Q&A: Deadly Combinations—How Mixing Psychiatric Medications Complicates Overdose Deaths

While the US has seen a decline in the number of overdose deaths, researchers at Brown are turning their attention to an emerging contributor to deaths around the nation. 

In a paper first published in March, Madeline Benz '14 ScM'15, PhD, assistant professor of psychiatry and human behavior (research), and Brandon Gaudiano, PhD, professor of behavioral and social sciences and of psychiatry and human behavior, dove into psychotropic polypharmacy—the use of multiple psychiatric medications at the same time—and its role in overdose mortality rates. 

Benz and Gaudiano discuss the dangers and prevalence of mixing drugs, and what can be done to address a growing public health challenge.

This interview has been edited for length and clarity.

What is psychotropic polypharmacy?

Benz: This is the use of two or more psychiatric medications that act on the central nervous system. Often you'll find that people can be prescribed an antidepressant to treat depressive symptoms, and then they'll also maybe be prescribed something like a sedative in order to treat anxiety symptoms, and so that person then would have two medications that are considered psychotropic medicines. In some cases, patients are prescribed multiple psychotropic medications for valid reasons, but more complex regimens can also increase the need for careful monitoring and patient education.

Gaudiano: It’s important to state upfront that psychiatric medications can be highly beneficial when prescribed appropriately and taken as directed. In some cases, combining medications is clinically indicated and helpful. The key risk is often not just polypharmacy in general, but specific combinations of medications with known risk, such as sedating or cognitively impairing substances, including alcohol, opioids, benzodiazepines, and sleep medications. Our aim here is not to suggest that all medication combinations are unsafe, but to raise awareness that certain combinations can increase overdose risk and need to be carefully considered. In the end, treatment decisions have to be individualized and made by a clinician who knows the patient’s history best.

What sorts of medications are typically used in this approach?

Benz: Beyond antidepressants and antipsychotics, we are also seeing benzodiazepines in the mix and medications with sedating properties.

Gaudiano: The greatest concern is with medication combinations that are unnecessary, poorly monitored, or not taken appropriately, particularly when other substances like drugs or alcohol are also involved.

How did you first begin researching psychotropic polypharmacy and its effects?

Benz: My research has been primarily at the nexus of substance use and suicide, and I started to notice that the narrative about the overdose epidemic was primarily around illicit fentanyl, heroin, and polysubstance use involving opioids. We were really missing this whole group of people who were coming into the office and talking about overdoses on psychiatric medications, and overdoses with these combinations of such psychiatric medications and other substances. I wanted to highlight that it's not just opioids, and we need to be thinking beyond that when we examine the overdose epidemic.

What are some of the risks associated with it?

Benz: One of the big dangers is with drug interactions. We know that when you have two substances that are taken either together or in close proximity, you have not just the effects of one and the other, but a compounded impact of how the chemicals are interacting. The other problem is the way in which these substances interact don’t simply cause problems from a chemical standpoint, but also from a behavioral one. You have to keep in mind how somebody under the influence of a substance may act differently than they would when they were sober. A patient might be experiencing the impact of psychotropic polypharmacy and then behave in ways they wouldn't have if they weren't under the influence. For example, if they take an extra sedative, their inhibitions are lowered and they might be more likely to take another sedative. Suddenly our behavior is leading in a potentially dangerous direction. One pathway by which these combinations may contribute to overdose risk is through the lowering of inhibitions, as people are more inclined to add more drugs.

This also creates a gray area for what may be considered intentional or unintentional overdoses. We have for a long time conceptualized overdose intentionality as this binary choice: either we totally planned on doing it, and that's where the suicide focus comes in, or it was 100 percent an accident, and that's where the opioid field tends to focus. However, we misunderstand why many of these overdoses happen, and, from a clinical context, we see a lot of patients who will come in and they'll say they weren’t really trying to die, but they didn’t care about living either.

The emergence of self-medicating approaches also complicates this issue. The prescription landscape and the illicit substance landscape are both constantly shifting in the US, and we need to be better at staying on top of that. Ketamine is certainly something that we're seeing come up in both intentional and unintentional overdose events and Xylazine had similar attention recently as well. The idea behind acquiring and using these drugs is that people are hoping that they can essentially rewire their brains to operate differently. To be fair, drugs like ketamine are utilized for folks who have tried other treatments and haven’t had the success they wanted, like treatment-resistant depression. 

How prevalent is psychotropic polypharmacy in overdoses?

Benz: We've seen an increase in psychiatric medications in intentional overdoses. Antidepressants actually were the most implicated prescription substance in intentional overdoses in 2022, and we also have seen an increase in the co-prescription of psychiatric medications. They're happening in parallel, which suggests there's some overlap.

What can be done to address this?

Benz: We need to ask how we can work collaboratively with patients to reduce unnecessary prescriptions, or whether we can use one that may address multiple symptoms. One good aspect of this deprescribing approach is that there's room for pharmacy to be involved as well, so it doesn't just have to be at the prescriber level, but also at the point where it's dispensed. We’ve seen this process work for deprescribing certain medications for geriatric patients because of increased fall risk among older folks.

Treatment planning should consider both pharmacologic and nonpharmacologic options. It is also important to consider behavioral treatment options, which we know are evidence-based but are not used as frequently. Treatments like cognitive behavioral therapy have a strong evidence base for treating depression, anxiety, and chronic pain. Other approaches, like acceptance and commitment therapy, also have a strong evidence base, so if a doctor knows that a patient is dealing with multiple comorbidities, we can explore a more overarching therapeutic approach.

For patients themselves, it’s important to be honest with your provider about any medications that you're taking from other prescribers. Also, something as simple as just asking to understand what the medication is for is very helpful. Not enough people really understand why that medication is being added, so having those conversations with your doctor is essential. There are certainly instances where polypharmacy is indicated and helpful, but other instances where it's not helpful or can be risky.

Gaudiano: I don't think the public is aware of the risks of combining things, and I don't think there's enough attention in the health care system on educating patients and monitoring those risks. People are using other substances that they're not talking about, using over-the-counter things that again aren't being reported. My impression is that most people just aren't aware of how, when you combine things that have sedative properties in particular, those effects aren't just additive. They interact and synergistically create an effect that I think people don't realize can be lethal. 

What other research needs to be done?

Benz: We’d like to see more research on overdose intentionality so that we can better develop treatments to understand how to prevent overdose across that full spectrum. I would also look for research into how we can do a better job with our overdose surveillance methods because it's so disparate across states. For example, improving how we track which substances are screened after death. We need to standardize these practices to accurately analyze and develop a concrete understanding of how and why these patients are mixing these medications.

Gaudiano: Right now, we’re focusing a lot on the big, clearly identified opioids, or on medications in the headlines like ketamine. People might be aware of that, but we’re missing an opportunity to have a major public health impact by highlighting other drugs that, when combined or misused, also pose risks. This motivates us to talk about this issue.