Todd M. Durell

Atomoxetine treatment of attention-deficit/hyperactivity disorder in young adults with assessment of functional outcomes: a randomized, double-blind, placebo-controlled clinical trial

Background Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairment in multiple functional domains. This trial evaluated efficacy in ADHD symptoms and functional outcomes in young adults treated with atomoxetine. Methods Young adults (18–30 years old) with ADHD were randomized to 12 weeks of double-blind treatment with atomoxetine (n = 220) or placebo (n = 225). The primary efficacy measure of ADHD symptom change was Conners’ Adult ADHD Rating Scale (CAARS): Investigator-Rated: Screening Version Total ADHD Symptoms score with adult prompts. Secondary outcomes scales included the Adult ADHD Quality of Life-29, Clinical Global Impression-ADHD-Severity, Patient Global Impression-Improvement, CAARS Self-Report, Behavior Rating Inventory of Executive Function-Adult Version Self-Report, and assessments of depression, anxiety, sleepiness, driving behaviors, social adaptation, and substance use. Results Atomoxetine was superior to placebo on CAARS: Investigator-Rated: Screening Version (atomoxetine [least-squares mean ± SE, −13.6 ± 0.8] vs placebo [−9.3 ± 0.8], 95% confidence interval [−6.35 to −2.37], P < 0.001), Clinical Global Impression-ADHD-Severity (atomoxetine [−1.1 ± 0.1] vs placebo [−0.7 ± 0.1], 95% confidence interval [−0.63 to −0.24], P < 0.001), and CAARS Self-Report (atomoxetine [−11.9 ± 0.8] vs placebo [−7.8 ± 0.7], 95% confidence interval [−5.94 to −2.15], P < 0.001) but not on Patient Global Impression-Improvement. In addition, atomoxetine was superior to placebo on Adult ADHD Quality of Life-29 and Behavior Rating Inventory of Executive Function-Adult Version Self-Report. Additional assessments failed to detect significant differences (P ≥ 0.05) between atomoxetine and placebo. The adverse event profile was similar to that observed in other atomoxetine studies. Nausea, decreased appetite, insomnia, dry mouth, irritability, dizziness, and dyspepsia were reported significantly more often with atomoxetine than with placebo. Conclusions Atomoxetine reduced ADHD symptoms and improved quality of life and executive functioning deficits in young adults compared with placebo. Atomoxetine was also generally well tolerated.

Prevalence of nonmedical methamphetamine use in the United States

BackgroundIllicit methamphetamine use continues to be a public health concern in the United States. The goal of the current study was to use a relatively inexpensive methodology to examine the prevalence and demographic correlates of nonmedical methamphetamine use in the United States.MethodsThe sample was obtained through an internet survey of noninstitutionalized adults (n = 4,297) aged 18 to 49 in the United States in 2005. Propensity weighting methods using information from the U.S. Census and the 2003 National Survey on Drug Use and Health (NSDUH) were used to estimate national-level prevalence rates.ResultsThe overall prevalence of current nonmedical methamphetamine use was estimated to be 0.27%. Lifetime use was estimated to be 8.6%. Current use rates for men (0.32%) and women (0.23%) did not differ, although men had a higher 3-year prevalence rate (3.1%) than women (1.1%). Within the age subgroup with the highest overall methamphetamine use (18 to 25 year olds), non-students had substantially higher methamphetamine use (0.85% current; 2.4% past year) than students (0.23% current; 0.79% past year). Methamphetamine use was not constrained to those with publicly funded health care insurance.ConclusionThrough the use of an internet panel weighted to reflect U.S. population norms, the estimated lifetime prevalence of methamphetamine use among 18 to 49 year olds was 8.6%. These findings give rates of use comparable to those reported in the 2005 NSDUH. Internet surveys are a relatively inexpensive way to provide complimentary data to telephone or in-person interviews.

Olanzapine/Fluoxetine Combination in Patients With Treatment-Resistant Depression: Rapid Onset of Therapeutic Response and Its Predictive Value for Subsequent Overall Response in a Pooled Analysis of 5 Studies

OBJECTIVE To characterize response profiles of olanzapine/fluoxetine combination therapy in treatment-resistant depression (TRD) and to investigate predictive relationships of early improvement with olanzapine/fluoxetine combination for subsequent response/remission during the acute phase of treatment. METHOD Results were pooled from 5 outpatient studies comparing oral olanzapine/fluoxetine combination, fluoxetine, or olanzapine for a maximum of 8 weeks in patients with TRD who had at least 1 historical antidepressant treatment failure during the current episode and who failed a prospective antidepressant therapy during the study lead-in period. Mean Montgomery-Asberg Depression Rating Scale (MADRS) total and core mood items scores from the 8-week evaluation period were compared across treatment groups. Positive and negative predictive values (PPVs, NPVs) were computed from olanzapine/fluoxetine combination-treated patients demonstrating response and remission based on whether they demonstrated early improvement. RESULTS Mean olanzapine/fluoxetine combination MADRS score reductions were significantly greater than fluoxetine by week 0.5 and olanzapine by week 1. Significantly more olanzapine/fluoxetine combination patients demonstrated MADRS onset of response compared with fluoxetine and olanzapine patients (P < .001 for both MADRS total and core mood items). In olanzapine/fluoxetine combination patients, 38.1% exhibited MADRS total score response versus 26.9% of fluoxetine patients (P < .001) and 22.2% of olanzapine patients (P < .001). NPVs for MADRS total and core mood items response and remission ranged from 85.7% to 92.1%; PPVs ranged from 29.9% to 45.1%. CONCLUSIONS Olanzapine/fluoxetine combination is superior to fluoxetine and olanzapine in producing early improvement in patients with TRD. The absence of early improvement is highly predictive for overall response failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00035321.

Retrospective Safety Analysis of Atomoxetine in Adult ADHD Patients with or without Comorbid Alcohol Abuse and Dependence

This post hoc analysis compared the safety of atomoxetine treatment of ADHD in adults with or without comorbid alcohol abuse/dependence. Study completion rates in patients receiving atomoxetine were comparable between heavy drinkers (60.9%) and patients with no alcohol-use disorder (71.0%) but lower in nonheavy drinkers (35.7%); however, there was no significant difference in discontinuation rates due to adverse events or lack of efficacy among these groups. Alcohol-use disorder patients, especially heavy drinkers, generally experienced the greatest frequency of treatment-emergent adverse events in both the atomoxetine and placebo groups. Vital signs and measures of hepatic function were not significantly different among the 3 drinking status groups taking atomoxetine.

Atomoxetine Treatment for ADHD: Younger Adults Compared with Older Adults

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 patients older than 25 years. Results: In younger adults (mean age = 21.7), atomoxetine produces greater improvement than placebo on the Conners’ Adult ADHD Rating Scale’s total ADHD symptom score (p = .041, effect size = .797) and the clinical global impressions severity (p = .006, effect size = 1.121). In older adults (mean age = 43.4 years), atomoxetine also produces significant benefit on the CAARS—Inv:SV (p < .001, effect size = .326) and CGI-ADHD-S (p < .001, effect size = .346). The study findings reveal response rates to be 56.4% and 47.8% for the younger and older adults, respectively (p = .188). Tolerability is similar although older adults reported more sexual side effects. Conclusion: Younger and older adults show similar improvements at endpoint. The effect size is higher in younger adults, but this is due primarily to greater variability of response in older patients. (J. of Att. Dis. 2010; 13(4) 401-406)

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

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

Impact of race on efficacy and safety during treatment with olanzapine in schizophrenia, schizophreniform or schizoaffective disorder

BackgroundTo examine potential differences in efficacy and safety of treatment with olanzapine in patients with schizophrenia of white and black descent.MethodsA post-hoc, pooled analysis of 6 randomized, double-blind trials in the treatment of schizophrenia, schizophreniform disorder, or schizoaffective disorder compared white (N = 605) and black (N = 375) patients treated with olanzapine (5 to 20 mg/day) for 24 to 28 weeks. Efficacy measurements included the Positive and Negative Syndrome Scale (PANSS) total score; and positive, negative, and general psychopathology scores; and the Clinical Global Impression of Severity (CGI-S) scores at 6 months. Safety measures included differences in the frequencies of adverse events along with measures of extrapyramidal symptoms, weight, glucose, and lipid changes over time.Results51% of black patients and 45% of white patients experienced early study discontinuation (P = .133). Of those who discontinued, significantly more white patients experienced psychiatric worsening (P = .002) while significantly more black patients discontinued for reasons other than efficacy or tolerability (P = .014). Discontinuation for intolerability was not different between groups (P = .320). For the estimated change in PANSS total score over 6 months, there was no significant difference in efficacy between white and black patients (P = .928), nor on the estimated PANSS positive (P = .435), negative (P = .756) or general psychopathology (P = .165) scores. Overall, there was no significant difference in the change in CGI-S score between groups from baseline to endpoint (P = .979). Weight change was not significantly different in white and black patients over 6 months (P = .127). However, mean weight change was significantly greater in black versus white patients at Weeks 12 and 20 only (P = .028 and P = .026, respectively). Additionally, a significantly greater percentage of black patients experienced clinically significant weight gain (≥7%) at anytime compared to white patients (36.1% vs. 30.4%, P = .021). Changes across metabolic parameters (combined fasting and random lipids and glucose) were also not significantly different between groups, with the exception of a greater categorical change in total cholesterol from borderline to high among white subjects and a categorical change from normal to low in high density lipoprotein (HDL) cholesterol among white males.ConclusionsThe findings did not demonstrate overall substantive differences in efficacy or safety between white and black patients diagnosed with schizophrenia or related disorders treated with olanzapine. However, a significantly greater percentage of black patients (36.1%) experienced clinically significant weight gain compared to white patients (30.4%).

Relationship between African―American or Caucasian origin and outcomes in the olanzapine treatment of acute mania: a pooled analysis of three adult studies conducted in the United States of America

The aim of this study was to explore the role of ethnic origin in the treatment of acute bipolar mania. Treatment outcomes were studied in a post-hoc analysis of African–American (AA, n=41) and Caucasian (CA, n=190) adults treated with olanzapine in three studies conducted in the United States of America. Baseline demographics were similar except that the AA cohort had fewer women compared with the CA cohort (37 vs. 58%; P=0.01). Daily mean modal olanzapine dose and study discontinuation rate for AA and CA were: 16.2 mg vs. 16.6 mg and 41.5 vs. 25.3% (P=0.03), respectively. There were four (23.5% of discontinuers) and 19 (39.6% of discontinuers, P=0.14) discontinuations because of a poor response in the AA and CA groups, respectively. Drug exposure for the AA cohort was 18.7 days and that of the CA cohort was 19.3 days. Both cohorts showed similar symptom improvements, and safety outcomes were not statistically significantly different except for the following treatment-emergent adverse event frequencies for AA and CA cohorts, respectively: agitation (24.4 vs. 10.5%, P=0.04); dysmenorrhoea (20.0 vs. 3.6%, P=0.04); and dizziness postural (7.3 vs. 1.1%, P=0.04). Although study findings [limited by a smaller (18% of total population) AA cohort] need replication, they suggest that while many outcomes were similar in both cohorts, clinicians could benefit from the awareness of factors in the AA population that possibly influence study discontinuation rates, treatment-emergent adverse event reporting, and participation by sex.

IMPACT OF ETHNICITY ON EFFICACY AND SAFETY DURING TREATMENT WITH OLANZAPINE IN SCHIZOPHRENIA

Background: Treatment compliance is a crucial pronostic factor regarding the longitudinal course of patients with First Episode Psychosis (FEP). The rate of oral antipsychotic treatment discontinuation at first year is about 70% (1). Risperidone injectable longacting treatment (RILD) has shown high rates of clinical remission, as well as improvement in treatment compliance. As far as we know, there is no RCT that compared RILD vs oral atipic antipsychotics in FEP. Methods: Eighty-seven FEP patients were randomly located on two groups: patients receiving RILD (N=18) and patients receiving oral antipsychotic treatment (N=21). Both underwent a baseline assessment and one year follow-up, including: medical interview, PAS Scale, neuropsychological battery, diagnostic assessment (SCID-I) and stability at one year follow-up, clinical assessment (PANSS; CGI; SUMD; HDRS and YMRS), functional assessment(GAF), quality of life (WHO/DAS), hospitalizations, urgency episodes and treatment compliance (subjective for oral antipsychotics). Results: Both groups significantly reduced positive and general psychopathology scales from PANNS at one year follow-up. There were no differences regarding the course of cognitive symptoms. The group receiving RILD significantly improved in functional disability, quality of life and negative symptoms, and showed a trend toward significance in insight and compliance. Two patients receiving oral antipsychotics were rehospitalized, while the rate of rehospitalization for RILD groups was 0. Discussion: RILD an reasonable and treatment alternative for FEP. It treatment compliance, which turns to improvements in insight, negative symptomatology, functional capacity and quality of life.