Polypharmacy in Psychiatry: Good, Bad, or Just Unavoidable?

Although most clinicians instinctively try to avoid prescribing multiple medications concurrently, there is evidence that polypharmacy is increasing. Some estimates suggest up to 65% of US adults aged 65 years or older experience polypharmacy. European estimates in this population range from 26% to 4src%. Even the World Health Organization has sounded the alarm, identifying the reduction of polypharmacy as a priority.

But whether polypharmacy is a growing phenomenon in psychiatry is debatable. Some recent studies suggest a modest rise in psychotropic polypharmacy in adults and a significant increase in children. Others point to a decline.

Even if polypharmacy — commonly defined as the concurrent prescription of five or more medications — is on the rise, the question of whether the practice is appropriate or inappropriate in psychiatric care is complex, and specialists in the field have a nuanced view.

“It’s not about risks vs benefits, but risks and benefits. But the potential risks start to multiply as more and more medicines are piled on,” Caleb Alexander, MD, a pharmacoepidemiologist and co-director of the Center for Drug Safety and Effectiveness at Johns Hopkins University, Baltimore, MD, told Medscape Medical News.

“We’ve all seen patients that come to us on just shocking combinations of psychotropic medicines, and you just think to yourself, ‘What’s going on here? Is there a captain at the head of the ship?’”

‘Rational’ Polypharmacy?

Examinations of psychotropic polypharmacy have yielded mixed results. A cross-sectional study of 34,189 adults in the US National Health and Nutrition Examination Study showed only a modest increase in prevalence of central nervous system–active polypharmacy from 2.1% in 2srcsrc9-2src1src to 2.6% in 2src17-2src2src. But another US analysis showed that psychotropic polypharmacy in children and adolescents has increased “substantially” over the past 2src years.

A recent Australian study revealed psychotropic polypharmacy decreased between 2src11 and 2src2src among primary care patients with dementia, even though it still affected 1 in 5 patients. Studies also suggest antipsychotic polypharmacy is common, occurring in 2src%-4src% of cases.

“The context in which drugs are used in the real world is enormously different from the context in which they’re studied in clinical trials,” Alexander said. “Typically, medicines are evaluated individually to gain regulatory approval, and psychiatric medicines are often prescribed in numbers and combinations that simply haven’t been evaluated in well done scientific studies.”

However, there is an argument for “rational” polypharmacy, said Robert Buchanan, MD, professor of psychiatry at the University of Maryland School of Medicine, Baltimore, and chief of the Outpatient Research Program, Maryland Psychiatric Research Center, in Catonsville, Maryland.

“People are not always going to respond to antipsychotics, antidepressants, or antianxiety agents and so are sometimes going to potentially need combinations, where combinations have been shown to be more effective,” Buchanan told Medscape Medical News.

As an expert in schizophrenia, Buchanan previously co-authored several guidelines that recommend against antipsychotic polypharmacy. Now, “I’ve changed my mind on this a little bit,” he said.

In a recent commentary in the American Journal of Psychiatry on the safety and efficacy of antipsychotic polypharmacy, Buchanan noted that some studies suggest that compared with monotherapy, polypharmacy may sometimes carry lower risks for hospitalization and be advantageous for acute exacerbations.

“There is an emerging literature to suggest that antipsychotic polypharmacy may offer some advantages in effectiveness compared with antipsychotic monotherapy,” he wrote.

One possible reason for this could be that combining medications with slightly different mechanisms may provide a more comprehensive response than a single antipsychotic medication, he said.

Titrate, De-Prescribe…or Add On?

But clinical decisions about the efficacy of treatment are fraught with the “challenges and sometimes vagaries of understanding whether or not a patient is truly responding,” Alexander pointed out. “There are plenty of instances where the only way to figure out that a medicine is really providing the value that we think it is, is to discontinue the medicine or titrate it down to assess what happens.”

But de-prescribing is not a focus in medical school. In one study, less than half the 24 clinicians working in pediatric settings had heard the term. In addition, there are few guidelines to help clinicians navigate this process, which may further discourage de-prescribing.

“So rather than discontinuing and then trying something else, something else just gets added on,” said Buchanan.

A patient’s psychiatric stability is another reason to avoid disrupting polypharmacy, he added.

“Just imagine you see this person who’s on, say, five or seven medications, and they’re stable. You know they’re probably on too many medications, but you don’t know which is the linchpin — the critical medication,” Buchanan said. “It’s uncommon in outpatient community practice for psychiatrists to be spending a large amount of time with each patient, so it’s hard under those circumstances to reduce some of the cocktails that can occur.”

Untangling the Knot

Sometimes, polypharmacy is the result of a cascade of treatment responses, making it hard to untangle the knot, said Alexander.

“You put someone on an atypical antipsychotic and they feel sluggish, and pretty soon someone suggests a stimulant for them, and then they feel anxious, so then someone else is suggesting an anxiolytic, and so on,” he said.

In fact, a recent review urged clinicians to be mindful of the strong role that pharmaceutical companies play in “exaggerated claims of the effectiveness of psychotropic medications and an underreporting of harms.”

While complex or refractory cases should probably be referred to psychiatrists, the majority of psychotropic medications are prescribed by primary care physicians, and that’s not likely to change, Alexander said.

“Mental illness is too common for us to fathom a world where all psychiatric illness is treated only by psychiatrists, and I think many primary care physicians are well equipped do so,” he said.

When faced with polypharmacy, Alexander suggests having a frank discussion with the patient. “I’ll carefully interview them and ask why they’re on each medicine, what the value is that they think the medicine provides, how long they’ve been on it, what they think would happen if they stopped it, how regularly they take it, and how interested they are in tapering their regimen.”

But adequately monitoring a taper is a challenge — even for psychiatrists.

“A lot of medical illnesses have biomarkers. So if I’m switching someone’s diabetic medications, I can just monitor their glucose level,” said Buchanan. “It’s a lot harder to monitor someone’s internal thoughts and hallucinations and delusions, particularly if they’re not that willing to share those with you.”

Aging adds another level of complexity.

“The physiologic reserve in every organ declines with age, so patients are much more susceptible to adverse events,” Alexander said. “And I think polypharmacy is especially a threat and a risk among the elderly with psychiatric illness. People develop sensory impairments, balance impairments, fall risk increases a lot, and it can be very difficult to manage.”

Importantly, clinicians should keep in mind that “drugs are not inherently good or bad. Their value depends upon how they’re applied,” he said. “This is where the art and science of medicine really come together, and where there’s a crucial opportunity for well-trained clinicians to help manage these complex patients.”

Buchanan consulted for Boehringer Ingelheim; served on the Data Safety and Monitoring Boards of Roche, Merck, and Newron; and served on the advisory boards of Merck, Acadia, Karuna, and Neurocrine. Alexander reported no relevant financial conflicts.