Stephanie C. Koke

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.

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.

Fluoxetine versus placebo in posttraumatic stress disorder

BACKGROUND This study was designed to address the efficacy and tolerability of fluoxetine in patients with posttraumatic stress disorder (PTSD) as diagnosed using the Structured Clinical Interview for DSM-IV Axis I Disorders and the Clinician-Administered PTSD Scale (CAPS). The patient population included both civilians and combat veterans. METHOD This was a double-blind, randomized, placebo-controlled study conducted in Europe, Israel, and South Africa, primarily in war-torn countries. Patients were predominantly male (81%) and white (91%), with 48% exposed to a combat-related traumatic episode. Patients were randomly assigned to 12 weeks of acute treatment with fluoxetine, 20 to 80 mg/day (N = 226), or placebo (N = 75). The primary efficacy measurement was the mean change from baseline in the Treatment Outcome PTSD rating scale (TOP-8) total score, which was analyzed using a repeated-measures analysis of variance. Secondary assessments included the CAPS, the Davidson Trauma Scale, the Clinical Global Impressions-Severity of Illness scale (CGI-S), the CGI-Improvement scale (CGI-I), the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Anxiety (HAM-A), and the Hopkins 90-Item Symptom Checklist-Revised. RESULTS Fluoxetine was associated with a greater improvement from baseline in total TOP-8 score than was placebo. This difference was statistically significant by week 6 of treatment (p < .001) through the end of the acute phase of the study (week 12; p = .006). Compared with placebo, fluoxetine was also associated with significantly greater improvement in CAPS total score as well as intrusive and hyperarousal subscores and in CGI-S, CGI-I, HAM-A, and MADRS scores (p < .05). The presence of dissociative symptoms at baseline appeared to be a predictor of high placebo response. The mean fluoxetine dose at endpoint was 57 mg. There were no clinically significant safety differences. CONCLUSION Fluoxetine is effective and well tolerated in the treatment of PTSD. Most PTSD patients will respond satisfactorily at doses in the upper normal range for the usual antidepressant doses of fluoxetine.