Time Course of Psychiatric Drug Interactions

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

Drugs have the potential to interact as long as they and/or their effects persist in the body. Thus, the potential for an interaction may persist for days to weeks and even months after one of the drugs has been discontinued. This fact is illustrated in the following figure from a study examining the effect of fluoxetine on the metabolism of the CYP 2D6 model substrate desipramine.

In this study, genotypically normal metabolizers via CYP 2D6 (>95% of the population) were first treated with desipramine 50 mg/day for 7 days to achieve steady-state conditions. On day 8, fluoxetine 20 mg/day was added to their regimen. Without changing the dose of desipramine, its levels increased >4-fold over the next 3 weeks as fluoxetine and its active metabolite, norfluoxetine, accumulated, resulting in the inhibition of CYP 2D6. The inhibition of CYP 2D6 resulted in a reduction in the clearance of desipramine and hence an increase in desipramine levels without a change in dose.

On day 28, fluoxetine was discontinued but desipramine was continued at the same dose. Over the next 3 weeks, the desipramine levels fell as fluoxetine and norfluoxetine cleared from the body and CYP 2D6 inhibition in parallel was reversed, leading to an increase in desipramine clearance. Nevertheless, desipramine levels even 3 weeks after fluoxetine was discontinued were still double what they were before fluoxetine was added, because norfluoxetine was still present in the body and still inhibiting CYP 2D6-mediated clearance.

This study graphically illustrates the point that the effect of a co-prescribed perpetrator drug (eg, fluoxetine) on the response to the victim drug (eg, desipramine) can continue to increase for weeks after the perpetrator has been started and can persist for weeks after the perpetrator has been stopped. Sometimes that is because the perpetrator has a long residual time in the body, as in the case of fluoxetine, and sometimes it is because the perpetrator’s effect persists long after it has been cleared. These delayed onsets and offsets are not simply limited to pharmacokinetic interactions but can be applied to all interactions in which the effect of the perpetrator persists for a sustained period after the perpetrator has been discontinued.

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.