A new study published online in PLOS ONE suggests adding second-generation antipsychotics to antidepressants carries an increased mortality risk for middle-aged adults.  The study builds on previous reports that doing so increases risk in older adults with prior research showing increased mortality for the elderly with dementia.“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,” said lead investigator Tobias Gerhard, PhD, Center for Pharmacoepidemiology and Treatment Science, Rutgers University, New Brunswick, New Jersey.  The results, he added, “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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The methods used by 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 results demonstrated 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.”  The study also concluded there “was a 45% increased risk of dying during follow-up (adjusted hazard ratio, 1.45; 95% CI, 1.02 – 2.06).”“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. “The results emphasize the importance of considering newer antipsychotics only after nonresponse to less risky, evidence-based treatment options have been established.  We don’t know the mechanisms of the increased mortality risk, but cardiac and infectious causes are leading candidates.”He added, “Antipsychotics have well-recognized and often serious adverse effects, including a more than 50 percent increased mortality risk in older adults with dementia…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 study authors concluded that adding a newer antipsychotic in patients with depression was riskier than supplementing with a second antidepressant.  However, more research is needed to determine causality.  Overall, “physicians managing adults with depression should be aware of this potential for increased mortality associated with newer antipsychotic augmentation,” they wrote.  It is also important to note that the focus was not on antipsychotics that have been approved and on the market for years.  It concentrated on newer, atypical treatments.

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Add-On Atypicals for Depression Carry ‘Substantial’ Death RiskMortality risk of antipsychotic augmentation for adult depressionAntipsychotic Added to Antidepressant Linked to Higher MortalityAntipsychotics for Treating Adult Depression Linked With Higher Mortality