Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: An updated meta-analysis

Abstract

Background: A 1993 meta-analysis of US Investigational New Drug clinical trials of fluoxetine reinforced this agent's 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 (≥2%) leading to discontinuation were asthenia, dizziness, insomnia, nausea, nervousness, somnolence, and tremor in fluoxetine-treated patients and abnormal vision, agitation, constipation, dizzines, 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.