Antipsychotic augmentation for adults with depression linked to rise in mortality risk

Adults with depression who initiated augmentation with newer antipsychotics appeared at increased risk for mortality vs. those who added a second antidepressant, according to results of a population-based cohort study published in PLOS ONE.

“Antipsychotics have well-recognized and often serious adverse effects, including a more than 50% increased mortality risk in older adults with dementia,” Tobias Gerhard, PhD, associate professor in the department of pharmacy practice and administration at Rutgers University Ernest Mario School of Pharmacy, said in a press release. “It had been previously unknown whether this mortality risk applies to non-elderly adults using newer antipsychotics as augmentation treatment for depression. The clinical trials that led to the approval of various newer antipsychotics for depression were just too small and too short to be informative for this question.”

Specifically, results of randomized controlled trials of augmentation with newer antipsychotics showed efficacy in reducing depressive symptoms according to observer rating; however, these studies received criticism for the methodology used and a lack of demonstrated benefit on functional outcomes and quality of life.

To determine whether all-cause mortality risk related to augmentation with newer antipsychotics extended beyond older-aged populations, Gerhard and colleagues conducted the current population-based, new user/active comparator cohort study using national health care claims data from the U.S. Medicaid program between 2001 and 2010 that was linked to the National Death Index. They analyzed data of 39,582 Medicaid beneficiaries aged 25 to 64 years, of whom 78.5% were women. Individuals included in the study initiated either augmentation with a newer antipsychotic, which was quetiapine (40%), risperidone (21%), aripiprazole (17%) or olanzapine (16%), or with a second antidepressant following a treatment period with a single antidepressant.

Results showed a 45% relative increase in mortality risk among those who initiated a newer antipsychotic, which among the study cohort translated to one additional death for every 265 people who took the antipsychotic for 1 year. A total of 153 patients died during 13,328 person-years of follow-up.

“Our results require replication, ideally with a publicly financed pragmatic randomized controlled trial,” Gehard said in the release. “However, in the meantime, our study suggests that physicians should consider prescribing antipsychotics to adults with depression carefully, as the potential health risks are substantial and the benefits are quite modest and controversially debated. Of particular relevance for our results is a finding from our previous work. It is well-known that most antidepressants take about 4 to 6 weeks to be fully effective.

“However, contrary to the drug label and treatment guidelines, many patients in the United States initiate antipsychotic treatment for depression without having completed an adequate prior trial with a single antidepressant,” Gerhard added. “Our results emphasize the importance of considering newer antipsychotics only after non-response to less risky, evidence-based treatment options has been established.”