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 REVIEW ARTICLE

A current review of cytochrome P450 interactions of psychotropic drugs

Subramoniam Madhusoodanan, MD

St. John’s Episcopal Hospital, Far Rockaway, New York, USA, SUNY, Brooklyn, New York, USA

Umamaheswararao Velama, MD

Department of Psychiatry, St. John’s Episcopal Hospital, Far Rockaway, New York, USA

Jeniel Parmar, PhD

Ross University School Of Medicine, Commonwealth of Dominica, West Indies

Diana Goia, MD

Department of Psychiatry, St. John’s Episcopal Hospital, Far Rockaway, New York, USA

Ronald Brenner, MD

St. John’s Episcopal Hospital, Far Rockaway, New York, USA, SUNY Downstate College of Medicine, Brooklyn, New York, USA

Background: The number of psychotropic drugs has expanded tremendously over the past few decades with a proportional increase in drug-drug interactions. The majority of psychotropic agents are biotransformed by hepatic enzymes, which can lead to significant drug-drug interactions. Most drug-drug interactions of psychotropics occur at metabolic level involving the hepatic cytochrome P450 enzyme system.

Methods: We searched the National Library of Medicine, PsycINFO, and Cochrane reviews from 1981 to 2012 for original studies including clinical trials, double-blind, placebo-controlled studies, and randomized controlled trials. In addition, case reports, books, review articles, and hand-selected journals were utilized to supplement this review.

Results: Based on the clinical intensity of outcome, cytochrome interactions can be classified as severe, moderate, and mild. Severe interactions include effects that might be acutely life threatening. They are mainly inhibitory interactions with cardiovascular drugs. Moderate interactions include efficacy issues. Mild interactions include nonserious side effects, such as somnolence.

Conclusions: Psychotropic drugs may interact with other prescribed medications used to treat concomitant medical illnesses. A thorough understanding of the most prescribed medications and patient education will help reduce the likelihood of potentially fatal drug-drug interactions.

Keywords: cytochrome P450, interactions, psychotropic drugs

ANNALS OF CLINICAL PSYCHIATRY 2014;26(2):120-138

  Introduction

The number of psychotropic drugs has expanded tremendously over the past few decades with a proportional increase in drug-drug interactions.1,2 Treatment of comorbid psychiatric or other medical conditions often necessitates combined use of psychotropic and non-psychotropic drugs, the former being metabolized primarily by the cytochrome CYP450 enzyme system (CYP450). These drugs can serve as substrates, inducers, and/or inhibitors of the CYP450 enzymes. The ultimate challenge for most psychiatrists is to understand the drug metabolism and prevent serious drug interactions.

The CYP450s are a super-family of oxidative enzymes that are essential for oxidative metabolism of endogenous and exogenous therapeutic compounds.3 The majority of CYP450s are located on the endoplasmic reticulum of the hepatocytes designated as the microsomal type. A small percentage also are found on the inner mitochondrial membranes of the adrenocortical cells designated as the mitochondrial type. When microsomal fractions from different organs are processed, investigators have found that the hepatocytes contain the highest amount of CYP450s, followed by enterocytes and adrenocortical cells.4,5 The liver is the primary site for these enzymes and the location where most psychotropic drugs are metabolized.6,7

CYP450s such as CYP1A2, CYP3A4, CYP2C19, and CYP2D6 have the largest substrate population and are responsible for the majority of psychotropic drug-drug interactions8 (TABLE 12,9-17). Although each enzyme has a specific gene responsible for individual messenger ribonucleic acid expression, these enzymes possess a broad spectrum of substrate selection.18,19 In other words, CYP450s have redundancy and ambiguity; they share specific substrates and each enzyme has multiple substrates. They also have interindividual variability in terms of quantity and activity. Hence, biotransformation of any given drug will vary largely, depending on the concentration of these enzymes and their level of activity. Drug metabolism is divided into 2 phases: phase I and phase II. We will discuss these phases in greater detail under pathophysiological considerations.


TABLE 1

Substrates, inhibitors, and inducers of major cytochrome isozymes for psychotropic drugs

Enzyme Substrate Inhibitors Inducers
CYP2D6 Antipsychotics: Fluphenazine, perphenazine, thioridazine, haloperidol, chlorpromazine, clozapine, risperidone, olanzapine, aripiprazole, iloperidone, zuclopenthixol
Antidepressants: Citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, amitriptyline, nortriptyline, clomipramine, desipramine, imipramine, mirtazapine, venlafaxine
Bupropion
Duloxetine
Paroxetine
Fluoxetine
None known
CYP3A4 Antipsychotics: Haloperidol, pimozide, clozapine, risperidone, quetiapine, ziprasidone, aripiprazole, iloperidone, lurasidone
Antidepressants: Citalopram, escitalopram, amitriptyline, clomipramine, imipramine, mirtazapine, nefazodone, sertraline, venlafaxine
Anxiolytics: Alprazolam, clonazepam, diazepam, buspiron
Sedatives/hypnotics: Zolpidem, zaleplon, flurazepam, triazolam
Nefazodone Carbamazepine
CYP1A2 Antipsychotics: Haloperidol, chlorpromazine, perphenazine, thioridazine, clozapine, olanzapine, asenapine, pimozide, loxapine, thiothixene, trifluoperazine
Antidepressants: Fluvoxamine, amitriptyline, clomipramine, imipramine, duloxetine, mirtazapine
Fluvoxamine Carbamazepine
CYP2C9 Valproic acid Fluoxetine
Fluvoxamine
Carbamazepine
CYP2C19 Antipsychotics: Clozapine
Antidepressants: Citalopram, escitalopram, clomipramine, imipramine, amitriptyline
Fluvoxamine Carbamazepine
Source: References 2,9-17.

Our review focuses on the psychotropic drug interactions involving the CYP450 system. These interactions are quite common and contribute significantly to increased hospital admissions, treatment failures, and an increased financial burden to the health care system.20-22 Yet clinicians frequently overlook these drug-drug interactions, causing morbidity and mortality from drug-drug interactions to escalate.23 Therapeutic management of psychiatric disorders such as schizophrenia, major depressive disorder, bipolar disorders, anxiety, dementia, sleep disorders, and pain depend largely on psychopharmacological agents.24 Antipsychotics, antidepressants, mood stabilizers, and anxiolytics comprise the major group of psychotropic drugs that frequently are used by psychiatrists, emergency physicians, and primary care physicians. Therefore, clinicians need to be aware of potential drug-drug interaction to avoid iatrogenic accidents.25

Pathophysiological considerations

Pharmacokinetic interactions represent the effect of a drug on another drug’s absorption, distribution, metabolism, or excretion. They are determined by the quantity of active drug that reaches its site of action after the addition of another drug. Pharmacokinetic processes are catalyzed by various enzyme systems and are divided into phase I and phase II reactions.26 The most important interactions in pharmacokinetics occur at the metabolic level, by phase I enzymes. Psychotropic drugs initially are subjected to phase I metabolism.

Phase I reactions occur primarily in the endoplasmic reticulum of hepatic cells. These reactions may occur by oxidation, cyclization, reduction, hydrolysis, and decyclization. The most important enzymes that carry out these reactions are called mixed function oxidases. They typically involve a cytochrome CYP450 monooxygenase, nicotinamide adenine dinucleotide phosphate oxidase (NADPH), and oxygen. These reactions can convert a pharmacologically inactive compound—a prodrug, such as carbamazepine, for example—into a pharmacologically active compound such as carbamazepine-10,11-epoxide.27 Phase I reactions generally lead to loss of pharmacological activity for antidepressants, antipsychotics, and many other drugs. CYP450 enzymes turn drugs more hydrophilic, thus rendering them partially or completely inactive. Most psychotropic drugs are insufficiently hydrophilic at phase I to be excreted by the kidneys and therefore require further modifications. The most prominent phase I enzymatic family is cytochrome P450s.

Drugs that are metabolised by a particular CYP450 enzyme are called substrates. For example, nortriptyline is metabolized primarily by CYP450 2D6, and is therefore a substrate of this enzyme.28 Enzyme inhibitors impair the ability of specific CYP450s to metabolize their target substrates by competing for the same enzyme binding site. This leads to a decrease in the rate of hepatic biotransformation of drugs, causing increased serum concentration and toxicity.29 If fluvoxamine, a CYP2C19 inhibitor, and diazepam, a substrate for this enzyme, are administered together, plasma diazepam will increase, leading to potential clinical toxicity (TABLE 22,10,12,13,16,17). Competitive inhibition occurs within 24 hours following ingestion of the inhibiting drug. It is dose dependent and the time to reach maximal inhibition depends on the half-life of the substrate and the inhibiting agent.29


TABLE 2

Major cytochrome-based interactions of anxiolytics

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
Alprazolam CYP3A4 + - - Propoxyphene and ketoconazole Increased level of alprazolam
Diazepam CYP3A4 + - - Ketoconazole Increased level of diazepam
CYP2C19 + - - Barbiturates and carbamazepine
Fluoxamine
Decreased level of diazepam
Increased level of diazepam
Clonazepam CYP3A4 + - - Ketoconazole and nefazodone Increased level of clonazepam
Chlordiazepoxide CYP3A4 + - - Grapefruit juice Increased level of chlordiazepoxide
Buspirone CYP3A4 + - - Grapefruit juice and nefazodone Increased level of buspirone
Source: References 2,10,12,13,16,17.

Inhibition of an enzyme can be reversible or irreversible, the latter being the most common type. Irreversible inhibition occurs when the inhibitor and the substrate compete for the same binding site on the CYP450 enzyme. The strength of the bond between the enzyme and the drug determines the potency of the inhibitor. Irreversible inhibition is caused by reactive metabolites generated from CYP-catalyzed reactions that in turn bind tightly to the CYP450 enzyme and render it inactive. Erythromycin is one example of this reaction. The metabolite produced binds tightly to CYP3A4, forming a stable complex that inactivates the enzyme. As a result, erythromycin inhibits a number of drug oxidation reactions catalyzed by CYP3A4.30

Conversely enzyme inducers increase the metabolism of CYP450 substrates by increasing the production of the particular CYP450. Carbamazepine is a CYP3A4 inducer. Coadministration of carbamazepine with risperidone, which is a substrate of the same enzyme, can result in decreased plasma risperidone and possibly loss of its clinical efficacy (TABLE 32,10,12,13,16,17,31-33).


TABLE 3

Cytochrome-based interactions of mood stabilizers

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
Carbamazepine CYP3A4 + + - Aripiprazole, risperidone, quetiapine, and ziprasidone Decreased levels of these antipsychotics
CYP1A2 + + - Clozapine and olanzapine Decreased levels of these drugs
CYP2C9 - + - Sertraline Decreased level of sertraline
CYP2C19 - + + Phenytoin Increased level of phenytoin
CYP2B6 - + - Bupropion Decreased level of bupropion
Valproate CYP2C19 + - - Carbamazepine Increased level of valproate metabolite
CYP2C9 + - + Phenytoin Increased level of phenytoin
Topiramate CYP3A4 - - + Carbamazepine Decreased level of carbamazepine
CYP2C19 - - + Phenytoin Increased level of phenytoin
Oxcarbazepine CYP2C19 - - + Phenytoin Increased level of phenytoin
Source: References 2,10,12,13,16,17,31-33.

Enzyme induction is a slow process and is dose- and time-dependent. The extent of induction is proportional to the dose of the inducing agent. This process occurs with some delay after exposure to the inducing agent, usually from a few days to 2 weeks, because it requires synthesis of the new enzyme.34,35 When the patient stops taking the inducing agent, the time frame for deinduction is similarly gradual. It depends both on the kinetics of the drug and half life of the CYP450, and ranges from 1 to 6 days.29,36,37 Usually it takes 4 to 14 days for peak induction. After discontinuing the inducer, the CYP450 returns to its original level in 1 to 3 weeks.38

As a result of these interactions, plasma concentrations of coadministered drugs may increase or decrease. This can lead to toxicity or diminished therapeutic effects. Therefore clinicians may have to adjust dosage to balance these interactions.

The second metabolic system implicated in drug-drug interactions is phase II metabolism. Phase II reactions involve conjugation and take place in the cell’s cytoplasmic matrix. They involve interactions between polar functional groups of phase I metabolites. Sites on drugs where conjugation reactions occur include carboxyl (COOH), hydroxyl (OH), amino (NH2), and sulfhydryl (SH) groups. Products of conjugation reactions tend to be less active than their substrates, unlike phase I reactions, which often produce active metabolites. Phase II conjugation makes phase I metabolites more hydrophilic and therefore more readily excretable. For this reason, phase II drug-drug interactions are not as significant as the CYP450 interactions.28

Phase II metabolism, which also occurs in the liver, follows phase I metabolism. A prodrug, codeine, is metabolized initially by CYP2D6 to its active metabolite, morphine. This takes place during a phase I reaction. Morphine is converted later to its inactive metabolite, morphine 3-O-glucuronide by uridine diphosphate glucoronosyltransferase 1 family, polypeptide A1 (UGT1A1) enzyme. This is considered a phase II reaction.39 The most significant enzymatic family that carries out phase II reactions is the uridine 5’-diphosphate glucuronosyltransferases (UGTs). UGTs are identified by a number-letter-number scheme (1A1, 1A4, 2B7, 2B15, etc.). Similar to the CYP450 system, UGT enzymes have their own substrates, inhibitors, and inducers. Several drugs, including lamotrigine, olanzapine, and many narcotic analgesics, are metabolised primarily by the UGTs.2

Pharmacogenetics

Since introduction of psychotropic drugs such as tricyclic antidepressants (TCAs) and monamine oxidase inhibitors, researchers have discovered that plasma concentration of these drugs vary tremendously among patients given the same dose.40 This perplexing phenomenon is because of variation in the activity of CYP450s.41 Pharmacogenetics focuses on the study of the effects of DNA on drug response, which has revealed tremendous inter-individual genetic variation that alters gene expression leading to changes in enzyme production.

Several CYP450 isoforms exist in a given population because a variable number of alleles are spontaneously generated from genetic mutations.42 Among others, single nucleotide polymorphisms (SNPs) and copy number variabilities (CNVs) are the 2 genetic mutations that can alter a patient’s response to a given drug.43,44 These mutations can generate isoforms of CYP450s with higher, lower, or similar activity as the parent enzyme.45 Numerous diseases are caused by genetic mutations, and >60% of these diseases involve SNPs.46 A single nucleotide base pair is changed compared with the normal population, and must be observed in at least 1% of the population to be identified as an SNP.47 Importantly, the majority of the CYP450 genes encoding enzymes contain SNPs. SNPs of CYP450 genes can cause either accelerated or diminished metabolism of a substrate. Patients with a specific SNP leading to accelerated metabolism of a substrate are classified as ultra-rapid metabolizers (UM), and those with SNPs leading to diminished metabolism of a substrate are classified as poor metabolizers (PMs).48 Normal metabolizers (NM) have expected levels of substrate metabolism. Therefore, a particular genotype can dictate an appropriate phenotype depending on the SNPs of the CYP450 gene. Interestingly, NMs exposed to a particular CYP450 inhibitor will appear clinically similar to PMs not exposed to CYP450 inhibitors.

Combinations of different in vitro methods have been used to identify accurately the CYP450 isozyme responsible for metabolizing a particular drug. These methods include metabolism by microsome derived from cDNA-expressed enzyme, use of selective inhibitors with microsomes, immunoinhibition of CYP by isoform-specific anti-P450 antibodies in microsomes, and correlation of drug candidate metabolites formation with several isoform-specific P450 activities in a panel of liver microsomes. A combination of the above approaches is required to accurately pinpoint a specific enzyme.49

Diagnostic genotyping tests for certain CYP450 enzymes are now available. The AmpliChipTM CYP450 test (Roche Molecular Systems, Inc.) is the first pharmacogenetic clinical tool that has been introduced into clinical practice and is a major step toward introducing personalized prescribing into the clinical environment. It is based on microarray technology used to analyze a patient’s genome for CYP2D6 and CYP2C19 genes.50 It has a low DNA concentration detection limit, which means practitioners can use samples of bucal swabs, saliva, or whole blood to collect the DNA. It classifies individuals into 2 CYP2C19 phenotypes (extensive metabolizers [EM] and PM) associated with 3 tested alleles from the DNA sample. It also can test for 27 alleles associated with 4 CYP2D6 phenotypes (UM, EM, PM, intermediate metabolizers [IM]). It is FDA approved “based on results of a study conducted by the manufacturers of hundreds of DNA samples as well as on a broad range of supporting peer reviewed literature.” According to FDA, “Information about CYP2D6 genotype may be used as an aid to clinicians in determining therapeutic strategy and treatment doses for therapeutics that are metabolized by the CYP2D6 product.” Costs for an individual sample range from $250 to $500, depending on the number of alleles tested. It is not covered by insurance companies and patients have to meet the expenses,51,52 which explains why it is not commonly used in the United States.

Major drug metabolizing enzymes: Cytochrome P450 isoenzymes

The cytochrome P450 system is a superfamily of isoenzymes. The substrates of CYP450s include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances such as drugs and other toxic chemicals. The metabolism of a substrate by a CYP450 consumes 1 molecule of oxygen and produces an oxidized substrate plus 1 molecule of oxygen as a byproduct. For this reason, they are called mixed function oxidases. One CYP450 isoenzyme can work on multiple substrates, and they also are called polysubstrate monooxygenases. The most common reaction catalysed by CYP450 is a monooxygenase reaction. It involves the insertion of 1 atom of oxygen into a parent drug (RH) while the other oxygen atom is reduced to water: NADPH + H+ + (O2)O2 + RH → NADP+ + H2O + R-OH, where the R-OH is the oxidized product.53

CYP450 nomenclature was proposed by Nebert et al.54 Cytochrome P450 isoenzymes are assigned the letters “CYP” followed by an Arabic numeral, a letter, and another Arabic numeral. “P” in cytochrome P450 stands for “pigment.” The number 450 represents the wavelength of maximum absorption of the enzyme when it is in a reduced state and combined with carbon monoxide. Each enzyme is transcribed by related genes and is called an isoform. These enzymes are grouped based on their common amino acid sequence in families, subfamilies, and individual genes.

There are 21 families (CYP2, CYP3 etc.) described in humans. They are grouped based on 40% amino acid sequence homology. There are 20 subfamilies described (CYP2D, CYP3A, for example). They must have 55% amino acid sequence homology to be grouped as members of the same family. There are 57 individual genes described in humans.55

Of the 21 families, CYP450 1, 2, and 3 are the most predominant and account for 70% of the total hepatic CYP450 content. They also are responsible for 94% of the drug metabolism in the liver.56

Besides enzyme induction and enzyme inhibition, discussed previously, another reason for drug-drug interaction is overlapping of substrate specificities by the CYP450s. Elevated plasma levels of 1 of 2 coadministered drugs can result when those 2 drugs compete for the same enzyme’s active site. This competition may result in the inhibition of metabolism of either of the 2 drugs and can cause unwanted toxicities.57

CYP1A2 is located in the endoplasmic reticulum of liver cells and it accounts for 13% of the total hepatic content of isoenzymes.58 CYP1A2 can be induced by polycyclic aromatic hydrocarbons found in charbroiled foods and cigarette smoke.59 This is the only P450 isoform that cigarette smoke acts on, and so it can increase its synthesis threefold.59 Certain spices such as cumin and turmeric used in curry dishes seem to lower the level of this enzyme. Lower levels of CYP1A2 have been found in South Asians.60 TABLE 12,9-17 shows the substrates, inducers, and inhibitors of CYP1A2.

CYP2C9 makes up about 20% of the cytochrome P450 protein in liver microsomes.61 Many therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such as warfarin and phenytoin. CYP2C9 exhibits genetic polymorphism. Approximately 3% to 5% of whites are PMs of this enzyme, as well as 18% to 23% of the Asian population.62 TABLE 12,9-17 shows the substrates, inducers, and inhibitors of CYP2C9.

CYP2C19 also exhibits polymorphism. About 20% of Asians, 3% to 5% of whites,and 20% of Japanese are PMs of this enzyme.63,64 TABLE 12,9-17 shows the substrates, inhibitors, and inducers of CYP2C19.

CYP2D6 is one of the most important enzymes involved in the metabolism of xenobiotics. The gene is located near 2 cytochrome P450 pseudogenes on chromosome 22q13.1 and it exhibits polymorphism.65 It is known to metabolize as many as 20% of commonly prescribed drugs.66 Seven percent to 10% of whites are PMs of this enzyme.67 Five percent to 10% Mexican-Americans and 1% to 2% of Asians lack this enzyme and are characterized as PMs.68,69 Unlike most other CYP450 enzymes, CYP2D6 is not very susceptible to enzyme induction.70 Several antipsychotics such as haloperidol, clozapine, risperidone, and olanzapine are metabolized by CYP2D6. As a result, PMs of antipsychotic drugs are at risk for side effects such as postural hypotension and extrapyramidal side effects. TABLE 12,9-17 lists the substrates and inhibitors of CYP2D6.

Of the total CYP450 content in the liver, only 7% represents the CYP2E1 enzyme. CYP2E1, along with alcohol dehydrogenase and aldehyde dehydrogenase, converts ethanol into acetaldehyde. Although its role in nonalcoholics is minor, CYP2E1 has a major metabolic role in chronic alcoholics because it is induced by ethanol. An association between CYP2E1 polymorphism and alcoholic liver disease has been reported.71 This isoform also is responsible for the metabolism of acetaminophen.

CYP3A4 represents 30% of the total hepatic content and 70% of intestinal wall CYP450 content.72 Intestinal CYP3A4 metabolism and P-glycoprotein efflux of an absorbed drug are the major determinants of an orally administered drug’s dose that reaches the systemic circulation.73,74 CYP3A4 does not exhibit genetic polymorphism.75 The endogenous compounds metabolized by CYP3A4 include progesterone, estradiol, testosterone, and cortisol. Psychotropic drugs metabolized by CYP3A4 include many antipsychotics, antidepressants, and some benzodiazepides. Inhibitors include grapefruit juice and nefazodone. Inducers include carbamazepine, and St. John’s wort (TABLE 12,9-17 and TABLE 42,10,12,13,16,17,54,76-80). Inhibition of CYP450s by various endogenous and exogenous compounds appears to be responsible for the majority of serious drug-drug interactions. Pharmacokinetics of both the substrate and inhibitor ultimately determine the total inhibitory effects.81


TABLE 4

Major cytochrome-based interactions of herbal and food products

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
St. John’s wort CYP3A4 - + - Buspirone and statins Decreased levels of these drugs
CYP1A2 - + - Clozapine and olanzapine Decreased levels of these drugs
CYP2C9 - + - Valproic acid Decreased level of valproic acid
Ginkgo biloba CYP2C9 - - + S-warfarin Increased level of s-warfarin
Grapefruit juice CYP3A4 - - + Aripiprazole and alprazolam Increased levels of these drugs
Star fruit juice CYP3A4 - - + Atorvastatin and alprazolam Increased levels of these drugs
Cranberry juice CYP2C9 - - + S-warfarin Increased level of s-warfarin
CYP3A4 - - + Midazolam Increased level of midazolam
Caffeine CYP1A2 + - + Clozapine, olanzapine, and fluvoxamine Increased levels of these drugs
Source: References 2,10,12,13,16,17,54,76-80.
Intensity-based classification of CYP interactions

Based on the clinical intensity of outcome, we have classified cytochrome interactions as severe, moderate, and mild.

Severe interactions (TABLE 5) include effects that may be acutely life-threatening. They are mainly inhibitory interactions with cardiovascular drugs. Coadministration of metoprolol, carvedilol, verapamil, losartan, or mexiletine with fluoxetine, fluvoxamine, paroxetine, or duloxetine causing life-threatening bradycardia or arrythmias are examples of severe interactions. Similarly coadministration of fluvoxamine and warfarin can lead to severe bleeding. Several medications such as cesapride, astemizole, nefazodone, and sertindole have been withdrawn from the market because of severe cytochrome interaction potential.


TABLE 5

Outcome-based classification of severe psychotropic CYP interactions

Involved drugs Involved CYP isozymes Mechanism Outcome
1. Fluoxetine and paroxetine CYP2D6 Inhibitors Severe bradycardia, atrioventricular block
Metoprolol CYP2D6 and CYP3A4 Substrate
2. Fluvoxamine CYP1A2, CYP2C19 and CYP2C9 Inhibitor Increase in INR and risk of severe bleeding
Warfarin CYP1A2, CYP3A4, CYP2C9 and CYP2C19 Substrate
3. Fluoxetine and paroxetine CYP2D6 Inhibitors Pathologic bradycardia and hypotension
Carvedilol CYP2D6 and CYP2C9 Substrate
4. Duloxetine, fluoxetine, and paroxetine CYP2D6 Inhibitors Rebound arrhythmias, ataxia, nausea, vomiting, and heartburn
Mexiletine CYP2D6 and CYP1A2 Substrate
5. Fluvoxamine CYP1A2 and CYP2C9 Inhibitor Bradycardia, hypotension, and cardiac arrhythmias
Verapamil CYP1A2, CYP3A4 and CYP2C9 Substrate
6. Fluvoxamine CYP2C9 Inhibitor Hypotension, severe dizziness, and fainting
Losartan CYP2C9 and CYP3A4 Substrate
INR: international normalized ratio.

Moderate interactions (TABLE 6) include efficacy issues such as failure of anticonvulsants from coadministration of fluvoxamine and primidone, failure of cancer drugs such as tamoxifen with duloxetine and failure of therapeutic action of drugs that are metabolized by cytochrome inducers such as carbamazapine or rifampin. Coadministration of pioglitazone (anti-diabetic, a potent CYP3A4 inducer) with clozapine (a CYP3A4 substrate) could cause a marked decrease in plasma clozapine, reducing the antipsychotic’s efficacy.82,83 Simultaneous administration of prednisone (a potent CYP2C19 inducer) with citalopram (a CYP2C19 substrate) can cause suboptimal citalopram levels leading to failure of antidepressive treatment.84


TABLE 6

Outcome-based classification of moderate psychotropic CYP interactions

Involved drugs Involved CYP isozymes Mechanism Outcome
1. Duloxetine, fluoxetine, and paroxetine CYP2D6 Inhibitors Failure of breast cancer therapy
Tamoxifen CYP2D6, CYP3A4, and CYP2C9 Substrate
2. Fluvoxamine CYP2C19 Inhibitor Failure of anticonvulsant therapy
Primidone CYP2C19 Substrate
3. Pioglitazone CYP3A4 Inducer Decreased antipsychotic therapeutic efficacy
Clozapine CYP1A2, CYP3A4, CYP2D6, and CYP2C19 Substrate
4. Prednisone and rifampin CYP2C19 Inducers Failure of antidepressive treatment
Citalopram and escitalopram CYP2C19, CYP3A4, and CYP2D6 Substrates
5. Smoking and St. John’s wort CYP1A2 Inducers Decreased antipsychotic therapeutic efficacy
Clozapine CYP1A2, CYP3A4, CYP2D6, and CYP2C19 Substrate

Mild interactions (TABLE 7) include minor efficacy issues such as coadministration of erythromycin and benzodiazapines leading to somnolence, paroxetine and hydrocodone causing reduction in analgesic effect or fluvoxamine and caffeine causing anxiety and palpitation.


TABLE 7

Outcome-based classification of mild psychotropic CYP interactions

Involved drugs Involved CYP isozymes Mechanism Outcome
1. Erythromycin CYP3A4 Inhibitor Somnolence, headache, and nausea
Hypnotic sedatives CYP3A4 Substrates
2. Paroxetine and fluoxetine CYP2D6 Inhibitors Marked reduction in analgesic effect
Hydrocodone CYP2D6 Substrate
3. Fluvoxamine CYP1A2 Inhibitor Anxiety and palpitation
Caffeine CYP1A2 Substrate
Selected interactions of prescription drugs due to CYP inhibition

CYP450 inhibition could decrease the metabolism and reduce clearance of psychotropic drugs, leading to increased plasma levels of a drug, increased duration of action, and bioavailability, and risk of adverse effects from drug toxicity.85 Sansone and Sansone86 showed that coadministration of fluvoxamine (a potent CYP1A2 inhibitor) with warfarin (a CYP1A2 substrate) causes a larger than expected increase in international normalized ratio (INR)—prolonged prothrombin time (PT). This leads to augmented risk of bleeding as a result of increased plasma warfarin (TABLE 82,10,12,13,16,17,82-84). Administration of fluoxetine (a potent CYP2D6 inhibitor) with carvedilol (a CYP2D6 substrate) can cause bradycardia and hypotension from increased plasma carvedilol.90-92


TABLE 8

Major cytochrome-based interactions of SSRI and SNRI antidepressants

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
Selective serotonin reuptake inhibitors
Citalopram CYP2C19 + - - Carbamazepine and rifampin Decreased level of citalopram
CYP3A4 + - - Ketoconazole and ritonavir Increased level of citalopram
CYP2D6 + - - Quinidine and bupropion Increased level of citalopram
Escitalopram CYP2C19 + - - Carbamazepine and rifampin Decreased level of escitalopram
CYP3A4 + - - Grapefruit juice and ritonavir Increased level of escitalopram
CYP2D6 + - - Quinidine and bupropion Increased level of escitalopram
Fluoxetine CYP2D6 + - ++ Risperidone and aripiprazole Increased levels of these drugs
CYP2C9 + - + S-warfarin and valproic acid Increased levels of these drugs
CYP2C19 + - + Omeprazole and amitriptyline Increased levels of these drugs
CYP3A4 + - + Statins and nifedipine Increased levels of these drugs
Fluvoxamine CYP2D6 + - + Risperidone and aripiprazole Increased levels of these drugs
CYP1A2 + - ++ Clozapine and olanzapine Increased levels of these drugs
CYP2C19 - - ++ Omeprazole and amitriptyline Increased levels of these drugs
CYP2C9 - - + S-warfarin and valproic acid Increased levels of these drugs
CYP3A4 - - + Statins and nifedipine Increased levels of these drugs
Paroxetine CYP2D6 + - ++ Risperidone and aripiprazole Increased levels of these drugs
CYP3A4 + - + Statins and nifedipine Increased levels of these drugs
CYP1A2 - - + Clozapine and olanzapine Increased levels of these drugs
CYP2C9 - - + S-warfarin and valproic acid Increased levels of these drugs
CYP2C19 - - + Omeprazole and amitriptyline Increased levels of these drugs
Sertraline CYP2C9 + - + Barbiturates and carbamazepine Decreased level of sertraline
CYP2C19 + - + Omeprazole and amitriptyline Increased levels of these drugs
CYP3A4 + - + Statins and nifedipine Increased levels of these drugs
CYP1A2 - - + Clozapine and olanzapine Increased levels of these drugs
CYP2D6 - - + Risperidone and aripiprazole Increased levels of these drugs
Serotonin-norepinephrine reuptake inhibitors
Duloxetine CYP2D6 + - + Bupropion and quinidine Increased level of duloxetine
CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of duloxetine
Venlafaxine CYP2D6 + - - Bupropion and quinidine Increased level of venlafaxine
+ indicates mild to moderate inhibitors
++ indicates strong inhibitors.
Source: References 2,10,12,13,16,17,82-84.

According to the Institute for Healthcare Informatics, Vicodin (a combination of acetaminophen and hydrocodone) was the most prescribed drug of 2011 in the United States.93-95 Hydrocodone, a prodrug, is converted to morphine (active drug) by CYP2D6.96 Analgesics often are administered simultaneously to patients with psychiatric disorders. A marked reduction in analgesic effect was noted when paroxetine (a CYP2D6 inhibitor) was coadministered with hydrocodone (prodrug, a CYP2D6 substrate) in a patient with major depressive disorder.97,98 Crewe et al87 pretreated healthy volunteers with paroxetine (potent CYP2D6 inhibitor) and then treated the volunteers with tamadol or codeine (prodrug) and found significantly reduced blood concentration of the active metabolite of tramadol and decreased analgesic activity in electric pain stimulation tests.

Similarly, inhibition of CYP2C19 may reduce the conversion of primidone (prodrug) into phenobarbital (active drug) leading to reduced concentration of phenobarbital and failure of anticonvulsant therapy. Hence, clinicians should administer primidone cautiously with fluvoxamine (a potent CYP2C19 inhibitor).99 Tamoxifen is utilized frequently to treat estrogen receptor positive breast cancers. Tamoxifen also is a prodrug that is converted to endoxifen by CYP2D6. Therefore simultaneous administration of duloxetine (a CYP2D6 inhibitor) can cause failure of tamoxifen action and therefore a dose adjustment may be required.100,101 Macrolides, noticeably erythromycin, are inhibitors of CYP3A4.102 Simultaneous administration of erythromycin with midazolam and other benzodiazepines have led to higher than expected levels of these agents, causing an increase in adverse effects such as somnolence, headache, and nausea.103

Cardiovascular diseases in patients with psychiatric disorders require special attention, as potential side effects can exacerbate the condition quickly. Several selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibits are potent inhibitors of CYP450s, and have a high potential to interact with commonly prescribed cardiovascular drugs such as anti-arrhythmics, anti-coagulants, and lipid lowering drugs.104 For example, co-administration of mexiletine (a CYP2D6 substrate) and duloxetine (a CYP2D6 inhibitor) can increase plasma mexiletine, which in turn can cause serious adverse reactions such as rebound arrhythmias, ataxia, nausea, vomiting, and heartburn.86,105-107 Beta blockers (carvedilol, a CYP2D6 substrate), calcium channel blockers (verapamil, a CYP1A2 substrate), and angiotension receptor blockers (losartan, a CYP2C9 substrate), when concurrently administered with fluoxetine, paroxetine, or fluvoxamine, which are inhibitors of the respective enzymes, can lead to excessive concentrations of the individual cardiovascular drugs.108,109

Selected interactions of prescription drugs due to CYP induction

A CYP450 inducer drug coadministered with a prodrug can cause rapid conversion of the prodrug into the active metabolite, leading to rapid increase in plasma concentration of the active metabolites. A randomized crossover study by Nichols et al110 showed that risperidone and venlafaxine are converted into active metabolites—paliperidone and desvenlafaxine, respectively. Both are substrates of CYP2D6 and CYP3A4.110,111 Therefore, combining rifampin and phenytoin, which are inducers of these enzymes, can cause accelerated activation of prdrugs, leading to elevated plasma concentration of the metabolites.112 Another interesting interaction is possible between ethinylestradiol (EE) and psychotropic drugs. EE is an orally ingested synthetic derivative of estrogen metabolized by CYP3A4.113 EE is utilized in most formulations of combined oral contraceptive pills. Clinicians need to monitor any drug-drug interaction that may lead to unintended pregnancies and/or breakthrough bleeding episodes. Commonly prescribed anti-epileptic drugs such as barbiturates, carbamazepine, and phenytoin can cause a strong induction of CYP3A4 that can accelerate the breakdown of EE and reduce plasma EE levels, causing loss of contraceptive effect.114,115

Selected interactions by dietary supplements, OTC substances and natural products

Also consider drug-drug interactions caused by dietary supplements.1 Approximately two-thirds of patients do not readily report their use of dietary supplements. Drug-drug interactions of other medications including over-the-counter (OTC) substances, non-prescribed medications, natural products, and dietary food products are listed in TABLE 4.2,10,12,13,16,17,54,76-80 According to the National Center for Complementary and Alternative Medicine (NCCAM), natural products including herbals, minerals, vitamins, amino acids, and plant extracts are considered dietary supplements.116,117 Such supplements have been shown to antagonize or augment the pharmacokinetic properties of psychotropic drugs.118 The array of in-vitro, in-vivo, and clinical trials required for the approval of a prescription drug are not required for dietary supplements.119 Thus the safety and efficacy of these substances remain largely unexplored. These dietary supplements contain variable amounts of the respective products. Batches from the same company are available in different concentrations.120,121 According to NCCAM, 1 out of 4 patients takes dietary supplements along with their prescribed drugs and 2 out of 3 of these patients do not voluntarily inform their physicians about their the supplements they take. Some of these supplements have significant pharmacologic action that can affect the pharmacokinetics of psychotropic drugs.118 Concurrent administration of grapefruit juice (a significant CYP3A4 inhibitor) with apriprazole (a CYP3A4 substrate) can increase plasma aripripazole122-126 (TABLE 42,10,12,13,16,17,54,76-80).

St. John’s wort is one of the most important herbal products with regard to drug-drug interactions.127-133 Double-blind, placebo-controlled studies have shown that St. John’s wort is a potent CYP3A4 inducer and a mild inducer of CYP2C9 and CYP1A2128,134,135 (TABLE 42,10,12,13,16,17,54,76-80). Psychotropic drugs are metabolized largely by these enzymes and therefore, their induction can decrease psychotropic drug levels if taken simultaneously. Many of the TCAs, benzodiazepines, and antipsychotics are metabolized primarily by CYP3A4 and if a patient on these medications takes St. John’s wort, the psychotropic drug may prove ineffective136-138 (TABLE 42,10,12,13,16,17,54,76-80). Cardiovascular complications such as congestive heart failure and cardiac arrhythmias require many drugs with narrow therapeutic index; therefore, we advise special caution if administered with St. John’s wort.139 A marked decrease in the plasma levels of verapamil and statins has been reported with concurrent use of St. John’s wort in patients with cardiovascular diseases.140,141

Toxic levels of acetaminophen (a CYP1A2 substrate) can occur with concomitant administration of fluvoxamine142 (a CYP1A2 inhibitor) (TABLE 92,9,10,12,13,16,17). Meta-analysis of randomized controlled trials has proven that acetaminophen in excess of 4 g within 24 hours can cause hepatotoxicity.143,144 The majority of acetaminophen in the liver is conjugated by glucuronidation or sulfation to an inactive, readily excreted compound. Less than 5% of acetaminophen is subject to metabolism by CYP2E1145,146 (TABLE 92,9,10,12,13,16,17). The CYP2E1 metabolized compound is called N-acetyl-para-benzoquinoneimine (NAPQI), which is highly active and hepatotoxic.147 Many depressed patients on SSRIs self-medicate with higher than average doses of acetaminophen and alcohol, an especially dangerous scenario in light of the fact that chronic alcohol consumption causes induction in liver enzymes while acute large consumption of alcohol causes alcoholic steato-hepatitis leading to inhibition of liver enzymes. In addition, alcohol is an inducer of CYP2E1, which increases the production of NAPQI and therefore is hepatotoxic.148-150 Patients should cautiously combine acetaminophen-containing products with alcohol.151


TABLE 9

Major cytochrome-based interactions of over-the-counter drugs

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
Acetaminophen CYP2E1 + - - Isoniazid and ethanol Decreased level of acetaminophen
Ibuprofen CYP2C9 + - - Fluvoxamine and fluconazole Increased level of ibuprofen
Naproxen CYP2C9 + - - Fluoxetine and fluvoxamine Increased level of naproxen
Dextromethorphan CYP2D6 + - - Bupropion and fluoxetine Increased level of dextromethorphan
CYP3A4 + - - Carbamazepine and barbiturates Decreased level of dextromethorphan
Source: References 2,9,10,12,13,16,17.

Although we found that the interaction of psychotropic drugs with non-steroidal anti-inflammatory drugs (NSAID) was infrequent, there were studies that advised caution.152,153 Defromont et al152 show that antidepressants that inhibit many of the CYP450s interact with NSAIDs (TABLE 92,9,10,12,13,16,17). NSAIDs have an anti-platelet effect and therefore excessive plasma levels of these drugs lead to bleeding episodes.154 NSAIDs are substrates of CYP2C9, which can be inhibited by fluvoxamine and paroxetine causing potential bleeding episodes.155,156

Caffeine presents a challenging conundrum since it is metabolized by CYP1A2 and it inhibits CYP1A2157 (TABLE 42,10,12,13,16,17,54,76-80). There are several reports of caffeine interacting with psychotropic drugs.158,159 Plasma clozapine has been shown to increase with caffeine consumption, presumably through inhibition of CYP1A2.160-162 Any inhibitor of CYP1A2 (such as fluvoxamine) would cause decreased breakdown of caffeine leading to augmentation of caffeine’s effects. Anxiety, tachycardia, palpitation, agitation, irritation, and diuresis are side effects of caffeine that have been reported with excessive plasma caffeine levels.

Grapefruit juice causes CYP3A4 inhibition, not the liver isoform (TABLE 42,10,12,13,16,17,54,76-80), but the enzyme present in the enterocytes.163,164 As with all other medications, psychotropic drugs also are subjected to first pass clearance by the gut, where CYP450s play a crucial role. Grapefruit juice has been reported to cause significant inhibition of CYP3A4 leading to increase in plasma levels of buspirone (causing headaches, nausea, somnolence) and carbamazepine (causing headaches, nausea, ataxia, tremor, dysarthria, diplopia, and sedation).123 According to Kim et al,76 cranberry juice also inhibits CYP3A4.Reduced first-pass metabolism of midazolam (a CYP3A4 substrate) was observed in 16 healthy volunteers when simultaneously given cranberry juice. A recent case report by Goldberg et al165 adds additional evidence of CYP3A4 inhibition by cranberry juice. An elderly woman—stable on simvastatin for 2 years—presented with rhabdomyolysis and hepatitis after addition of cranberry juice to her diet. Hidaka et al166 tested 8 tropical fruits including common papaw, dragon fruit, kiwi fruit, mango, passion fruit, pomegranate, rambutan, and star fruit and found that star fruit causes dose-dependent inhibition of CYP3A4 activity.77,166

Cigarette smoke contains many compounds, the roles of which remain to be elucidated. Nevertheless, smoking causes a strong induction of CYP1A2 leading to sub-therapeutic levels of many psychotropic drugs167 (TABLE 102,10,12,13,16,17,78,79,168-170). A complete or partial reduction in therapeutic efficacy of antipsychotics has been reported in smokers receiving typical antipsychotics (haloperidol) and atypical antipsychotics (clozapine and olanzapine).171 Decreased plasma level of antidepressants such as TCAs and SSRIs also have been reported in smokers.167


TABLE 10

Major cytochrome-based interactions of smoking and alcohol

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
Smoking CYP1A2 - + - Clozapine, olanzapine, and fluvoxamine Decreased levels of these psychotropic drugs
Alcohol CYP2E1 + + - Disulfiram Increased level of alcohol
Source: References 2,10,12,13,16,17,78,79,168-170.

Ginkgo biloba, a popular dietary supplement utilized by the Chinese for thousands of years, is a CYP2C9 inhibitor.132,172 (TABLE 42,10,12,13,16,17,54,76-80). A case report by Galluzzi et al,173 in 2000 suggested adverse interactions between psychotropic drugs and ginkgo biloba.174 According to the report, an Alzheimer’s patient taking a low dose of trazadone went into coma. Thorough investigation of all of the patient’s medications revealed ginkgo biloba self-supplementation.174 Another plant extract interacting with CYP450s is ginseng. Inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 has been reported by Hao et al.175 Advise patients to avoid concurrent usage of ginkgo biloba or ginseng with psychotropic drugs.


TABLE 11

Major cytochrome-based interactions of hypnotic sedatives

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
Flurazepam CYP3A4 + - - Cimetidine and erythromycin Increased level of flurazepam
Triazolam CYP3A4 + - - Nefazodone and diltiazem Increased level of flurazepam
Zolpidem CYP3A4 + - - Grapefruit juice and fluconazole Increased level of zolpidem
Zaleplon CYP3A4 + - - Cimetidine Increased level of zaleplon
Zopiclone CYP3A4 + - - Grapefruit juice and erythromycin Increased level of zopiclone
Source: References 2,10,12,13,17,178.

  Discussion

Available software programs that track drug interactions lack sensitivity and specificity.176 They often exaggerate drug-drug interactions and are not user friendly. Internet-based databases are an improvement over software programs but they too lack sensitivity and specificity.177 Online databases include Epocrates, Medscape Drug Interaction Checker, Medwatch, NCCAM, and the FDA Center for Drug Evaluation and Research. Review articles and publications related to psychotropic drugs and drug-drug interactions are the best sources of information. Drug-drug interactions can alter plasma medication levels significantly. Any drug or substance (OTC medications, herbal products, dietary products, or narcotics) that affects the pharmacokinetics of another drug or substance will lead to drug-drug interactions9 (TABLES 1-4,8-141,2,9-17,26,31-33,54,76-80,82-84,88,168-170,179-195). These interactions are largely due to the direct consequence of alterations in CYP450s.196,197 Interestingly, depending on the chemical property (eg, chirality) of drugs, CYP450s process substrates differently. A specific CYP450 may metabolize a parent drug extensively, when compared to its active metabolite. For instance, venlafaxine (parent drug) is a substrate of CYP3A4 and is therefore extensively metabolized, while desvenlafaxine (active metabolite) is modestly altered by CYP3A4, and as a result, desvenlafaxine largely is unaltered and excreted primarily by the kidneys198 (TABLE 82,10,12,13,16,17,82-84).


TABLE 12

Major cytochrome-based interactions of atypical antidepressants

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
Mirtazapine CYP2D6 + - - Bupropion and quinidine Increased level of mirtazapine
CYP3A4 + - - Erythromycin and grapefruit juice Increased level of mirtazapine
CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of mirtazapine
Bupropion CYP2D6 + - + Risperidone and aripiprazole Increased levels of these drugs
CYP2B6 + - - Carbamazepine Decreased level of bupropion
Trazodone CYP3A4 + - - Erythromycin and grapefruit juice Increased level of trazodone
Nefazodone CYP3A4 + - + Benzodiazepines and statins Increased levels of these drugs
CYP2D6 + - - Bupropion and quinidine Increased level of nefazodone
Source: References 2,8,10,12,13,17,26,88,179-185.

Classification of the CYP interactions based on the clinical intensity of outcome is a very useful tool for practicing psychiatrists. Since it is very difficult to remember the multitudes of reactions, the outcome-based classification of reactions can help (TABLES 5-7).


TABLE 13

Major cytochrome-based interactions of tricyclic antidepressants

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
Tricyclics
Amitriptyline CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of amitriptyline
CYP2C19 + - - Barbiturates and carbamazepine Decreased level of amitriptyline
CYP2D6 + - - Bupropion and quinidine Increased level of amitriptyline
CYP3A4 + - - Erythromycin and grapefruit juice Increased level of amitriptyline
Nortriptyline CYP2D6 + - - Bupropion Increased level of nortriptyline
Protriptyline CYP2D6 + - - Fluoxetine and duloxetine Increased level of protriptyline
Imipramine CYP2C19 + - - Barbiturates and carbamazepine Decreased level of imipramine
CYP3A4 + - - Erythromycin and grapefruit juice Increased level of imipramine
CYP2D6 + - - Bupropion and paroxetine Increased level of imipramine
CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of imipramine
Desipramine CYP2D6 + - - Bupropion and quinidine Bupropion and quinidine
Clomipramine CYP3A4 + - - Erythromycin and grapefruit juice Increased level of clomipramine
CYP2D6 + - + Paroxetine and quinidine Increased level of clomipramine
CYP2C19 + - - Barbiturates and carbamazepine Decreased level of clomipramine
Source: References 2,8,10,12,13,16,17,26,83,179-184.

SNPs of CYP3A4, CYP2C9, CYP2C19, and CYP2D6 have been identified as clinically the most important genetic mutations, affecting up to 70% of all therapeutic medications used by humans.199 Almost 25% of drugs, including most of the psychotropic drugs, are believed to be metabolized by the CYP2D648 (TABLE 12,9-17). Substrates such as amitriptyline and risperidone both are metabolized by CYP2D6. However, amitriptyline is an active compound and its metabolism by CYP2D6 leads to inactivation of the drug. Risperidone is metabolized to 9-hydroxy-risperidone, which also has anti-dopaminergic activity. Therapeutic efficacy of risperidone in PMs as well as in UMs could be increased, while amitriptyline’s duration of action could be increased in PMs and could be decreased in UMs of CYP2D6. Keeping these SNPs in mind, practitioners will need to make appropriate dose modifications of psychotropic drugs to avoid serious adverse effects. CYP2C9 PMs of clopidogrel have been identified, resulting in unexpectedly high levels of the drug that led to spontaneous bleeding episodes.200 The FDA has issued a black-box warning for clopidogrel notifying physicians of this clinically significant interaction.

CNVs have multiple copies of a functional gene, for instance, multiple copies of a particular P450 gene leading to decreased response to a drug. Steiner et al67 showed that among the Swedish white population, 1% to 2% had multiple copies of the CYP2D6 gene, and up to 29% of Ethiopians likewise had multiple copies of the gene. Thus patients’ genotype (variable copies of a gene) closely predicts their phenotype. Two different patients taking the same combination of buspirone and venlafaxine, both of which are substrates of CYP3A4, will respond differently depending on the number of copies of CYP3A4 genes they express.113 High CNVs will metabolize both the drugs rapidly leading to sub-therapeutic levels of the substrate (buspirone) and supra-therapeutic levels of the prodrug (venlafaxine). Because most psychotropic drugs are substrates for the P450 family of enzymes, clinicians should take a thorough history before starting these medications, with special emphasis on previous adverse drug-drug interactions. Bertilsson et al47 showed an example of dose adjustment according to the patient’s pharmagenomic profile. Nortriptyline’s recommended dose range is between 10 mg and 75 mg. Bertilsson et al47 effectively administered nortriptyline, 500 mg/d, in a UM to compensate for the genetic variability. Therefore, it is crucial to keep in mind that UMs require a higher than recommended dose of a particular drug to have the same effect as NM, while PMs require lower than the recommended dose.


TABLE 14

Major cytochrome-based interactions of antipsychotics

Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction
Chlorpromazine CYP2D6 + - - Bupropion and fluoxetine Increased level of chlorpromazine
CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of chlorpromazine
Thioridazine CYP2D6 + - - Bupropion and fluoxetine Increased level of thioridazine
CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of thioridazine
Fluphenazine CYP2D6 + - - Paroxetine and fluoxetine Increased level of fluphenazine
Perphenazine CYP2D6 + - - Bupropion and fluoxetine Increased level of perphenazine
CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of perphenazine
Pimozide CYP3A4 + - - Grapefruit juice Increased level of pimozide
CYP1A2 + - - Fluvoxamine and fluoxetine Increased level of pimozide
Trifluoperazine CYP1A2 + - - Fluvoxamine and fluoxetine Increased level of trifluoperazine
Thiothixene CYP1A2 + - - Fluvoxamine and fluoxetine Increased level of thiothixene
Zuclopenthixol CYP2D6 + - - Paroxetine and fluoxetine Increased level of zuclopenthixol
Loxapine CYP1A2 + - - Ciprofloxacin Increased level of loxapine
Haloperidol CYP2D6 + - - Bupropion and fluoxetine Increased level of haloperidol
CYP3A4 + - - Carbamazepine and phenytoin Decreased level of haloperidol
CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of haloperidol
Clozapine CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of clozapine
CYP3A4 + - - Ketoconazole and ritonavir Increased level of clozapine
CYP2D6 + - - Paroxetine and fluoxetine Increased level of clozapine
CYP2C19 + - - Barbiturates and carbamazepine Decreased level of clozapine
Risperidone CYP2D6 + - - Bupropion and fluoxetine Increased level of risperidone
CYP3A4 + - - Ketoconazole and ritonavir Increased level of risperidone
Olanzapine CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of olanzapine
CYP2D6 + - - Paroxetine and fluoxetine Increased level of olanzapine
Quetiapine CYP3A4 + - - Carbamazepine and phenytoin Decreased level of quetiapine
Ziprasidone CYP3A4 + - - Ketoconazole and ritonavir Increased level of ziprasidone
Aripiprazole CYP2D6 + - - Bupropion and fluoxetine Increased level of aripiprazole
CYP3A4 + - - Carbamazepine and phenytoin Decreased level of aripiprazole
Asenapine CYP1A2 + - - Ciprofloxacin and fluvoxamine Increased level of asenapine
Iloperidone CYP2D6 + - - Paroxetine and fluoxetine Increased level of iloperidone
CYP3A4 + - - Carbamazepine and phenytoin Decreased level of iloperidone
Lurasidone CYP3A4 + - - Ketoconazole and ritonavir Increased level of lurasidone
Bold type indicates the primary metabolizing enzymes.
Source: References 1,2,10-17,186-195.

Chronicity of the disease and the baseline health of a patient also are important factors in the development of possible adverse effects due to CYP450 alterations. Clozapine is a substrate for CYP3A4, while fluconazole is an inhibitor of the same enzyme.201,202 Prolonged treatment of a patient with schizophrenia on clozapine with fluconazole will cause a marked decrease in CYP3A4 levels leading to high levels of clozapine.203 This can lead to augmentation of side effects (anti-cholinergic, sedative, and orthostatic abnormalities) and adverse effects (agranulocytosis, seizures, weight gain, diabetes, and hyperlipidemia) of clozapine. Therefore, short-term treatment with drugs that are substrates, inhibitors, or inducers may be permissible, but caution is advised. Most psychotropic drugs are prescribed for an extended period of time. SSRIs take >2 weeks for onset of action and must be continued for minimum of 6 months.204,205 Coadministration of a beta-blocker such as metoprolol (a CYP2D6 substrate) with paroxetine can cause substantial rise in plasma metoprolol levels that can cause life-threatening bradycardia.206,207 Patients with depression can have other comorbidities and we advise a close look at drug-drug interactions.133 As the chronicity of diseases increases, likelihood of drug-drug interactions leading to dangerous and sometimes lethal adverse effects also increase.

Patients typically neglect the serious drug interactions that could result from dietary supplements and OTC medications. The adverse reaction from drug-drug interactions is directly proportional to the number of medications a patient takes.208 These interactions lead to serious and deleterious outcomes, burdening both patients and healthcare providers.209

  Conclusions

Psychiatrists not only need a thorough knowledge of psychiatric disorders, but of the mechanism of action of drugs and the role of CYP450s to provide optimal patient care. However, the multitude of CYP450s and the drug interactions challenge most psychiatrists. Knowledge of the psychotropic drug’s pharmacokinetics is paramount. Psychiatrists need to develop approaches that will offer a reasonable yet accurate solution to the drug-drug interaction problem. Reviews that compile tables and electronic databases are recommended to deal with the numerous drug-drug interactions. Psychiatrists need to be proactive, ask appropriate questions, identify possible interactions and most importantly, avoid serious adverse reactions.

Clinicians also must encourage patients to make a list of all the prescribed drugs, non-prescribed medications, OTC drugs, herbal products, and foods such as grapefruit, star fruit, and kiwi. Also educate patients to present this list to all health care providers and pharmacists so that programs that monitor drug-drug interactions can be tailored to their medication regimen. These measures have great potential to reduce the likelihood of adverse drug-drug interactions and will lead to improved quality of care for patients.

Disclosures: Dr. Brenner receives grant/research support from EnVivo, Forest Pharmaceuticals, Johnson & Johnson, Lundbeck, Otsuka, Roche, Sunovion, and Takeda; is a consultant to Lundbeck and Otsuka; and is speaker for Lundbeck, Novartis,and Otsuka. Drs. Madhusoodanan, Velama, Parmar, and Goia report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

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CORRESPONDENCE: Subramoniam Madhusoodanan, St. John’s Episcopal Hospital, 327 Beach 19th Street, Far Rockaway, NY 11691 USA E-MAIL: sdanan@EHS.org