Piscataway, NJ—Adults diagnosed with depression who augment with a newer antipsychotic medication instead of a second antidepressant are at increased risk of dying, according to new research.

The study published in the journal PLOS ONE points out that, although antidepressants are the first-line pharmacologic treatment for depression, many patients fail to respond to the first course of treatment. At that point, clinicians can either switch to another antidepressant followed by various augmentation strategies, including augmentation with a second antidepressant and augmentation with newer antipsychotics, such as aripiprazole, quetiapine, and olanzapine.

“Antipsychotics have well-recognized and often serious adverse effects, including a more than 50 percent increased mortality risk in older adults with dementia,” explained lead author Tobias Gerhard, PhD, an associate professor at Rutgers Ernest Mario School of Pharmacy. “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.”

Background information in the report notes that, while randomized controlled trials have demonstrated increased all-cause mortality in elderly patients with dementia treated with newer antipsychotics, it had remained unknown whether this risk generalizes to nonelderly adults using newer antipsychotics as augmentation treatment for depression.

To help answer that question, researchers in conjunction with colleagues from Columbia University in New York sought to examine all-cause mortality risk of newer antipsychotic augmentation for adult depression. A population-based new-user/active comparator cohort study was conducted using national healthcare claims data from the U.S. Medicaid program from 2001–2010 linked to the National Death Index.

Participants were nearly 40,000 nonelderly adults (aged 25–64 years) diagnosed with depression who after 3 or more months of antidepressant monotherapy either had their treatment regimen augmented with a newer antipsychotic or with a second antidepressant. The study excluded patients with alternative indications for antipsychotic medications, such as schizophrenia, psychotic depression, or bipolar disorder. Defined as the primary outcome was all-cause mortality during study follow-up ascertained from the National Death Index.

The analytic cohort included 39,582 patients, mostly female, 78.5%, with a mean age of 44.5 years. About 22,000 of the participants had initiated augmentation with a newer antipsychotic—40% with quetiapine, 21% with risperidone, 17% with aripiprazole, or 16% with olanzapine. Approximately 17,000 additional participants had added a second antidepressant. The authors explain that the median chlorpromazine equivalent starting dose for all newer antipsychotics was 68 mg/d, increasing to 100 mg/d during follow-up.

Results indicate that 153 patients died during 13,328 person-years of follow-up, with the mortality rate at 138.1/10,000 person-years for newer antipsychotic augmentation versus 83.8/10,000 person-years for antidepressant augmentation. Researchers write that an adjusted hazard ratio of 1.45 (95% CI,1.02- 2.06) indicated increased all-cause mortality risk for newer antipsychotic augmentation compared with antidepressant augmentation (risk difference = 37.7 [95% CI, 1.7- 88.8] per 10,000 person-years). Results were robust across several sensitivity analyses, they add.

“Augmentation with newer antipsychotics in non-elderly patients with depression was associated with increased mortality risk compared with adding a second antidepressant,” the authors conclude. “Though these findings require replication and cannot prove causality, physicians managing adults with depression should be aware of this potential for increased mortality associated with newer antipsychotic augmentation.”

The 45% relative increase in mortality risk for those initiating a newer antipsychotic translated to one additional death for every 265 people taking the antipsychotic for 1 year, according to the report.

“Our results require replication, ideally with a publicly financed pragmatic randomized controlled trial. 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,” Dr. Gerhard emphasized. “Of particular relevance for our results is a finding from our previous work. It is well-known that most antidepressants take about four to six 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. Our results emphasize the importance of considering newer antipsychotics only after non-response to less risky, evidence-based treatment options has been established.”

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