A Current Review of Cytochrome P450 Interactions of Psychotropic Drugs

CYTOCHROME P450 INTERACTIONS
REVIEW ARTICLE
ANNALS OF CLINICAL PSYCHIATRY 2014;26(2):120-138
A current review of cytochrome P450

interactions of psychotropic drugs
Subramoniam Madhusoodanan, MD
St. Johns Episcopal Hospital
Far Rockaway, New York, USA
SUNY
Brooklyn, New York, USA
Umamaheswararao Velama, MD
Department of Psychiatry
Jeniel Parmar, PhD

Ross University School Of Medicine
Commonwealth of Dominica, West Indies
Diana Goia, MD
Department of Psychiatry
Ronald Brenner, MD
SUNY Downstate College of Medicine
Brooklyn, New York, USA
The number of psychotropic drugs has expanded tremendously over the past few decades with a proportional increase in drugdrug 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.
BACKGROUND:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
CORRESPONDENCE
Subramoniam Madhusoodanan
327 Beach 19th Street
Far Rockaway, NY 11691 USA
KEYWORDS: cytochrome P450, interactions, psychotropic drugs
E-MAIL
sdanan@EHS.org
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May 2014 | Vol. 26 No. 2 | Annals of Clinical Psychiatry
ANNALS OF CLINICAL PSYCHIATRY
I N T RO D U C T I O N
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.
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
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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 drugs 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 compounda prodrug,
such as carbamazepine, for exampleinto a pharmacologically active compound such as carbamazepine10,11-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 sub-
Annals of Clinical Psychiatry | Vol. 26 No. 2 | May 2014
121
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.
strates 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
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
122
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).
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.
TABLE 2
Major cytochrome-based interactions of anxiolytics

Drug
CYP
isozymes
Substrate
Inducer
Inhibitor
Alprazolam
CYP3A4
Diazepam
CYP3A4
CYP2C19
Clonazepam
Important interacting drugs
Interaction
Propoxyphene and ketoconazole
Increased level of alprazolam
Ketoconazole
Increased level of diazepam
Barbiturates and carbamazepine

Fluoxamine
Decreased level of diazepam

Increased level of diazepam
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.
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 drugdrug interactions is phase II metabolism. Phase II reactions
involve conjugation and take place in the cells 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
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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 patients 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 sub-
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TABLE 3
Cytochrome-based interactions of mood stabilizers

Drug
CYP
isozymes
Important interacting
drugs
Carbamazepine
Interaction
Aripiprazole, risperidone,
quetiapine, and ziprasidone
Decreased levels of these

antipsychotics
Clozapine and olanzapine
Decreased levels of these drugs
Sertraline
Decreased level of sertraline
CYP2C19
Phenytoin
Increased level of phenytoin
Substrate
Inducer
Inhibitor
CYP3A4
CYP1A2
CYP2C9
CYP2B6
Bupropion
Decreased level of bupropion
Valproate
CYP2C19
CYP2C9
+
+
Carbamazepine
Phenytoin
Increased level of valproate

metabolite
Topiramate
CYP3A4
Carbamazepine
Decreased level of carbamazepine
CYP2C19
Phenytoin
CYP2C19
Phenytoin
Oxcarbazepine
Source: References 2,10,12,13,16,17,31-33.
strate 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 cDNAexpressed 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 patients 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
124
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
TABLE 4
Major cytochrome-based interactions of herbal and food products

Drug
CYP
isozymes
Substrate
Inducer
Inhibitor
St. Johns wort
CYP3A4
CYP1A2
Interaction
Buspirone and statins
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
Cranberry juice
CYP2C9
S-warfarin
Increased level of s-warfarin
CYP3A4
Midazolam
Increased level of midazolam
CYP1A2
Clozapine, olanzapine,
and fluvoxamine
Caffeine
Source: References 2,10,12,13,16,17,54,76-80.
is reduced to water: NADPH + H+ + (O2 )O2 + RH NADP+

+ HO + 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
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enzymes 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
125
TABLE 5
Outcome-based classification of severe psychotropic CYP interactions

Involved drugs
1.
Fluoxetine and paroxetine

Metoprolol
2.
Fluvoxamine
Warfarin
3.
Fluoxetine and paroxetine
5.
Outcome
Inhibitors
CYP2D6 and CYP3A4
Substrate
Severe bradycardia, atrioventricular

block
CYP1A2, CYP2C19 and CYP2C9
Inhibitor
CYP1A2, CYP3A4, CYP2C9 and CYP2C19
Substrate
CYP2D6
Inhibitors
Substrate
CYP2D6
Inhibitors
Mexiletine
CYP2D6 and CYP1A2
Substrate
Fluvoxamine
CYP1A2 and CYP2C9
Inhibitor
Duloxetine, fluoxetine,
and paroxetine
Verapamil
6.
Mechanism
CYP2D6
CYP2D6 and CYP2C9
Carvedilol
4.
Involved CYP isozymes
Fluvoxamine
Losartan
CYP1A2, CYP3A4 and CYP2C9

CYP2C9
Substrate
Inhibitor
CYP2C9 and CYP3A4
Substrate
Increase in INR and risk of severe

bleeding
Pathologic bradycardia and
hypotension
Rebound arrhythmias, ataxia, nausea,
vomiting, and heartburn
Bradycardia, hypotension, and cardiac
arrhythmias
Hypotension, severe dizziness,
and fainting
INR: international normalized ratio.
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 drugs dose that reaches the systemic circulation.73,74 CYP3A4 does not exhibit genetic polymorphism.75 The endogenous compounds metabolized by
126
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. Johns 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
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.
Moderate interactions (TABLE 6) include efficacy issues
such as failure of anticonvulsants from coadministration of
TABLE 6
Outcome-based classification of moderate psychotropic CYP interactions

Involved drugs
1.
Duloxetine, fluoxetine,
and paroxetine
Tamoxifen
2.
3.
5.
Mechanism
Outcome
CYP2D6
Inhibitors
Failure of breast cancer therapy
CYP2D6, CYP3A4, and CYP2C9
Substrate
Fluvoxamine
CYP2C19
Inhibitor
Primidone
CYP2C19
Substrate
Pioglitazone
Clozapine
4.
Prednisone and rifampin
CYP3A4
Inducer
CYP1A2, CYP3A4, CYP2D6,

and CYP2C19
Substrate
CYP2C19
Inducers
Citalopram and escitalopram
CYP2C19, CYP3A4, and

CYP2D6
Smoking and St. Johns wort
CYP1A2
Inducers
CYP1A2, CYP3A4, CYP2D6,

and CYP2C19
Substrate
Clozapine
Failure of anticonvulsant therapy

Decreased antipsychotic therapeutic efficacy
Failure of antidepressive treatment
Substrates
Decreased antipsychotic therapeutic efficacy
TABLE 7
Outcome-based classification of mild psychotropic CYP interactions

Involved drugs
1.
2.
3.
Mechanism
Outcome
Erythromycin

CYP3A4
Inhibitor
Somnolence, headache, and nausea
Hypnotic sedatives
CYP3A4
Substrates
Paroxetine and fluoxetine
CYP2D6
Inhibitors
Hydrocodone
CYP2D6
Substrate
Fluvoxamine
CYP1A2
Inhibitor
Caffeine
CYP1A2
Substrate
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 antipsychotics
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
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.
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Marked reduction in analgesic effect

Anxiety and palpitation
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
127
TABLE 8
Major cytochrome-based interactions of SSRI and SNRI antidepressants

CYP
isozymes
Drug
Substrate
Inducer
Inhibitor
Interaction
Selective serotonin reuptake inhibitors

Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
CYP2C19
Carbamazepine and rifampin
Decreased level of citalopram
CYP3A4
Ketoconazole and ritonavir
Increased level of citalopram
CYP2D6
Quinidine and bupropion
Increased level of citalopram
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
CYP2D6
++
Risperidone and aripiprazole
CYP2C9
S-warfarin and valproic acid
CYP2C19
Omeprazole and amitriptyline
CYP3A4
Statins and nifedipine
CYP2D6
CYP1A2
++
CYP2C19
++
CYP2C9
CYP3A4
CYP2D6
++
CYP3A4
CYP1A2
CYP2C9
CYP2C19
CYP2C9
Decreased level of sertraline
CYP2C19
CYP3A4
CYP1A2
CYP2D6
Serotonin-norepinephrine reuptake inhibitors

Duloxetine
Venlafaxine
CYP2D6
Bupropion and quinidine
Increased level of duloxetine
CYP1A2
Ciprofloxacin and fluvoxamine
Increased level of duloxetine
CYP2D6
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
128
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
TABLE 9
Major cytochrome-based interactions of over-the-counter drugs

CYP
isozymes
Substrate
Inducer
Inhibitor
Acetaminophen
CYP2E1
Ibuprofen
CYP2C9
Naproxen
CYP2C9
Dextromethorphan
Drug
drugs
Interaction
Isoniazid and ethanol
Decreased level of acetaminophen
Fluvoxamine and
fluconazole
Increased level of ibuprofen
Fluoxetine and
fluvoxamine
Increased level of naproxen
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.
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, coadministration 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
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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 metabolitespaliperidone
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 antiepileptic 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
129
TABLE 10
Major cytochrome-based interactions of smoking and alcohol

CYP
isozymes
Substrate
Inducer
Inhibitor
Smoking
CYP1A2
Alcohol
CYP2E1
Drug
drugs
Interaction
Clozapine, olanzapine,
and fluvoxamine
Decreased levels of these psychotropic

drugs
Disulfiram
Increased level of alcohol
Source: References 2,10,12,13,16,17,78,79,168-170.
TABLE 11
Major cytochrome-based interactions of hypnotic sedatives

CYP
isozymes
Substrate
Inducer
Inhibitor
Flurazepam
CYP3A4
Triazolam
CYP3A4
Zolpidem
CYP3A4
Zaleplon
CYP3A4
Zopiclone
CYP3A4
Drug
Interaction
Cimetidine and erythromycin
Increased level of flurazepam
Nefazodone and diltiazem
Increased level of flurazepam
Grapefruit juice and fluconazole
Increased level of zolpidem
Cimetidine
Increased level of zaleplon
Grapefruit juice and erythromycin
Increased level of zopiclone
Source: References 2,10,12,13,17,178.
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. Drugdrug interactions of other medications including over-thecounter (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 psycho-
130
tropic 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. Johns 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. Johns 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. Johns
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. Johns wort.139 A marked decrease in the plasma levels
of verapamil and statins has been reported with concurrent use of St. Johns 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).
TABLE 12
Major cytochrome-based interactions of atypical antidepressants

Drug
Mirtazapine
Bupropion
Trazodone
Nefazodone
CYP
isozymes
Substrate
Inducer
Inhibitor
CYP2D6
CYP3A4
CYP1A2
CYP2D6
CYP2B6
Interaction
Increased level of mirtazapine
Erythromycin and grapefruit juice
Carbamazepine
Decreased level of bupropion
CYP3A4
Increased level of trazodone
CYP3A4
Benzodiazepines and statins
CYP2D6
Increased level of nefazodone
Source: References 2,8,10,12,13,17,26,88,179-185.
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-acetylpara-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
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
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(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 caffeines 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 womanstable
on simvastatin for 2 yearspresented 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
131
TABLE 13
Major cytochrome-based interactions of tricyclic antidepressants

CYP
isozymes
Drug
Substrate
Inducer
Inhibitor
Interaction
CYP1A2
Increased level of amitriptyline
CYP2C19
Decreased level of amitriptyline
CYP2D6
CYP3A4
Nortriptyline
CYP2D6
Bupropion
Increased level of nortriptyline
Protriptyline
CYP2D6
Fluoxetine and duloxetine
Increased level of protriptyline
Imipramine
CYP2C19
Decreased level of imipramine
CYP3A4
Increased level of imipramine
CYP2D6
Bupropion and paroxetine
CYP1A2
Desipramine
CYP2D6
Clomipramine
CYP3A4
Increased level of clomipramine
CYP2D6
Paroxetine and quinidine
Increased level of clomipramine
CYP2C19
Decreased level of clomipramine
Tricyclics
Amitriptyline
Source: References 2,8,10,12,13,16,17,26,83,179-184.
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
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 Alzheimers patient taking a low dose of
trazadone went into coma. Thorough investigation of all
of the patients medications revealed ginkgo biloba selfsupplementation.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.
132
DISCUSSION
Available software programs that track drug interactions
lack sensitivity and specificity.176 They often exaggerate
drug-drug interactions and are not user friendly. Internetbased 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
TABLE 14
Major cytochrome-based interactions of antipsychotics

CYP
isozymes
Substrate
Inducer
Inhibitor
Interaction
Chlorpromazine
CYP2D6
Bupropion and fluoxetine
Increased level of chlorpromazine
CYP1A2
Increased level of chlorpromazine
Thioridazine
CYP2D6
Increased level of thioridazine
CYP1A2
Increased level of thioridazine
Fluphenazine
CYP2D6
Increased level of fluphenazine
Perphenazine
CYP2D6
Increased level of perphenazine
CYP1A2
Increased level of perphenazine
CYP3A4
Grapefruit juice
Increased level of pimozide
CYP1A2
Fluvoxamine and fluoxetine
Increased level of pimozide
CYP1A2
Increased level of trifluoperazine
Thiothixene
CYP1A2
Increased level of thiothixene
Zuclopenthixol
CYP2D6
Increased level of zuclopenthixol
Loxapine
CYP1A2
Ciprofloxacin
Increased level of loxapine
Haloperidol
CYP2D6
Increased level of haloperidol
CYP3A4
Carbamazepine and phenytoin
Decreased level of haloperidol
CYP1A2
Increased level of haloperidol
CYP1A2
Increased level of clozapine
CYP3A4

Drug
Pimozide
Trifluoperazine
Clozapine
CYP2D6
CYP2C19
Barbiturates and carbamazepine Decreased level of clozapine
CYP2D6
Increased level of risperidone
CYP3A4
Increased level of risperidone
Olanzapine
CYP1A2
Increased level of olanzapine
CYP2D6
Increased level of olanzapine
Quetiapine
CYP3A4
Decreased level of quetiapine
Ziprasidone
CYP3A4
Increased level of ziprasidone
Aripiprazole
CYP2D6
Increased level of aripiprazole
Risperidone
CYP3A4
Decreased level of aripiprazole
Asenapine
CYP1A2
Increased level of asenapine
Iloperidone
CYP2D6
Increased level of iloperidone
CYP3A4
Decreased level of iloperidone
CYP3A4
Increased level of lurasidone
Lurasidone
Bold type indicates the primary metabolizing enzymes.

Source: References 1,2,10-17,186-195.
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).
Classification of the CYP interactions based on the
clinical intensity of outcome is a very useful tool for prac-
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ticing psychiatrists. Since it is very difficult to remember

the multitudes of reactions, the outcome-based classification of reactions can help (TABLES 5-7).
SNPs of CYP3A4, CYP2C9, CYP2C19, and CYP2D6
have been identified as clinically the most important
genetic mutations, affecting up to 70% of all therapeu-
133
tic 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-hydroxyrisperidone, which also has anti-dopaminergic activity.
Therapeutic efficacy of risperidone in PMs as well as in
UMs could be increased, while amitriptylines 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 blackbox 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 patients pharmagenomic profile. Nortriptylines 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.
Chronicity of the disease and the baseline health of
a patient also are important factors in the development
134
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 betablocker 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 drugs pharmacokinetics is paramount. Psychiatrists need to develop approaches that
will offer a reasonable yet accurate solution to the drugdrug 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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CYTOCHROME P450 INTERACTIONS

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

A current review of cytochrome P450

Jeniel Parmar, PhD

We searched the National Library of Medicine, PsycINFO,

Psychotropic drugs may interact with other prescribed

KEYWORDS: cytochrome P450, interactions, psychotropic drugs

May 2014 | Vol. 26 No. 2 | Annals of Clinical Psychiatry

ANNALS OF CLINICAL PSYCHIATRY

frequently overlook these drug-drug interactions, causing

Annals of Clinical Psychiatry | Vol. 26 No. 2 | May 2014

CYTOCHROME P450 INTERACTIONS

Antipsychotics: Fluphenazine, perphenazine, thioridazine, haloperidol,

Antipsychotics: Haloperidol, pimozide, clozapine, risperidone, quetiapine,

Antipsychotics: Haloperidol, chlorpromazine, perphenazine, thioridazine, clozapine,

Source: References 2,9-17.

strates by competing for the same enzyme binding site.

inhibits a number of drug oxidation reactions catalyzed

May 2014 | Vol. 26 No. 2 | Annals of Clinical Psychiatry

ANNALS OF CLINICAL PSYCHIATRY

Major cytochrome-based interactions of anxiolytics

Important interacting drugs

Propoxyphene and ketoconazole

Increased level of alprazolam

Increased level of diazepam

Barbiturates and carbamazepine

Decreased level of diazepam

Ketoconazole and nefazodone

Grapefruit juice and nefazodone

Increased level of buspirone

Source: References 2,10,12,13,16,17.

This can lead to toxicity or diminished therapeutic effects.

Annals of Clinical Psychiatry | Vol. 26 No. 2 | May 2014

CYTOCHROME P450 INTERACTIONS

Cytochrome-based interactions of mood stabilizers

Decreased levels of these

Clozapine and olanzapine

Decreased levels of these drugs

Decreased level of sertraline

Increased level of phenytoin

Decreased level of bupropion

Increased level of valproate

Decreased level of carbamazepine

Increased level of phenytoin

Increased level of phenytoin

Source: References 2,10,12,13,16,17,31-33.

strate metabolism. Therefore, a particular genotype can

27 alleles associated with 4 CYP2D6 phenotypes (UM, EM,

Major drug metabolizing enzymes:

May 2014 | Vol. 26 No. 2 | Annals of Clinical Psychiatry

ANNALS OF CLINICAL PSYCHIATRY

Major cytochrome-based interactions of herbal and food products

St. Johns wort

Important interacting drugs

Buspirone and statins

Decreased levels of these drugs

Clozapine and olanzapine

Decreased levels of these drugs

Decreased level of valproic acid

Increased level of s-warfarin

Aripiprazole and alprazolam

Increased levels of these drugs

Star fruit juice