Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine

Abstract

Context: The US Food and Drug Administration issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults.

Objective: To determine the short-term safety of antidepressants by standard assessments of suicidal thoughts and behavior in youth, adult, and geriatric populations and the mediating effect of changes in depressive symptoms.

Data sources: All intent-to-treat person-level longitudinal data of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride.

Study selection: All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine.

Data extraction: The suicide items from the Children's Depression Rating Scale-Revised and the Hamilton Depression Rating Scale as well as adverse event reports of suicide attempts and suicide during active treatment were analyzed in 9185 patients (fluoxetine: 2635 adults, 960 geriatric patients, 708 youths; venlafaxine: 2421 adults with immediate-release venlafaxine and 2461 adults with extended-release venlafaxine) for a total of 53 260 person-week observations.

Data synthesis: Suicidal thoughts and behavior decreased over time for adult and geriatric patients randomized to fluoxetine or venlafaxine compared with placebo, but no differences were found for youths. In adults, reduction in suicide ideation and attempts occurred through a reduction in depressive symptoms. In all age groups, severity of depression improved with medication and was significantly related to suicide ideation or behavior.

Conclusions: Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric patients. This protective effect is mediated by decreases in depressive symptoms with treatment. For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication. To our knowledge, this is the first research synthesis of suicidal thoughts and behavior in depressed patients treated with antidepressants that examined the mediating role of depressive symptoms using complete longitudinal person-level data from a large set of published and unpublished studies.

Figure 1

Probabilities of suicide risk in adult and geriatric fluoxetine hydrochloride and venlafaxine hydrochloride studies. Solid lines indicate estimated probabilities for control patients receiving placebo; dashed lines, estimated probabilities for treated patients; thoughts of death curves, “wishes he or she were dead or any thoughts of possible death to self” or worse; ideation curves, “suicide ideas or gestures” or worse; and attempts or completion curves, “suicide attempts or suicides.”

Figure 2

Probabilities of suicide risk adjusting for depression severity in adult and geriatric fluoxetine hydrochloride and venlafaxine hydrochloride studies. Solid lines indicate estimated probabilities for control patients; dashed lines, estimated probabilities for treated patients; thoughts of death curves, “wishes he or she were dead or any thoughts of possible death to self” or worse; ideation curves, “suicide ideas or gestures” or worse; and attempts or completion curves, “suicide attempts or suicides.”