Adding a second-generation antipsychotic to an antidepressant to treat depression carries an increased mortality risk for middle-aged adults, results of a large, observational study show.
Dr. Tobias Gerhard
“Our study suggests 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,” lead investigator Tobias Gerhard, PhD, Center for Pharmacoepidemiology and Treatment Science, Rutgers University, New Brunswick, N.J., said in a news release.
The results, he added, “emphasize the importance of considering newer antipsychotics only after nonresponse to less risky, evidence-based treatment options has been established.”
The study was published online September 30 in PLOS ONE.
A last resort
Previous research has demonstrated an increased mortality risk for elderly patients with dementia who take an atypical antipsychotic, but it’s unclear whether this risk occurs among nonelderly adults who use newer antipsychotics as augmentation treatment for depression.
To investigate, Gerhard and colleagues analyzed national healthcare claims from the Medicaid program from 2001 to 2010 for 39,582 Medicaid beneficiaries (mean age, 44.5 years; 78.5% women) who had been diagnosed with depression. Patients with alternative indications for antipsychotic therapy, such as schizophrenia, psychotic depression, or bipolar disorder, were excluded.
After at least 3 months of treatment with a single antidepressant, for more than half of the patients (56.6%), treatment was augmented with an atypical antipsychotic (quetiapine, risperidone, aripiprazole or olanzapine). For the remainder (43.4%), a second antidepressant was added.
The average chlorpromazine equivalent starting dose for all atypical antipsychotics was 68 mg/d. The dose was increased to 100 mg/d during follow-up.
A total of 153 patients died during 13,328 person-years of follow-up, including 105 for whom treatment was augmented with an atypical antipsychotic and 48 for whom treatment was augmented with a second antidepressant.
(adjusted hazard ratio, 1.45; 95% CI, 1.02 – 2.06).
This equates to an absolute risk difference of 37.7 deaths per 10,000 person-years of treatment (0.38% per year) and a number needed to harm of roughly 265 per year. For higher-risk subgroups, the number needed to harm decreased substantially, the authors note. The results were robust across several sensitivity analyses.
“We don’t know the mechanisms of the increased mortality risk, but cardiac and infectious causes are leading candidates,” said Gerhard.
“Our study in nonelderly adults with depression did not identify a single predominant cause of death. However, this may be a result of both the relatively small number of deaths in our study as well as of the well-recognized concerns regarding the accuracy of cause-of-death attribution in death certificates,” Gerhard said.
“As with the potential causes of death, the pathophysiological pathways involved are not well understood but could, among others, involve adverse metabolic effects, including weight gain, diabetes, dyslipidemia, QT prolongation, sedation, and falls – all of which have been associated with at least some of the newer antipsychotics,” he added.
The researchers state that atypical antipsychotics should be considered only “after non-response to evidence-based treatment options that are less risky.”