Cooper H.D. Sherman...School of Business, 1981, entitled "Measurement of Hospital Efficiency: A Comparative Analysis of Data Envelopment Analysis and Other Approaches for

Aligning Collaborative and Culturally Responsive Evaluation Approaches

ERIC Educational Resources Information Center

Askew, Karyl; Beverly, Monifa Green; Jay, Michelle L.

2012-01-01

The authors, three African-American women trained as collaborative evaluators, offer a comparative analysis of collaborative evaluation (O'Sullivan, 2004) and culturally responsive evaluation approaches (Frierson, Hood, & Hughes, 2002; Kirkhart & Hopson, 2010). Collaborative evaluation techniques immerse evaluators in the cultural milieu…

The Validity and Precision of the Comparative Interrupted Time Series Design and the Difference-in-Difference Design in Educational Evaluation

ERIC Educational Resources Information Center

Somers, Marie-Andrée; Zhu, Pei; Jacob, Robin; Bloom, Howard

2013-01-01

In this paper, we examine the validity and precision of two nonexperimental study designs (NXDs) that can be used in educational evaluation: the comparative interrupted time series (CITS) design and the difference-in-difference (DD) design. In a CITS design, program impacts are evaluated by looking at whether the treatment group deviates from its…

Sustaining and Improving Study Abroad Experiences Through Comparative Evaluation.

PubMed

Johanson, Linda S

Researchers have related participation in study abroad experiences to many positive outcomes for nursing students; however, educators are faced with the task of not only developing meaningful study abroad opportunities but sustaining and improving them as well. Educators can evaluate repeat study abroad programs by comparing experiences, looking for trends, and conjecturing rationales. To illustrate this process, an example of a study abroad opportunity that has been repeated over 11 years is presented. The first six years have been compared to the most recent five years, revealing three categories of change for evaluation and the resulting course improvements.

Microbiological evaluation of chronic blepharitis among Iranian veterans exposed to mustard gas: a case-controlled study.

PubMed

Karimian, Farid; Zarei-Ghanavati, Siamak; A, Baradaran-Rafii; Jadidi, Khosrow; Lotfi-Kian, Alireza

2011-06-01

To evaluate the microbiological characteristics of eyelid margin flora in chronic blepharitis in mustard gas-exposed individuals and compare the results with those in age- and sex-matched unexposed people. In this comparative case series, 289 patients with ocular manifestations of mustard gas exposure (case) were evaluated for signs of chronic blepharitis. Additionally, microbiological evaluation of eyelid margins was conducted in these patients and compared with results of 100 unexposed patients with chronic blepharitis (control). One-hundred fifty (52.0%) of 289 mustard gas casualties had signs of chronic blepharitis. Microbiological evaluation revealed higher isolation rates of Staphylococcus epidermidis (78%) and Staphylococcus aureus (57%) in the case in comparison to control group (P < 0.01). Moreover, S. aureus isolated from the cases exhibited greater resistance to common antibiotics compared with control group. Fungi were isolated more frequent in the case compared with controls (30% vs. 4%, P < 0.01), with Cladosporium and Candida species being most common in the case group. Exposure to mustard gas seems to alter the microbiological flora of the eyelid margin. Staphylococcus spp., including antibiotic-resistant strains, and fungi were more frequently isolated in these patients. The relationship between microbial culture results and the severity of ocular surface manifestations in mustard gas-injured cases warrant further investigation.

Randomized Trial of Smartphone-Based Evaluation for an Obstetrics and Gynecology Clerkship.

PubMed

Sobhani, Nasim C; Fay, Emily E; Schiff, Melissa A; Stephenson-Famy, Alyssa; Debiec, Katherine E

2017-12-19

We hypothesized that compared to paper evaluations, a smartphone-based quick response (QR) evaluation tool would improve timeliness of feedback, enhance efficacy of giving and receiving feedback, and be as easy to use. We performed a randomized controlled trial of student and instructor experience with two evaluation tools in the OB/GYN clerkship at University of Washington School of Medicine (UWSOM). Sites were randomized to the QR or paper tool; students at QR sites received individualized QR codes at the beginning of the clerkship. Instructors and students completed postintervention surveys regarding the evaluation tool and associated feedback. We compared responses between groups using chi-squared tests. Participating clerkship sites included primary, tertiary, private practice and institutional settings affiliated with the University of Washington in the Washington, Wyoming, Alaska, Montana and Idaho region. Of the 29 OB/GYN UWSOM clerkship sites, 18 agreed to participate and were randomized. Of 29 eligible instructors, 25 (86%) completed the survey, with n = 18 using QR and n = 7 using paper. Of 161 eligible students, 102 (63%) completed the survey, with n = 54 using QR and n = 48 using paper. Compared to those using paper evaluations, instructors using QR evaluations were significantly more likely to agree that the evaluation tool was easy to understand (100% QR vs 43% paper, p = 0.002), the tool was effective in providing feedback (78% QR vs 29% paper, p = 0.002), and they felt comfortable approaching students with the tool (89% QR vs 43% paper, p = 0.002). Compared to those using paper evaluations, students using QR evaluations were less likely to agree the tool was effective in eliciting feedback (QR 43% vs paper 55%, p = 0.042). Instructors found QR evaluations superior to paper evaluations for providing feedback to medical students, whereas students found QR evaluations less effective for feedback. Copyright © 2017 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

Comparative study between ultrasonography and optical coherence tomography in interventional cardiology

NASA Astrophysics Data System (ADS)

Fanjul-Vélez, Félix; de la Torre-Hernández, José María; Ortega-Quijano, Noé; Zueco-Gil, José Javier; Arce-Diego, José Luis

2009-07-01

In this work, we present clinical images of IVUS and OCT in the evaluation of pharmacological stent endothelization. These preliminary imaging results are analyzed and compared in order to determine the ability of these technologies to visualize relevant intravascular features of interest in interventional cardiology. The results enable to compare the performance of both techniques and to evaluate their potential for clinical purposes.

Evaluating the Comparability of Paper-and-Pencil and Computerized Versions of a Large-Scale Certification Test. Research Report. ETS RR-05-21

ERIC Educational Resources Information Center

Puhan, Gautam; Boughton, Keith A.; Kim, Sooyeon

2005-01-01

The study evaluated the comparability of two versions of a teacher certification test: a paper-and-pencil test (PPT) and computer-based test (CBT). Standardized mean difference (SMD) and differential item functioning (DIF) analyses were used as measures of comparability at the test and item levels, respectively. Results indicated that effect sizes…

Three-dimensional ultrasonography of the breast; An adequate replacement for MRI in neoadjuvant chemotherapy tumour response evaluation? - RESPONDER trial.

PubMed

van Egdom, L S E; Lagendijk, M; Heijkoop, E H M; Koning, A H J; van Deurzen, C H M; Jager, A; van Lankeren, W; Koppert, L B

2018-07-01

Accurate measurement of tumour response during and after neoadjuvant chemotherapy (NAC) is important and may influence treatment decisions in invasive breast cancer patients. Breast MRI forms the gold standard but is more burdensome, time consuming and costly. In this study response measurement was done with 3-D ultrasound by Automated Breast Volume Scanner (ABVS) and compared to breast MRI. Moreover, patient satisfaction with both techniques was compared. A single-institution, prospective observational pilot study evaluating tumour response by ABVS in addition to breast MRI (standard care) was performed in 25 invasive breast cancer patients receiving NAC. Tumour response was evaluated comparing longest tumour diameters as well as tumour volumes at predefined time points using Bland-Altman analysis. Volume measurements for breast MRI were obtained using a fully immersive virtual reality system (a Barco I-Space) and V-Scope software. Same software was used to obtain ABVS volume measurements using an in-house developed desktop VR system. Inter- and intra-observer agreement was evaluated by Intraclass Correlation Coefficient (ICC). Twenty-five patients were eligible for baseline measurement, 20 for a mid-NAC response evaluation, and five for a post-NAC response evaluation. MRI and ABVS showed absolute concordance in 73% of patients for the mid-NAC evaluation, with a 'good' correlation for the difference in longest diameter measurement (ICC 0.73, p < 0.01) as compared to baseline assessment. Concerning difference in volume measurement in the mid-NAC response evaluation showed a 'fair' correlation (ICC 0.52, p < 0.01) and in the post-NAC response evaluation an 'excellent' correlation (ICC 0.98, p < 0.01). 'Excellent' inter- and intra-observer agreement was found (ICC 0.88, p < 0.01) with comparable limits of agreement (LOA) for observer 1 and 2 in both diameter and volume measurement. Patient satisfaction was higher for ABVS compared to breast MRI, 93% versus 12% respectively. ABVS showed 'good' correlation with MRI tumour response evaluation in breast cancer patients during NAC with 'excellent' inter- and intra-observer agreement. ABVS has patients' preference over breast MRI and could be considered as alternative to breast MRI, in case results on an on-going prospective trial confirm these results (NTR6799). Copyright © 2018 Elsevier B.V. All rights reserved.

Performance of two different digital evaluation systems used for assessing pre-clinical dental students' prosthodontic technical skills.

PubMed

Gratton, D G; Kwon, S R; Blanchette, D R; Aquilino, S A

2017-11-01

Proper integration of newly emerging digital assessment tools is a central issue in dental education in an effort to provide more accurate and objective feedback to students. The study examined how the outcomes of students' tooth preparation were correlated when evaluated using traditional faculty assessment and two types of digital assessment approaches. Specifically, incorporation of the Romexis Compare 2.0 (Compare) and Sirona prepCheck 1.1 (prepCheck) systems was evaluated. Additionally, satisfaction of students based on the type of software was evaluated through a survey. Students in a second-year pre-clinical prosthodontics course were allocated to either Compare (n = 42) or prepCheck (n = 37) systems. All students received conventional instruction and used their assigned digital system as an additional evaluation tool to aid in assessing their work. Examinations assessed crown preparations of the maxillary right central incisor (#8) and the mandibular left first molar (#19). All submissions were graded by faculty, Compare and prepCheck. Technical scores did not differ between student groups for any of the assessment approaches. Compare and prepCheck had modest, statistically significant correlations with faculty scores with a minimum correlation of 0.3944 (P = 0.0011) and strong, statistically significant correlations with each other with a minimum correlation of 0.8203 (P < 0.0001). A post-course student survey found that 55.26% of the students felt unfavourably about learning the digital evaluation protocols. A total of 62.31% felt favourably about the integration of these digital tools into the curriculum. Comparison of Compare and prepCheck showed no evidence of significant difference in students' prosthodontics technical performance and perception. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Academic detailing can play a key role in assessing and implementing comparative effectiveness research findings.

PubMed

Fischer, Michael A; Avorn, Jerry

2012-10-01

Comparative effectiveness research evaluates the relative effectiveness, safety, and value of competing treatment options in clinically realistic settings. Such evaluations can be methodologically complex and difficult to interpret. There will be a growing need for critical evaluation of comparative effectiveness studies to assess the adequacy of their design and to put new information into a broader context. Equally important, this knowledge will have to be communicated to clinicians in a way that will actually change practice. We identify three challenges to effective dissemination of comparative effectiveness research findings: the difficulty of interpreting comparative effectiveness research data, the need for trusted sources of information, and the challenge of turning research results into clinical action. We suggest that academic detailing-direct outreach education that gives clinicians an accurate and unbiased synthesis of the best evidence for practice in a given clinical area-can translate comparative effectiveness research findings into actions that improve health care decision making and patient outcomes.

Evaluation of low-cost, objective instruments for assessing physical activity in 10-11-year-old children.

PubMed

Hart, Teresa L; Brusseau, Timothy; Kulinna, Pamela Hodges; McClain, James J; Tudor-Locke, Catrine

2011-12-01

This study compared step counts detected by four, low-cost, objective, physical-activity-assessment instruments and evaluated their ability to detect moderate-to-vigorous physical activity (MVPA) compared to the ActiGraph accelerometer (AG). Thirty-six 10-11-year-old children wore the NL-1000, Yamax Digiwalker SW 200, Omron HJ-151, and Walk4Life MVP concurrently with the AG during school hours on a single day. AG MVPA was derived from activity count data using previously validated cut points. Two of the evaluated instruments provided similar group mean MVPA and step counts compared to AG (dependent on cut point). Low-cost instruments may be useful for measurement of both MVPA and steps in children's physical activity interventions and program evaluation.

Classification of microscopy images of Langerhans islets

NASA Astrophysics Data System (ADS)

Å vihlík, Jan; Kybic, Jan; Habart, David; Berková, Zuzana; Girman, Peter; Kříž, Jan; Zacharovová, Klára

2014-03-01

Evaluation of images of Langerhans islets is a crucial procedure for planning an islet transplantation, which is a promising diabetes treatment. This paper deals with segmentation of microscopy images of Langerhans islets and evaluation of islet parameters such as area, diameter, or volume (IE). For all the available images, the ground truth and the islet parameters were independently evaluated by four medical experts. We use a pixelwise linear classifier (perceptron algorithm) and SVM (support vector machine) for image segmentation. The volume is estimated based on circle or ellipse fitting to individual islets. The segmentations were compared with the corresponding ground truth. Quantitative islet parameters were also evaluated and compared with parameters given by medical experts. We can conclude that accuracy of the presented fully automatic algorithm is fully comparable with medical experts.

Recommendations for a step‐wise comparative approach to the evaluation of new screening tests for colorectal cancer

PubMed Central

Senore, Carlo; Mandel, Jack S.; Allison, James E.; Atkin, Wendy S.; Benamouzig, Robert; Bossuyt, Patrick M. M.; Silva, Mahinda De; Guittet, Lydia; Halloran, Stephen P.; Haug, Ulrike; Hoff, Geir; Itzkowitz, Steven H.; Leja, Marcis; Levin, Bernard; Meijer, Gerrit A.; O'Morain, Colm A.; Parry, Susan; Rabeneck, Linda; Rozen, Paul; Saito, Hiroshi; Schoen, Robert E.; Seaman, Helen E.; Steele, Robert J. C.; Sung, Joseph J. Y.; Winawer, Sidney J.

2016-01-01

BACKGROUND New screening tests for colorectal cancer continue to emerge, but the evidence needed to justify their adoption in screening programs remains uncertain. METHODS A review of the literature and a consensus approach by experts was undertaken to provide practical guidance on how to compare new screening tests with proven screening tests. RESULTS Findings and recommendations from the review included the following: Adoption of a new screening test requires evidence of effectiveness relative to a proven comparator test. Clinical accuracy supported by programmatic population evaluation in the screening context on an intention‐to‐screen basis, including acceptability, is essential. Cancer‐specific mortality is not essential as an endpoint provided that the mortality benefit of the comparator has been demonstrated and that the biologic basis of detection is similar. Effectiveness of the guaiac‐based fecal occult blood test provides the minimum standard to be achieved by a new test. A 4‐phase evaluation is recommended. An initial retrospective evaluation in cancer cases and controls (Phase 1) is followed by a prospective evaluation of performance across the continuum of neoplastic lesions (Phase 2). Phase 3 follows the demonstration of adequate accuracy in these 2 prescreening phases and addresses programmatic outcomes at 1 screening round on an intention‐to‐screen basis. Phase 4 involves more comprehensive evaluation of ongoing screening over multiple rounds. Key information is provided from the following parameters: the test positivity rate in a screening population, the true‐positive and false‐positive rates, and the number needed to colonoscope to detect a target lesion. CONCLUSIONS New screening tests can be evaluated efficiently by this stepwise comparative approach. Cancer 2016;122:826–39. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. PMID:26828588

Recommendations for a step-wise comparative approach to the evaluation of new screening tests for colorectal cancer.

PubMed

Young, Graeme P; Senore, Carlo; Mandel, Jack S; Allison, James E; Atkin, Wendy S; Benamouzig, Robert; Bossuyt, Patrick M M; Silva, Mahinda De; Guittet, Lydia; Halloran, Stephen P; Haug, Ulrike; Hoff, Geir; Itzkowitz, Steven H; Leja, Marcis; Levin, Bernard; Meijer, Gerrit A; O'Morain, Colm A; Parry, Susan; Rabeneck, Linda; Rozen, Paul; Saito, Hiroshi; Schoen, Robert E; Seaman, Helen E; Steele, Robert J C; Sung, Joseph J Y; Winawer, Sidney J

2016-03-15

New screening tests for colorectal cancer continue to emerge, but the evidence needed to justify their adoption in screening programs remains uncertain. A review of the literature and a consensus approach by experts was undertaken to provide practical guidance on how to compare new screening tests with proven screening tests. Findings and recommendations from the review included the following: Adoption of a new screening test requires evidence of effectiveness relative to a proven comparator test. Clinical accuracy supported by programmatic population evaluation in the screening context on an intention-to-screen basis, including acceptability, is essential. Cancer-specific mortality is not essential as an endpoint provided that the mortality benefit of the comparator has been demonstrated and that the biologic basis of detection is similar. Effectiveness of the guaiac-based fecal occult blood test provides the minimum standard to be achieved by a new test. A 4-phase evaluation is recommended. An initial retrospective evaluation in cancer cases and controls (Phase 1) is followed by a prospective evaluation of performance across the continuum of neoplastic lesions (Phase 2). Phase 3 follows the demonstration of adequate accuracy in these 2 prescreening phases and addresses programmatic outcomes at 1 screening round on an intention-to-screen basis. Phase 4 involves more comprehensive evaluation of ongoing screening over multiple rounds. Key information is provided from the following parameters: the test positivity rate in a screening population, the true-positive and false-positive rates, and the number needed to colonoscope to detect a target lesion. New screening tests can be evaluated efficiently by this stepwise comparative approach. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Electrophysiological responses to evaluative priming: the LPP is sensitive to incongruity.

PubMed

Herring, David R; Taylor, Jennifer H; White, Katherine R; Crites, Stephen L

2011-08-01

Previous studies examining event-related potentials and evaluative priming have been mixed; some find evidence that evaluative priming influences the N400, whereas others find evidence that it affects the late positive potential (LPP). Three experiments were conducted using either affective pictures (Experiments 1 and 2) or words (Experiment 3) in a sequential evaluative priming paradigm. In line with previous behavioral findings, participants responded slower to targets that were evaluatively incongruent with the preceding prime (e.g., negative preceded by positive) compared to evaluatively congruent targets (e.g., negative preceded by negative). In all three studies, the LPP was larger to evaluatively incongruent targets compared to evaluatively congruent ones, and there was no evidence that evaluative incongruity influenced the N400 component. Thus, the present results provide additional support for the notion that evaluative priming influences the LPP and not the N400. We discuss possible reasons for the inconsistent findings in prior research and the theoretical implications of the findings for both evaluative and semantic priming. 2011 APA, all rights reserved

Pulse Transit Time Measurement Using Seismocardiogram, Photoplethysmogram, and Acoustic Recordings: Evaluation and Comparison.

PubMed

Yang, Chenxi; Tavassolian, Negar

2018-05-01

This work proposes a novel method of pulse transit time (PTT) measurement. The proximal arterial location data are collected from seismocardiogram (SCG) recordings by placing a micro-electromechanical accelerometer on the chest wall. The distal arterial location data are recorded using an acoustic sensor placed inside the ear. The performance of distal location recordings is evaluated by comparing SCG-acoustic and SCG-photoplethysmogram (PPG) measurements. PPG and acoustic performances under motion noise are also compared. Experimental results suggest comparable performances for the acoustic-based and PPG-based devices. The feasibility of each PTT measurement method is validated for blood pressure evaluations and its limitations are analyzed.

Northwestern University Flexible Subischial Vacuum Socket for persons with transfemoral amputation: Part 2 Description and Preliminary evaluation.

PubMed

Fatone, Stefania; Caldwell, Ryan

2017-06-01

Current transfemoral prosthetic sockets are problematic as they restrict function, lack comfort, and cause residual limb problems. Development of a subischial socket with lower proximal trim lines is an appealing way to address this problem and may contribute to improving quality of life of persons with transfemoral amputation. The purpose of this study was to illustrate the use of a new subischial socket in two subjects. Case series. Two unilateral transfemoral prosthesis users participated in preliminary socket evaluations comparing functional performance of the new subischial socket to ischial containment sockets. Testing included gait analysis, socket comfort score, and performance-based clinical outcome measures (Rapid-Sit-To-Stand, Four-Square-Step-Test, and Agility T-Test). For both subjects, comfort was better in the subischial socket, while gait and clinical outcomes were generally comparable between sockets. While these evaluations are promising regarding the ability to function in this new socket design, more definitive evaluation is needed. Clinical relevance Using gait analysis, socket comfort score and performance-based outcome measures, use of the Northwestern University Flexible Subischial Vaccum Socket was evaluated in two transfemoral prosthesis users. Socket comfort improved for both subjects with comparable function compared to ischial containment sockets.

Comparative evaluation of rail and truck fuel efficiency on competitive corridors : final report

DOT National Transportation Integrated Search

2009-11-19

This study provides a comparative evaluation of rail and truck fuel efficiency on corridors and services in which both modes compete. For the purposes of this study, competitive movements are defined as those of the same commodity having the same (or...

Evaluating Domestic and International Web-Site Strategies.

ERIC Educational Resources Information Center

Simeon, Roblyn

1999-01-01

Presents the AIPD (attracting, informing, positioning, and delivering) approach to the evaluation of commercial Web sites that assess the strategic potential of Web sites, provides a framework for the development of competitive sites, and compares Web site strategies within and across national boundaries. Compares Internet strategies of Japanese…

[The role of the quality of hospital discharge records on the comparative evaluation of outcomes: the example of chronic obstructive pulmonary disease (COPD)].

PubMed

Fano, Valeria; D'Ovidio, Mariangela; del Zio, Katiuscia; Renzi, Davide; Tariciotti, Daniela; Agabiti, Nera; Argenti, Lucia; Cattaruzza, Maria Sofia; Fortino, Antonio

2012-01-01

To analyse the results of the regional comparative evaluation of the outcome "thirty days mortality after admission for reacutized Chronic obstructive pulmonary disease (COPD)" before and after a reabstract study. Reabstract study of clinical records included in the regional comparative evaluation. 232 clinical records retrieved from Grassi Hospital archives (years 2006-2007) and reviewed by two physicians and one nurse specifically trained. Models performed before and after reabstract study for comparative evaluation of the outcome were compared. Blind coding of diagnosis and interventions/procedures was completed according to a standard grid consistent with regional guidelines for Hospital Discharge Record coding. Other information was registered, if present on discharge record: smoking habit, number of reacutizations occurred within previous year, use of oxigen and/or other therapies, pneumological visit at discharge. The majority (94%) of reviewed cases were confirmed as being cases of COPD. A total of 168 cases (72%) have been identified as reacutized COPD coherent with enrolment criteria of regional program, 49 (21%) have been identified as COPD and only 15 cases (6%) resulted not affected by COPD. Results of the regional comparative model were substantially unchanged for Grassi hospital (RR =23 vs RR =24). Accurateness of clinical documentation resulted inadequate especially regarding information at discharge (50% missing information on smoking habit, 83% on previous year reacutizations, 22% on follow-up organization after discharge). This study contributes to the debate on the role of administrative data on the comparative evaluation of health outcomes. Other relevant issues are to promote the collaboration among different health professionals working in the same hospital, and to increase the awareness of the importance of the quality of health and administrative data.

Evaluation of Cariogenic Bacteria

PubMed Central

Nishikawara, Fusao; Nomura, Yoshiaki; Imai, Susumu; Senda, Akira; Hanada, Nobuhiro

2007-01-01

Objectives The evaluation of Mutans streptococci (MS) is one of the index for caries risk. DentocultTM and CRTTM are commercial kits to detect and evaluate MS, conveniently. However, the evaluation of MS has also been carried out simply using an instruction manual. But the instruction manual is not easy to use for evaluation of MS. The aim of this study was to examine the utility of modified Mitis-Salivalius Bacitracin (MSB) agar medium compared with MSB agar medium and commercial kits, and to establish a convenient kit (mMSB-kit) using modified MSB agar. Methods The MS in stimulated saliva from 27 subjects were detected by MSB, modified MSB agar medium and commercial kits. Laboratory and clinically isolated strains of MS were similarly evaluated. The ratios of MS in detected bacteria were compared by ELISA. Results The scores using an mMSB-kit on the basis of modified MSB agar medium were tabulated. Saliva samples showed different levels of MS between culture methods and the commercial kit. Some samples which were full of MS were not detected by the commercial kit. The detection of MS by modified MSB agar medium and mMSB-kit were significantly higher when compared with MSB agar medium,CRTTM, (P< .01) and Dentocult SMTM (P<.05). Conclusion The sensitivity for detection of MS is higher for modified MSB agar medium when compared with MSB agar medium. The mMSB-kit can be used simply, and can be an important contributor for the evaluation of MS as a caries risk factor. PMID:19212495

Initial evaluation of rectal bleeding in young persons: a cost-effectiveness analysis.

PubMed

Lewis, James D; Brown, Alphonso; Localio, A Russell; Schwartz, J Sanford

2002-01-15

Evaluation of rectal bleeding in young patients is a frequent diagnostic challenge. To determine the relative cost-effectiveness of alternative diagnostic strategies for young patients with rectal bleeding. Cost-effectiveness analysis using a Markov model. Probability estimates were based on published medical literature. Cost estimates were based on Medicare reimbursement rates and published medical literature. Persons 25 to 45 years of age with otherwise asymptomatic rectal bleeding. The patient's lifetime. Modified societal perspective. Diagnostic strategies included no evaluation, colonoscopy, flexible sigmoidoscopy, barium enema, anoscopy, or any feasible combination of these procedures. Life expectancy and costs. For 35-year-old patients, the no-evaluation strategy yielded the least life expectancy. The incremental cost-effectiveness of flexible sigmoidoscopy compared with no evaluation or with any strategy incorporating anoscopy (followed by further evaluation if no anal disease was found on anoscopy) was less than $5300 per year of life gained. A strategy of flexible sigmoidoscopy plus barium enema yielded the greatest life expectancy, with an incremental cost of $23 918 per additional life-year gained compared with flexible sigmoidoscopy alone. As patient age at presentation of rectal bleeding increased, evaluation of the entire colon became more cost-effective. The incremental cost-effectiveness of flexible sigmoidoscopy plus barium enema compared with colonoscopy was sensitive to estimates of the sensitivity of the tests. In a probabilistic sensitivity analysis comparing flexible sigmoidoscopy with anoscopy followed by flexible sigmoidoscopy if needed, the middle 95th percentile of the distribution of the incremental cost-effectiveness ratios ranged from flexible sigmoidoscopy yielding an increased life expectancy at reduced cost to $52 158 per year of life gained (mean, $11 461 per year of life saved). Evaluation of the colon of persons 25 to 45 years of age with otherwise asymptomatic rectal bleeding increases the life expectancy at a cost comparable to that of colon cancer screening.

On the Evaluation of Curriculum Reforms

ERIC Educational Resources Information Center

Hopmann, Stefan Thomas

2003-01-01

The paper considers the current international trend towards standards-based evaluation in a historical and comparative perspective. Based on a systematization of evaluation perspectives and tools, two basic patterns of curriculum control are discussed: process evaluation, and product evaluation. Whereas the first type has dominated the Continental…

Single-case synthesis tools I: Comparing tools to evaluate SCD quality and rigor.

PubMed

Zimmerman, Kathleen N; Ledford, Jennifer R; Severini, Katherine E; Pustejovsky, James E; Barton, Erin E; Lloyd, Blair P

2018-03-03

Tools for evaluating the quality and rigor of single case research designs (SCD) are often used when conducting SCD syntheses. Preferred components include evaluations of design features related to the internal validity of SCD to obtain quality and/or rigor ratings. Three tools for evaluating the quality and rigor of SCD (Council for Exceptional Children, What Works Clearinghouse, and Single-Case Analysis and Design Framework) were compared to determine if conclusions regarding the effectiveness of antecedent sensory-based interventions for young children changed based on choice of quality evaluation tool. Evaluation of SCD quality differed across tools, suggesting selection of quality evaluation tools impacts evaluation findings. Suggestions for selecting an appropriate quality and rigor assessment tool are provided and across-tool conclusions are drawn regarding the quality and rigor of studies. Finally, authors provide guidance for using quality evaluations in conjunction with outcome analyses when conducting syntheses of interventions evaluated in the context of SCD. Copyright © 2018 Elsevier Ltd. All rights reserved.

A systematic review of model-based economic evaluations of diagnostic and therapeutic strategies for lower extremity artery disease.

PubMed

Vaidya, Anil; Joore, Manuela A; ten Cate-Hoek, Arina J; Kleinegris, Marie-Claire; ten Cate, Hugo; Severens, Johan L

2014-01-01

Lower extremity artery disease (LEAD) is a sign of wide spread atherosclerosis also affecting coronary, cerebral and renal arteries and is associated with increased risk of cardiovascular events. Many economic evaluations have been published for LEAD due to its clinical, social and economic importance. The aim of this systematic review was to assess modelling methods used in published economic evaluations in the field of LEAD. Our review appraised and compared the general characteristics, model structure and methodological quality of published models. Electronic databases MEDLINE and EMBASE were searched until February 2013 via OVID interface. Cochrane database of systematic reviews, Health Technology Assessment database hosted by National Institute for Health research and National Health Services Economic Evaluation Database (NHSEED) were also searched. The methodological quality of the included studies was assessed by using the Philips' checklist. Sixteen model-based economic evaluations were identified and included. Eleven models compared therapeutic health technologies; three models compared diagnostic tests and two models compared a combination of diagnostic and therapeutic options for LEAD. Results of this systematic review revealed an acceptable to low methodological quality of the included studies. Methodological diversity and insufficient information posed a challenge for valid comparison of the included studies. In conclusion, there is a need for transparent, methodologically comparable and scientifically credible model-based economic evaluations in the field of LEAD. Future modelling studies should include clinically and economically important cardiovascular outcomes to reflect the wider impact of LEAD on individual patients and on the society.

[Principles of health economic evaluation for use by caregivers].

PubMed

Derumeaux-Burel, Hélène; Derancourt, Christian; Rambhojan, Christine; Branchard, Olivier; Hayes, Nathalie; Bénard, Antoine

2017-01-01

The aim of health economic evaluation is to maximize health gains from limited resources. By definition, health economic evaluation is comparative, based on average costs and outcomes of compared interventions. Incremental costs and outcomes are used to calculate the cost-effectiveness ratio, which represents the average incremental cost per gained unit of effectiveness (i.e.: a year of life) with the evaluated intervention compared to the reference. The health economic rationale applies to all health domains. We cannot spend collective resources (health insurance) without asking ourselves about their potential alternative uses. This reasoning is useful to caregivers for understanding resources allocation decisions and healthcare recommandations. Caregivers should grab this field of expertise because they are central in this strategic reflection for defining the future French healthcare landscape. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

WOODSTOVE EMISSION SAMPLING METHODS COMPARABILITY ANALYSIS AND IN-SITU EVALUATION OF NEW TECHNOLOGY WOODSTOVES

EPA Science Inventory

This report compares simultaneous results from three woodstove sampling methods and evaluates particulate emission rates of conventional and Oregon-certified catalytic and noncatalytic woodstoves in six Portland, OR, houses. EPA Methods 5G and 5H and the field emission sampler (A...

Modulated evaluation metrics for drug-based ontologies.

PubMed

Amith, Muhammad; Tao, Cui

2017-04-24

Research for ontology evaluation is scarce. If biomedical ontological datasets and knowledgebases are to be widely used, there needs to be quality control and evaluation for the content and structure of the ontology. This paper introduces how to effectively utilize a semiotic-inspired approach to ontology evaluation, specifically towards drug-related ontologies hosted on the National Center for Biomedical Ontology BioPortal. Using the semiotic-based evaluation framework for drug-based ontologies, we adjusted the quality metrics based on the semiotic features of drug ontologies. Then, we compared the quality scores before and after tailoring. The scores revealed a more precise measurement and a closer distribution compared to the before-tailoring. The results of this study reveal that a tailored semiotic evaluation produced a more meaningful and accurate assessment of drug-based ontologies, lending to the possible usefulness of semiotics in ontology evaluation.

Effects of priming self-construals on self-evaluations: Cultural game player perspective.

PubMed

Kim, Jungsik; Song, Eugene; Takemoto, Timothy

2016-12-01

This study examined the validity of situational view on culture-specific behaviours focusing on self-evaluation. Two experiments with American students as samples were conducted to examine whether priming their self-construals would affect individuals' self-evaluation. In Experiment 1, the participants' self-evaluation was compared across different conditions of primed self-contruals. In Experiment 2, the participants were split into 2 groups based on their initial default self-consturals and, the self-evaluations were compared across the 2 groups after priming self-contruals. The results demonstrated that although the participants' self-evaluation was initially in accord with their default self-construal, it changed into accord with the primed self-construals. The findings supported the proposed cultural game player view. Implications on situational view of self-evaluation are also discussed. © 2015 International Union of Psychological Science.

Cost-effectiveness of pharmaceutical management for osteoarthritis pain: a systematic review of the literature and recommendations for future economic evaluation.

PubMed

Xie, Feng; Tanvejsilp, Pimwara; Campbell, Kaitryn; Gaebel, Kathryn

2013-05-01

Osteoarthritis (OA) is a highly prevalent and chronic condition characterized by pain and physical disability. Currently, many treatments are available, and they primarily target pain relief. The objectives of this study were to systematically review economic evaluations for pharmaceutical management of OA pain and to provide methodological recommendations for future economic evaluation. Published literature was identified by searching the following bibliographic databases: MEDLINE (1948-16 November 2011) with In-Process records and EMBASE (1980-2011 Week 47) via Ovid; The Cochrane Library (Issue 4 of 4, 2011) and the Health Economic Evaluations Database (HEED) via Wiley; and PubMed (for non-MEDLINE records). The main search terms were OA and economic evaluations. Two reviewers independently screened all identified articles and extracted the data from those included in the final review. Twelve articles reporting the cost-effectiveness of various pharmaceuticals were included, with five being trial-based and seven being model-based economic evaluations. The mean health economics quality score of the included articles was 84 (minimum-maximum: 63-99). These evaluations varied in study design, treatments compared, and outcomes measured. The existing economic evaluations on pharmaceutical management of OA pain were of acceptable quality. Comparability of economic evaluations could be improved by selecting standard comparators, adopting a longer time horizon, and directly measuring health utilities.

The Practice of Educational Evaluation: A View from the Inside.

ERIC Educational Resources Information Center

Jolly, S. Jean; Gramenz, Gary W.

The literature on the practice of educational evaluation is reviewed, and internal and external evaluations in a school setting are compared. The paper states that the typical external evaluation is conducted as if school districts were rational organizations, a view which permeated 19th century evaluation activities. The internal evaluator, on…

Pharmacotherapy for social anxiety disorder (SAnD).

PubMed

Williams, Taryn; Hattingh, Coenraad J; Kariuki, Catherine M; Tromp, Sean A; van Balkom, Anton J; Ipser, Jonathan C; Stein, Dan J

2017-10-19

Recognition is growing that social anxiety disorder (SAnD) is a chronic and disabling disorder, and data from early trials demonstrate that medication may be effective in its treatment. This systematic review is an update of an earlier review of pharmacotherapy of SAnD. To assess the effects of pharmacotherapy for social anxiety disorder in adults and identify which factors (methodological or clinical) predict response to treatment. We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR-Studies and CCMDCTR-References) to 17 August 2015. The CCMDCTR contains reports of relevant RCTs from MEDLINE (1950-), Embase (1974-), PsycINFO (1967-) and CENTRAL (all years). We scanned the reference lists of articles for additional studies. We updated the search in August 2017 and placed additional studies in Awaiting Classification, these will be incorporated in the next version of the review, as appropriate. We restricted studies to randomised controlled trials (RCTs) of pharmacotherapy versus placebo in the treatment of SAnD in adults. Two authors (TW and JI) assessed trials for eligibility and inclusion for this review update. We extracted descriptive, methodological and outcome information from each trial, contacting investigators for missing information where necessary. We calculated summary statistics for continuous and dichotomous variables (if provided) and undertook subgroup and sensitivity analyses. We included 66 RCTs in the review (> 24 weeks; 11,597 participants; age range 18 to 70 years) and 63 in the meta-analysis. For the primary outcome of treatment response, we found very low-quality evidence of treatment response for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (number of studies (k) = 24, risk ratio (RR) 1.65; 95% confidence interval (CI) 1.48 to 1.85, N = 4984). On this outcome there was also evidence of benefit for monoamine oxidase inhibitors (MAOIs) (k = 4, RR 2.36; 95% CI 1.48 to 3.75, N = 235), reversible inhibitors of monoamine oxidase A (RIMAs) (k = 8, RR 1.83; 95% CI 1.32 to 2.55, N = 1270), and the benzodiazepines (k = 2, RR 4.03; 95% CI 2.45 to 6.65, N = 132), although the evidence was low quality. We also found clinical response for the anticonvulsants with gamma-amino butyric acid (GABA) analogues (k = 3, RR 1.60; 95% CI 1.16 to 2.20, N = 532; moderate-quality evidence). The SSRIs were the only medication proving effective in reducing relapse based on moderate-quality evidence. We assessed tolerability of SSRIs and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine on the basis of treatment withdrawal; this was higher for medication than placebo (SSRIs: k = 24, RR 2.59; 95% CI 1.97 to 3.39, N = 5131, low-quality evidence; venlafaxine: k = 4, RR 3.23; 95% CI 2.15 to 4.86, N = 1213, moderate-quality evidence), but there were low absolute rates of withdrawal for both these medications classes compared to placebo. We did not find evidence of a benefit for the rest of the medications compared to placebo.For the secondary outcome of SAnD symptom severity, there was benefit for the SSRIs, the SNRI venlafaxine, MAOIs, RIMAs, benzodiazepines, the antipsychotic olanzapine, and the noradrenergic and specific serotonergic antidepressant (NaSSA) atomoxetine in the reduction of SAnD symptoms, but most of the evidence was of very low quality. Treatment with SSRIs and RIMAs was also associated with a reduction in depression symptoms. The SSRIs were the only medication class that demonstrated evidence of reduction in disability across a number of domains.We observed a response to long-term treatment with medication for the SSRIs (low-quality evidence), for the MAOIs (very low-quality evidence) and for the RIMAs (moderate-quality evidence). We found evidence of treatment efficacy for the SSRIs, but it is based on very low- to moderate-quality evidence. Tolerability of SSRIs was lower than placebo, but absolute withdrawal rates were low.While a small number of trials did report treatment efficacy for benzodiazepines, anticonvulsants, MAOIs, and RIMAs, readers should consider this finding in the context of potential for abuse or unfavourable side effects.

Objective measurements to evaluate glottal space segmentation from laryngeal images.

PubMed

Gutiérrez-Arriola, J M; Osma-Ruiz, V; Sáenz-Lechón, N; Godino-Llorente, J I; Fraile, R; Arias-Londoño, J D

2012-01-01

Objective evaluation of the results of medical image segmentation is a known problem. Applied to the task of automatically detecting the glottal area from laryngeal images, this paper proposes a new objective measurement to evaluate the quality of a segmentation algorithm by comparing with the results given by a human expert. The new figure of merit is called Area Index, and its effectiveness is compared with one of the most used figures of merit found in the literature: the Pratt Index. Results over 110 laryngeal images presented high correlations between both indexes, demonstrating that the proposed measure is comparable to the Pratt Index and it is a good indicator of the segmentation quality.

Impact of Educational Level on Study Attrition and Evaluation of Web-Based Computer-Tailored Interventions: Results From Seven Randomized Controlled Trials.

PubMed

Reinwand, Dominique A; Crutzen, Rik; Elfeddali, Iman; Schneider, Francine; Schulz, Daniela Nadine; Smit, Eline Suzanne; Stanczyk, Nicola Esther; Tange, Huibert; Voncken-Brewster, Viola; Walthouwer, Michel Jean Louis; Hoving, Ciska; de Vries, Hein

2015-10-07

Web-based computer-tailored interventions have shown to be effective in improving health behavior; however, high dropout attrition is a major issue in these interventions. The aim of this study is to assess whether people with a lower educational level drop out from studies more frequently compared to people with a higher educational level and to what extent this depends on evaluation of these interventions. Data from 7 randomized controlled trials of Web-based computer-tailored interventions were used to investigate dropout rates among participants with different educational levels. To be able to compare higher and lower educated participants, intervention evaluation was assessed by pooling data from these studies. Logistic regression analysis was used to assess whether intervention evaluation predicted dropout at follow-up measurements. In 3 studies, we found a higher study dropout attrition rate among participants with a lower educational level, whereas in 2 studies we found that middle educated participants had a higher dropout attrition rate compared to highly educated participants. In 4 studies, no such significant difference was found. Three of 7 studies showed that participants with a lower or middle educational level evaluated the interventions significantly better than highly educated participants ("Alcohol-Everything within the Limit": F2,376=5.97, P=.003; "My Healthy Behavior": F2,359=5.52, P=.004; "Master Your Breath": F2,317=3.17, P=.04). One study found lower intervention evaluation by lower educated participants compared to participants with a middle educational level ("Weight in Balance": F2,37=3.17, P=.05). Low evaluation of the interventions was not a significant predictor of dropout at a later follow-up measurement in any of the studies. Dropout attrition rates were higher among participants with a lower or middle educational level compared with highly educated participants. Although lower educated participants evaluated the interventions better in approximately half of the studies, evaluation did not predict dropout attrition. Further research is needed to find other explanations for high dropout rates among lower educated participants.

Evaluative Priming of Naming and Semantic Categorization Responses Revisited: A Mutual Facilitation Explanation

ERIC Educational Resources Information Center

Schmitz, Melanie; Wentura, Dirk

2012-01-01

The evaluative priming effect (i.e., faster target responses following evaluatively congruent compared with evaluatively incongruent primes) in nonevaluative priming tasks (such as naming or semantic categorization tasks) is considered important for the question of how evaluative connotations are represented in memory. However, the empirical…

Assessing the Subsequent Effect of a Formative Evaluation on a Program.

ERIC Educational Resources Information Center

Brown, J. Lynne; Kiernan, Nancy Ellen

2001-01-01

Conducted a formative evaluation of an osteoporosis prevention health education program using several methods, including questionnaires completed by 256 women, and then compared formative evaluation results to those of a summative evaluation focusing on the same target group. Results show the usefulness of formative evaluation for strengthening…

An Analysis of State and Local Alignment of Teacher Evaluation in Maryland

ERIC Educational Resources Information Center

Peterson, Serene N.

2014-01-01

This study explored the components of Maryland's newly-implemented teacher evaluation framework and compared state requirements with evaluations to three local school systems' evaluation procedures. The study sought to investigate the relationship between three evaluation protocols in comparison to the state requirements. Three local school…

Atmospheric Model Evaluation Tool for meteorological and air quality simulations

EPA Pesticide Factsheets

The Atmospheric Model Evaluation Tool compares model predictions to observed data from various meteorological and air quality observation networks to help evaluate meteorological and air quality simulations.

WASTE REDUCTION TECHNOLOGY EVALUATIONS AT THREE PRINTED WIRE BOARD MANUFACTURERS

EPA Science Inventory

Technologies at three printed wire board (PWB) manufacturers were evaluated for waste reduction, and costs were compared to existing operations. rom 1989 to 1993, these evaluations were conducted under US EPA's Waste Reduction Innovative Technology Evaluation (WRITE) Program, in ...

Comparing Propensity Score Methods in Balancing Covariates and Recovering Impact in Small Sample Educational Program Evaluations

ERIC Educational Resources Information Center

Stone, Clement A.; Tang, Yun

2013-01-01

Propensity score applications are often used to evaluate educational program impact. However, various options are available to estimate both propensity scores and construct comparison groups. This study used a student achievement dataset with commonly available covariates to compare different propensity scoring estimation methods (logistic…

Computer-Assisted, Programmed Text, and Lecture Modes of Instruction in Three Medical Training Courses: Comparative Evaluation. Final Report.

ERIC Educational Resources Information Center

Deignan, Gerard M.; And Others

This report contains a comparative analysis of the differential effectiveness of computer-assisted instruction (CAI), programmed instructional text (PIT), and lecture methods of instruction in three medical courses--Medical Laboratory, Radiology, and Dental. The summative evaluation includes (1) multiple regression analyses conducted to predict…

Principal Holistic Judgments and High-Stakes Evaluations of Teachers

ERIC Educational Resources Information Center

Briggs, Derek C.; Dadey, Nathan

2017-01-01

Results from a sample of 1,013 Georgia principals who rated 12,617 teachers are used to compare holistic and analytic principal judgments with indicators of student growth central to the state's teacher evaluation system. Holistic principal judgments were compared to mean student growth percentiles (MGPs) and analytic judgments from a formal…

The Positive Alternative Credit Experience (PACE) Program a Quantitative Comparative Study

ERIC Educational Resources Information Center

Warren, Rebecca Anne

2011-01-01

The purpose of this quantitative comparative study was to evaluate the Positive Alternative Credit Experience (PACE) Program using an objectives-oriented approach to a formative program evaluation. The PACE Program was a semester-long high school alternative education program designed to serve students at-risk for academic failure or dropping out…

Integrating quantitative and qualitative evaluation methods to compare two teacher inservice training programs

NASA Astrophysics Data System (ADS)

Lawrenz, Frances; McCreath, Heather

Qualitative and quantitative evaluation procedures were used to compare two physical-science teacher inservice training programs. The two programs followed the master teacher training model espoused by NSF but used different types of master teachers and types of activities. The two evaluation procedures produced different results and together they provided a much clearer picture of the strengths and weaknesses of the two programs. Using only one approach or the other would have substantially altered the conclusions.

An Evaluation of Output Quality of Machine Translation (Padideh Software vs. Google Translate)

ERIC Educational Resources Information Center

Azer, Haniyeh Sadeghi; Aghayi, Mohammad Bagher

2015-01-01

This study aims to evaluate the translation quality of two machine translation systems in translating six different text-types, from English to Persian. The evaluation was based on criteria proposed by Van Slype (1979). The proposed model for evaluation is a black-box type, comparative and adequacy-oriented evaluation. To conduct the evaluation, a…

White LED compared with other light sources: age-dependent photobiological effects and parameters for evaluation.

PubMed

Rebec, Katja Malovrh; Klanjšek-Gunde, Marta; Bizjak, Grega; Kobav, Matej B

2015-01-01

Ergonomic science at work and living places should appraise human factors concerning the photobiological effects of lighting. Thorough knowledge on this subject has been gained in the past; however, few attempts have been made to propose suitable evaluation parameters. The blue light hazard and its influence on melatonin secretion in age-dependent observers is considered in this paper and parameters for its evaluation are proposed. New parameters were applied to analyse the effects of white light-emitting diode (LED) light sources and to compare them with the currently applied light sources. The photobiological effects of light sources with the same illuminance but different spectral power distribution were determined for healthy 4-76-year-old observers. The suitability of new parameters is discussed. Correlated colour temperature, the only parameter currently used to assess photobiological effects, is evaluated and compared to new parameters.

Economic evaluations in pain management: principles and methods.

PubMed

Asche, Carl V; Seal, Brian; Jackson, Kenneth C; Oderda, Gary M

2006-01-01

This paper describes how investigators may design, conduct, and report economic evaluations of pharmacotherapy for pain and symptom management. Because economic evaluation of therapeutic interventions is becoming increasingly important, there is a need for guidance on how economic evaluations can be optimally conducted. The steps required to conduct an economic evaluation are described to provide this guidance. Economic evaluations require two or more therapeutic interventions to be compared in relation to costs and effects. There are five types of economic evaluations, based on analysis of: (1) cost-effectiveness, (2) cost-utility, (3) cost-minimization, (4) cost-consequence, and (5) cost-benefit analyses. The six required steps are: identify the perspective of the study; identify the alternatives that will be compared; identify the relevant costs and effects; determine how to collect the cost and effect data; determine how to perform calculation for cost and effects data; and determine the manner in which to depict the results and draw comparisons.

Accuracy and content of medical student midclerkship self-evaluations.

PubMed

Torres, Madeline B; Cochran, Amalia

2016-06-01

Midclerkship self-evaluations (MCSEs) require students to reflect on their knowledge, skills, and behaviors. We hypothesized that MCSEs would be consistent with supervisor midpoint evaluations during a surgical clerkship. MCSEs of 153 students who completed our surgery clerkship in 2 academic years were compared with supervisor midclerkship evaluations. The quantitative domains of the MCSE and supervisor evaluation were compared for accuracy. Identified areas of strengths and weakness were evaluated for thematic consistency. Student MCSE scoring was accurate across evaluated domains most of the time; when students were inaccurate, they tended to underrate themselves. Students and supervisors most often identified cognitive skills as areas for improvement and noncognitive skills predominated as student strengths. Medical students can accurately identify their strengths and weaknesses in the context of an MCSE. Based on these findings, knowledge acquisition and application by medical students in the clinical setting should be emphasized in undergraduate medical education. Copyright © 2016 Elsevier Inc. All rights reserved.

Northwestern University Flexible Subischial Vacuum Socket for persons with transfemoral amputation: Part 2 Description and Preliminary evaluation

PubMed Central

Fatone, Stefania; Caldwell, Ryan

2017-01-01

Background: Current transfemoral prosthetic sockets are problematic as they restrict function, lack comfort, and cause residual limb problems. Development of a subischial socket with lower proximal trim lines is an appealing way to address this problem and may contribute to improving quality of life of persons with transfemoral amputation. Objectives: The purpose of this study was to illustrate the use of a new subischial socket in two subjects. Study design: Case series. Methods: Two unilateral transfemoral prosthesis users participated in preliminary socket evaluations comparing functional performance of the new subischial socket to ischial containment sockets. Testing included gait analysis, socket comfort score, and performance-based clinical outcome measures (Rapid-Sit-To-Stand, Four-Square-Step-Test, and Agility T-Test). Results: For both subjects, comfort was better in the subischial socket, while gait and clinical outcomes were generally comparable between sockets. Conclusion: While these evaluations are promising regarding the ability to function in this new socket design, more definitive evaluation is needed. Clinical relevance Using gait analysis, socket comfort score and performance-based outcome measures, use of the Northwestern University Flexible Subischial Vaccum Socket was evaluated in two transfemoral prosthesis users. Socket comfort improved for both subjects with comparable function compared to ischial containment sockets. PMID:28132589

Evaluation Theory Tree Re-Examined

ERIC Educational Resources Information Center

Christie, Christina A.; Alkin, Marvin C.

2008-01-01

When examining various evaluation prescriptive theories comparatively, we find it helpful to have a framework showing how they are related that highlights features that distinguish theoretical perspectives, thus a "theory" about theories. The evaluation theory tree that we presented in Alkin's recent book, "Evaluation Roots"…

Evaluation, Language, and Untranslatables

ERIC Educational Resources Information Center

Dahler-Larsen, Peter; Abma, Tineke; Bustelo, María; Irimia, Roxana; Kosunen, Sonja; Kravchuk, Iryna; Minina, Elena; Segerholm, Christina; Shiroma, Eneida; Stame, Nicoletta; Tshali, Charlie Kabanga

2017-01-01

The issue of translatability is pressing in international evaluation, in global transfer of evaluative instruments, in comparative performance management, and in culturally responsive evaluation. Terms that are never fully understood, digested, or accepted may continue to influence issues, problems, and social interactions in and around and after…

Comparative evaluation between cervical vertebral morphology and hand-wrist morphology for skeletal maturation assessment.

PubMed

Grippaudo, C; Garcovich, D; Volpe, G; Lajolo, C

2006-05-01

The aim of the study was to find a correlation between the evaluation of skeletal maturation performed by the study of cervical vertebrae maturation indicators and the evaluation obtained by the hand and wrist maturation indicators. Left hand wrist radiographs and the corresponding lateral cephalograms of 90 patients (48 males and 42 females; aged 6 to 14 years) were paired and a study group of 128 pair of radiographs was obtained, having some patients 2 or more radiographs at different times. Hand and wrist radiographs were evaluated according to the protocol proposed by Grave (scores 0 to 9); corresponding lateral cephalograms were evaluated according to the method reported by Baccetti (scores 1 to 5). Values obtained with the 2 methods were analyzed by Spearman's correlation test. When the values were compared globally in the 2 genders a good correlation was obtained (r=0.795; P<0.001); when the correlation was compared separately in the 2 genders a better correlation was observed in females (r=0.84; P<0.001) than in males (r=0.70; P<0.001). The results obtained clearly underline the accuracy of the skeletal maturation evaluation by the analysis of cervical vertebrae in laterolateral cephalograms which can substitute the hand and wrist radiograph for the skeletal maturation evaluation in orthodontic diagnosis.

Blindness and social trust: The effect of early visual deprivation on judgments of trustworthiness.

PubMed

Ferrari, C; Vecchi, T; Merabet, L B; Cattaneo, Z

2017-10-01

Investigating the impact of early visual deprivation on evaluations related to social trust has received little attention to date. This is despite consistent evidence suggesting that early onset blindness may interfere with the normal development of social skills. In this study, we investigated whether early blindness affects judgments of trustworthiness regarding the actions of an agent, with trustworthiness representing the fundamental dimension in the social evaluation. Specifically, we compared performance between a group of early blind individuals with that of sighted controls in their evaluation of trustworthiness of an agent after hearing a pair of two positive or two negative social behaviors (impression formation). Participants then repeated the same evaluation following the presentation of a third (consistent or inconsistent) behavior regarding the same agent (impression updating). Overall, blind individuals tended to give similar evaluations compared to their sighted counterparts. However, they also valued positive behaviors significantly more than sighted controls when forming their impression of an agent's trustworthiness. Moreover, when inconsistent information was provided, blind individuals were more prone to revise their initial evaluation compared to controls. These results suggest that early visual deprivation may have a dramatic effect on the evaluation of social factors such as trustworthiness. Copyright © 2017 Elsevier Inc. All rights reserved.

Interdisciplinary Team Evaluation: An Effective Method for the Diagnostic Assessment of Autism Spectrum Disorder.

PubMed

Gerdts, Jennifer; Mancini, James; Fox, Emily; Rhoads, Candace; Ward, Tracey; Easley, Erin; Bernier, Raphael A

2018-05-01

The objective of this research is to assess the feasibility of an interdisciplinary team diagnostic assessment model for autism spectrum disorder (ASD). Medical records from 366 patients evaluated for ASD at the Seattle Children's Autism Center (SCAC) were reviewed. ASD diagnostic outcomes, provider satisfaction, engagement in follow-up care, billed time, and reimbursement amounts were compared in patients evaluated through an interdisciplinary team approach (n = 91) with those seen in multidisciplinary evaluations led by either a psychologist (n = 165) or a physician (n = 110). Diagnostic determination was made in 90% of patients evaluated through the interdisciplinary team model in a single day. Rates of ASD diagnosis were similar across the 3 tracks, ranging from 61% to 72%. Demographic characteristics did not impact the likelihood of ASD diagnosis. Rates of patient follow-up care and provider satisfaction were significantly higher in interdisciplinary versus multidisciplinary teams. Interdisciplinary team evaluations billed 1.8 fewer hours yet generated more net hourly clinic income compared with psychology-led multidisciplinary evaluations. An interdisciplinary team approach, focusing on ruling-in or ruling-out ASD, was sufficient to determine ASD diagnosis in most patients seen at the SCAC Interdisciplinary teams generated more clinic income and decreased the time spent in evaluation compared with a psychology-led approach. They did so while maintaining consistency in diagnostic rates, demonstrating increased provider satisfaction and an increased likelihood of engagement in follow-up care.

Proposed evaluation framework for assessing operator performance with multisensor displays

NASA Technical Reports Server (NTRS)

Foyle, David C.

1992-01-01

Despite aggressive work on the development of sensor fusion algorithms and techniques, no formal evaluation procedures have been proposed. Based on existing integration models in the literature, an evaluation framework is developed to assess an operator's ability to use multisensor, or sensor fusion, displays. The proposed evaluation framework for evaluating the operator's ability to use such systems is a normative approach: The operator's performance with the sensor fusion display can be compared to the models' predictions based on the operator's performance when viewing the original sensor displays prior to fusion. This allows for the determination as to when a sensor fusion system leads to: 1) poorer performance than one of the original sensor displays (clearly an undesirable system in which the fused sensor system causes some distortion or interference); 2) better performance than with either single sensor system alone, but at a sub-optimal (compared to the model predictions) level; 3) optimal performance (compared to model predictions); or, 4) super-optimal performance, which may occur if the operator were able to use some highly diagnostic 'emergent features' in the sensor fusion display, which were unavailable in the original sensor displays. An experiment demonstrating the usefulness of the proposed evaluation framework is discussed.

A comparative evaluation of the effect of Internet-based CME delivery format on satisfaction, knowledge and confidence.

PubMed

Curran, Vernon R; Fleet, Lisa J; Kirby, Fran

2010-01-29

Internet-based instruction in continuing medical education (CME) has been associated with favorable outcomes. However, more direct comparative studies of different Internet-based interventions, instructional methods, presentation formats, and approaches to implementation are needed. The purpose of this study was to conduct a comparative evaluation of two Internet-based CME delivery formats and the effect on satisfaction, knowledge and confidence outcomes. Evaluative outcomes of two differing formats of an Internet-based CME course with identical subject matter were compared. A Scheduled Group Learning format involved case-based asynchronous discussions with peers and a facilitator over a scheduled 3-week delivery period. An eCME On Demand format did not include facilitated discussion and was not based on a schedule; participants could start and finish at any time. A retrospective, pre-post evaluation study design comparing identical satisfaction, knowledge and confidence outcome measures was conducted. Participants in the Scheduled Group Learning format reported significantly higher mean satisfaction ratings in some areas, performed significantly higher on a post-knowledge assessment and reported significantly higher post-confidence scores than participants in the eCME On Demand format that was not scheduled and did not include facilitated discussion activity. The findings support the instructional benefits of a scheduled delivery format and facilitated asynchronous discussion in Internet-based CME.

Comparison of Knowledge-based Iterative Model Reconstruction and Hybrid Reconstruction Techniques for Liver CT Evaluation of Hypervascular Hepatocellular Carcinoma.

PubMed

Park, Hyun Jeong; Lee, Jeong Min; Park, Sung Bin; Lee, Jong Beum; Jeong, Yoong Ki; Yoon, Jeong Hee

The purpose of this work was to evaluate the image quality, lesion conspicuity, and dose reduction provided by knowledge-based iterative model reconstruction (IMR) in computed tomography (CT) of the liver compared with hybrid iterative reconstruction (IR) and filtered back projection (FBP) in patients with hepatocellular carcinoma (HCC). Fifty-six patients with 61 HCCs who underwent multiphasic reduced-dose CT (RDCT; n = 33) or standard-dose CT (SDCT; n = 28) were retrospectively evaluated. Reconstructed images with FBP, hybrid IR (iDose), IMR were evaluated for image quality using CT attenuation and image noise. Objective and subjective image quality of RDCT and SDCT sets were independently assessed by 2 observers in a blinded manner. Image quality and lesion conspicuity were better with IMR for both RDCT and SDCT than either FBP or IR (P < 0.001). Contrast-to-noise ratio of HCCs in IMR-RDCT was significantly higher on delayed phase (DP) (P < 0.001), and comparable on arterial phase, than with IR-SDCT (P = 0.501). Iterative model reconstruction RDCT was significantly superior to FBP-SDCT (P < 0.001). Compared with IR-SDCT, IMR-RDCT was comparable in image sharpness and tumor conspicuity on arterial phase, and superior in image quality, noise, and lesion conspicuity on DP. With the use of IMR, a 27% reduction of effective dose was achieved with RDCT (12.7 ± 0.6 mSv) compared with SDCT (17.4 ± 1.1 mSv) without loss of image quality (P < 0.001). Iterative model reconstruction provides better image quality and tumor conspicuity than FBP and IR with considerable noise reduction. In addition, more than comparable results were achieved with IMR-RDCT to IR-SDCT for the evaluation of HCCs.

Comparison of Methods for Evaluating Urban Transportation Alternatives

DOT National Transportation Integrated Search

1975-02-01

The objective of the report was to compare five alternative methods for evaluating urban transportation improvement options: unaided judgmental evaluation cost-benefit analysis, cost-effectiveness analysis based on a single measure of effectiveness, ...

Evaluation of meniscus tears of the knee by radionuclide imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marymont, J.V.; Lynch, M.A.; Henning, C.E.

We compare the accuracy of radionuclide imaging of the knee with Tc99m-pyrophosphate with arthrography for the evaluation of meniscus tears in young athletes with clinically suspected knee injury. All patients had arthroscopy which was used as the standard against which the other two diagnostic procedures were compared. Radionuclide scintigraphy and arthrography were comparable in their ability to detect tears of the medial meniscus. Scintigraphy was superior for the detection of tears of the lateral meniscus and of both menisci.

Comparing Web search engine performance in searching consumer health information: evaluation and recommendations.

PubMed Central

Wu, G; Li, J

1999-01-01

Identifying and accessing reliable, relevant consumer health information rapidly on the Internet may challenge the health sciences librarian and layperson alike. In this study, seven search engines are compared using representative consumer health topics for their content relevancy, system features, and attributes. The paper discusses evaluation criteria; systematically compares relevant results; analyzes performance in terms of the strengths and weaknesses of the search engines; and illustrates effective search engine selection, search formulation, and strategies. PMID:10550031

Evaluating Change in Medical School Curricula: How Did We Know Where We Were Going?

ERIC Educational Resources Information Center

Mahaffy, John; Gerrity, Martha S.

1998-01-01

Compares and contrasts the primary outcomes and methods used to evaluate curricular changes at eight medical schools participating in a large-scale medical curriculum development project. Describes how the evaluative data, both quantitative and qualitative, were collected, and how evaluation drove curricular change. Although the evaluations were…

A Comparison of Formative and Summative Evaluation.

ERIC Educational Resources Information Center

Belenski, Mary Jo

Formative and summative evaluations in education are compared, and appropriate uses of these methods in program evaluation are discussed. The main purpose of formative evaluation is to determine a level of mastery of a learning task, along with discovering any part of the task that was not mastered. In other words, formative evaluation focuses the…

Designs for Evaluating the Community-Level Impact of Comprehensive Prevention Programs: Examples from the CDC Centers of Excellence in Youth Violence Prevention.

PubMed

Farrell, Albert D; Henry, David; Bradshaw, Catherine; Reischl, Thomas

2016-04-01

This article discusses the opportunities and challenges of developing research designs to evaluate the impact of community-level prevention efforts. To illustrate examples of evaluation designs, we describe six projects funded by the Centers for Disease Control and Prevention to evaluate multifaceted approaches to reduce youth violence in high-risk communities. Each of these projects was designed to evaluate the community-level impact of multiple intervention strategies to address individual and contextual factors that place youth at risk for violent behavior. Communities differed across projects in their setting, size, and how their boundaries were defined. Each project is using multiple approaches to compare outcomes in one or more intervention communities to those in comparison communities. Five of the projects are using comparative interrupted time-series designs to compare outcomes in an intervention community to matched comparison communities. A sixth project is using a multiple baseline design in which the order and timing of intervention activities is randomized across three communities. All six projects are also using regression point displacement designs to compare outcomes within intervention communities to those within broader sets of similar communities. Projects are using a variety of approaches to assess outcomes including archival records, surveys, and direct observations. We discuss the strengths and weaknesses of the designs of these projects and illustrate the challenges of designing high-quality evaluations of comprehensive prevention approaches implemented at the community level.

Evaluation systems for clinical governance development: a comparative study.

PubMed

Hooshmand, Elaheh; Tourani, Sogand; Ravaghi, Hamid; Ebrahimipour, Hossein

2014-01-01

Lack of scientific and confirmed researches and expert knowledge about evaluation systems for clinical governance development in Iran have made studies on different evaluation systems for clinical governance development a necessity. These studies must provide applied strategies to design criteria of implementing clinical governance for hospital's accreditation. This is a descriptive and comparative study on development of clinical governance models all over the world. Data have been gathered by reviewing related articles. Models have been studied in comprehensive review method. The evaluated models of clinical governance development were Australian, NHS, SPOCK and OPTIGOV. The final aspects extracted from these models were Responsiveness, Policies and Strategies, Organizational Structure, Allocating Resources, Education and Occupational Development, Performance Evaluation, External Evaluation, Patient Oriented Approach, Risk Management, Personnel's Participation, Information Technology, Human Resources, Research and Development, Evidence Based Medicine, Clinical Audit, Health Technology Assessment and Quality. These results are applicable for completing the present criteria which evaluating clinical governance application and provide practical framework to evaluate country's hospital on the basis of clinical governance elements.

Class Attendance and Students' Evaluations of Teaching: Do No-Shows Bias Course Ratings and Rankings?

ERIC Educational Resources Information Center

Wolbring, Tobias

2012-01-01

Background: Many university departments use students' evaluations of teaching (SET) to compare and rank courses. However, absenteeism from class is often nonrandom and, therefore, SET for different courses might not be comparable. Objective: The present study aims to answer two questions. Are SET positively biased due to absenteeism? Do…

Evaluating the Intervention of an Ethics Class in Students' Ethical Decision-Making

ERIC Educational Resources Information Center

Walker, Marquita

2011-01-01

In this pilot study, the author evaluated the impact of an ethics class in terms of students' ethical decision-making. The research compares aggregate responses from scenario-based pre- and post-survey open-ended survey questions designed to elicit changes in ethical decision-making by comparing students' cognitive and affective perceptions about…

Comparative analysis of mosqito (Diptera: Culicidae: Aedes aegypti Liston) responses to the insecticide Temephos and plant derived essential oil derived from Piper betle

USDA-ARS?s Scientific Manuscript database

Insecticide resistance development is a problem where insecticides are heavily used. Evaluation of a plant extracted oil compound as a 'green pesticide' was compared to treatments with Temephos. Evaluations on two insect populations either Wild strain (WS), or a susceptible laboratory strain (LS),...

Poem Generator: A Comparative Quantitative Evaluation of a Microworlds-Based Learning Approach for Teaching English

ERIC Educational Resources Information Center

Jenkins, Craig

2015-01-01

This paper is a comparative quantitative evaluation of an approach to teaching poetry in the subject domain of English that employs a "guided discovery" pedagogy using computer-based microworlds. It uses a quasi-experimental design in order to measure performance gains in computational thinking and poetic thinking following a…

Comparing the Level of Positive Tendency in a Life Satisfaction Evaluation between Chinese and Western People

ERIC Educational Resources Information Center

Lee, Shih-jung; Wu, Chia-huei

2008-01-01

We demonstrate that people from Chinese cultural backgrounds have a smaller positive tendency in life evaluation compared to people in typical Western cultures. Participants first described their imagined best and worst life and then rated their current life on scale anchored by those imaginings (Mellor et al. "International Journal of Social…

Multi-criteria comparative evaluation of spallation reaction models

NASA Astrophysics Data System (ADS)

Andrianov, Andrey; Andrianova, Olga; Konobeev, Alexandr; Korovin, Yury; Kuptsov, Ilya

2017-09-01

This paper presents an approach to a comparative evaluation of the predictive ability of spallation reaction models based on widely used, well-proven multiple-criteria decision analysis methods (MAVT/MAUT, AHP, TOPSIS, PROMETHEE) and the results of such a comparison for 17 spallation reaction models in the presence of the interaction of high-energy protons with natPb.

Cost Effectiveness Ratio: Evaluation Tool for Comparing the Effectiveness of Similar Extension Programs

ERIC Educational Resources Information Center

Jayaratne, K. S. U.

2015-01-01

Extension educators have been challenged to be cost effective in their educational programming. The cost effectiveness ratio is a versatile evaluation indicator for Extension educators to compare the cost of achieving a unit of outcomes or educating a client in similar educational programs. This article describes the cost effectiveness ratio and…

Comparison of Outcomes for Youth Apprenticeship Projects and Youth Career Development Projects. Supplementary Report.

ERIC Educational Resources Information Center

Richards, James M., Jr.; And Others

The New Youth Initiatives in Apprenticeship Program (YAP) was compared with the Youth Career Development Program (YCD). Data for 1979 and 1980 came from an evaluation of YAP projects by CSR, Incorporated, and an evaluation of the YCD projects by the Educational Testing Service. A multiple regression approach was used to compare student…

OER Quality and Adaptation in K-12: Comparing Teacher Evaluations of Copyright-Restricted, Open, and Open/Adapted Textbooks

ERIC Educational Resources Information Center

Kimmons, Royce

2015-01-01

Conducted in conjunction with an institute on open textbook adaptation, this study compares textbook evaluations from practicing K-12 classroom teachers (n = 30) on three different types of textbooks utilized in their contexts: copyright-restricted, open, and open/adapted. Copyright-restricted textbooks consisted of those textbooks already in use…

Kraft pulping of industrial wood waste

Treesearch

Aziz Ahmed; Masood Akhtar; Gary C. Myers; Gary M. Scott

1998-01-01

Most of the approximately 25 to 30 million tons of industrial wood waste generated in the United States per year is burned for energy and/or landfilled. In this study, kraft pulp from industrial wood waste was evaluated and compared with softwood (loblolly pine, Douglas-fir) and hardwood (aspen) pulp. Pulp bleachability was also evaluated. Compared to loblolly pine...

Transfer Credit Evaluations at New York State Colleges: Comparative Case Studies of Process Effectiveness

ERIC Educational Resources Information Center

Ott, Alexander Paul

2012-01-01

For the nearly one third of students who transfer from 1 college to another, transfer credit represents time and money. Unfortunately, many colleges provide degree-specific transfer credit evaluations only after students financially commit to attend the institution. The purpose of this study was to investigate, analyze, and compare early and late…

Implicit affective evaluation bias in hypochondriasis: findings from the Affect Misattribution Procedure.

PubMed

Schreiber, Franziska; Neng, Julia M B; Heimlich, Christiane; Witthöft, Michael; Weck, Florian

2014-10-01

Cognitive theories of hypochondriasis (HYP) suggest that catastrophic misinterpretations of benign body sensations are a core feature for the maintenance of the disorder. There is tentative support from an analog sample that the interpretation of illness-related information also involves an implicit affective component. This is the first study to examine this negative affective evaluation bias implicitly in patients with HYP. An adapted version of the Affect Misattribution Procedure (AMP) with illness, symptom and neutral primes was used in 80 patients with HYP, and compared to 83 patients with an anxiety disorder (AD), as well as 90 healthy controls (CG). The HYP group showed significantly more negative affective reactions in illness prime trials, compared to both control groups, as well as more negative implicit evaluations on symptom prime trials, compared to the CG. Significant inverse relationships were observed only between the implicit evaluations of illness words and health anxiety questionnaires. Thus, an implicit negative affective evaluation bias of serious illnesses rather than symptoms is a unique feature of HYP. Copyright © 2014 Elsevier Ltd. All rights reserved.

Segmentation quality evaluation using region-based precision and recall measures for remote sensing images

NASA Astrophysics Data System (ADS)

Zhang, Xueliang; Feng, Xuezhi; Xiao, Pengfeng; He, Guangjun; Zhu, Liujun

2015-04-01

Segmentation of remote sensing images is a critical step in geographic object-based image analysis. Evaluating the performance of segmentation algorithms is essential to identify effective segmentation methods and optimize their parameters. In this study, we propose region-based precision and recall measures and use them to compare two image partitions for the purpose of evaluating segmentation quality. The two measures are calculated based on region overlapping and presented as a point or a curve in a precision-recall space, which can indicate segmentation quality in both geometric and arithmetic respects. Furthermore, the precision and recall measures are combined by using four different methods. We examine and compare the effectiveness of the combined indicators through geometric illustration, in an effort to reveal segmentation quality clearly and capture the trade-off between the two measures. In the experiments, we adopted the multiresolution segmentation (MRS) method for evaluation. The proposed measures are compared with four existing discrepancy measures to further confirm their capabilities. Finally, we suggest using a combination of the region-based precision-recall curve and the F-measure for supervised segmentation evaluation.

Multidisciplinary eHealth Survey Evaluation Methods

ERIC Educational Resources Information Center

Karras, Bryant T.; Tufano, James T.

2006-01-01

This paper describes the development process of an evaluation framework for describing and comparing web survey tools. We believe that this approach will help shape the design, development, deployment, and evaluation of population-based health interventions. A conceptual framework for describing and evaluating web survey systems will enable the…

The impact of domain knowledge on structured data collection and templated note design.

PubMed

Windle, T; McClay, J C; Windle, J R

2013-01-01

The objective of this case report is to evaluate the importance of specialized domain knowledge when designing and using structured templated notes in a clinical environment. To analyze the impact of specialization on structured note generation we compared notes generated for three scenarios: 1) We compared the templated history of present illness (HPI) for patients presenting with a dermatology concern to the dermatologist versus the emergency department. 2) We compared the evaluation of chest pain by ED physicians versus cardiologists. 3) Finally, we compared the data elements asked for in the evaluation of the gastrointestinal system between cardiologists and the liver transplant service (LTS). We used the SNOMED CT representation via BioPortal to evaluate specificity and grouping between data elements and specialized physician groups. We found few similarities in structured data elements designed by and for the specific physician groups. The distinctness represented both differences in granularity as well as fundamental differences in data elements requested. When compared to ED physicians, dermatologists had different and more granular elements while cardiologists requested much more granular data. Comparing cardiologists and LTS, there were differences in the data elements requested. This case study supports the importance of domain knowledge in EHR design and implementation. That different specialities should want and use different information is well supported by cognitive science literature. Despite this, it is rare for domain knowledge to be considered in EHR implementation. Physicians with correct domain knowledge should be involved in the design process of templated notes.

Pharmacotherapies for cannabis dependence

PubMed Central

Marshall, Kushani; Gowing, Linda; Ali, Robert; Le Foll, Bernard

2015-01-01

Background Cannabis is the most prevalent illicit drug in the world. Demand for treatment of cannabis use disorders is increasing. There are currently no pharmacotherapies approved for treatment of cannabis use disorders. Objectives To assess the effectiveness and safety of pharmacotherapies as compared with each other, placebo or supportive care for reducing symptoms of cannabis withdrawal and promoting cessation or reduction of cannabis use. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (to 4 March 2014), MEDLINE (to week 3 February 2014), EMBASE (to 3 March 2014) and PsycINFO (to week 4 February 2014). We also searched reference lists of articles, electronic sources of ongoing trials and conference proceedings, and contacted selected researchers active in the area. Selection criteria Randomised and quasi-randomised controlled trials involving the use of medications to reduce the symptoms and signs of cannabis withdrawal or to promote cessation or reduction of cannabis use, or both, in comparison with other medications, placebo or no medication (supportive care) in participants diagnosed as cannabis dependent or who were likely to be dependent. Data collection and analysis We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors assessed studies for inclusion and extracted data. All review authors confirmed the inclusion decisions and the overall process. Main results We included 14 randomised controlled trials involving 958 participants. For 10 studies the average age was 33 years; two studies targeted young people; and age data were not available for two studies. Approximately 80% of study participants were male. The studies were at low risk of selection, performance, detection and selective outcome reporting bias. Three studies were at risk of attrition bias. All studies involved comparison of active medication and placebo. The medications included preparations containing tetrahydrocannabinol (THC) (two studies), selective serotonin reuptake inhibitor (SSRI) antidepressants (two studies), mixed action antidepressants (three studies), anticonvulsants and mood stabilisers (three studies), an atypical antidepressant (two studies), an anxiolytic (one study), a norepinephrine reuptake inhibitor (one study) and a glutamatergic modulator (one study). One study examined more than one medication. Diversity in the medications and the outcomes reported limited the extent that analysis was possible. Insufficient data were available to assess the utility of most of the medications to promote cannabis abstinence at the end of treatment. There was moderate quality evidence that completion of treatment was more likely with preparations containing THC compared to placebo (RR 1.29, 95% CI 1.08 to 1.55; 2 studies, 207 participants, P = 0.006). There was some evidence that treatment with preparations containing THC was associated with reduced cannabis withdrawal symptoms and craving, but this latter outcome could not be quantified. For mixed action antidepressants compared with placebo (2 studies, 179 participants) there was very low quality evidence on the likelihood of abstinence from cannabis at the end of follow-up (RR 0.82, 95% CI 0.12 to 5.41), and moderate quality evidence on the likelihood of treatment completion (RR 0.93, 95% CI 0.71 to 1.21). For this same outcome there was very low quality evidence for the effects of SSRI antidepressants (RR 0.82, 95% CI 0.44 to 1.53; 2 studies, 122 participants), anticonvulsants and mood stabilisers (RR 0.78, 95% CI 0.42 to 1.46; 2 studies, 75 participants), and the atypical antidepressant, bupropion (RR 1.06, 95% CI 0.67 to 1.67; 2 studies, 92 participants). Available evidence on gabapentin (anticonvulsant) and N-acetylcysteine (glutamatergic modulator) was insufficient for quantitative estimates of their effectiveness, but these medications may be worth further investigation. Authors’ conclusions There is incomplete evidence for all of the pharmacotherapies investigated, and for many of the outcomes the quality was downgraded due to small sample sizes, inconsistency and risk of attrition bias. The quantitative analyses that were possible, combined with general findings of the studies reviewed, indicate that SSRI antidepressants, mixed action antidepressants, atypical antidepressants (bupropion), anxiolytics (buspirone) and norepinephrine reuptake inhibitors (atomoxetine) are probably of little value in the treatment of cannabis dependence. Preparations containing THC are of potential value but, given the limited evidence, this application of THC preparations should be considered still experimental. Further studies should compare different preparations of THC, dose and duration of treatment, adjunct medications and therapies. The evidence base for the anticonvulsant gabapentin and the glutamatergic modulator N-acetylcysteine is weak, but these medications are also worth further investigation. PMID:25515775

The Ethical Tipping Points of Evaluators in Conflict Zones

ERIC Educational Resources Information Center

Duggan, Colleen; Bush, Kenneth

2014-01-01

What is different about the conduct of evaluations in conflict zones compared to nonconflict zones--and how do these differences affect (if at all) the ethical calculations and behavior of evaluators? When are ethical issues too risky, or too uncertain, for evaluators to accept--or to continue--an evaluation? These are the core questions guiding…