REVIEW OF: Gerhard T et al, PLoS One 2020;15(9):e0239206

TYPE OF STUDY: Population-based comparator cohort study

We know that atypical antipsychotics increase mortality in elderly patients with dementia—the FDA has long required a black box warning to that effect. But are these medications also dangerous when prescribed to younger people with depression?

To answer this question, researchers analyzed mortality rates of depressed adults (ages 25–64) enrolled in Medicaid between 2001–2010. Patients with major depression (but not other major Axis I disorders) who had failed to respond to > 3 months of antidepressant monotherapy were included. The researchers compared two cohorts: patients who had their antidepressant augmented with an antipsychotic (n = 22,410) vs those who had it augmented with a second antidepressant (n = 17,172). The outcome of interest was all-cause mortality rates over the next year for patients who remained on their medications.

In total, 105 deaths occurred during 7,601 person-years of follow-up in the antipsychotic augmentation cohort (138 per 100,000 person-years) versus 48 deaths during 5,727 person-years of follow-up in the antidepressant augmentation cohort (84 per 100,000 person-years). These numbers translate into an absolute risk of about 0.4% per year with antipsychotic augmentation, and a relative risk of 45% compared to antidepressant augmentation. To contextualize this figure, the relative risk in elderly patients with dementia is just slightly higher (around 54%), and this was concerning enough to the FDA to trigger a black box warning. Among the four antipsychotics with sufficient sample sizes, olanzapine and risperidone were associated with the highest risks of mortality, while quetiapine and aripiprazole the lowest—findings that are consistent with geriatric research.

The main weakness of the study was the lack of randomization, leaving open the possibility that prescribing bias could have contributed to the excess mortality in the antipsychotic augmentation group. For example, clinicians might have chosen atypicals for more severely depressed patients. Working in the opposite direction, however, clinicians might have preferred antidepressant augmentation for patients with medical comorbidities, which would artificially inflate mortality rates in this cohort instead. Furthermore, we should be cautious in generalizing results from Medicaid patients to the overall population.

TCPR’s Take
While this is only one study, and the increased mortality risk is small, the results should still give us pause before prescribing atypical antipsychotics in depression. It may be time to recalibrate their risk-benefit ratio.