Brown University psychiatrists have identified psychotropic polypharmacy—the use of multiple psychiatric medications simultaneously—as an underappreciated factor in overdose mortality rates. In recent commentary published in the Journal of Addiction Medicine, Assistant Professor Madeline Benz and Professor Brandon Gaudiano highlighted the emerging public health concern, noting that while the U.S. has seen a decline in overall overdose deaths, the picture becomes more complex when psychiatric medication combinations are considered.
The Mechanisms of Risk
Certain medication combinations pose particular dangers when mixed with sedating or cognitively impairing substances, including alcohol, opioids, benzodiazepines, and sleep medications. The risks operate on multiple levels: chemically, two substances taken together produce not just their individual effects but a compounded impact from their interaction. Behaviorally, these combinations can lower inhibitions, potentially leading users to add more drugs. Antidepressants were the most implicated prescription substance in intentional overdoses in 2022, and the co-prescription of psychiatric medications has increased in parallel, suggesting overlap in these trends.
Benz noted that medication combinations create ambiguity around overdose intentionality. “We have for a long time conceptualized overdose intentionality as this binary choice: either we totally planned on doing it… or it was 100% an accident,” she said. However, clinically, patients often report “they weren’t really trying to die, but they didn’t care about living either,” representing a middle ground that current frameworks often miss.
A Collaborative Approach to Prevention
Addressing this challenge requires systemic change at multiple levels. Benz recommended working collaboratively with patients to reduce unnecessary prescriptions or consolidate medications to address multiple symptoms with a single drug. Pharmacists can play a role at the dispensing level, building on successful de-prescribing models used with geriatric patients to reduce fall risk. Behavioral treatments like cognitive behavioral therapy, which have strong evidence bases for treating depression, anxiety, and chronic pain, should be considered as overarching therapeutic approaches when patients have multiple comorbidities. For patients, honesty with providers about all medications from different prescribers and simply asking what each medication is for can be crucial steps toward safer treatment.
This article is an AI-assisted summary. All facts and figures are drawn from the original report: https://www.brown.edu/news/2026-04-13/mixing-psychiatric-drugs