Mary E. Nilsson

Fluoxetine for acute treatment of depression in children and adolescents: A placebo-controlled, randomized clinical trial

BACKGROUND This report presents results from the acute treatment phase of a clinical trial designed to confirm efficacy of a fixed dose of 20 mg of fluoxetine in children and adolescents with major depressive disorder (MDD). METHOD After a 3-week screening period, 122 children and 97 adolescents with MDD ( ) were randomly assigned to placebo or fluoxetine. After a 1-week placebo lead-in, fluoxetine-treated patients received fluoxetine 10 mg/day for 1 week, then fluoxetine 20 mg/day for 8 weeks. RESULTS Fluoxetine was associated with greater mean improvement in Childrens Depression Rating Scale-Revised (CDRS-R) score than placebo after 1 week ( <.05) and throughout the study period. Significantly more fluoxetine-treated patients (41%) met the prospectively defined criteria for remission than did placebo-treated patients (20%) ( <.01). More fluoxetine- (65%) than placebo-treated (53%) patients met the prospectively defined response criterion of > or =30% decrease in CDRS-R score, but this difference was not significant ( =.093). Significantly more fluoxetine-than placebo-treated patients completed acute treatment ( =.001). There were no significant differences between treatment groups in discontinuations due to adverse events ( =.408). CONCLUSION Fluoxetine 20 mg daily appears to be well tolerated and effective for acute treatment of MDD in child and adolescent outpatients. Fluoxetine is the only antidepressant that has demonstrated efficacy in two placebo-controlled, randomized clinical trials of pediatric depression.

Fluoxetine versus sertraline and paroxetine in major depression: tolerability and efficacy in anxious depression

BACKGROUND Major depression with high levels of anxiety (anxious depression) is a common subtype of depression associated with greater psychosocial impairment and poorer response to antidepressant treatment. It is unclear whether in this population there are differences in efficacy or tolerability across selective serotonin reuptake inhibitors. For this reason, using head-to-head acute treatment comparison, we compared efficacy and tolerability of fluoxetine, sertraline, and paroxetine among depressed patients with high levels of anxiety. METHODS Patients (N = 108) with DSM-IV major depression and high levels of anxiety (a HAM-D-Anxiety/Somatization Factor score > or =7) were randomized to fluoxetine, sertraline, or paroxetine treatment in a double-blind fashion. Changes in overall depression and anxiety were assessed. RESULTS Patients demonstrated similar baseline-to-endpoint improvement in HAM-D-17 and HAM-D-Anxiety/Somatization Factor scores. Patients also demonstrated similar change-over-time improvement in HAM-D-17 and HAM-D-Anxiety/Somatization Factor scores, except at week one where fluoxetine- and sertraline-treated patients had statistically significantly greater improvement than paroxetine-treated patients in the HAM-D-Anxiety/Somatization Factor score. There were no significant differences across treatments in percentages of patients with substantial emergence, any worsening, or improvement at endpoint in individual HAM-D Items 9 (agitation), 10 (psychic anxiety), and 11 (somatic anxiety). Overall, all treatments were well tolerated. CONCLUSION These data showed no significant differences in efficacy and tolerability of fluoxetine, sertraline, and paroxetine in patients with high levels of baseline anxiety symptoms during the acute treatment of major depression. Each treatment was similarly effective in improving depression in this subtype of patients with anxious depression.

Acute efficacy of fluoxetine versus sertraline and paroxetine in major depressive disorder including effects of baseline insomnia.

This study assessed whether fluoxetine, sertraline, and paroxetine differ in efficacy and tolerability in depressed patients and the impact of baseline insomnia on outcomes. Patients (N = 284) with DSM-IV major depressive disorder were randomly assigned in a double-blind fashion to fluoxetine, paroxetine, or sertraline for 10 to 16 weeks of treatment. Using the Hamilton Rating Scale for Depression (HAM-D) sleep disturbance factor score, patients were categorized into low (<4) or high (≥4) baseline insomnia subgroups. Changes in depression and insomnia were assessed. Safety assessments included treatment-emergent adverse events (AEs), reasons for discontinuation, and AEs leading to discontinuation. In addition, AEs were evaluated within insomnia subgroups to determine emergence of activation or sedation. Depression improvement, assessed with the HAM-D-17 total score, was similar among treatments in all patients (p = 0.365) and the high (p = 0.853) and low insomnia (p = 0.415) subgroups. Insomnia improvement, assessed with the HAM-D sleep disturbance factor score, was similar among treatments in all patients (p = 0.868) and in the high (p = 0.852) and low insomnia (p = 0.982) subgroups. Analyses revealed no significant differences between treatments in the percentages of patients with substantial worsening, any worsening, worsening at endpoint, or improvement at endpoint in the HAM-D sleep disturbance factor in either insomnia subgroup. Treatments were well tolerated in most patients. No significant differences between treatments in the incidence of AEs suggestive of activation or sedation were seen in the insomnia subgroups. These data show no significant differences in acute treatment efficacy and tolerability across fluoxetine, sertraline, and paroxetine in major depressive disorder patients. Improvement in overall depression and in associated insomnia was achieved by most patients regardless of baseline insomnia.

Adverse Events and Treatment Discontinuations in Clinical Trials of Fluoxetine in Major Depressive Disorder: An Updated Meta-Analysis

BACKGROUND A 1993 meta-analysis of US Investigational New Drug clinical trials of fluoxetine reinforced this agents more favorable adverse-event profile compared with tricyclic antidepressants (TCAs). OBJECTIVES The present meta-analysis sought to provide a reanalysis of updated adverse-event and discontinuation data for fluoxetine 20 to 80 mg/d compared with TCAs and placebo in the treatment of major depressive disorder (MDD) in adults. A subanalysis to assess the safety profile of the most commonly used effective dose of fluoxetine in MDD (20 mg) was also conducted. METHODS Data were obtained from 25 double-blind clinical trials involving 4016 patients with MDD randomized to treatment with fluoxetine 20 to 80 mg/d, TCAs, or placebo. The subanalysis included data from 6 trials involving 1258 patients treated with fixed 20-mg doses of fluoxetine or placebo. Spontaneously reported treatment-emergent adverse events, reasons for discontinuation, and events leading to discontinuation were compared between groups. RESULTS The age of the 4016 randomized patients ranged from 12 to 90 years, with a mean age of 46 years. Most patients were white (92%), and 62% were female. The age of the 1258 patients in the 20-mg fixed-dose population ranged from 18 to 90 years, with a mean age of 54 years; as in the total population, most of these patients were white (92%), and 57% were female. The adverse-event profiles of fluoxetine and TCAs in these trials were consistent with the typical profiles of selective serotonin reuptake inhibitors and TCAs. At a dose of 20 mg/d, fluoxetine-treated patients had a discontinuation rate due to adverse events that was not statistically significantly different from that in placebo recipients. Discontinuation rates due to lack of efficacy were not significantly different between fluoxetine and TCAs. However, significantly more TCA-treated patients discontinued therapy because of adverse events and significantly fewer completed treatment compared with fluoxetine-treated patients (both, P < 0.001). The most common events (> or = 2%) leading to discontinuation were asthenia, dizziness, insomnia, nausea, nervousness, somnolence, and tremor in fluoxetine-treated patients and abnormal vision, agitation, constipation, dizziness, dry mouth, headache, nausea, nervousness, rash, somnolence, sweating, and tremor in TCA-treated patients. CONCLUSIONS Data from this large series of clinical trials confirm that fluoxetine is well tolerated in the acute treatment of MDD in adults, especially at a dosage of 20 mg/d, and is better tolerated than the recommended doses of TCAs.

No gender differences in placebo responses of patients with major depressive disorder.

BACKGROUND This study was designed to compare placebo responses in men and women. METHODS Data for 501 women and 375 men with major depressive disorder treated with placebo from seven investigational randomized double-blind trials comparing fluoxetine with placebo were analyzed. Changes in major depressive disorder symptoms with placebo administration were measured as changes in total Hamilton Depression Rating Scale scores and adverse (nocebo) effects were measured by comparing treatment-emergent signs and symptoms. RESULTS Both women and men with major depressive disorder showed significant symptomatic improvement following placebo administration, similar in magnitude and time course of response. Women on placebo reported slightly more nocebo effects than men. CONCLUSIONS The finding that women and men with major depressive disorder demonstrated a similar therapeutic outcome after placebo administration suggests that gender is not a predictor of placebo response.

Fluoxetine and adult suicidality revisited: an updated meta-analysis using expanded data sources from placebo-controlled trials

Selective serotonin reuptake inhibitor treatments have been suggested by some to induce emergence of suicidality (ideation and behaviors). The objective of this study was to assess suicidality emergence by adverse event and rating scale data in the largest available, adult, major depression, double-blind, placebo-controlled, fluoxetine trial database (18 trials). Adverse event reports and comments for patients (fluoxetine, n = 2200; placebo, n = 1551) were searched for suicide-related events that were then classified into Food and Drug Administration categories. For 16 trials, suicidality was also examined by Hamilton Depression Scale item 3 (suicide) scores, and these data were analyzed along with the combination of event-based data and scale-based data. Comparisons between treatments were made for various estimates of worsening (risk) and improvement (benefit) of suicidality. Fluoxetine treatment did not result in greater worsening but was associated with greater improvement and faster resolution of ideation (P ≤ 0.05 vs placebo). Data sources were differentially sensitive in detecting changes in suicidal ideation and behaviors. Fluoxetine treatment led to greater benefit rather than risk for suicidality.

DEFINING TREATMENT-EMERGENT ADVERSE EVENTS WITH THE MEDICAL DICTIONARY FOR REGULATORY ACTIVITIES (MedDRA)*

Summaries of safety data collected in a clinical trial typically include an analysis of the crude rate of treatment-emergent signs and symptoms. This paper outlines the issues in defining treatment-emergent events and discusses the impact of choosing different methodologies for event classification and data collection. It also relates these issues to the adoption of the Medical Dictionary for Regulatory Activities (MedDRA) as the standard coding dictionary for regulatory reports. While pharmaceutical companies are addressing the conversion of their existing dictionary system to MedDRA, it may be beneficial to address the issue of defining treatment-emergent so that any changes can be incorporated at the same time. Examples and recommendations are provided.

Identifying Potential Adverse Events Dose-Response Relationships Via Bayesian Indirect and Mixed Treatment Comparison Models

Patients and prescribers need to be fully informed regarding the safety profile of approved medications. This includes knowledge and information regarding whether an adverse event of interest exhibits a potential dose-response relationship. In order to thoroughly evaluate whether an adverse event rate increases with increasing dose level, evidence from multiple clinical trials needs to be combined and analyzed. The various clinical trials that need to be combined often include different dose levels. If one evaluates the dose-response relationship by including only the trials with all of the common dose levels, this will lead to the exclusion of potentially several clinical trials as well as dose levels, and thus the loss of important information. Other methods, such as crudely pooling patients on the same dose level across different studies, are subject to bias due to the breakdown of randomization. It is preferable to include all studies and relevant dose levels, even if all studies do not contain the same dose levels. Bayesian methodology has been shown to be useful in the context of indirect and mixed treatment comparison methods, to combine information from different therapies in different studies in order to make treatment effect inferences. This type of approach is foundational to the models presented here, but instead of modeling different dose arms in different studies, we extend the methodology to allow for assessment of the dose-response relationship across multiple clinical trials. In this paper, we propose three Bayesian indirect/mixed treatment comparison models to assess adverse event dose-response relationships. These three models are designed to handle binary responses and time to event responses. We apply the methods to real data sets and demonstrate that our proposed methods are useful in discovering potential dose-response relationships.

Reference Limits for Outlier Analyses in Randomized Clinical Trials

Background: Reference limits used in clinical medicine to screen and manage patients are typically developed nonparametrically using reference values from a limited number of healthy subjects using a 95th percentile reference interval. We have evaluated alternative methods of computation and the resulting limits for use in the analyses of treatment-emergent outliers in clinical trials. Methods: We developed a set of alternative reference limits for 38 laboratory analytes based on alternative statistical methods and assessed their relative performance in clinical trial analysis. Performance assessment was based on the clinical credibility of the limits, inferential statistical performance, consideration of incidences for the test drug and control (placebo) in cases where the drug was reasonably believed to be associated with a change in an analyte (positive cases), and in cases where prior analyses failed to demonstrate a change associated with the drug (negative cases). Results: Based on consideration of these cases, no single method resulted in optimal limits for all cases considered. However, with the limits developed using clinical trial subjects’ values at baseline as reference values, excluding outliers, the robust method and the 98th percentile interval appeared to produce optimal limits across the greatest number of cases considered. Conclusion: Although no single method of limit computation will result in optimal limits for all outlier analyses for all analytes across all clinical trials, the 98th percentile reference interval robust limits based on clinical trial reference values appeared superior to multiple alternatives considered for such analyses.