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Antipsychotics do not increase mortality

No evidence supported a link between antipsychotic medications and increased short-term mortality, according to findings from a systematic review and meta-analysis of placebo-controlled randomized trials.

However, secondary analyses revealed an increased mortality risk in people with dementia who took antipsychotics, data published in The Lancet Psychiatry revealed.

“Results of several observational studies have found that antipsychotic drugs either have no effect on mortality, or they reduce mortality when compared with no treatment. Conversely, other observational studies have reported increased mortality associated with antipsychotic treatment,” Johannes Schneider-Thoma, MD, department of psychiatry and psychotherapy, Technical University of Munich, and colleagues wrote. “Randomized controlled trials offer the best source of evidence for estimating treatment effects, but single trials in this area are clearly underpowered because of the rarity of the mortality outcome.”

Researchers conducted a systematic review and meta-analysis of deaths in placebo-controlled trials of antipsychotic medications to determine whether any acute, life-threatening side-effects of these drugs contributed to reduced life expectancy in patients with severe mental disorders.

Studies that compared second-generation antipsychotics — amisulpride, aripiprazole, asenapine, Rexulti (brexpiprazole; Otsuka, Lundbeck) Vraylar (cariprazine, Allergan), clozapine, Fanapt (iloperidone, Vanda Pharmaceuticals), Latuda (lurasidone, Sunovion) olanzapine, Invega (paliperidone, Janssen) quetiapine, risperidone, sertindole, ziprasidone and zotepine — with placebo across several diagnostic categories were included in the analyses. Using data from clinical databases, researchers evaluated mortality from any cause as well as death from natural causes, suicide and other non-natural causes. In subgroup and meta-regression analyses, they studied the effects of age, diagnostic category, sex, study duration, drug used, dose and polypharmacy.

Of 596 randomized controlled trials, 352, which comprised 84,988 participants with available mortality data, were included in this meta-analysis and most of these trials (85%) were 3 months or shorter in duration. The researchers found that 207 (0.4%) deaths occurred in 53,804 patients on an antipsychotic medication and 99 (0.3%) deaths occurred in 31,184 patients on placebo.

Analysis revealed no evidence supported a difference between antipsychotic medication and placebo in death by any cause (OR = 1.19; 95% CI, 0.93-1.53), natural causes (OR = 1.29; 95% CI, 0.85-1.94), suicide (OR = 1.15; 95% CI, 0.47-2.81) and other non-natural causes (OR = 1.55; 95% CI, 0.66-3.63). There was no evidence of an increased mortality risk for patients with schizophrenia (OR = 0.69; 95% CI, 0.35-1.35).

Subgroup and meta-regression analyses did not show any significant effect moderators other than increased mortality in patients with dementia (OR = 1.56; 95% CI, 1.1-2.21), in elderly patients (OR = 1.38; 95% CI, 1.01-1.89), in patients treated with aripiprazole (OR = 2.2; 95% CI, 1-4.86) and in studies with a higher proportion of females. However, the results showed that the effects in elderly adults, aripiprazole-treated patients and women were mainly based on trials that examined dementia.

“We did not find evidence of differing mortality related to acute antipsychotic drug effects between patients treated with antipsychotic drugs or those treated with placebo,” the authors wrote. “We ... hope that our work, which represents, to our knowledge, the largest systematic review and meta-analysis of mortality in randomized antipsychotic drugs trials to date, will inform the polarized discussion about the safety of these drugs.” – by Savannah Demko

Disclosure: Schneider-Thoma reports no relevant financial disclosures. Please see the study for other authors’ relevant financial disclosures.