Psychiatric Drug Interactions: Special Considerations for How DDIs Present in Psychiatry

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

The term “drug-drug interaction” frequently conjures images of a sudden catastrophic or even fatal outcome. While such an event can occur, and is obviously important to prevent, DDIs can present as virtually anything, including the worsening of the illness being treated or the emergence of a new illness. For this reason, such “masked” DDIs can, ironically, lead to the use of more medications to treat the apparent worsening of the primary condition or to treat the apparent emergence of a new condition. All drugs, except anti-infectives, are given to change human physiology. Those changes can present in every way clinically imaginable.

Understanding and identifying DDIs with psychiatric medications is perhaps more challenging than in any other area of medicine. The reason is the complexity of the organ they affect and the complexity of its output.

The average human adult is composed of ~10–20 billion cells arranged in hierarchal and integrated systems. 75 neurotransmitters have been identified in the human brain. That number may double in the next 10 years as a result of discoveries made possible by the human genome project. Every identified neurotransmitter has 2–17 receptor subtypes. Thus, the human brain may contain thousands of receptors, which are the primary targets of drug action. There are also different enzymes for the synthesis and degradation of these neurotransmitters, different uptake pumps, and storage mechanisms. All of these regulatory proteins can be the target for drug action. Thus, current drugs may interact pharmacodynamically in ways that are neither understood nor predictable at the present time. Their detection is dependent on the careful assessment at the time of a medication check by the prescriber. As psychiatric drugs are more rationally developed to affect only the brain, their adverse effects will not be on peripheral systems but on the brain itself. Psychiatric DDIs can present as changes in mentation, reality testing, emotional control, interpersonal relationships, and memory function. The prescriber of psychiatric medications must be a good behavioral pharmacologist, as well as a good diagnostician, and must also keep in mind that changes in these outputs of the human brain may be because of the medications that the patient is receiving rather than in spite of them.

There is much more that needs to be known. In the interim, it is important to summarize what is known, to explain the limits of current knowledge, and to define good clinical practices as they relate to avoiding untoward DDIs.

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.

The Human Brain

*This number is likely to increase as more neurotransmitters
are discovered through molecular biology.

Reproduced with permission. ©Preskorn