Assessing the infrequent oral supplementation of olanzapine long-acting injection in the treatment of schizophrenia.

OBJECTIVE: Adding another antipsychotic to a treatment regimen was previously used in evaluating the medication's efficacy. Supplementation of depot antipsychotics with oral antipsychotics is particularly meaningful because depot formulations are typically chosen for patients struggling with adherence to oral antipsychotics. This post-hoc analysis assessed supplementation of olanzapine long-acting injection (olanzapine-LAI) with oral olanzapine. SUBJECTS AND METHODS: We used 12 months of data from an open-label, single-arm extension study of patients with schizophrenia or schizoaffective disorder (N=931) treated with olanzapine-LAI. The prevalence, duration, time to first supplementation, and best predictors of oral supplementation were assessed. RESULTS: Oral supplementation occurred in 21% of patients for a median of 31 days with mean modal dose of 10.8 mg/day. Mean time to first supplementation was shorter for patients who were at least moderately ill at baseline compared to less ill patients (47 vs. 97 days, p<0.001). Best predictors of oral supplementation included a more severe illness profile at baseline, lower olanzapine-LAI dose prior to oral supplementation, supervised living arrangements, and being African-American. CONCLUSION: Supplementation of olanzapine-LAI appears to be infrequent, of relatively short duration, and reserved for more severely ill patients who may require a targeted rescue medication due to signs of impending relapse.

ADHD Rating Scale IV: psychometric properties from a multinational study as a clinician-administered instrument.

The development of rating scales for attention-deficit/hyperactivity disorder (ADHD) has traditionally focused on parent-or teacher-rated scales. However, clinician-based instruments are valuable tools for assessing ADHD symptom severity. The ADHD Rating Scale IV (ADHD RS), clinician administered and scored, has been validated as a useful instrument to assess ADHD symptoms among American children and adolescents. In this study, we assessed the psychometric properties of the scale in a recent clinical trial conducted mainly in Europe with over 600 children and adolescents diagnosed with ADHD. The trial was conducted in 11 European countries plus Australia, Israel, and South Africa. Results based on data in the study indicate that this version of the scale has acceptable psychometric properties including inter-rater reliability, test-retest reliability, internal consistency, factor structure, convergent and divergent validity, discriminant validity, and responsiveness. There were low-to-moderate ceiling and floor effects. The psychometric properties were comparable with other validated scales for assessing ADHD symptom severity. These results were consistent across the 14 countries participating in this trial. Overall, the data from this study support the use of the ADHD RS as a clinician-rated instrument for assessing the severity of ADHD symptoms in children and adolescents in Europe.

Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users.

This study compared the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate with placebo in healthy volunteers. Sixteen non-dependent light drug users participated in six experimental sessions, receiving placebo, atomoxetine (20, 45 and 90 mg) and methylphenidate (20 and 40 mg) using a double-blind, Latin square design. Subjective drug effects were assessed using Visual Analog Scales (VAS), the Addiction Research Center Inventory (ARCI) and Adjective Rating Scales (ARS). Psychomotor performance was evaluated using the Digit Symbol Substitution Test (DSST). Physiological measures were also collected throughout the sessions. Assessments were conducted before drug administration and 30, 60, 90, 120, 150, 180 and 240 min following dosing. Forty milligrams methylphenidate produced significant increases on the stimulant portions of the VAS and ARS and the benzedrine, amphetamine, morphine-benzedrine and lysergic acid diethylamine (LSD) subscales of the ARCI relative to placebo. Ninety mg atomoxetine was reported to be unpleasurable relative to placebo as indicated by significant increases on the 'bad' and 'sick' portions of the VAS, and on the LSD subscale of the ARCI. Compared with placebo, both methylphenidate doses significantly increased systolic blood pressure (BP) and heart rate (HR). For atomoxetine, 90 mg increased diastolic BP, 45 and 90 mg increased systolic BP, and all three doses increased HR relative to placebo. Neither compound produced significant differences from placebo on DSST performance. These results suggest that atomoxetine does not induce subjective effects similar to methylphenidate and suggest that it is unlikely that atomoxetine will have abuse liability.

The double-blind variable placebo lead-in period: results from two antidepressant clinical trials.

The 1-week single-blind placebo lead-in has long been a standard in double-blind psychopharmacology clinical trials. Although a lead-in period is often necessary (e.g., to receive laboratory results before randomization), some authors have demonstrated that the standard single-blind placebo lead-in's performance was similar to having a lead-in in which placebo was not administered. The single-blind placebo lead-in did not decrease postrandomization placebo response, nor did it increase drug-placebo differences. To eliminate a higher percentage of placebo responders before randomization and to reduce potential biases in baseline ratings, the authors designed and implemented two depression studies with a double-blind variable placebo lead-in period. In these designs, both the patients and personnel at the investigative sites were blinded to the length of the placebo lead-in period and the start of the active treatment period. Approximately 28% of the patients in the double-blind placebo lead-in studies met criteria to be placebo lead-in responders, as compared with fewer than 10% from two single-blind placebo lead-in studies conducted in a similar time frame. Although all patients continued in the study (including placebo lead-in responders), the primary efficacy analysis prospectively excluded double-blind placebo lead-in responders. Analysis of postrandomization changes revealed that double-blind placebo lead-in responders, even when continuing to receive placebo treatment, maintained their response. At the study endpoint, these placebo lead-in responders had significantly lower severity scores than their counterparts who were not lead-in responders. The prospective removal of lead-in responders thus resulted in an increase in mean endpoint placebo group severity scores. This resulted in an increased drug-placebo treatment difference in one of the two studies but had no effect on the treatment difference in the other study.

Comparing time to onset of response in antidepressant clinical trials using the cure model and the Cramer-von Mises test.

Currently available antidepressants have a delayed onset of action and there is considerable interest in developing new products which exhibit a shorter time to response. Previous authors have suggested using a cure model to characterize the time to response for the combination of the patients who respond and the patients who do not respond. In this paper, we use the cure model and propose a Cramer-von Mises statistic to compare the time to response distributions for patients who respond to therapy. The asymptotic null distribution of the statistic is derived. A bootstap procedure is also proposed for sample sizes typical in antidepressant clinical trials. Results of the simulation study suggest that for common designs and sample sizes used in such trials, the statistic has reasonable size and power properties as long as censoring is moderate.

A two-stage dose selection strategy in phase I trials with wide dose ranges.

At early stages of drug development, the maximum tolerated dose (MTD) must be determined in order to have a range of doses that can be safely administered in humans. This is necessary before the compound can be tested in phase II clinical trials to find the optimal dose in terms of clinical outcome. Although heavily criticized, traditional dose escalation methods are still widely used to estimate the MTD. The recently developed Continual Reassessment Method (CRM) and Logistic Dose Ranging Strategy (LDRS) offer advantages compared to the traditional approach, including improved estimation of the MTD. However, the CRM utilizes a prior distribution that must be specified before having any data from the current trial. The LDRS requires the use of hypothesized data through a seed data set established before the start of the trial. When a wide dose range needs to be tested, the assumed information (prior distribution or seed data set) can have a great impact on dosages used during the trial and on the final estimates of the MTD. This paper combines the LDRS and the traditional dose escalation procedure to suggest a practical two-stage method that provides reliable estimates through relatively easy computation, and yet requires almost no prior information.

Latency to rapid eye movement sleep as a predictor of treatment response to fluoxetine and placebo in nonpsychotic depressed outpatients.

Fluoxetine and placebo were compared in 89 outpatients with major depression with (n = 45) or without (n = 44) a reduced or shortened rapid eye movement latency (SREML) (< or = 65 minutes) to determine whether rapid eye movement latency (REML) predicted placebo and/or antidepressant response. Men and women were stratified based on polysomnographic recordings and then randomly assigned to receive double-blind fluoxetine (20 mg/day) or placebo for 8 weeks after a 2-week, single-blind, placebo lead-in period. Fluoxetine-treated patients demonstrated a significantly greater reduction in the Hamilton Rating Scale for Depression total score and a significantly greater response rate than placebo-treated patients in both the SREML and the combined strata. Treatment differences in the non-SREML stratum were not statistically significant. Results supported REML as a predictor of placebo nonresponse but did not predict a differential fluoxetine response in patients with SREML compared with patients without SREML.

Response patterns of depressed outpatients with and without melancholia: a double-blind, placebo-controlled trial of fluoxetine versus placebo.

Fluoxetine (20 mg/day) and placebo were compared in 89 outpatient men and women with major depression with (n = 52) or without (n = 37) DSM-III-R melancholia in an 8-week double-blind study to determine predictors of treatment response. Fluoxetine was statistically superior to placebo both within the melancholic subtype and in the total patient group (all measures). Response rate and mean decrease in 17-item Hamilton Depression Rating Scale total score approached statistical significance in favor of fluoxetine-treated melancholic patients compared with fluoxetine-treated non-melancholic patients. There were no statistically significant differences between fluoxetine-treated and placebo-treated non-melancholic patients. Results support DSM-III-R melancholia as a predictor of antidepressant response.

Evaluation of suicidality during pharmacologic treatment of mood and nonmood disorders.

Double-blind, controlled clinical trial data were evaluated to assess a hypothetical relationship between fluoxetine and suicidality (suicidal acts and ideation) in patients with mood (n = 5,655) and nonmood disorders (n = 4,959) (Mantel-Haenszel incidence difference method). In mood disorders, act rates (suicide attempts/completions) were low (treatment differences nonsignificant). Substantial suicidal ideation emerged less frequently with fluoxetine than placebo and was comparable with fluoxetine and tricyclic antidepressants. Improvement in ideation was greater with fluoxetine than placebo; it was comparable with fluoxetine and tricyclic antidepressants (United States trials) and greater with tricyclic antidepressants than fluoxetine (international trials). In nonmood disorders, no suicides occurred. Act and emergent ideation rates were low (treatment differences nonsignificant). Results do not suggest a causal relationship between pharmacotherapy and emergence of suicidality. Fluoxetine or tricyclic antidepressants reduce suicidal ideation and may protect against the emergence of substantial suicidal ideation.

A double-blind trial of fluoxetine, 20 mg, and placebo in out-patients with DSM-III-R major depression and melancholia.

As part of a study in which reduced rapid eye movement latency was used to predict treatment response, fluoxetine and placebo were compared in 89 outpatients with major depression with (n = 52) and without (n = 37) DSM-III-R melancholia, to determine whether the presence or absence of melancholia predicted antidepressant and/or placebo response. Following a 2-week, single-blind placebo lead-in, men and women were assigned by random allocation to double-blind fluoxetine, 20 mg/day, or placebo for 8 weeks. Fluoxetine was statistically significantly superior to placebo in patients with melancholia (endpoint change in the Montgomery-Asberg Depression Rating Scale [MADRS] score, response rates and remission rates). A weekly analysis demonstrated statistical superiority of fluoxetine compared with placebo at week 3 and continuing for the remainder of the study. Fluoxetine was statistically significantly more likely to reduce suicidal ideation compared with placebo, using the MADRS item 10 (suicidal ideation question).