Summary: Study reveals a link between people with depression who are prescribed newer antipsychotic medications and higher mortality risk.
Source: Rutgers University
Rutgers researchers, together with colleagues at Columbia University, have reported an increased mortality risk in adults with depression who initiated augmentation with newer antipsychotic medications compared to a control group that initiated augmentation with a second antidepressant.
The study was published in the journal PLOS ONE.
Although antidepressants are the first-line pharmacological treatment for depression, many people do not respond to the first course of treatment. Subsequent treatment options include switching 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,” said lead author Tobias Gerhard, 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.”
The researchers looked at data of 39,582 Medicaid beneficiaries ages 25 to 64 from 2001 to 2010, linked to the National Death Index. After a period of treatment with a single antidepressant, study patients initiated either augmentation with a newer antipsychotic or with a second antidepressant.
The researchers found a 45 percent relative increase in mortality risk for those initiating a newer antipsychotic, which for the study cohort translated to one additional death for every 265 people taking the antipsychotic for one year.
“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,” said Gerhard.
“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.”
Mortality risk of antipsychotic augmentation for adult depression
Importance Randomized controlled trials have demonstrated increased all-cause mortality in elderly patients with dementia treated with newer antipsychotics. It is unknown whether this risk generalizes to non-elderly adults using newer antipsychotics as augmentation treatment for depression.
Setting National healthcare claims data from the US Medicaid program from 2001–2010 linked to the National Death Index.
Participants Non-elderly adults (25–64 years) diagnosed with depression who after ≥3 months of antidepressant monotherapy initiated either augmentation with a newer antipsychotic or with a second antidepressant. Patients with alternative indications for antipsychotic medications, such as schizophrenia, psychotic depression, or bipolar disorder, were excluded.
Exposure Augmentation treatment for depression with a newer antipsychotic or with a second antidepressant.
Main outcome All-cause mortality during study follow-up ascertained from the National Death Index.
Results The analytic cohort included 39,582 patients (female = 78.5%, mean age = 44.5 years) who initiated augmentation with a newer antipsychotic (n = 22,410; 40% = quetiapine, 21% = risperidone, 17% = aripiprazole, 16% = olanzapine) or with a second antidepressant (n = 17,172). The median chlorpromazine equivalent starting dose for all newer antipsychotics was 68mg/d, increasing to 100 mg/d during follow-up. Altogether, 153 patients died during 13,328 person-years of follow-up (newer antipsychotic augmentation: n = 105, follow-up = 7,601 person-years, mortality rate = 138.1/10,000 person-years; antidepressant augmentation: n = 48, follow-up = 5,727 person-years, mortality rate = 83.8/10,000 person-years). An adjusted hazard ratio of 1.45 (95% confidence interval, 1.02 to 2.06) indicated increased all-cause mortality risk for newer antipsychotic augmentation compared to antidepressant augmentation (risk difference = 37.7 (95%CI, 1.7 to 88.8) per 10,000 person-years). Results were robust across several sensitivity analyses.
Conclusion Augmentation with newer antipsychotics in non-elderly patients with depression was associated with increased mortality risk compared with adding a second antidepressant. 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.