Authors: Hengartner MP, Ploderi M

PMID: 31234169 DOI: 10.1159/000501215


Studies disagree whether antidepressants may trigger suicide attempts in adults with major depression. Some meta-analyses of randomized controlled trials (RCT) found significantly elevated rates of (attempted) suicide in antidepressant arms relative to placebo, whereas others did not. A recent study by Khan et al. likewise found no statistically significant differences between antidepressants and placebo, but their study was based on patient exposure years (PEY). This approach has been questioned, since the vast majority of (attempted) suicides in RCT occur within the first 3–4 weeks of acute treatment. Patients who do not tolerate the drugs are more likely to terminate trials early due to adverse events, for example because of extreme agitation/akathisia, which may trigger suicide attempts. Population-wide, register-based observational studies confirmed that the suicide risk is highest during the first few weeks after treatment initiation and close to zero thereafter when there is no change in the dosage. Statisticians stressed that PEY must not be applied when hazards (i.e., the risk of adverse events) are not constant over time. Since the constant-hazard requirement for (attempted) suicide is violated in antidepressant trials, PEY may obscure a truly increased suicide risk related to the initiation of antidepressants. Therefore, FDA regulation requires that suicide events are analyzed based on the number of patients randomized to treatment arms, and this is the method the FDA applies in its own evaluations.

The aim of this paper was to examine whether the use of newer-generation antidepressants, relative to placebo, bear an increased risk of (attempted) suicide when the analysis is based on the number of patients instead of PEY.

Keywords: antidepressants, suicide, depression