Rational Polypharmacy

Sheldon H. Preskorn, MD
David Flockhart, MD, PhD

Dr. Preskorn is Professor, Chair, Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine, CEO, Clinical Research Institute

Dr. Flockhart is Professor of Medicine, Genetics, and Pharmacology; Chief, Division of Clinical Pharmacology, Indiana University School of Medicine

For polypharmacy to be rational, the prescriber in any area of medicine must be able to answer the following questions:

1. Why am I using more than one drug?
2. Do the drugs interact?
3. If so, what are the data that support the safety, tolerability, and efficacy of the combination?

The following table lists five major reasons why a prescriber may use more than one drug to treat a patient.

The first reason is the most obvious: The patient has more than one disease process and the prescriber must employ one or more agents for each disease. In this example, the prescriber is not planning a DDI, though one may occur because drugs interact on the basis of the mechanisms underlying their pharmacodynamics and pharmacokinetics rather than on the basis of their therapeutic indication.

The second reason is particularly relevant to psychiatry. Conditions such as bipolar and schizoaffective disorder have complex symptom clusters that wax and wane over the course of the illness. Patients with these illnesses may need different medications for different phases of their illness. While mood stabilizers (eg, lithium) are usually the foundation for the treatment of a patient with bipolar disorder, at different phases of the illness the patient may need to have antidepressants, antipsychotics, or anxiolytics added and may even need treatment with >1 mood stabilizer.

The remaining reasons are based on planned therapeutic DDIs, whether or not the prescriber thinks in these terms. When a second drug diminishes, amplifies, or speeds the onset of the effect of a first drug, that is, by definition, a DDI. When using a drug for these purposes, the ideal situation would be one in which the pathophysiology of the illness and the effects of each drug on that pathophysiology are all clearly understood.

The problem in psychiatry is that the pathophysiology of psychiatric illnesses is not well understood and, thus, the effects of the drugs on that pathophysiology cannot be well understood. Nevertheless, the following table lists a series of features that can be used to rationally prescribe ≥2 psychiatric medications together to accomplish the last three goals listed in Table 2.

Disclosure: Dr. Preskorn is a consultant to Bristol-Myers Squibb, Cyberonics, Eli Lilly, Johnson&Johnson, Memory, Otsuka, Pfizer, Shire, Somerset, and Wyeth; is on the speaker’s bureaus of Bristol-Myers Squibb, Cyberonics, Forest, Otsuka, and Pfizer; and receives grant support from Brtistol-Myers Squibb, Cyberonics, Johnson&Johnson, Memory, Merck, The National Institute of Mental Health, Novartis, Organon, Otsuka, Pfizer, Predix, Sepracor, and Somerset.

Disclosure: Dr. Flockhart is a consultant to Hoffman-La-Roche.