Polypharmacy Is Common in Psychiatry, But Is More Better?

Caroline Helwick

September 07, 2010

September 7, 2010 (Amsterdam, The Netherlands) — A study of antidepressant and antipsychotic treatment effects showed there is an emphasis on "polypharmacy" in clinical practice, without much evidence of benefit and an increase in adverse effects. Swiss investigators reported these findings at the 23rd European College of Neuropsychopharmacology Congress.

"In our study, we found no advantages for 'complex' treatment approaches over conventional monotherapeutic approaches," said senior investigator Hans H. Stassen, PhD, of University Hospital of Psychiatry in Zurich, Switzerland, in an interview during the meeting. "There appear to be no controlled studies showing the superiority of combinations of drugs over monotherapy. We looked at this because we have observed in clinical practice that response rates are less and side effects are greater. We believe that the issue of polypharmacy in psychiatric practice deserves more scientific attention."

Treatment with antidepressants and antipsychotics, though effective, is unspecific in a number of ways, the study authors pointed out. For instance, agents that differ greatly in their biochemical and pharmacological actions can have virtually the same efficacy, patients with initial improvement often show incomplete response, and many patients are clinically refractory to all treatments. As a strategy for overcoming this unsatisfactory situation, polypharmaceutical approaches have gained favor in recent years. Today's "standard" treatment regimens rely on various combinations of antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, analgesics, antiparkinson drugs, cardiovascular agents, and other somatic treatments, the study authors noted.

In a post hoc analysis of 2 studies led by Katharina Lötscher, MD, from University Hospital of Psychiatry, patients with a diagnosis of depression given antidepressants and/or antipsychotics were evaluated for outcomes. The analysis included a monotherapeutic reference study of 2848 inpatients receiving 7 different antidepressants or placebo and a naturalistic study of 296 inpatients and 363 outpatients under current polypharmaceutic treatment regimens. The studies were conducted at the Zurich hospital.

The proportion of "mild" cases was comparable between the treatment modalities under comparison, which is important because aggressive treatment of "mild" cases has rarely been shown to be superior to placebo, the investigators noted. This may explain why response rates have continuously decreased in recent years, whereas the proportion of incomplete responders has increased.

Treatment modalities were documented at weekly intervals for inpatients and at the beginning and end of the observation period for outpatients.

One-Third of Patients With Depression Received Both an Antidepressant and an Antipsychotic

At study entry, 65% of patients were already under drug treatment, increasing to 99% after 1 week even though many patients had mild forms of depression. By the end of the second week, 26% of patients were treated with a combination of 2 or more antidepressants, and 32.6% with a combination of antidepressants and antipsychotics. During the observation period of 6 weeks, the polypharmacy patients received an average of 8.3 different drugs, with a maximum number of 20, Dr. Lötscher and colleagues reported.

"The observed polypharmaceutical treatment patterns appeared to be primarily associated with the psychiatrist in charge and much less with the patients' severity at baseline," she noted.

Throughout the first 2 weeks, the time course of improvement under a polypharmaceutical treatment regimen was identical with that seen in the monotherapeutic reference study. "Yet unexpectedly, in the polypharmacy group, there was a much larger proportion of patients who got 'stuck' in their recovery after initial improvement, thus becoming incomplete responders," Dr. Stassen added.

For example, in a comparison of imipramine (n = 337) monotherapy, polypharmaceutic treatment regimens (n = 153), and placebo (n = 127), mean change in Hamilton Depression score among patients matched for severity at baseline was −16 with imipramine monotherapy and −8 with both the combination approach and placebo.

"This was one of the most clinically relevant findings," Dr. Stassen said. "Maybe it has to do with drug interactions or side effects. We don’t know. This tells us that monotherapy controls more episodes than polypharmacy, and there are other emerging studies showing this as well."

In addition, during the 6-week study, the percentage of patients with cardiovascular problems increased from 8.8% to 30.7%.

The investigators found no disproportion in number of mild cases or medical comorbidities that could explain the general reduction in response rates under the polypharmaceutic antidepressant and antipsychotic regimens they studied.

"Rather, polypharmaceutic approaches to treating psychiatric disorders may be part of the problem. At least there is no advantage over conventional monotherapies," the study authors maintained in their poster presentation.

Cristoph Correll, MD, associate professor of psychiatry at Albert Einstein College of Medicine in New York City, and medical director of the Recognition and Prevention Program of the Department of Psychiatric Research at Zucker Hillside Hospital in Glen Oaks, New York, spoke at another session on medical comorbidities associated with psychotropic drugs. He commented in an interview with Medscape Medical News, "Polypharmacy can certainly cause interactions, for example, when you augment an antidepressant with an antipsychotic you can increase the weight gain. The other problem with polypharmacy is that the regimens that are now routine in clinical practice have not been well studied with regard to efficacy. We know in some cases efficacy may be greater with combinations. For example, as when you combine mirtazapine and venlafaxine. But the data are not strong for this as a group, and clearly this area needs more study."

Dr. Lotscher and Dr. Stassen have disclosed no relevant financial relationships. Dr. Correll has disclosed financial relationships (consulting, advising) with Actelion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Cephalon, Eli Lilly, Janssen, Johnson & Johnson, GlaxoSmithKline, F. Hoffmann-La Roche, Medicure, Otsuka, Pfizer, Schering-Plough, Supernus, Takeda, and Vanda and has served on the Data Safety Monitoring Board for Bristol-Myers Squibb, Cephalon, Otsuka, and Supernus.

23rd European College of Neuropsychopharmacology (ECNP) Congress: Abstract P.2.c.019. Presented August 31, 2010.


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