Antipsychotic Added to Antidepressant Linked to Higher Mortality

Megan Brooks

October 07, 2020

Adding an atypical antipsychotic to depression treatment is associated with an increased risk of mortality, new research suggests.

Results from a population-based cohort study showed that among middle-aged adults with depression taking an antidepressant, those who also took a second-generation antipsychotic were at increased mortality risk compared with their peers who instead took a second antidepressant.

Tobias Gerhard, PhD

"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," lead investigator Tobias Gerhard, PhD, Center for Pharmacoepidemiology and Treatment Science, Rutgers University, New Brunswick, New Jersey, said in a news release.

The results, "emphasize the importance of considering newer antipsychotics only after nonresponse to less risky, evidence-based treatment options has been established," Gerhard added.

The study findings were published online September 30 in PLOS ONE.

Option of Last Resort

Prior research has demonstrated an increased mortality risk in elderly patients with dementia who take an atypical antipsychotic, but it has been unclear whether this risk would be found in nonelderly adults using newer antipsychotics as augmentation treatment for depression.

The current investigators analyzed national healthcare claims from the US Medicaid program from 2001 to 2010 for 39,582 Medicaid beneficiaries (mean age, 44.5 years; 78.5% women) diagnosed with depression. Patients with alternative indications for antipsychotic therapy, such as schizophrenia, psychotic depression or bipolar disorder, were excluded.

After a period of at least 3 months of treatment with a single antidepressant, more than half of the patients (56.6%) augmented their treatment with one of these atypical antipsychotics: quetiapine, risperidone, aripiprazole or olanzapine. The remaining patients (43.4%) added a second antidepressant. The average chlorpromazine-equivalent starting dose for all atypical antipsychotics was 68 mg/day, which increased to 100 mg/day during follow-up.

A total of 153 patients died during 13,328 person-years of follow-up, including 105 who augmented with an atypical antipsychotic and 48 who augmented with a second antidepressant.

Compared with those who added a second antidepressant, those who added an antipsychotic had a 45% increased risk of dying during follow up (adjusted hazard ratio,1.45; 95% CI, 1.02 - 2.06).

That equated 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, adding that the results were robust across several sensitivity analyses.

"We don't know the mechanisms of the increased mortality risk, but that cardiac and infectious causes are leading candidates," Gerhard told Medscape Medical News.

Importantly, no single predominant cause of death was identified, Gerhard stressed, which may be a result of the relatively small number of deaths overall in the study, "as well as of the well-recognized concerns regarding the accuracy of cause-of-death attribution in death certificates."

"As with the potential causes of death, the pathophysiological pathways involved are not well understood but could, among others, involve adverse metabolic effects (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 note that use of newer antipsychotics should be considered "only after nonresponse to evidence-based treatment options that are less risky."

"Valid Contribution"

Commenting for Medscape Medical News, Timothy Sullivan, MD, chair of psychiatry and behavioral sciences at Northwell Health's Staten Island University Hospital in New York City, called the research a "valid contribution" and represents the second large study to raise the same concerns about antipsychotics.

"We've been probably underestimating the risk in administering them and that's something people really need to know. Because if you're prescribing it for someone with mild to moderate depression, it may be helpful; but is it really worth the risk if you're significantly increasing their risk of death?" said Sullivan, who wasn’t involved in the research.

Clearly, this "raises a flag — we have to look at this a little more carefully and be a little more clear with patients about the risk. One could argue that we should be not so quick to add these drugs, even though they could be helpful, before we exhaust other less potentially risky options," he added.

Sullivan's advice: "Do the three trials of antidepressants, look at antidepressant combinations, don't be quick to jump to this particular option because of the concerns. Certainly there are situations like psychotic depression where the risk of use is outweighed by the benefits given the clinical syndrome; but for less severe forms we probably should reformulate some of our algorithms."

Th e study was supported by the National Institute of Mental Health (NIMH). Gerhard reports grants from NIMH and the National Institute on Aging; grants and personal fees from Bristol-Myers Squibb; and personal fees from Eisai, Merck, Pfizer, Lilly, and IntraCellular Therapies outside the submitted work. Sullivan has disclosed no relevant financial relationships.

PLOS ONE. Published online September 30, 2020. Full text

For more Medscape Psychiatry news, join us on Facebook and Twitter


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.