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An Overview of Psychotropic Drug-Drug Interactions

Dr. Sandson is the Director of the Division of Education and Residency Training for the Sheppard Pratt Health System, Towson, Md., Associate Director of the University of Maryland/Sheppard Pratt Psychiatry Residency Program, Baltimore, and Clinical Assistant Professor in the Department of Psychiatry at the University of Maryland Medical System, Baltimore. Dr. Armstrong is the Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, Ore., and Associate Clinical Professor of Psychiatry, Oregon Health Sciences University, Portland, Ore. Dr. Cozza is a staff psychiatrist for the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, D.C., and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, Md. Dr. Sandson is the author of Drug Interactions Case Book: The Cytochrome P450 System and Beyond (American Psychiatric Publishing Inc., 2003). Drs. Armstrong and Cozza are co-authors, along with Dr. Jessica R. Oesterheld, of the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-Glycoproteins, 2nd edition (American Psychiatric Publishing, Inc., 2003). Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple St., Forest Grove, OR 97116; scott.armstrong{at}tuality.org (e-mail).
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

ABSTRACT

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The psychotropic drug-drug interactions most likely to be relevant to psychiatrists’ practices are examined. The metabolism and the enzymatic and P-glycoprotein inhibition/induction profiles of all antidepressants, antipsychotics, and mood stabilizers are described; all clinically meaningful drug-drug interactions between agents in these psychotropic classes, as well as with frequently encountered nonpsychotropic agents, are detailed; and information on the pharmacokinetic/pharmacodynamic results, mechanisms, and clinical consequences of these interactions is presented. Although the range of drug-drug interactions involving psychotropic agents is large, it is a finite and manageable subset of the much larger domain of all possible drug-drug interactions. Sophisticated computer programs will ultimately provide the best means of avoiding drug-drug interactions. Until these programs are developed, the best defense against drug-drug interactions is awareness and focused attention to this issue.

INTRODUCTION

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The array of available psychopharmacologic agents has expanded tremendously over the last 20 years. The growing range of treatment options has made treating patients more complex. It is a formidable challenge to remain familiar with the evolving evidence base. Choosing appropriate agents for patients and making shrewd changes when faced with medication intolerance or treatment resistance occupy the bulk of most psychiatrists’ pharmacological concerns. However, another domain of psychopharmacology is critical to best practice, and it should precede the quest for efficacy. To paraphrase Hippocrates, it is incumbent on clinicians to "First, do no harm." Unfortunately, practitioners often fall well short of that dictum, especially where drug-drug interactions are concerned.

Drug-drug interactions are actually quite commonplace^1–5 and are responsible for considerable patient morbidity and mortality.^6–8 A growing and sobering evidence base implicates drug-drug interactions as a major contributor to hospital admissions, treatment failures, avoidable medical complications, and subsequent health care costs.^4,5,9–11 Yet, drug-drug interactions are rarely foremost in the minds of otherwise excellent clinicians. This disconnection is explained, in part, by our relatively primitive ability to detect drug-drug interactions.^12,13 However, as understanding of the importance of drug-drug interactions grows, concerned physicians are eager to know more.

Most current drug-drug interaction software programs have problems with both sensitivity and specificity¹⁴ and are not especially user friendly. They often promote a therapeutic paralysis that is almost as undesirable as an ignorance of drug-drug interactions. There are some excellent publications on this topic, which appropriately examine the issue of drug-drug interactions across medical disciplines.^15,16 However, for many psychiatrists, this wide range presents an overwhelming flood of information. Grappling with the entire array of drug-drug interactions is a worthwhile goal for anyone who prescribes medications, but it can be a daunting enterprise. An ideal starting point for psychiatrists is to examine drug-drug interactions involving the familiar psychotropic agents that are most relevant to their practices. This review focuses on intrapsychotropic drug-drug interactions involving antidepressants, antipsychotics, and mood stabilizers.

Types of Drug-Drug Interactions
The two major varieties of drug-drug interactions are pharmacodynamic interactions and pharmacokinetic interactions. Pharmacodynamic interactions represent the synergy or antagonism of each drug’s effects at target receptors. For example, the synergistic anticholinergic activity of amitriptyline combined with benztropine can produce constipation, heat stroke, urinary retention, and other related difficulties.¹⁷ Another familiar example is central serotonin syndrome, which results from the combination of a monoamine oxidase inhibitor (MAOI) with a selective serotonin reuptake inhibitor (SSRI).^18,19 In pharmacokinetic interactions, one agent causes the blood level of another agent to be raised or lowered. Pharmacokinetic drug-drug interactions may occur through multiple mechanisms, including alterations in drug metabolism, absorption, excretion, and distribution.

Pharmacodynamic drug-drug interactions are usually intuitively straightforward. If one has a basic sense of a drug’s mechanism of action and receptor occupancies, these interactions can often be predicted and avoided. Pharmacokinetic drug-drug interactions are much more difficult to anticipate. Knowing how a drug accomplishes its intended therapeutic effect rarely confers any knowledge of its kinetic parameters or of the ways these parameters will interact with those of another drug. Most of the challenge posed by drug-drug interactions rests in the pharmacokinetic domain, which is predominantly concerned with metabolic alterations.

Metabolic Enzymes
Several key enzymatic systems are frequently involved in pharmacokinetic drug-drug interactions. The most prominent is the cytochrome P450 system. The P450 system is a family of mostly hepatic enzymes that perform oxidative (phase I) metabolism. Specific P450 enzymes are named by number-letter-number sequences; the major enzymes in this group are 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. P450 substrates are agents that are metabolized by particular P450 enzymes. For instance, nortriptyline is metabolized primarily by P450 2D6, and it is therefore a substrate of this enzyme.^20,21 P450 inhibitors impair the ability of specific P450 enzymes to metabolize their target substrates, thus producing increased blood levels of those substrates. Conversely, inducers cause an increase in the production of particular P450 enzymes, leading to increased metabolism of substrates of those P450 enzymes. Enzymatic inhibition is usually immediate, whereas induction usually requires several days to 2 or more weeks to exert a meaningful effect on drug metabolism.

A related metabolic system implicated in drug-drug interactions is phase II conjugative metabolism. The most prominent phase II enzymatic family is the uridine 5'-diphosphate glucuronosyltransferases (UGTs). Like the P450 system, UGTs are identified by a number-letter-number scheme (1A1, 1A4, 2B7, 2B15, etc.), and each enzyme has a unique array of substrates, inhibitors, and inducers. Phase I enzymes usually perform the bulk of the metabolic workload. Phase II conjugation generally serves as a metabolic capstone, rendering substances that have already undergone phase I oxidation more hydrophilic and thus more readily excretable. For this reason, the contribution of phase II metabolism to drug-drug interactions is typically not as significant as that of phase I metabolism. However, the metabolism of several agents, including lamotrigine,²² olanzapine,²³ and many narcotic analgesics,^24,25 is handled solely or primarily by the UGTs. A familiarity with prominent UGT inhibitors and inducers is thus important in order to anticipate and prevent drug-drug interactions involving these agents.

P-Glycoproteins
Of the nonmetabolic systems that mediate pharmacokinetic drug-drug interactions, the P-glycoprotein transporter is emerging as a critically important contributor. P-glycoprotein is an ATP-dependent, extruding transporter. It resides in the plasma membrane of enterocytes that line the gut lumen, and in this location it is an important regulator of drug absorption and bioavailability. It also lines the capillaries of the blood-brain barrier, where it constitutes one of the core elements preventing various substances from gaining access to the CNS. P-glycoprotein is also found in the cells lining renal tubules. Like the P450 and UGT metabolic systems, the P-glycoprotein transporter has substrates, inhibitors, and inducers. P-glycoprotein functions by extruding substrates from the cytosol of enterocytes back into the gut lumen, or from the capillaries of the blood-brain barrier back into the bloodstream. P-glycoprotein inhibitors antagonize this process and lead to greater retention and absorption of P-glycoprotein substrates. P-glycoprotein inducers increase the amount of active P-glycoprotein and thus lead to more extrusion and excretion of P-glycoprotein substrates. The net effect of this activity is that P-glycoprotein inhibitors increase the blood levels of P-glycoprotein substrates, and P-glycoprotein inducers decrease the levels of P-glycoprotein substrates. The list of known P-glycoprotein substrates, inhibitors, and inducers is already quite large and is growing with each passing month.

Other Pharmacokinetic Processes
Other pharmacokinetic drug-drug interactions are caused by alterations in absorption (not relating to P-glycoprotein), excretion, and distribution. Alterations in gastrointestinal pH, the presence or absence of food, and the rate of bowel motility are only a few of the factors that can affect absorption. For instance, the absorption of ziprasidone is much greater when it is consumed with food.²⁶ Drugs that affect renal excretion can alter the blood level of lithium.^27,28 Distribution issues are actually somewhat infrequent for psychotropics, although the blood level of unbound or free valproate can be significantly increased by daily antipyretic doses of aspirin.^29,30

Current Practical Resources
Tables of drug-drug interactions involving the P450, UGT, and P-glycoprotein systems are available from multiple published and online sources. An exhaustive set of P450 tables may be found in the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-Glycoproteins, by Kelly Cozza, M.D., Scott Armstrong, M.D., and Jessica Oesterheld, M.D (American Psychiatric Publishing, Inc., 2003). David Flockhart, M.D., provides an excellent P450 table online at http://medicine.iupui.edu/flockhart/. Dr. Oesterheld is the coauthor of a website, www.mhc.com/Cytochromes, which contains a P450 table tailored for psychiatrists, as well as very complete UGT and P-glycoprotein tables.

Specific Pharmacokinetic Features of Psychotropic Agents

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Antidepressants SSRIs
Citalopram
Citalopram is metabolized primarily by P450 2C19, 2D6, and3A4.^31–33 It is likely a mild to moderate inhibitor of 2D6,^31,34 as evidenced by its ability to increase blood levels of desipramine and metoprolol.³⁵ Citalopram is a substrate of P-glycoprotein.³⁶

Escitalopram
The pharmacokinetic features of escitalopram are basically the same as those of citalopram.^37,38

Fluoxetine (norfluoxetine)
Fluoxetine and its active metabolite norfluoxetine are together metabolized by P450 2C9, 2C19, 2D6, and 3A4.^15,39 Together, they potently inhibit 2D6^34,40 and mildly to moderately inhibit 1A2, 2B6, 2C9, 2C19, and 3A4.^41–46 Fluoxetine can reasonably be considered a P450 pan-inhibitor, much like cimetidine. It is also a P-glycoprotein inhibitor.⁴⁷

Fluvoxamine
Fluvoxamine is primarily metabolized by P450 1A2 and secondarily by 2D6.^48,49 It is a pan-inhibitor like fluoxetine. It is a potent inhibitor of 1A2 and 2C19,^45,48,50 and a mild to moderate inhibitor of 2B6, 2C9, 2D6, and 3A4.^{34,42,43,45,50,51} It is also both a substrate and an inhibitor of P-glycoprotein.^47,52

Paroxetine
Paroxetine is primarily metabolized by P450 2D6 and secondarily by 3A4.^45,53 It is a potent inhibitor of 2B6 and 2D6^34,42,54,55 but only a mild inhibitor of other P450 enzymes.^41,44 It is also both a substrate and an inhibitor of P-glycoprotein.⁴⁷

Sertraline
Sertraline and its mildly active metabolite desmethylsertraline are substrates of multiple P450 enzymes.^56,57 Sertraline inhibits 2D6 in a dose-dependent manner. At doses under 100 mg/day, sertraline may only mildly inhibit 2D6. At doses above 150 mg/day, 2D6 inhibition may become moderate to potent.^34,58 Sertraline is also a moderate inhibitor of 2B6 and 2C19^42,44 and a mild inhibitor of 1A2 and 3A4.^41,59–61 Possibly unique among the SSRIs, sertraline also appears to be a specific and potent inhibitor of UGT 1A4, as evidenced by the ability of 25 mg/day of sertraline to double the blood level of lamotrigine.⁶² Sertraline is also a P-glycoprotein inhibitor.⁴⁷

Tricyclic Antidepressants
Secondary amine tricyclic antidepressants
Secondary amine tricyclic antidepressants (TCAs), including desipramine, nortriptyline, and protriptyline, are primarily substrates of P450 2D6, which performs hydroxylation on these compounds.^{20,21,63–66} They are also moderate 2D6 inhibitors.^34,67,68 These TCAs also appear to be inhibitors of P-glycoprotein, and nortriptyline has been demonstrated to be a P-glycoprotein substrate.^69–72

Tertiary amine TCAs
The metabolism of tertiary amine TCAs, including amitriptyline, clomipramine, trimipramine, imipramine, and doxepin, is much more complex than that of the secondary amine TCAs. Tertiary amine TCAs undergo both demethylation to secondary amine TCAs through the action of 1A2, 2C19, and 3A4 and hydroxylation by 2D6.^{63,65,73–77} UGT 1A4 also makes a minor contribution to the metabolism of tertiary amine TCAs.^23,78,79 Tertiary amine TCA inhibition of 2D6, considered without the contribution of the secondary amine metabolites, tends to be only mild, and there is some evidence that amitriptyline and imipramine are mild inhibitors of 2C19.⁶⁸ These TCAs also appear to be both substrates and inhibitors of P-glycoprotein.^{69–71,80,81}

Other Antidepressants
Bupropion
Bupropion is primarily metabolized by P450 2B6.^82,83 It is a moderate to potent inhibitor of 2D6.^84,85

Duloxetine
Duloxetine is metabolized by P450 1A2 and 2D6.^37,86 It is a moderate inhibitor of 2D6.^86,87

Mirtazapine
Mirtazepine has multiple metabolic pathways, including metabolism by P450 1A2, 2D6, and 3A4.^88,89 It has no significant inhibitory or inductive capabilities.⁹⁰

MAOIs
Phenelzine is a substrate of monamine oxidase A (MAOA) and lacks any significant P450 inhibitory or inductive capabilities.^18,91 Tranylcypromine is also a substrate of MAOA,⁹¹ but it is also a potent inhibitor of P450 2A6^92,93 (a minor P450 enzyme) and a mild to moderate inhibitor of 1A2, 2C19, and 2E1.^19,94

Nefazodone
Nefazodone is primarily metabolized by P450 3A4 into three major metabolites.⁹⁵ One of these is metachlorophenylpiperazine (mCPP),⁹⁶ an acutely anxiogenic, partial serotonin agonist that relies on 2D6 for its metabolism.^97–99 Nefazodone is a potent inhibitor of 3A4.^46,100 Also, it is initially an acute inhibitor and later a chronic inducer, of P-glycoprotein.¹⁰¹

Trazodone
Like nefazodone, trazodone relies primarily on P450 3A4 for its metabolism, and one of the principle metabolites resulting from its metabolism by 3A4 is mCPP.¹⁰² Trazadone is also an inducer of P-glycoprotein.¹⁰¹

Venlafaxine
Venlafaxine’s metabolism relies primarily on P450 2D6, and it is a mild 2D6 inhibitor.⁶⁷ It is also both a substrate and a mild inhibitor of P-glycoprotein.⁴⁷

Antipsychotics Typical Antipsychotics
Phenothiazines
As a general rule, phenothiazines are metabolized primarily by P450 2D6,^103–107 with frequent contributions from 1A2 and phase II metabolism.^{23,79,103,107,108} 3A4 makes only a minor contribution to the metabolism of most phenothiazines.^106,109 Most of these agents display moderate to potent 2D6 inhibition.^110,111 As a class, they appear to be P-glycoprotein inhibitors, although several typical agents are P-glycoprotein substrates as well.^52,112,113

Haloperidol
Haloperidol’s metabolism is quite complex, relying principally on P450 3A4 and phase II metabolism (not yet elucidated), with secondary contributions from 2D6 and 1A2.¹¹⁴ It appears to be an in vitro P-glycoprotein substrate of weak affinity.^112,115 One of haloperidol’s metabolites is a potent 2D6 inhibitor.¹¹⁶ Haloperidol is also a P-glycoprotein inhibitor.^52,115

Pimozide
Pimozide is metabolized primarily by P450 3A4, with a secondary contribution by 1A2.¹¹⁷ It is a potent inhibitor of 2D6 and moderate inhibitor of 3A4.¹¹⁷ It is also an inhibitor of P-glycoprotein.⁸⁰ Because of its arrhythmogenic potential, this agent has a relatively low therapeutic index.

Atypical Antipsychotics
Aripiprazole
Aripiprazole’s metabolism is roughly equally divided between P450 2D6 and 3A4.¹¹⁸ It lacks any known inhibitory or inductive capabilities. This agent, a partial dopamine agonist, displays more avid binding to the dopamine D₂ receptor than any other antipsychotic.^119–122

Clozapine
Clozapine is principally metabolized by P450 1A2 with numerous secondary pathways, including 2C9/19, 2D6, 3A4, and UGT 1A3/4.^50,123–125 It appears to be an in vitro P-glycoprotein substrate of weak affinity.¹¹² It is also a known mild inhibitor of 2D6.^111,126 This agent has a fairly low therapeutic index.

Olanzapine
Olanzapine is mostly metabolized by P450 1A2 and UGT 1A4, with 2D6 serving as a minor pathway.^23,127 It is also an in vitro P-glycoprotein substrate of low to moderate affinity¹¹² and a P-glycoprotein inhibitor.⁵²

Quetiapine
Quetiapine is mostly metabolized by P450 3A4.^128,129 It is also an in vitro P-glycoprotein substrate of moderate to strong affinity¹¹² and a P-glycoprotein inhibitor.⁵²

Risperidone
Most of risperidone’s metabolism occurs through P45 2D6, although 3A4 also makes a significant contribution.^130–132 It is also an in vitro P-glycoprotein substrate of moderate to strong affinity.¹¹² Risperidone acts as a mild to moderate 2D6 inhibitor.^111,133

Ziprasidone
In healthy adults, ziprasidone is principally metabolized by aldehyde oxidase, with P450 3A4 serving as a secondary pathway.^26,134 It lacks any known inhibitory or inductive capabilities.

Mood Stabilizers
Carbamazepine
Carbamazepine is primarily metabolized by P450 3A4, although 1A2, 2B6, 2C8/9, 2E1, and phase II metabolism (UGT 2B7) serve as minor pathways.^135–137 It is both a substrate and an inhibitor of P-glycoprotein, although its inhibitory capability is unlikely to be clinically significant.^138–140 It is also likely an inhibitor of 2C19, as evidenced by carbamazepine’s ability to increase blood levels of both phenytoin and clomipramine.^141–143 Carbamazepine is a potent inducer of 3A4,^{134,137,144,145} and it also induces 1A2, 2B6, 2C8/9, and UGT 1A4.^146–149

Lamotrigine
Lamotrigine is primarily metabolized by UGT 1A4,^22,23 although one or more P450 enzymes, not yet well characterized, serve as a secondary pathway. However, this P450 pathway leads to the generation of toxic metabolites.¹⁵⁰ In the presence of a UGT 1A4 inhibitor such as valproate, a greater proportion of lamotrigine is metabolized through this P450 metabolic pathway, leading to production of these toxic metabolites. This effect helps to explain why the combination of valproate and lamotrigine is associated with a greater incidence of both Stevens-Johnson syndrome and toxic epidermal necrolysis, even when low dosages of lamotrigine are used. Some weak autoinduction (at UGT 1A4) has been noted.¹⁵¹

Lithium
Lithium is purely renally excreted, with no hepatic metabolic component. It lacks any inhibitory or inductive capabilities.

Oxcarbazepine
Oxcarbazepine is quickly metabolized to an active monohydroxyoxcarbazepine (MHD) metabolite by the action of arylketone reductase. Both oxcarbazepine and MHD are metabolized in part through phase II glucuronidation.¹⁵² Oxcarbazepine is a mild inducer of 3A4,¹⁵³ and a moderate inducer of UGT 1A4.¹⁵⁴ MHD is an inhibitor of 2C19.¹⁴¹

Phenytoin
Phenytoin is primarily a substrate of P450 2C9 and 2C19,^141,155,156 with minor contributions from multiple UGT 1A family enzymes.¹⁵⁷ It is also a P-glycoprotein substrate.¹⁵⁸ It induces multiple enzymes, including 2B6, 2C9/19, 3A4, and UGTs 1A1 and 1A4.^{147,149,159–162}

Topiramate
Topiramate is primarily renally excreted. Its hepatic metabolism is mostly governed by phase II enzymes with a minor phase I contribution, neither of which has been well characterized.^163,164 It is likely to be a P-glycoprotein substrate.¹⁶⁵ It is an inhibitor of 2C19^166,167 and a mild inducer of 3A4.^168,169

Valproate
Valproate’s metabolism is exceedingly complex, involving multiple phase I and II pathways (P450 2A6 and 2C9¹⁷⁰; UGT 1A6, 1A9, and 2B7¹⁷¹) as well as ß-oxidation.¹⁷² It is a moderate inhibitor of 2C9.¹⁷³ It also inhibits multiple UGTs, including 1A4, 1A9, 2B7, and 2B15,^149,151,171 as well as epoxide hydrolase, the enzyme that metabolizes the principal metabolite of carbamazepine (carbamazepine-10,11-epoxide).^137,174,175 It is unclear if valproate has any meaningful inductive capabilities. Agents that induce the metabolism of valproate through 2C9 and 2A6 (such as phenytoin) lead to the increased production of the hepatotoxic 4-ene-valproate metabolite.¹⁷⁰

DISCUSSION

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Appendix 1 lists significant drug-drug interactions involving antidepressants and other psychotropic agents. In general, these interactions involve substrate-inhibitor pairings, in which substrate blood levels are increased. For instance, the combination of fluoxetine and risperidone will lead to an average increase of 75% in the blood level of the risperidone active moiety (the combined concentrations of risperidone and its equipotent 9-hydroxy-risperidone metabolite).¹⁷⁶ Appendix 2 lists significant drug-drug interactions involving antipsychotics and other psychotropic agents. In these interactions, the antipsychotic agents generally play the role of substrates in substrate-inhibitor and/or substrate-inducer pairings. Appendix 3 lists significant drug-drug interactions involving mood stabilizers and other psychotropic agents. Because several of these agents are anticonvulsants, they are often involved as inducers of the metabolism of other agents. Lithium and valproate are notable exceptions to this generalization.

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APPENDIX 1. Significant Drug-Drug Interactions Involving Antidepressants

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APPENDIX 2. Significant Drug-Drug Interactions Involving Antipsychotics

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APPENDIX 3. Significant Drug-Drug Interactions Involving Mood Stabilizers

In all of these drug-drug interactions tables, only those interactions that are both reasonably frequent and problematic are included. For instance, the combination of lithium and haloperidol can produce an encephalopathic state,^28,177 and lithium plus fluoxetine can yield a central serotonin syndrome.^178,179 However, both of these combinations are common and well tolerated the vast majority of the time. In contrast, the combination of fluoxetine and quetiapine reliably produces increases in the peak and trough concentrations of quetiapine that are statistically significant but usually not clinically significant.¹⁸⁰ Hence, none of these drug-drug interactions are included in the tables.

Some ubiquitous nonpsychotropic agents/influences, such as tobacco (smoked) and oral contraceptives containing ethinylestradiol, create drug-drug interactions with numerous psychotropic agents. "Classic" drug-drug interactions include those between lithium and diuretics^28,181 and between acetylsalicylic acid and valproate.¹⁸² By virtue of their special importance, selected examples of such interactions have been included in Appendix 4, along with some drug-drug interactions involving other psychotropic agents (anxiolytics, caffeine, etc.).

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APPENDIX 4. Significant Drug-Drug Interactions Involving Other Psychotropic Agents and Nonpsychotropic Agents

Although reviews such as this one may prove helpful to the clinician, they also make it clear that the broad range of information on drug-drug interactions severely tests the limits of human recall. It is simply not practical to insist that memorization of all the permutations of drug-drug interactions become the standard of care. However, recognition that the clinician cannot be expected to remember all of these details is small consolation to our patients, who will be harmed by drug-drug interactions. The only reasonable approach lies in the realm of computers. We urgently need programs that will supply information on drug-drug interactions in a manner that is both complete and efficient, but development of such tools presents considerable challenges. The more complete a drug-drug interactions database is, the more nonspecific the warnings become, and this characteristic increases obstructions to physicians’ workflow. However, programs that ideally optimize completeness and efficiency might not become available for decades. In the interim, for the sake of our patients, we must somehow grapple with this imposing and evolving body of information. In that spirit, the following practical drug-drug interaction "survival tips" are offered for the busy clinician:

1) Become an "expert" on the drugs you prescribe most frequently. In absolute terms, the number of psychotropic agents is fairly modest, and most psychiatrists prescribe a limited group of 10 to 20 drugs far more often than they prescribe the remaining psychotropic agents. It is both reasonable and practical for clinicians to acquire a solid knowledge of the drug-drug interactions involving this specific subset of agents.

2) Pay special attention to agents that have a low therapeutic index (the lethal dose for 50% of the population divided by the effective dose for 50% of the population [LD₅₀/ED₅₀]). Most of the more recently developed and released psychotropics are safer in overdose than their predecessors. Thus, a drug-drug interaction that produces a significant increase in the blood level of, for instance, mirtazapine, is unlikely to yield a truly dangerous outcome.⁹⁰ However, agents such as TCAs and lithium are potentially lethal in overdose.^183,184 Accordingly, drug-drug interactions that produce significant increases in the blood levels of these agents can lead to severe morbidity and mortality. Acquiring a detailed understanding of the drug-drug interactions involving these agents will largely prevent such adverse events.

3) Consult resources frequently. Gather reliable references (articles, books, tables, computer programs, etc.) and refer to them whenever a drug-drug interaction is suspected. This vigilance serves two functions. First, it encourages a mindset in which one does not rely solely on personal powers of recall to make clinical decisions. Although such reliance is consistent with typical modes of practice and the standard of care, it is manifestly dangerous to our patients. A physician who makes frequent use of auxiliary resources is a safer clinician. Second, repeated use of these resources when dealing with actual patients in real situations is the best way to become familiar with clinically relevant drug-drug interactions.

4) Educate your patients to be their own last, best line of defense in the prevention of drug-drug interactions. Patients should be encouraged to keep a current list of all medications, over-the-counter remedies, herbal products, and pertinent dietary and lifestyle concerns (smoking, consumption of grapefruit juice or green tea, etc.), and they should present this list to all health care providers and to their pharmacist(s). In addition, they should be encouraged to have all of their prescriptions filled at the same pharmacy and specifically to enroll in that pharmacy’s drug interaction monitoring program. This precaution will greatly reduce—although not eliminate¹⁸⁵—the likelihood of a drug-drug interaction.

5) Try to select agents that minimize the risk of precipitating a drug-drug interaction. For instance, among the macrolide antibiotics, azithromycin provides similar efficacy to erythromycin and clarithromycin. However, the latter two agents are potent inhibitors of both P450 3A4 and P-glycoprotein.^186,187 Azithromycin is not a significant inhibitor of either 3A4 or P-glycoprotein,¹⁸⁸ hence it is significantly less likely than its cousins to produce drug-drug interactions. Similar arguments can be made for the antidepressants venlafaxine and mirtazapine, which are not clinically significant P450 inhibitors,^90,189 and for pravastatin and rosuvastatin, hydroxymethylglutaryl–coenzyme A reductase inhibitors that are not P450 3A4 substrates and are less likely than other agents in the class to produce toxicity because of impaired metabolism.^190,191

CONCLUSION

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The understanding of intrapsychotropic drug-drug interactions has improved dramatically in recent years. However, the amount of information can seem overwhelming, leading the clinician to either ignore the topic or withdraw into a therapeutic paralysis. In the future, it is likely that sophisticated computer programs will allow clinicians to prescribe in an efficient yet truly safe manner. Until that day arrives, we hope that this review and these recommendations will prove useful in helping psychiatrists to anticipate and avoid drug-drug interactions.

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