Alvin H. Rampey

Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression.

OBJECTIVE--A comprehensive meta-analysis of clinical trial data was performed to assess the possible association of fluoxetine and suicidality (suicidal acts and ideation). DESIGN--Retrospective analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder comparing fluoxetine (n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. MAIN OUTCOME MEASURES--Multiple data sources were searched to identify patients with suicidal acts. Suicidal ideation was assessed with item 3 of the Hamilton depression rating scale, which systematically rates suicidality. Emergence of substantial suicidal ideation was defined as a change in the rating of this item from 0 or 1 at baseline to 3 or 4 during double blind treatment; worsening was defined as any increase from baseline; improvement was defined as a decrease from baseline at the last visit during the treatment. RESULTS--Suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0.2% v 0.2%, p = 0.494, Mantel-Haenszel adjusted incidence difference) and with tricyclic antidepressants (0.7% v 0.4%, p = 0.419). The pooled incidence of suicidal acts was 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclic antidepressants, and fluoxetine did not differ significantly from either placebo (p = 0.533, Pearsons chi 2) or tricyclic antidepressants (p = 0.789). Suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0.9% v 2.6%, p = 0.094) and numerically less often than with tricyclic antidepressants (1.7% v 3.6%, p = 0.102). The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants. The incidence was significantly lower with fluoxetine than with placebo (p = 0.042) and tricyclic antidepressants (p = 0.001). Any degree of worsening of suicidal ideation was similar with fluoxetine and placebo (15.4% v 17.9%, p = 0.196) and with fluoxetine and tricyclic antidepressants (15.6% v 16.3%, p = 0.793). The pooled incidence of worsening of suicidal ideation was 15.3% for fluoxetine, 17.9% for placebo, and 16.3% for tricyclic antidepressants. The incidence did not differ significantly with fluoxetine and placebo (p = 0.141) or tricyclic antidepressants (p = 0.542). Suicidal ideation improved significantly more with fluoxetine than with placebo (72.0% v 54.8%, p less than 0.001) and was similar to the improvement with tricyclic antidepressants (72.5% v 69.8%, p = 0.294). The pooled incidence of improvement of suicidal ideation was 72.2% for fluoxetine, 54.8% for placebo, and 69.8% for tricyclic antidepressants. The incidence with fluoxetine was significantly greater than with placebo (p less than 0.001) and did not differ from that with tricyclic antidepressants (p = 0.296). CONCLUSIONS--Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients.

Absence of a relationship between adverse events and suicidality during pharmacotherapy for depression

This study tested the hypothesis that some patients treated with an antidepressant who develop adverse events (e.g., activation, akathisia) experience emergent suicidality specifically associated with such events. Seventeen double-blind, controlled clinical trials conducted in the United States and Canada with 3,065 patients with major depression were evaluated for treatment-emergent adverse events (events that first occurred or worsened during therapy) and suicidality (a suicidal act or emergence of substantial suicidal ideation or both) with fluoxetine, placebo, and tricyclic antidepressants. Nine relevant adverse event clusters were evaluated: activation, sedation, activation and sedation, decreased libido, mania, psychosis, psychosis and mania, acute brain syndrome, and violence. Incidence rates were determined for suicidality that was and was not temporally associated with an adverse event cluster and were analyzed within and across treatments (incidence difference method). Most patients experienced neither a cluster event nor suicidality. Where suicidality was reported, it generally was not in temporal association with an adverse event cluster. In no cluster was the incidence of suicidality statistically significantly higher when reported in temporal association with an event than when not. Suicidality was associated infrequently with treatment-emergent activation and at comparable rates across treatments. No increased risk of suicidality associated with an adverse event cluster was observed between the treatment groups (fluoxetine versus tricyclic anti-depressants; fluoxetine versus placebo). These results from double-blind, placebo- and comparator-controlled fluoxetine clinical trials in patients with major depression do not suggest a relationship between a treatment-emergent adverse event pattern and suicidality in this population.

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.

Industrial publication of controlled clinical trial data

Clinical Pharmacology and Therapeutics (1993) 53, 496–496; doi:10.1038/clpt.1993.58