Can Antipsychotics Increase Mortality Risk? A New Study Shows It Might

A new study indicated high-dose antipsychotic use for schizophrenia was associated with increased mortality risk.¹

People with schizophrenia have a life expectancy 15 years shorter and a mortality rate nearly 3 times higher than the general population.² Prior research showed antipsychotics, antidepressants, and benzodiazepines may increase the mortality risk for people with schizophrenia.¹

However, many observational studies do not account for immortal time bias—the period when patients are alive and misclassified as exposed. Dismissing immortal time bias can lead to the misinterpretation of the link between these drugs and mortality.

“While these [observational] studies typically found a protective association of antipsychotics, we found no such association with mortality, whether correcting or not correcting for [immortal time bias],” wrote investigators, led by Sébastien Brodeur, MD, MSc, from the psychiatry and neuroscience department at Université Laval in Quebec.

The team sought to examine whether the cumulative dose of antipsychotics, antidepressants, and benzodiazepines is linked to the mortality risk in patients with schizophrenia. They also wanted to see how the mortality risk differed by considering immortal time bias. The primary outcome was all-cause mortality.

Leveraging administrative data from Quebec, the team included 32,240 patients aged 17 – 64 years (mean age: 46.1 years; 61.3% men) diagnosed with schizophrenia between January 1, 2002, and December 31, 2012. The data was analyzed from June 22, 2022, to September 30, 2024.

Participants were followed up from January 1, 2013, to December 31, 2017, or until death. 1941 (6%) died during follow-up. Investigators assessed the link between mortality risk and low, moderate, and high exposure to antipsychotics, antidepressants, and benzodiazepines. The team used Cox proportional hazard regression models with time-dependent and time-fixed exposure to control and not control for immortal time bias, respectively.

For antipsychotics, the mortality rate varied by exposure level: nonuse (5.5%), low (5.8%), moderate (5.4%), and high (7%) (P = .001).

Using the time-fixed method, the study found no dose-response association between antipsychotics and mortality. The time-fixed method showed antidepressants reduced the mortality risk and benzodiazepines increased the risk.

After controlling for immortal time bias with the time-dependent method, the study demonstrated high-dose antipsychotic use was linked to an increased mortality risk (adjusted hazard ratio [aHR], 1.28; 95% confidence interval [CI], 1.07 – 1.55; P = .008). Like before, antidepressants reduced the mortality risk, but only for high doses (aHR, 0.86; 95% CI, 0.74 – 1.00; P = .047). Benzodiazepines, once again, were associated with an increased mortality risk.

“The impact of not controlling for [immortal time bias], a well-documented issue in medical research, confirmed that it tends to overestimate the protective association of drugs or underestimate the harmful ones and reinforces the need for robust analytical techniques that account for [immortal time bias],” investigators wrote.

The team said the findings were limited by only including patients whose drug treatment is covered by the public drug plan.

Despite these findings, investigators emphasized the benefits of antipsychotics for treating schizophrenia.

“Our findings do not undermine the potential benefit of antipsychotic treatment; rather, they call for a reevaluation of the methods used to assess these effects,” investigators wrote. “The current study, together with evidence from previous research supporting the usefulness of antipsychotics in the treatment of schizophrenia, suggests that although antipsychotics have well-documented benefits, the assessment of their association with mortality requires careful consideration of dosage, patient characteristics, and methods of analysis.”

References

1. ^{Brodeur S, Chiu YM, Courteau J, Dorais M, Oliver D, Stip E, Fleury MJ, Roy MA, Vanasse A, Lesage A, Leclerc J. Medication Exposure and Mortality in Patients With Schizophrenia. JAMA Netw Open. 2024 Nov 4;7(11):e2447137. doi: 10.1001/jamanetworkopen.2024.47137. PMID: 39576638; PMCID: PMC11584925.}
2. ^{Correll CU, Solmi M, Croatto G, Schneider LK, Rohani-Montez SC, Fairley L, Smith N, Bitter I, Gorwood P, Taipale H, Tiihonen J. Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry. 2022 Jun;21(2):248-271. doi: 10.1002/wps.20994. PMID: 35524619; PMCID: PMC9077617.}