Av Referencein Pocketailable Format —pg. 59 Educational Review Primary Psychiatry. 2004;11(2):39-60 2004 Guide to Psychiatric Drug Interactions Sheldon H. Preskorn, MD, and David Flockhart, MD, PhD drug alone but is either more than or Focus Points less than what would normally be • In a drug-drug interaction (DDI), the presence of a second drug alters the expected for the specific dose ingested. nature, magnitude, or duration of the effect of a given dose of a first drug. “Altered duration” means that the These interactions can be therapeutic or adverse, planned or unintended, nature of the effect is reasonably the but are always determined by the pharmacodynamics and pharmacokinet- same as can be expected from the victim ics of the drugs involved rather than their therapeutic indication. drug alone, but the effect either is short- • The risk of unintended and untoward DDIs is increasing in concert with er or longer lived than would normally both the increasing number of pharmaceuticals available and the number of be expected for the dose given. patients on multiple medications. The goal of this guide is to provide a quick reference for prescribers about • To avoid adverse DDIs, the prescriber must keep in mind fundamental prin- some of the major psychiatric DDIs. ciples of pharmacology and good clinical management. Furthermore, it presents general con- • The prescriber must know all of the medications that the patient is taking cepts which can aid prescribers in and be able to use available knowledge about their pharmacodynamic and avoiding untoward DDIs when possible pharmacokinetic mechanisms to minimize the risk of untoward DDIs. and quickly recognizing them when they occur. This way, corrective steps Abstract can be instituted to minimize the conse- Why should physicians be concerned about drug-drug interactions (DDIs)? DDIs quences. This guide is not intended to have the potential for causing untoward outcomes, including morbidity and even be comprehensive or authoritative. mortality for the patient, liability for the prescriber, and increased costs for the health- Given the speed with which new drugs care system. The risk of unintended and untoward DDIs is increasing in concert with are entering the market and new discov- both the increasing number of pharmaceuticals available and the number of patients eries about the mechanisms underlying on multiple medications. A recent survey found that 10% of all Americans >18 years DDIs are being made, the authors rec- of age were taking five or more prescription medications. Additional studies have ognize that this educational review, like found that patients on psychiatric medications, such as antidepressants, are on more all printed material on this topic, will medications than patients not on psychiatric medication. In addition, medications quickly become dated. The authors have interact not on the basis of their therapeutic use but on the basis of their pharmaco- addressed some of these limitations by dynamics and pharmacokinetics. For these reasons, the prescriber of psychiatric med- providing the reader with a list of Web ications must consider all of the medications the patient is taking. This educational sites that are more comprehensive and review discusses major pharmacologic principles to guide the safe and effective use of continuously updated (Appendices I multiple medications with a focus on neuropsychiatric medications. It also presents and II). This general guide provides an tables outlining major pharmacodynamic and pharmacokinetic mechanisms mediat- introduction to the topic and serves as a ing DDIs relevant to the patient on psychiatric medications. gateway to ready sources of additional information via the Internet. Introduction used alone. An example is serotonin Both authors maintain Web sites rele- A drug-drug interaction (DDI) occurs syndrome, which consists of marked vant to DDIs. Dr. Flockhart’s Web site2 when the presence of a coprescribed autonomic instability and can be fatal. summarizes data on cytochrome P450 drug (the perpetrator) alters the nature, This syndrome can occur when a sero- (CYP) enzymes and the drugs they magnitude, or duration of the effect of a tonin uptake pump inhibitor is used in metabolize and outlines which drugs given dose of another drug (the victim). combination with a monoamine oxi- inhibit or induce CYP enzymes. This “Altered nature” means that the effect dase inhibitor (MAOI).1 “Altered magni- information can be used to predict and produced when the two drugs are used tude,” on the other hand, means that the avoid DDIs mediated by this mecha- together is qualitatively different than nature of the effect is the same as can be nism. Dr. Preskorn’s Web site3 provides would be expected when either drug is reasonably expected from the victim content on topics relevant to the Dr. Preskorn is professor and chair of the Department of Psychiatry and Behavioral Sciences at the University of Kansas School of Medicine in Wichita. Dr. Flockhart is professor of medicine, genetics, and pharmacology, and is chief of the Division of Clinical Pharmacology in Wishard Hospital at the Indiana University School of Medicine in Indianapolis. Disclosure: Dr. Preskorn is a consultant to Abbott, AstraZeneca, Biovail, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Merck, Organon, Pfizer, Solvay, Somerset, Sumitomo, Wyeth, and Yamanouchi; has served on the speaker’s bureaus of Bristol-Myers Squibb, GlaxoSmithKline, Organon, Pfizer, and Wyeth; and has received research support/grants from Aventis, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Janssen, Lundbeck, E. Merck, Neurosearch, Novartis, Organon, Otsuka, Pfizer, Roche, Solvay, Somerset, and Wyeth. Dr. Flockhart received a research grant from the National Institute of General Medical Sciences. Please direct all correspondence to: Sheldon H. Preskorn, MD, University of Kansas School of Medicine, 1010 North Kansas, Witchita, KA 67214; Tel: 316-293-2669; Fax: 316-293-1874; E-mail: [email protected]. Primary Psychiatry, February 2004 39 S.H. Preskorn, D. Flockhart safe and effective use of psychiatric blessed with an ever-expanding array of with patients seeing a primary care medications. For example, under options to treat a wide variety of psychi- physician.24 The use of multiple psychi- “Columns, Section 1: Polypharmacology,” atric maladies. The explosion in psychi- atric medications has also increased in Dr. Preskorn presents and discusses real atric medications began with the intro- favor over the last 2 decades, reflecting life case examples of how DDIs present duction of fluoxetine (Prozac) in 19886 both the increased availability of effec- clinically and the mechanisms responsi- and is likely to continue and even accel- tive medications and the fact that they ble for the DDI.4 The authors will refer to erate in the future as a result of the have a more focused pharmacology. The these and other Web sites as a reference human genome project and the charac- latter leads to better tolerability but may for the reader who wants a more extend- terization of novel therapeutic targets in also limit efficacy and thus require the ed discussion of a topic or for those who the human brain. use of more medications to optimize want to check for updates after this guide While a blessing in many ways, this patient outcomes. The use of multiple has been published. development poses serious challenges psychiatric medications to treat patients This guide has several other limita- for practitioners trying to keep abreast is on the rise; there was a 15-fold tions, starting with the one imposed by of new developments. The prescriber increase in percentage of patients on its title: drugs do not interact on the has more therapeutic options, each with three or more psychiatric medications basis of their therapeutic area (eg, psy- different pharmacodynamics and phar- being seen at the Biological Psychiatry chiatric medications) but instead on the macokinetics, to understand and weigh. Branch of the National Institute of basis of their pharmacodynamics (ie, Over the last several decades, treat- Mental Health from the early 1970s to their action on the body) and their phar- ment has moved from a focus on time- the mid 1990s (Figure 2).25 macokinetics (ie, the actions of the body limited therapy (ie, a few weeks) of an For all of the above reasons, patients on them, including their absorption acute illness (eg, antibiotics for an on psychiatric medications are at risk from the site of administration, their acute infection) to preventive or main- for DDIs and these DDIs are likely to distribution in the body, their metabo- tenance therapy for chronic illnesses involve more than just two drugs. Thus, lism, and their elimination).5 For this as diverse as major depressive disorder the problem may not just be the effect of reason, the authors acknowledge the (MDD), schizophrenia, Alzheimer’s drug A on drug B but this effect in the limitations inherent in focusing on ther- disease, hypertension, human immun- presence of drugs C and D as well. apeutic class—even one as broad as psy- odeficiency virus infection, and ather- To underscore the complexity of such chiatric or neuropsychiatric medica- osclerosis. As a result of this change in DDIs, consider the following questions, tions. In fact, the authors will reclassify focus, patients are more likely to be on which help to illustrate the size of the the drugs principally covered in this more than one medication at the same problem: (1) In 2003, how many dis- guide into other functional classes time.7-10 In fact, they are likely to accu- crete chemical entities could a physician based on their pharmacodynamics and mulate preventive therapy as they age, prescribe for his/her patient? (2) Given pharmacokinetics, such as CYP enzyme which can often continue for many the number of drugs, how many differ- substrates, inducers, and inhibitors. The months or years, to perhaps the entire ent combinations (up to five drugs) reason for taking this approach is that remaining lifespan of the individual could the physician prescribe for his/her those are mechanisms relevant to clini- once started.