Schizophrenia Research 149 (2013) 1–14

Contents lists available at SciVerse ScienceDirect

Schizophrenia Research

j ourna l homepage: www.e lsev ie r .com/ locate /schres

Review

CYP450 Pharmacogenetic treatment strategies forantipsychotics: A review of the evidence

Dana Ravyn a, Vipa Ravyn b, Robert Lowney a, Henry A. Nasrallah c,⁎a CMEology, West Hartford, CT, United Statesb Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, CO, United Statesc Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, United States

⁎ Corresponding author at: Psychiatry & Neuroscience,of Medicine, Department of Psychiatry and Behavioral NeSuite 3200, Cincinnati, OH 45219, United States. Tel.: +558 4616.

E-mail address: henry.nasrallah@uc.edu (H.A. Nasra

0920-9964/$ – see front matter © 2013 Elsevier B.V. Allhttp://dx.doi.org/10.1016/j.schres.2013.06.035

a b s t r a c t

a r t i c l e i n f o

Article history:Received 27 March 2013Received in revised form 3 June 2013Accepted 19 June 2013Available online 17 July 2013

Keywords:SchizophreniaAntipsychoticCytochromeMetabolismPharmacogenetics

Although a number of first- and second-generation antipsychotics are available, achieving optimal therapeu-tic response for patients with schizophrenia can be challenging. The presence of polymorphic alleles for cy-tochrome P (CYP) 450 may result in lack of expression, altered levels of expression, or altered function ofCYP450 enzymes. CYP2D6, CYP1A2, and CYP3A4/5 are major enzymes in the metabolism of antipsychoticsand polymorphisms of alleles for these proteins are associated with altered plasma levels. Consequently,standard dosing may result in drug plasma concentrations that are subtherapeutic or toxic in some patients.Patient CYP450 genotype testing can predict altered pharmacokinetics, and is currently available and rela-tively inexpensive. Evidence-based guidelines provide dose recommendations for some antipsychotics. Todate few studies have demonstrated a significant association with genotype-guided antipsychotic use andclinical efficacy. However, many studies have been small, retrospective or cohort designs, and many havenot been adequately powered. Numerous studies have shown a significant association between genotypeand adverse effects, such as CYP2D6 polymorphisms and tardive dyskinesia. This review summarizes evi-dence for the role of CYP450 genetic variants in the response to antipsychotic medications and the clinicalimplications of pharmacogenetics in the management of patients with schizophrenia.

© 2013 Elsevier B.V. All rights reserved.

1. Introduction

Antipsychotics accounted for over 14 million US treatment visitsin 2008 (Mark, 2010). There is significant interindividual variationin response to antipsychotics, much of which remains unexplained(Stroup, 2007). Antipsychotics are one of the most highly individual-ized classes of medications. Despite the fact that a number of first-and second-generation antipsychotics are available, achieving opti-mal therapeutic outcomes can be challenging for some individuals.The majority of patients with schizophrenia do not experience com-plete therapeutic benefit with antipsychotic therapy, which can leadto polypharmacy, a practice poorly supported by clinical evidenceand associated with risk of adverse effects (McEvoy et al., 2006;Zink et al., 2010). Further, risk of discontinuation and relapse canresult from treatment-limiting adverse effects and long-term side ef-fects such as weight gain and metabolic syndrome (Cha andMcIntyre,2012).

University of Cincinnati Collegeuroscience, 260 Stetson Street,1 513 558 4615; fax: +1 513

llah).

rights reserved.

Variability in response to antipsychotics can be influenced by anarray of factors, including age, sex, ethnicity, nutritional status,smoking, and alcohol use. There is strong evidence for the role ofgenetic variability in individual responses to antipsychotic therapy. Ad-vances in pharmacogenetic research have led to discovery of many poly-morphisms strongly linked to the metabolism and pharmacodynamicsof antipsychotic medications. The goal of clinical pharmacogenetics isto use individual-level genetic data to predict and optimize the responseto antipsychotics while preventing or minimizing adverse events. Use ofpharmacogenetics has demonstrated the ability to improve patient out-comes in many therapy areas, and is generally cost effective (Crews etal., 2012). Nevertheless, evidence-based guidelines for pharmacogeneticsremain scarce, and there are numerous barriers to its clinical implemen-tation (McCullough et al., 2011; Mrazek and Lerman, 2011; Schnoll andShields, 2011).

1.1. Methods

This review summarizes evidence for the role of genetic variantsof CYP450 enzymes in the metabolism of antipsychotic medicationsand the clinical implications of pharmacogenetics of cytochromeP (CYP) enzymes in the management of patients receiving antipsy-chotics. A literature search was conducted to examine the impact ofCYP450 variants on antipsychotic pharmacology and any known

2 D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

clinical outcomes. The search strategy [(pharmacogenetic* OR “cyto-chrome P*”) AND (antipsychotic* OR neuroleptic*)] was used to identifyrelevant literature in PubMed andOVID. The searchwas conducted for allarticles from inception to April 30, 2013. Eligible studies includedpharmacologic characteristics of antipsychotics relevant to CYP me-tabolism in vitro, in healthy volunteers, or in patients, or reports ofefficacy or adverse effects that defined patients according to CYP ge-notype or phenotype. Relevant literature was used to identify anyadditional primary studies. Research abstracts, unpublished studies,articles with non-English abstracts, commentaries, letters to the ed-itor, and editorials were excluded. As discussed in detail below, studyquality was limited by small study size, poorly defined populationsand ethnicity, and scarcity of outcomes studies.

2. Pharmacogenetic studies of antipsychotics

2.1. Overview

The term pharmacogenetics was coined by Vogel in 1959, and refersto the interaction between an individual's genetics and his or her re-sponse to drugs, often on the basis of a single gene polymorphism(Vogel, 1959). In contrast, pharmacogenomics is a relatively recentterm used in associationwith studies of the human genome and focuseson complex, multifactorial interactions. While pharmacogenetics seeksto individualize therapy, pharmacogenomics identifies targets fordrugs, and characterizes drug responses in populations.

Studies of the pharmacogenetics of antipsychotics evaluate the as-sociation between genetic variations with either the pharmacokinet-ics or pharmacodynamics of individual agents. In pharmacokineticstudies, pharmacogenetics aims to predict antipsychotic drug re-sponses by identifying variants in genes associated with the metabo-lism of specific agents. Such genetic variations affecting metabolismmay lead to alterations in the bioavailability of certain antipsychotics,resulting in loss of efficacy (decreased plasma levels) or increasedtoxicity (elevated plasma levels). In pharmacodynamic studies,pharmacogenetics evaluates the association of genetic polymor-phisms in drug targets with therapeutic outcomes or adverse effects.These targets may be receptors postulated to have a role in the etiol-ogy of disease, targets in the mechanism of action of the therapeuticagent, transporters, or intermediates in signaling pathways involvedin efficacy or side effects of the drug.

2.2. Pharmacogenetic testing

Pharmacogenetic testing of drug metabolism consists of two ap-proaches (Sheffield and Phillimore, 2009). Biochemical tests are used toevaluate the rate of metabolism by a patient after he or she takes aprobe drug, which is a well characterized target of a recognized meta-bolic pathway. The excretion of the parent drug and its metabolite arethen measured at regular intervals and a rate of metabolism calculated.The result is often referred to as an individual's phenotype, although theuse of the term to describe functional aspects of drugmetabolismdiffersfrom its connotation in genetics. Although the activity of a patient'smetabolic enzymes can be measured directly, this is not practical, par-ticularly for CYP450 enzymes, which would require a liver biopsy.

The other approach to pharmacogenetics is the use of moleculargenetic testing to characterize the alleles of a patient's gene relatedto metabolic enzymes, the drug target, or receptors. The genes of in-terest often have a number of alleles, and polymorphisms present inthese alleles may result in lack of expression, altered levels of expres-sion, or altered function.1

1 In this article, unitalicized capitals are used to indicate a protein and italicized cap-itals are used to indicate a gene. Alleles are indicated by an asterisk, followed by the al-lele number. In most cases, *1 represents the wild type; for example, CYP2C9 is theenzyme and CYP2CP*1 is the most common allele.

3. Pharmacokinetics and genetic variations in CYP450 enzymes

Historically, pharmacogenetics has focused on drug metabolizingenzymes as a result of their wide variation in comparison to allelicpolymorphisms of pharmacodynamic drug targets (Brosen, 2004).Further, outcomes of genetic variation are easier to measure becausedrug metabolism assays are standardized, and interpretation is rela-tively straightforward. For example, a low steady-state concentrationindicates rapid metabolism and a high concentration indicates slowmetabolism. Numerous enzymes associated with drug absorptionand elimination have been the subject of pharmacogenetic studies,which are recommended or required by the US Food and Drug Ad-ministration (FDA) for certain therapies. The FDA requires informa-tion related to pharmacogenetic biomarkers in the labeling of over100 drugs, 27 of which are for agents with a primary indication inpsychiatry (US Food and Drug Administration, 2012).

Association of an enzyme with metabolism of a drug is necessarybut not sufficient justification for pharmacogenetic testing, asmany drugs may be metabolized by alternative pathways. Further,pharmacogenetic results should be interpreted in context of thephysician's knowledge of other factors that influence efficacy and tox-icity of antipsychotic agents, such as comorbidities, adherence, bodyweight, and smoking (Rostami-Hodjegan et al., 2004). In addition topharmacogenetic considerations, CYP isoforms can be induced andinhibited by certain drugs, which can substantially alter metabolismof other drugs through drug–drug interactions.

Oral antipsychotics are substrates of CYP450 enzymes, which are cru-cial to their metabolism and elimination (Fig. 1). The efficacy and toxicityof antipsychotic agents is affected by factors that induce or inhibit CYP450expression and function, such as drug–drug interactions. Additionally,the multiallelic nature of CYP450 enzyme genetics can result in variousphenotypes. These polymorphisms reflect gene insertions and deletions,gene duplications, copy number variations, and single nucleotide poly-morphisms (SNPs), which can lead to decreased or elevatedmetabolism.The resulting phenotypes associated with these genetic variants areusually classified as one of four groups: poormetabolizers (PM), interme-diate metabolizers (IM), extensive metabolizers (EM) or normal, andultra-rapid metabolizers (UM) (Fig. 2) (van der Weide et al., 2005).

The clinical consequences of variations in metabolism depend onwhether the drug taken is pharmacologically active or is a prodrug thatneeds to be converted to an activemetabolite. If the antipsychotic is phar-macologically active, the PM phenotype will result in increased plasmaconcentration. Many antipsychotics have a narrow therapeutic windowand reduced metabolism can result in concentration-dependent adverseeffects, as illustrated in Fig. 2 (van der Weide et al., 2005). Patients withthe IM phenotype are also likely to have increased exposure to drugscompared with EMs. However, the degree to which plasma levels are el-evated and their clinical significance is often unclear. The UM phenotypecan result in subtherapeutic drug levels when conventional doses are ad-ministered as the antipsychotic will be metabolized before it has a phar-macologic effect. The PM is most extensively studied for antipsychotics,particularly in those agents with a narrow therapeutic index. UM pheno-type is clinically significant because of its wide distribution (Sistonen etal., 2009). In contrast to pharmacologically active agents, a prodrugmust be metabolized to an active form. For some antipsychotics, the par-ent drug and its metabolite will both have activity, and variations in me-tabolism can have complex outcomes.

3.1. CYP variations and dose recommendations

The human CYP2D6 gene is polymorphic and the resulting CYP2D6isozymes have significant implications in clinical medicine (Zhou,2009). Of 121 drug labels that included pharmacogenetic informationfrom 1945 to 2005, 35% pertained to CYP2D6 (Frueh et al., 2008). Themajority of antipsychotics are metabolized primarily or secondarilyby CYP2D6 (Fig. 1). Additionally, CYP2D6 variability is a significant

Fig. 1. Primary and secondary CYP450 enzymes responsible for metabolism of antipsy-chotics. Data are from prescribing information provided by the manufacturers.

3D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

factor in the metabolism of many other psychiatric drugs. Significant-ly decreased capacity to metabolize CYP2D6 substrates occurs inabout 8% of Caucasians, 3–8% of blacks and African Americans, and6% of Asians (Cascorbi, 2003). The CYP2D6 UM phenotype has beenobserved in 1–10% of Caucasians, 0–2% of East Asians, 2% of blacksand African Americans, and 10–29% of North African/Middle East-erners and 1% of Mexicans (Lovlie et al., 2001; Mendoza et al., 2001;Gaedigk et al., 2002). The CYP1A2*1C (rs2069514) allele is associatedwith decreased inducibility and occurs in 21–27% of Asians, 7% of Af-ricans, and 1–4% of Caucasians (McGraw and Waller, 2012). Ethnicdifferences in CYP3A4/5 activity may be explained by unidentified

Fig. 2. Genetic mechanisms for CYP450 metabolic phenotypes and t

polymorphisms. CYP3A4*1B (rs2740574) has been associated withdecreased metabolism in some studies, while others have shown itto be associated with increased metabolism, so its clinical relevanceremains to be determined (Amirimani et al., 2003). The CYP3A4*20(rs67666821) polymorphism, which results in a premature stopcodon and lack of enzyme activity, is prevalent in 26% of AfricanAmericans, 22% of Asians, and 6% of Caucasians (McGraw andWaller, 2012). As Fig. 1 shows, numerous antipsychotics are metabo-lized primarily by both CYP2D6 and either CYP1A2 or CYP3A4. Otherantipsychotic agents are primarily metabolized by CYP2D6 and sec-ondarily by others like CYP3A4 and CYP1A2 or primarily by CYP3A4or CYP1A2.

CYP3A is themost abundant CYP450 enzyme in the liver and small in-testine and the subfamily is involved in the metabolism of over 50% ofprescription drugs (Williams et al., 2002). CYP3A4 and CYP3A5 share se-quence homology and substrate specificity, and the large active sites con-tribute to their ability to accommodate myriad substrates (McGrawandWaller, 2012). There can be up to a 40-fold interindividual variationin CYP3A4 activity (Ingelman-Sundberg, 2004). The promiscuous andoverlapping nature of CYP3A enzymes hasmade it challenging to identifyphenotypic variants using substrate probes. However, identification ofSNPs have revealed several polymorphisms with potential clinical impli-cations. Several polymorphisms of CYP3A4 have been characterized, butmost are low frequency and occur as heterozygoteswith thewild type al-lele, while others have no demonstrable effect on substrate metabolism(Ozdemir et al., 2000). A SNP in the promoter region resulting in theCYP3A4*1B polymorphism is associated with increased promoter activityand a requirement for higher doses of cyclosporine in patients undergo-ing transplantation (Zochowska et al., 2012). Another polymorphismis CYP3A4*20, a SNP that results in a premature stop codon and loss of en-zymatic activity, conferring intermediate metabolism phenotype in het-erozygotes (Westlind-Johnsson et al., 2006). CYP3A4*22 (rs35599367) isa recently identified SNP in an intron of CYP3A4 that results in decreasedexpression (Elens et al., 2012). Some CYP3A4 polymorphisms have beenassociatedwith clinically significant findings related to patients receivingcyclosporine and tacrolimus (Shi et al., 2012; Zochowska et al., 2012).Unlike CYP2D6 and other CYP450 enzymes, there is no evidence for aCYP3A4 null allele (Lamba et al., 2012). Although commercial tests are

heir pharmacokinetic implications (van der Weide et al., 2005).

Table 1Clinically relevant pharmacokinetics of CYP2D6 phenotypes and dose recommendations.

Antipsychotics Phenotype Clinical Relevance Recommendations Refs

Aripiprazole PMa • 80% increase in aripiprazole exposure and30% decrease in exposure to the active me-tabolite resulting in 60% higher exposure tothe total active moieties

• Elimination half life for aripiprazole isincreased from 75 h to 146 h in PMs

Reduce to 67% of maximum dose Hendset et al. (2007), Oosterhuis et al. (2007),Swen et al. (2011), Aripiprazole package insert(2012)

IMb • Significant increase in aripiprazole exposure(27%) and total active moieties (15%) inpatients

None Kubo et al. (2005), Kim et al. (2006), Hendsetet al. (2007), Kubo et al. (2007)

UMc Not determined NoneClozapine PM, IM,

UMNo significant changes in steady state clozapinelevels or norclozapine or clozapine response

None Dahl et al. (1994), Arranz et al. (1995),Dettling et al. (2000a,b, 2001), Melkersson etal. (2007)

Haloperidol PM Significantly increased plasma concentrations;PM phenotype associated with increased riskof EPS

Reduce dose by 50% or select alternative drug Llerena et al. (1992a), Llerena et al. (1992b),Pan et al. (1999), Yasui-Furukori et al. (2001),Brockmoller et al. (2002), Desai et al. (2003),Llerena et al. (2004b), Panagiotidis et al. (2007)

IM Significantly increased plasma concentrationsassociated with the IM phenotype

None Llerena et al. (1992a), Llerena et al. (1992b),Suzuki et al. (1997), Mihara et al. (1999),Shimoda et al. (2000), Roh et al. (2001),Yasui-Furukori et al. (2001), Brockmoller et al.(2002), Desai et al. (2003), Ohara et al. (2003),Ohnuma et al. (2003), Someya et al. (2003),Llerena et al. (2004b), Park et al. (2006),Panagiotidis et al. (2007),

UM Patients with UM had higher frequency ofadverse effects, showed less improvement,and worsening symptoms

Insufficient data to allow calculation of doseadjustment. Be alert to decreased haloperidolplasma concentration and adjust maintenancedose or select alternative drug.

Brockmoller et al. (2002), Panagiotidis et al.(2007)

Iloperidone PM • Iloperidone and its primary metabolite (P88)have comparable activity; the second metab-olite (P95) has a unique receptor profile

• P95 is reduced from 48% of iloperidoneexposure in EMs to 25% in PMs

• P88 levels increase from19% of iloperidone expo-sure in EMs to 34% in PMs

Reduce dose by one-half Iloperidone package insert (2012)

IM Not determined NoneUM Not determined None

Olanzapine PM CYP2D6 is a minor metabolic pathway;olanzapine clearance is not reduced in subjectswho are deficient in this enzyme

None Hagg et al. (2001), Nozawa et al. (2008),Thomas et al. (2008), Olanzapine packageinsert (2009)

IM Not determined NoneUM Not determined None

Perphenazine PM Exposure is increased approximately 3-foldand clearance decreased

The US FDA recommends genetic testing priorto initiation or restarting therapy

Dahl-Puustinen et al. (1989), Jerling et al.(1996), Linnet and Wiborg (1996b), Ozdemiret al. (2007)

IM Not determined NoneUM Not determined None

Risperidone PM • CYP2D6 PM patients experienced a higher in-cidence of adverse drug reactions, includinglengthening of QTc interval and parkinsonism.

• A case–control study found that CYP2D6 PMshad a three times higher odds (OR 3.4; 95%CI 1.5–8.0) of significant risperidone adversedrug reactions and a six-times higher odds ofdiscontinuation (OR 6.0; 95% CI 1.4–25.4),compared with EMs.

Insufficient data to allow calculation of doseadjustment. Select alternative drug and bealert to adverse drug effects and adjust doseaccording to clinical response

Bork et al. (1999), Kohnke et al. (2002),Llerena et al. (2004a); de Leon et al. (2005a)

IM Not determined NoneUM Not determined None

Thioridazine PM • In healthy volunteers, thioridazine plasmalevels increased 4.5-fold; sum of thioridazineplusmesoridazine plus sulforidazine increased1.4-fold

• In patients with one or no CYPD6 alleles, plas-ma levels were increased 1.8-fold or 3.8-fold,respectively

• A small study in patients (n = 9) with nofunctional CYP2D6 alleles found elevatedplasma levels but no significant effect on QTcinterval

Thioridazine is associated with risk of QTcinterval prolongation in a dose-dependentmanner. Therefore, thioridazine is contraindi-cated in combination with other drugs thatreduce CYP2D6 activity or in patients knownto have a genetic defect leading to reducedlevels of CYP2D6 activity.

von Bahr et al. (1991), Berecz et al. (2003),Thanacoody et al. (2007)

IM Not determined NoneUM Patients with CYP2D6–1548C N G

polymorphism had lower thioridazine:mesoridazine ratios than those homozygous forthe CYP2D6–1548C allele.

Insufficient data to allow calculation of doseadjustment

Dorado et al. (2009)

4 D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

Table 1 (continued)

Antipsychotics Phenotype Clinical Relevance Recommendations Refs

Zuclopenthixol PM Steady state plasma levels were up to 1.9-foldhigher in healthy volunteers and up to 1.6-foldhigher in patientsPatients with CYP2D6*3 and *4 alleles hadhigher risk of neurologic adverse events withan OR of 1.7 for tardive dyskinesia and 2.3 forParkinsonism

Reduce dose by 50% or select alternative drug Jerling et al. (1996), Linnet and Wiborg(1996a), Jaanson et al. (2002), Swen et al.(2011)

IM Not determined Reduce dose by 25% or select alternative drug Jerling et al. (1996), Linnet and Wiborg(1996a), Jaanson et al. (2002)

UM Insufficient data to allow calculation of doseadjustment. Select alternative drug and bealert to adverse drug effects and adjust doseaccording to clinical response

Swen et al. (2011)

Active alleles = *1, *2, *33, *35.Decreased activity alleles = *9, *10, *17, *29, *36, *41.Inactive alleles = *3–*8, *11–*16, *19–*21, *38, *40, *42.

a Two inactive alleles.b Two decreased-activity alleles OR one active allele and one inactive allele OR one decreased-activity allele and one inactive allele.c A gene duplication in the absence of inactive or decreased alleles.

5D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

available to identify some variants of CYP3A4 associated with reducedactivity, there are currently no recommendations on their use (Leeet al., 2005; Miyazaki et al., 2008; Zanger et al., 2008). Nevertheless, it ispossible that as polymorphisms resulting in loss of function or decreasedexpression are characterized, theymay be found to have clinical implica-tions in dosing of antipsychotics forwhich CYP3A4 is amajor route ofme-tabolism, such as lurasidone, quetiapine, risperidol, and loxapine.

This following section summarizes relevant studies of CYP metabolicvariation in patients and healthy volunteers receiving antipsychotics.Knowledge of the pharmacology and clinical relevance of metabolic var-iations, as well as evidence-based dosing recommendations from expertpanels and/or drug labeling, where available, is summarized in Table 1.

3.2. First generation antipsychotics

3.2.1. ChlorpromazineA prototype phenothiazine antipsychotic, chlorpromazine undergoes

primary metabolism by both CYP2D6 and CYP1A2, to form more than100 metabolites with widely varying pharmacologic properties. A studyin Korea found that healthy volunteers who were heterozygous andhomozygous for the *10 allele of CYP2D6 (rs1065852) had 1.3- and1.7-fold higher chlorpromazine area under the curve (AUC), respectively(Yoshii et al., 2000; Sunwoo et al., 2004).

3.2.2. HaloperidolCYP3A4 is principally responsible for the metabolism of haloperidol

(Fang et al., 2001). Although in vitro data suggest a minor role forCYP2D6 in haloperidol metabolism, studies in have shown a significanteffect of CYP2D6 on pharmacokinetics of haloperidol plasma levels.These studies have consistently shown that patients and volunteerswith CYP2D6 PM phenotype had higher serum concentrations anddecreased haloperidol clearance than EMs (Llerena et al., 1992a;Young et al., 1993; Suzuki et al., 1997; Mihara et al., 1999; Pan et al.,1999; Shimoda et al., 2000; Someya et al., 2003). A study of 26 patientswith schizophrenia in Sweden who received haloperidol decanoatedepot treatments showed PMs had the highest dose-corrected plasmaconcentration and UMs had the lowest, with a sixfold difference(Panagiotidis et al., 2007). It is recommended that the haloperidoldose be reduced by 50% in PMs (Table 1) (Swen et al., 2011).

3.2.3. LoxapineA tricyclic typical antipsychotic, loxapine has a distinct pharmacologic

profile, with a ratio of serotonin to dopamine receptor binding similar toatypicals (Glazer, 1999). Loxapine undergoes extensive metabolism toform various metabolites, including the antidepressant amoxapine. The

major products are hydroxylation to 8-OH loxapine by CYP1A2 and7-OH loxapine by CYP2D6, formation of amoxapine by CYP3A4, and oxi-dation to loxapine N-oxide by CYP3A4 (Luo et al., 2011). Studies of oralloxapine in healthy volunteers showed that metabolites 8-OH loxapineand amoxapinewere below the levels atwhich theywouldhave pharma-cologic activity while 7-OH loxapine levels were substantial at steadystate (Cooper and Kelly, 1979).

Inhaled dosing of loxapine aerosol is currently being investigatedfor treatment of acute agitation (Allen et al., 2011). In a study ofhealthy volunteers administered loxapine aerosol, peak plasma levelconcentrations of loxapine and its metabolites were similar to thoseobserved after oral administration (Spyker et al., 2010). Notably,7-OH loxapine has a 5-fold higher affinity for the dopamine D2 recep-tor than loxapine. The clinical implications of these observations forpatients with CYP polymorphisms are not yet known.

3.2.4. PerphenazineAlthough 10–15 times more potent than chlorpromazine, perphena-

zine is associatedwith a high incidence of extrapyramidal adverse effectsand tardive dyskinesia (Hartung et al., 2005). Perphenazine is extensivelymetabolized in the liver to a number of metabolites by sulfoxidation, hy-droxylation, dealkylation, and glucuronidation. Perphenazine is primarilymetabolized by CYP2D6 to 7-OH perphenazine, which has about 70% ofthe biologic activity of the parent drug (Olesen and Linnet, 2000).In healthy volunteers, administration of a single dose resulted in a4-fold higher AUC of perphenazine in PMs, compared with EMs(Dahl-Puustinen et al., 1989). Similar results were observed in astudy of healthy Chinese-Canadian males (Ozdemir et al., 2007).After a single dose of perphenazine, those who were homozygousfor the CYP2D6*10 allele had a 2.9-fold higher AUC for perphenazine,compared with those who were homozygous for the wild typeCYP2D6*1 allele (P b 0.001) (Ozdemir et al., 2007).

A study of psychiatric inpatients in Denmark found PMs had a2-fold increase in perphenazine steady state levels, compared withEMs (Linnet and Wiborg, 1996b). Another study of psychiatric pa-tients in Sweden showed a 3-fold decrease in clearance of perphena-zine in PMs (Jerling et al., 1996). The US FDA recommends genetictesting before initiating or restarting treatment with perphenazine.

3.2.5. ThioridazineCYP2D6 and CYP3A4 are responsible for conversion of thioridazine

to mesoridazine, which is more active than the parent drug, and thesubsequent formation of the metabolite sulforidazine, which has com-parable activity to thioridazine (Eap et al., 1996; Berecz et al., 2003;Wojcikowski et al., 2006). A study of psychiatric patients in Spain

6 D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

with two active CYP2D6 alleles found that those with CYP2D6–1584C N G polymorphism (rs1080985) were ultrarapid metabolizersand had lower plasma thioridazine:mesoridazine ratios than thosehomozygous for CYP2D6–1584C allele (Dorado et al., 2009). Amonghealthy volunteers, the plasma concentration of thioridazine followinga single dose was increased 4.5-fold in PMs, compared with EMs, andthe sum of levels of thioridazine plus mesoridazine plus sulforidazinewere increased 1.4-fold (von Bahr et al., 1991). A study in Spain evalu-ated dose-corrected plasma concentrations in 76 psychiatric patientsreceiving thioridazine monotherapy (Berecz et al., 2003). In the pres-ence of one or no active CYP2D6 alleles, plasma thioridazine concentra-tions were 1.8- and 3.8-fold higher (P b 0.01 for both), compared withtwo or more functional alleles. No significant differences in plasmalevels of mesoridazine or sulforidazine were observed (Berecz et al.,2003). Another study in psychiatric patients receiving thioridazinefound that those with no functional CYP2D6 alleles had significantlyhigher dose-adjusted plasma concentrations than those with ≥1 func-tional CYP2D6 allele (P = 0.017) (Thanacoody et al., 2007). There wasno significant effect on QTc interval associated with CYP2D6 genotypes.Thioridazine is associated with risk of QTc interval prolongation in adose-dependent manner. Therefore, thioridazine is contraindicated incombination with other drugs that reduce CYP2D6 activity or in pa-tients known to have a genetic defect leading to reduced levels ofCYP2D6 activity (Table 1).

3.2.6. ZuclopenthixolA thioxanthene derivative, zuclopenthixol is metabolized by

sulfoxidation, N-dealkylation, and glucuronidation to form several me-tabolites, all of which are pharmacologically inactive (Dahl et al., 1991).CYP2D6 is mainly responsible for zuclopenthixol sulfoxidation andN-dealkylation. A study evaluated the cosegregation of zuclopenthixolclearance with debrisoquine hydroxylation in healthy volunteers (Dahlet al., 1991). AmongPMs, exposure to zuclopenthixolwas 1.9-fold higher,the half-life longer, and plasma clearance lower, compared with EMs.Among 36 patients with schizophrenia in Sweden, retrospective datafrom 113 therapeutic drug monitoring samples showed that, comparedwith CYP2D6 PM genotypes, those with homozygous or heterozygousEM genotypes had 2.2 or 1.5-fold higher clearance rates, respectively(Jerling et al., 1996). Another clinical study in 119 patients with schizo-phrenia in Denmark found that mean steady state plasma levels ofzuclopenthixol were 60% higher in PMs, compared with EMs (P b 0.01)(Linnet and Wiborg, 1996a). A study evaluated 52 outpatients withschizophrenia in Estonia who were receiving zuclopenthixol decanoatemaintenance dosages of 100 to 400 mg every 4 weeks (Jaanson et al.,2002). The study results showed that the median plasma concentrationsof zuclopenthixol were 1.6- and 1.4-fold higher in PMs and heterozygousEMs, respectively, compared with homozygous EMs. Further, those withthe CYP2D6*3 and *4 alleles (rs35742686 and rs3892097, respectively)had higher risk of neurological adverse events. Patients with at leastone of these alleles in CYP2D6 had an odds ratio (OR) of 1.7 (95% confi-dence interval [CI], 0.5–4.9) for tardive dyskinesia, and an OR of 2.3(95% CI, 0.7–6.9) for parkinsonism (Jaanson et al., 2002).

3.3. Second generation antipsychotics

3.3.1. AripiprazoleAripiprazole is metabolized by CYP2D6 and CYP3A4 to its activeme-

tabolite dehydroaripiprazole (DARI), which has similar pharmacologicproperties to the parent compound. Aripiprazole is the major moietyin systemic circulation, while DARI represents about 40% of aripiprazoleexposure (Aripiprazole package insert, 2012). Patients with the CYP2D6PM phenotype have an 80% increase in aripiprazole exposure and a 30%decrease in DARI exposure, resulting in a 60% higher exposure to thetotal active moieties; the elimination half life of aripiprazole and DARIincrease significantly in PMs (Table 1). Based on studies in patients(Hendset et al., 2007; Oosterhuis et al., 2007) and healthy volunteers

(Kubo et al., 2005; Kim et al., 2006; Kubo et al., 2007) it is recommendedthat the dose in PMs be reduced to 67% of themaximum recommendeddaily dose (i.e., a reduction to 67% of the maximum daily dose of 30 mgwould be approximately 20 mg) (Swen et al., 2011). The manufacturerrecommends that the initial dose of aripiprazole be reduced by one halfin PMs (Aripiprazole package insert, 2012).

A study of 62 psychiatric patients in Norway retrospectively evaluat-ed dose-adjusted serum concentrations of aripiprazole and DARI in pa-tients with CYP2D6 genotypes *1/*1 (EM), *1/*3–6 (IM), *3–6/*3–6 (PM)(Hendset et al., 2007). For PMs vs EMs, themedian serumconcentrationof aripiprazole was 1.7-fold higher (P b 0.01) and concentration ofaripiprazole plus DARI was 1.5-fold higher (P b 0.05). Although in-creased serum levels in IMs vs. EMs were less pronounced, they werestatistically significant for both aripiprazole (P b 0.05) and DARI(P b 0.05). Another study in 63 Japanese patients with schizophreniaprospectively evaluated the concentration/dose ratios of aripiprazoleand DARI in those with CYP2D6 wild type or *10 alleles (Suzuki et al.,2011). CYP2D6*10 is associated with decreased activity, and is presentin about 50% of the Asian population (Bertilsson et al., 2002). The con-centration/dose ratios in patients withwild type, one, or two *10 alleles,respectively, was 9.0, 12.7, and 19.0 ng/mL/mg for aripiprazole(P b 0.01); 4.9, 5.9, and 5.9 ng/mL/mg for DARI (P N 0.05); and 13.9,18.6, and 24.6 ng/mL/mg for aripiprazole plus DARI (P b 0.001). Thesedata demonstrate that the *10 alleles may lead to significantly elevatedlevels of aripiprazole and DARI in Asian patients, although the clinicalsignificance is unknown. Although it is likely that concentration-dependent adverse events may occur more frequently in Asians withthis phenotype, one prospective study in Korean patients found no sig-nificant difference with regard to ethnicity in response to aripiprazole(Kwon et al., 2009).

3.3.2. AsenapineAsenapine is sublingually administered and metabolized principally

through direct glucuronidation by glucuronosyltransferases (UGT)1A4and oxidation by CYP1A2. Notably, asenapine is a suicide substrate forCYP2D6. Administration could decrease the amount of CYP2D6 in PMs aswell as EMs, with recovery to previous levels requiring days or weeks.Therefore, caution is advised when switching to or coadministering an an-tipsychotic or other agent metabolized by CYP2D6, particularly in PMs(Sunwoo et al., 2004; Saphris package insert, 2013).

3.3.3. ClozapineClozapine ismetabolized byCYP1A2, CYP2D6, and CYP3A4 (Eiermann

et al., 1997; Clozapine package insert, 2010). CYP1A2 and CYP3A4are involved in metabolism of clozapine to N-desmethylclozapine(norclozapine) and CYP3A4 is responsible for its oxidation to clozapineN-oxide. Norclozapine is active with partial agonism at D2/D3 receptorsbut lacks serotonin-reuptake activity. Although clozapine is a substratefor CYP2D6, studies in patients with schizophrenia found no significantinfluence of CYP2D6 PM and IM phenotypes on levels of clozapine ornorclozapine (Dahl et al., 1994; Arranz et al., 1995; Dettling et al.,2000a,b; Melkersson et al., 2007). Another study in 108 patients foundno difference in the distribution of PM and UMmetabolism between pa-tientswith agranulocytosis and controls (Dettling et al., 2001). Evaluationof 58 patients with schizophrenia found CYP1A2*1F (rs762551), *1D(rs2069514), and *1C (rs35694136) allele frequencies of 67%, 6%, and1%, respectively (Kootstra-Ros et al., 2005). No significant correlationwas found between *1F, and *1C and clozapine plasma levels. The fre-quency of *1D was too low to draw any conclusions.

3.3.4. IloperidoneCYP2D6 catalyzes metabolism of iloperidone to P94, which is

converted to the active metabolite P95 (Iloperidone package insert,2012). Additionally, iloperidone undergoes interconversion to the ac-tive metabolite P88 and vice versa in the cytosol. In CYP2D6 PMs lessiloperidone is metabolized and plasma levels of the P95 metabolite

7D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

decrease (US Food andDrugAdministration, 2009). The increased levelsof the parent drug iloperidone results in more cytosolic conversion andhigher levels of P88 (Table 1) (US Food andDrug Administration, 2009).Consequently, PMs have lower P95 levels and higher P88 levels relativeto EMs (Fig. 3) (US Food and Drug Administration, 2009).

3.3.5. LurasidoneLurasidone is metabolized by CYP3A4 to form two inactive metab-

olites and two active metabolites, ID14283 and ID14326, present inthe plasma at 25% and 2% of the parent drug concentration, respec-tively (Lurasidone package insert, 2012). At the time this reviewwas undertaken, there were no published cases or studies evaluatinglurasidone in healthy persons or patients with CYP3A4 variants.

3.3.6. OlanzapineThe major pathways for olanzapine metabolism are direct

glucuronidation and CYP-mediated oxidation (Olanzapine packageinsert, 2009; Sheehan et al., 2010). The most important enzymes inolanzapine metabolism are uridine diphosphate (UDP) and UGTs(Kassahun et al., 1997). CYP1A2 and CYP2D6 catalyze metabolism ofolanzapine, although CYP2D6 does not appear to have a major rolein vivo as olanzapine levels are not significantly elevated in patientswith deficient CYP2D6 activity (Olanzapine package insert, 2009).Studies of patients with schizophrenia in India and Japan foundno significant correlation between CYP2D6 polymorphisms andolanzapine plasma levels (Nozawa et al., 2008; Thomas et al., 2008).A study of healthy volunteers in Sweden showed no significant differ-ences in olanzapine pharmacokinetic parameters between EMsand PMs for either CYP1A2 or CYP2D6 (Hagg et al., 2001). A studyof patients with schizophrenia receiving olanzapine found thatthe CYP1A2*1F/*1F genotype result in a 22% reduction of dose/body-weight normalized olanzapine plasma concentrations comparedwith CYP1A2*1A carriers, after controlling for smoking and other in-ducers (Laika et al., 2010). Approximately 50% of patients with theCYP3A43 AA genotype (rs472660) have high clearance of olanzapineand subtherapeutic blood levels. The A allele is much more frequent inAfrican Americans than Caucasians (67% vs. 14%), and patients withthis the CYP3A43 genotype had more symptoms and were more likelyto discontinue treatment (Bigos et al., 2011).

3.3.7. PaliperidoneAlthough paliperidone is the active metabolite of risperidone

(9-OH-risperidone), risperidone (see below) is metabolized by theliver whereas paliperidone is metabolized principally by the kidneys(de Leon et al., 2008). Therefore, paliperidone is a useful alternative

Fig. 3. Poor metabolizer phenotype both raises and lowers blood levels of active iloperidonethe cytosol, both of which are active metabolites. In CYP2D6 PMs, plasma levels of the P95 mcytosolic conversion and higher levels of P88. As a result, PMs have lower P95 levels and h

for patients that have moderate to severe hepatic impairment or aretaking medications that inhibit hepatic metabolism.

3.3.8. QuetiapineThe major enzyme responsible for quetiapine metabolism is CYP3A4,

and results in four metabolites: 7-hydroxyl, sulfoxide, N-desalkyland O-desalkyl products (Grimm et al., 2006). N-desalkylquetiapine(norquetiapine) is metabolically active and is also eliminated byCYP3A4. However, the AUC of norquetiapine is only 27% of the AUC ofquetiapine (Winter et al., 2008). The metabolite 7-hydroxyquetiapine isactive and formed by CYP2D6, but is unlikely to be a significant consider-ation in metabolism because of its low plasma concentration (Bakkenet al., 2009). In one case, a 47-year-old man with psychotic depressionwho experienced serious adverse drug reactions when treated withquetiapine and clomipramine was found to have very low CYP3A4/5activity (Stephan et al., 2006). After discontinuation of quetiapine andreduction of the clomipramine dose, adverse reactions subsided withthe exception of elevated liver enzymes.

3.3.9. RisperidoneRisperidone is metabolized by CYP2D6 to 9-OH-risperidone

(9-OHR) or paliperidone (de Leon et al., 2008). Early studies reportedthat risperidone and 9-OHR have equivalent pharmacodynamic activ-ity (Megens et al., 1994). These data, which were the basis for druglabeling, were based on a study of a single risperidone dose in 11healthy male volunteers, only 2 of whom were PMs (Huang et al.,1993). It was concluded on the basis of these data that CYP2D6 polymor-phisms should have no substantial clinical implications for risperidonemetabolism as decreased 9-OHR production would be compensated forby higher plasma levels of the parent drug, risperidone. Subsequently,studies found that CYP2D6 PM patients experienced a higher incidenceof adverse drug reactions, including lengthening of QTc interval and par-kinsonism (Bork et al., 1999; Kohnke et al., 2002; Llerena et al., 2004a; deLeon et al., 2005a). Although risperidone and 9-ROH have similar affini-ties for dopamine D2 receptor in the brain, they otherwise have distinctpharmacologic profiles thatmay explain the emergence of adverse effectsin patients with higher plasma risperidone/9-OHR ratios. Compared to9-OHR, the affinity of risperidone is 3.7, 10, and 6 times higher for theα1, α2, and 5-HT2A receptors, respectively (Schotte et al., 1996;Richelson and Souder, 2000). Elevated risperidone to 9-OHR ratios havebeen demonstrated to be associated with CYP2D6 polymorphismsamong Italian patients with schizophreniawhowere PMs or in heterozy-gous EMs, compared to homozygous EMs (Scordo et al., 1999). Otherstudies showed similar elevated ratios in Asian patients with schizophre-niawhohad recognized CYP2D6 PMalleles (Mihara et al., 1999; Roh et al.,2001; Mihara et al., 2003).

metabolites. Iloperidone is metabolized to P95 by CYP2D6 and interconverted to P88 inetabolite decrease. The increased levels of the parent drug iloperidone results in more

igher P88 levels relative to EMs (US Food and Drug Administration, 2009).

8 D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

There is currently insufficient data to allow calculation of dose ad-justment for PMs, IMs, or UMs receiving risperidone (Table 1). Theuse of conventional or microarray laboratory genotyping may be use-ful to identify patients with CYP2D6 polymorphisms. The clinical useof this test as it relates to risperidone therapy has been reviewed indetail by de Leon et al. (2006). Guidelines recommended that an al-ternative therapy be selected for patients with a relevant CYP2D6phenotype or vigilance be used for adverse drug events and dosageadjusted to clinical response (Table 1) (Swen et al., 2011).

3.3.10. ZiprasidoneZiprasidone is extensively metabolized in the liver by aldehyde oxi-

dase and CYP3A4 (Beedham et al., 2003). Approximately two-thirdsof the initial metabolism of ziprasidone results from generation ofS-methyldihydroziprasidone by aldehyde oxidase, and the remainingthird results in ziprasidone sulfoxide. These metabolites undergofurther degradation by CYP3A4 (Prakash et al., 1997). Although mostof the metabolism of ziprasidone is carried out by aldehyde oxidase,drug-drug interactions resulting from coadministration of CYP3A4 in-ducers or inhibitors may still occur (Miceli et al., 2000a,b; Ziprasidonepackage insert, 2012).

4. Clinical outcomes studies

4.1. Efficacy outcomes

Numerous studies have evaluated the association between CYP2D6,CYP2A4, and CYP2A5 genotypes and antipsychotic treatment outcomes,most with negative findings (Table 2) (Arranz et al., 1995; Aitchisonet al., 1999; Hamelin et al., 1999; Brockmoller et al., 2002; Kakiharaet al., 2005; Riedel et al., 2005; Panagiotidis et al., 2007; Alenius et al.,2008; Kohlrausch et al., 2008; Thomas et al., 2008; Laika et al., 2009;Zahari et al., 2009; Jurgens et al., 2012; Muller et al., 2012). The qualityof these investigations varies widely and methodologies include retro-spective and prospective open label studies as well as case–controlstudies. Most studies to date have been modest in size and there is awide variation in the data reported with regard to genotyping proce-dures, population stratification in groups of mixed ethnicity, andwhether populations were in Hardy–Weinberg equilibrium.

A single-center study in Denmark investigated the association ofCYP2D6 genotype with antipsychotic therapeutic and adverse effects in576 hospitalized patients diagnosed with schizophrenia (Jurgens et al.,2012). Antipsychotic, adjuvant, and anticholinergic drug utilization wasevaluated retrospectively as a surrogate measure of outcomes in geno-typed patients. Results showed that PMs and UM received 626 and 550median chlorpromazine equivalents (CPZEq), respectively, comparedwith 384 CPZEq. in EMs (P = 0.018). For CYP2D6-dependent anti-psychotics alone, the difference was not statistically significant(P = 0.096). Although it may be expected that UMs would requirehigher doses of antipsychotics, it is unclear why PMs also receivedhigher CPZEq. It is possible that adverse antipsychotic reactionsthat can resemble symptoms of schizophrenia led to increaseddoses in some patients (Lingjaerde et al., 1987).

A cross-sectional study in Sweden evaluated outcomes associatedwith genetic variants of CYP2D6 in 116 outpatients (78% diagnoseswith schizophrenia) receiving antipsychotic drugs (Alenius et al.,2008). Patients were genotyped and classified according to theCANSEPT method, which combines the Camberwell Assessment ofNeed (CAN), side-effect rating (SE) and previous treatments (PT).Patients were grouped according to treatment responders: (Group 1);those with significant side effects but no significant social or clinicalneeds (Group 2); those without significant side effects but with signif-icant social or clinical needs (Group 3); and those with significant sideeffects and significant social or clinical needs (Group 4). There weremore EMs in the groups without significant needs (67% in Groups1 + 2), compared with those with significant needs (46% in Groups

3 + 4) and the difference was statistically significant (P = 0.023).The haloperidol equivalents dose correlated with CYP2D6 phenotypeswith a significantly lower mean dose in PMs (2.4 mg) compared withthe mean dose of others (4.5–5.8 mg) (P = 0.012).

An open label study in Brazil evaluated CYP3A4/5 and CYP2D6polymorphisms in 186 patients with schizophrenia receiving typicalantipsychotics (Kohlrausch et al., 2008). Patients were separatedinto groups according to their response to therapy. The nonrefractorygroup (n = 65) consisted of those who had long-lasting response totreatment and the refractory, or treatment-resistant group had(n = 121) failed to respond to haloperidol or chlorpromazine for12 weeks or thioridazine for 24 weeks, did not have appropriate be-havior control, and showed continued symptoms. Patients underwentgenotyping for nine polymorphisms in the CYP3A4 gene, one in theCYP3A5 gene and 24 polymorphisms in the CYP2D6 gene (Table 2).There was no statistically significant association between CYP2D6 ge-notype and treatment response. Notably, the study found that thosewith the CYP3A4*1A variant (wild type) had a three times greaterodds of being refractory than those with the CYP3A4*1B polymor-phism CYP3A4–392A N G (OR = 3.32, P = 0.014). Similar resultswere found when analyzing data from only those taking haloperidol,which is metabolized by CYP3A4. The phenotype associated withCYP3A4*1B occurs in about 4–5% of Caucasians and is associatedwith increased promoter activity resulting from reduced binding of atranscriptional repressor (Amirimani et al., 2003). Patients with lowCYP3A5 expression (CYP3A5*3/CYP3A5*3) (rs776746) were also at asignificantly higher odds of being refractory to treatment (OR 3.16,P = 0.003).

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)study evaluated effectiveness of 5 antipsychotics in a double-blind ran-domized study. A post hoc analysis examined the impact of 25 geneticvariants of drug metabolizing enzymes among a subset of CATIE par-ticipants (n = 750) treated with olanzapine, quetiapine, risperi-done, ziprasidone, and perphenazine (Grossman et al., 2008). Thestudy included assessment of polymorphisms associated with CYP2D6,CYP1A2, CYP3A4, CYP3A5, and aldehyde oxidase 1 (AOX1). None of thevariants tested showed a significant association with dosing, efficacy,overall tolerability, or tardive dyskinesia.

4.2. Adverse effects

4.2.1. Extrapyramidal symptomsNumerous studies have examined the relationship between CYP2D6

genotype and extrapyramidal symptoms (EPS) in patients with schizo-phrenia receiving antipsychotics (Arthur et al., 1995; Andreassen et al.,1997; Armstrong et al., 1997; Chong, 1997; Sajjad, 1997; Kapitany et al.,1998; Ohmori et al., 1998, 1999; Scordo et al., 2000; Lam et al., 2001;Ellingrod et al., 2002b; Jaanson et al., 2002; Nikoloff et al., 2002; Inadaet al., 2003; Lohmann et al., 2003; Liou et al., 2004; de Leon et al.,2005b; Patsopoulos et al., 2005; Tiwari et al., 2005; Fu et al., 2006;Plesnicar et al., 2006). A recent meta analysis evaluated 20 studies andfound no significant association between tardive dyskinesia andCYP2D6 in overall populations (Fleeman et al., 2011).When the analysiswas limited to prospective studies, there was a significant associationbetween tardive dyskinesia and CYP2D6 homozygous mutant genotypecompared to the wild type (OR = 2.08, 95% CI 1.21–3.57) or the homo-zygous mutant compared to the heterozygotes with one copy of thewild type allele (OR = 1.83, 95% CI 1.09–3.08) (Fleeman et al., 2011).Tardive dyskinesia was significantly more severe in patients with ho-mozygous mutant CYP2D6 alleles compared with the homozygouswild type alleles. Patients with homozygous or heterozygous mutantCYP2D6 genotypes were significantly more likely to develop Parkinson-ism (OR = 1.64, 95% CI 1.04–2.58), but genotype was not associatedwith severity. There was no significant association between acutedystonia or akathisia and CYP2D6 genotypes, although the number ofpatients in studies reporting these outcomes was small.

Table 2Studies of association between CYP2D6, CYP3A4, and CYP1A2 polymorphisms and clinical efficacy of antipsychotics in adult patients with schizophrenic spectrum disorders (Arranzet al., 1995; Aitchison et al., 1999; Hamelin et al., 1999; Brockmoller et al., 2002; Kakihara et al., 2005; Riedel et al., 2005; Panagiotidis et al., 2007; Alenius et al., 2008; Kohlrauschet al., 2008; Thomas et al., 2008; Laika et al., 2009; Zahari et al., 2009; Jurgens et al., 2012; Muller et al., 2012).

Antipsychotic Patients (n) Gene/SNPs Key findings Ref.

Clozapine Caucasian (130) CYP2D6*3, *4, *5 No significant association with clinicalefficacy

Arranz et al. (1995)

Haloperidol Caucasian (172) CYP2D6*1 to *15, *17 Nonsignificant trend toward lowertherapeutic efficacy with increasing numberof active CYP2D6 genes

Brockmoller et al. (2002)

Haloperidol decanoate Caucasian (26) CYP2D6*3, *4, *5 No significant association with clinicalefficacy

Panagiotidis et al. (2007)

Haloperidol or chlorpromazine Brazilian (186) CYP2D6*1, *2A, *2D, *3, *4A, *4B, *4D, *4J,*4K, *5, *6A/B, *9, *10A, *10B, *15, *17, *35,*40, *41, *1XN, *2AXN, *4AXN, *35XN,*41XN; CYP3A4*1B, *8, *11, *12, *13, *16,*17, *18, *20; and CYP3A5*3

No significant association between CYP2D6and clinical efficacyCYP2A4*1B and CYP3A5*3 significantlyassociated with refractoriness to treatment

Kohlrausch et al. (2008)

Olanzapine South Asian (130) CYP2D6*4, CYP1A2*1C, *1F No significant association with clinicalefficacy

Thomas et al. (2008)

Olanzapine Caucasian (124) CYP1A2*1F No significant association with clinicalefficacy

Laika et al. (2010)

Risperidone Caucasian (82) CYP2D6*4, *6, *14 No significant association with clinicalefficacy

Riedel et al. (2005)

Risperidone Asian (136) CYP2D6*2, *10 No significant difference in clinicalimprovement

Kakihara et al. (2005)

Antipsychotics metabolized byCYP2D6

Caucasian (128) CYP2D6*1, *3, *4, *5, *6, *7 No significant association with diseasesymptom severity

Hamelin et al. (1999)

Typical antipsychotics Caucasian (308) CYP2D6*3, *4, *5 More UM in the nonrefractory than refrac-tory group (4.1% vs. 0.9%; P = 0.9)

Aitchison et al. (1999)

Various antipsychotics Caucasian (365) CYP2D6*1, *2, *3, *4, *6 to *10, *41 Clinical efficacy was lower in IMs receivingdrugs metabolized by CYP2D6 than IMsreceiving other medications (P = 0.017)

Laika et al. (2009)

Various antipsychotics Asian (156) CYP2D6*3, *4, *5, *6, *9, *10, *14, *17 UMs had significantly more severe negativesymptoms (P = 0.001)

Zahari et al. (2009)

Various antipsychotics Caucasian (576) CYP2D6*3, *4, *5, *6 No significant association with observableclinical impact in dosing or use ofanticholinergic drugs

Jurgens et al. (2012)

Various antipsychotics Caucasian (116) CYP2D6*1 to *8 More EM in nonrefractory than refractorygroup (67% vs. 46%; P = 0.02)

Alenius et al. (2008)

Various antipsychotics Caucasian (116) CYP2D6*1 to *10, *15, *17, *29, *35, *36, *40,*41, *1XN, *2XN, *4XN, *10XN, *17XN, *35XN*41XN

No significant association with clinicalefficacy

Muller et al. (2012)

SNP = single nucleotide polymorphism; UM = ultrarapid metabolism; IM = intermediate metabolism.

9D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

A prospective study in 172 psychiatric inpatients evaluated therelationship between CYP2D6 phenotype and haloperidol adverse events(Brockmoller et al., 2002). PMs had significantly higher event rates of EPSthan those with one or more active CYP2D6 genes (P = 0.02). Thehighest percentage of patients with grade 2 or 3 adverse effects wereUMs (100%) and this group also experienced the smallest therapeuticimprovement or a worsening of symptoms. Another study evaluatedEPS in 26 outpatients with schizophrenia receiving depot haloperidolmonotherapy (Panagiotidis et al., 2007). Although there was a signifi-cant association between haloperidol plasma concentration and thenumber of active CYP2D6 alleles, no relationship to treatment outcomesor EPSwas observed. A case–control study found that CYP2D6 PMshad asignificant three times higher odds of risperidone adverse drug reac-tions (OR 3.4, 95% CI 1.5–8.0) and a six-times higher odds of discontin-uation (OR 6.0, 95% CI 1.4–25.4), compared with EMs (de Leon et al.,2005a).

A study of 85 patients with schizophrenia evaluated the severity oftardive dyskinesia in association with CYP1A2*1F polymorphisms(Basile et al., 2000). Those with the C/C genotype for CYP1A2 wereat significantly increased risk of tardive dyskinesia induced by typicalantipsychotics, compared with those who were heterozygous orhomozygous for the CYP1A2 A allele (P = 0.0007).

4.2.2. Weight gainThe most common CYP2D6 polymorphism among Asians is

CYP2D6*10, which occurs in up to 50% of various Asian subpopulationsand results in an unstable enzyme and diminished activity (Kurose et

al., 2012). A study of 123 Chinese inpatientswith schizophrenia receivingrisperidone monotherapy found that those with homozygous wild typeCYP2D6 alleles had significantly lower weight gain than those with theheterozygous (P b 0.004) or homozygous (P = 0.04) CYP2D6*10 poly-morphisms (Lane et al., 2006). Another study in 11 patients with schizo-phrenia receiving olanzapine examined the relationship betweenCYP2D6polymorphisms and weight gain. Genotype was significantly associatedwith bodymass index change,with patients having a *1/*3 or *4 genotypeexperiencing a larger percent change in BMI, compared with thosewith the wild type (*1/*1) genotype (P b 0.001) (Ellingrod et al.,2002a). An open label prospective study investigated the associationbetween weight gain and CYP1A2 and CYP2D6 genotype in 130 SouthAsian patients with schizophrenia or schizoaffective disorder (Thomaset al., 2008). No significant correlation was seen between weight gainand the presence of CYP2D6*4, CYP1A2*1C, or CYP1A2*1F.

5. Is CYP pharmacogenetics ready for clinical practice?

Several laboratories offer Clinical Laboratory Improvement Amend-ments (CLIA)-approved CYP450 genotyping to identify known polymor-phisms and these test results are currently being used in treatmentdecision making. In its Critical Path Initiative 2010, the US FDA em-phasized the need to include pharmacogenetics language on productlabeling where appropriate, and specific CYP450 pharmacogeneticrecommendations can now be found on numerous package inserts(US Food and Drug Administration, 2012); however, the issue ofwhether to use pharmacogenetic testing to enhance outcomes in

Fig. 4. Hypothetical analytic framework for evaluating the use of genetic testing in antipsychotic treatment decision making according to the EGAPP approach to creating a “chain ofevidence” assessment (Teutsch et al., 2009).

10 D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

patients receiving antipsychotics is complex. There is a plausiblebiologic rationale, accumulating evidence linking genetic variation withdrug response, and availability of reliable laboratory tests (Mrazek andLerman, 2011). Conversely, the lack of large, high-quality studies has hin-dered consensus and widespread evidence-based recommendations.

The major question is whether there is sufficient evidence thatpharmacogenetic testing improves efficacy or safety in specific set-tings, such as the use of antipsychotics in adult patients with schizo-phrenia. Given the urgency of implementation and the plethora ofpotentially confounding factors involved in drug metabolism, it is un-likely that randomized controlled trials will be conducted for everyclinical application of pharmacogenetic testing desirable. Therefore,the level of evidence needed for clinical implementation is currentlybeing debated. The Clinical Pharmacogenetics ImplementationConsortium (CPIC) of the Pharmacogenomics Research Network hasargued that, given biologic plausibility and evidence of a gene–drugassociation, noninferiority when compared with current standardsof prescribing is an acceptable threshold (Altman, 2011).

There are numerous resources clinicians may use to gather infor-mation on the strength of evidence related to pharmacogenetic-based dosing and treatment decisions, as well as specific dosingguidelines, some of which are summarized in this review. Theseinclude resources from CPIC, which provides peer-reviewed recom-mendations and drug/gene guidelines (Swen et al., 2011). ThePharmacogenomic Knowledge Base (PharmGKB), curates knowledgeand evidence for the impact of specific genetic variations on drugmetabolism (Altman, 2007). The Pharmacogenetic Research Networkis funded by the National Institutes of Health and brings togethernumerous research initiatives.

The Royal Dutch Association for the Advancement of Pharmacyhas developed pharmacogenetics-based therapeutic dose recommen-dations based on the available evidence (Swen et al., 2011). Theguidelines currently provide recommendations for over 50 drugsand 100 genotype/phenotype–drug combinations. Identified studiesare graded for the quality of evidence and clinical relevance for thegene–drug interaction. Risk analysis is then used to develop recom-mendations for dose adjustments and therapeutic strategies, such astherapeutic drug monitoring, alternative drug selections, or warningfor adverse events.

The Evaluation of Genomic Applications in Practice and Prevention(EGAPP) initiative, establishedby the Centers forDisease Control andPre-vention (CDC), has created guidelines for evaluation and evidence-basedapplication of genetic tests (Teutsch et al., 2009). The EGAPP provides ananalytic framework for examining evidence related to pharmacogenetictesting. Fig. 4 illustrates a hypothetical application of this framework tothe problem of genotype testing for antipsychotic use. This approach em-phasizes the analytic validity (sensitivity and specificity of the genotypetest), clinical validity (ability of the test to predict the association of geno-typewith the circulating levels or clinical response predictedby the geno-type), and clinical utility (likelihood that use of the test to guide drugchoice will improve outcomes). A recent meta analysis of CYP450 testingfor prescribing antipsychotics in adults with schizophrenia found 41 of2841 studies reported analytic validity, 47 of 2151 reported data on

clinical validity, and only 1 of 1234 reported clinical utility (Fleeman etal., 2011).

6. Conclusion

The US FDA has increasingly required inclusion of pharmacogeneticinformation in product labeling, and provides guidance on incorpora-tion of pharmacogenetic studies in drug development. Plasma levels—and potentially the efficacy and safety—of many antipsychotic drugsare influenced by known CYP450 genetic variants. CLIA-approved as-says are available to test for these polymorphisms in patients and arerelatively inexpensive. No randomized clinical trials have yet evaluatedwhether use of CYP450 genotyping in antipsychotic treatment decisionmaking is associated with better treatment response or reduced likeli-hood of adverse events in adult psychiatric patients. Randomized trialsare not only cost prohibitive, they may not be practical because somepolymorphisms are too infrequent (Mrazek and Lerman, 2011). Addi-tionally, given the current high predictive value of pharmacogenetictests, it would not be ethical to randomize patients to treatments thatare potentially toxic for known phenotypes.

Most studies to date have been unable to provide sufficient evidenceto support the use of CYP450 genotype testing to improve therapeuticefficacy in the use of antipsychotic medications and the clinical utilityof this strategy has not been determined. The inability to conclusivelydemonstrate a therapeutic benefit of genotype testing may be limitedby several factors, including: 1) retrospective or cross-sectional design,2) inadequate statistical power from small study groups and/or infre-quent alleles, 3) heterogeneous patient groups with regard to ethnicity,diagnoses, illness severity, medication, treatment duration, and dose,and 4) a wide variety of outcomes measures. Collectively, the literatureprovides a consistent body of evidence supporting the use of genotypictesting to prevent adverse events in adults receiving some antipsy-chotics. The role of additional genetic variants beyond CYP450 in thetherapeutic and adverse responses to antipsychotics is currently beingevaluated, including those polymorphisms related to pharmacodynam-ic targets such as dopamine and serotonin receptors, and cellular trans-porters (Arranz et al., 2011; Zhang and Malhotra, 2011). These studiesoffer additional avenues to predict efficacy andmay be useful to preventadverse effects, including weight gain and EPS (Fraguas and Kirchoff,2006; Lett et al., 2012).

Guidelines provide an important resource for the clinical applicationof pharmacogenetics to antipsychotic use where sufficient evidencecurrently exists to make a recommendation. Although in many casesthe evidence base clinical implementation of pharmacogenetics is suffi-cient, conclusive recommendations for routine use of pharmacogenetictesting to guide antipsychotic use in adults with schizophrenia awaitsresults of large prospective trials with generalizable results.

Role of funding sourceThere was no funding for this article.

ContributorsContributors:

11D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

Dr. Nasrallah conceptualized the article and its themes.Dr. Dana Ravyn drafted the initial manuscript.Dr. Vipa Ravyn collected the literature and contributed to the writing.Mr. Robert Lowney assisted in tabulation of data.

Conflict of interestDrs. Ravyn and Mr. Lowney have no conflict of interest.Dr. Nasrallah has received research grants from Genentech, Otsuka, Roche, and

Shire. He has received honoraria from Boehringer-Ingelheim, Genentech, Janssen,Merck, Novartis, Otsuka, Lunbeck, Roche, and Sunovion.

AcknowledgmentThere are no acknowledgments.

References

Aitchison, K.J., Munro, J., Wright, P., Smith, S., Makoff, A.J., Sachse, C., Sham, P.C.,Murray, R.M., Collier, D.A., Kerwin, R.W., 1999. Failure to respond to treatmentwith typical antipsychotics is not associated with CYP2D6 ultrarapid hydroxyl-ation. Br. J. Clin. Pharmacol. 48 (3), 388–394.

Alenius, M., Wadelius, M., Dahl, M.L., Hartvig, P., Lindstrom, L., Hammarlund-Udenaes,M., 2008. Gene polymorphism influencing treatment response in psychoticpatients in a naturalistic setting. J. Psychiatr. Res. 42 (11), 884–893.

Allen, M.H., Feifel, D., Lesem, M.D., Zimbroff, D.L., Ross, R., Munzar, P., Spyker, D.A.,Cassella, J.V., 2011. Efficacy and safety of loxapine for inhalation in the treatmentof agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. J. Clin. Psychiatry 72 (10), 1313–1321.

Altman, R.B., 2007. PharmGKB: a logical home for knowledge relating genotype to drugresponse phenotype. Nat. Genet. 39 (4), 426.

Altman, R.B., 2011. Pharmacogenomics: “noninferiority” is sufficient for initial imple-mentation. Clin. Pharmacol. Ther. 89 (3), 348–350.

Amirimani, B., Ning, B., Deitz, A.C., Weber, B.L., Kadlubar, F.F., Rebbeck, T.R., 2003.Increased transcriptional activity of the CYP3A4*1B promoter variant. Environ.Mol. Mutagen. 42 (4), 299–305.

Andreassen, O.A., MacEwan, T., Gulbrandsen, A.K., McCreadie, R.G., Steen, V.M., 1997.Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disor-ders in schizophrenic patients. Psychopharmacology (Berl) 131 (2), 174–179.

Aripiprazole package insert, 2012. Princeton, NJ: Bristol-Myers Squibb Company.Armstrong, M., Daly, A.K., Blennerhassett, R., Ferrier, N., Idle, J.R., 1997. Antipsychotic

drug-induced movement disorders in schizophrenics in relation to CYP2D6 geno-type. Br. J. Psychiatry 170, 23–26.

Arranz, M.J., Dawson, E., Shaikh, S., Sham, P., Sharma, T., Aitchison, K., Crocq, M.A., Gill, M.,Kerwin, R., Collier, D.A., 1995. Cytochrome P4502D6 genotype does not determine re-sponse to clozapine. Br. J. Clin. Pharmacol. 39 (4), 417–420.

Arranz, M.J., Rivera, M., Munro, J.C., 2011. Pharmacogenetics of response to antipsy-chotics in patients with schizophrenia. CNS Drugs 25 (11), 933–969.

Arthur, H., Dahl, M.L., Siwers, B., Sjoqvist, F., 1995. Polymorphic drug metabolism inschizophrenic patients with tardive dyskinesia. J. Clin. Psychopharmacol. 15 (3),211–216.

Bakken, G.V., Rudberg, I., Christensen, H., Molden, E., Refsum, H., Hermann, M., 2009.Metabolism of quetiapine by CYP3A4 and CYP3A5 in presence or absence of cyto-chrome B5. Drug Metab. Dispos. 37 (2), 254–258.

Basile, V.S., Ozdemir, V., Masellis, M., Walker, M.L., Meltzer, H.Y., Lieberman, J.A., Potkin,S.G., Alva, G., Kalow, W., Macciardi, F.M., Kennedy, J.L., 2000. A functional polymor-phism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyski-nesia in schizophrenia. Mol. Psychiatry 5 (4), 410–417.

Beedham, C., Miceli, J.J., Obach, R.S., 2003. Ziprasidone metabolism, aldehyde oxidase,and clinical implications. J. Clin. Psychopharmacol. 23 (3), 229–232.

Berecz, R., de la Rubia, A., Dorado, P., Fernandez-Salguero, P., Dahl, M.L., A, L.L., 2003.Thioridazine steady-state plasma concentrations are influenced by tobaccosmoking and CYP2D6, but not by the CYP2C9 genotype. Eur. J. Clin. Pharmacol.59 (1), 45–50.

Bertilsson, L., Dahl, M.L., Dalen, P., Al-Shurbaji, A., 2002. Molecular genetics of CYP2D6: clin-ical relevance with focus on psychotropic drugs. Br. J. Clin. Pharmacol. 53 (2), 111–122.

Bigos, L., Bies, R.R., Pollack, B.G., Lowy, J.J., Zhang, F., Weinberger, D.R., 2011.Genetic variation in CYP3A43 explains racial difference in olanzapine clearance.Mol. Psychiatry 16 (6), 620–625.

Bork, J.A., Rogers, T., Wedlund, P.J., de Leon, J., 1999. A pilot study on risperidone metab-olism: the role of cytochromes P450 2D6 and 3A. J. Clin. Psychiatry 60 (7), 469–476.

Brockmoller, J., Kirchheiner, J., Schmider, J., Walter, S., Sachse, C., Muller-Oerlinghausen, B.,Roots, I., 2002. The impact of the CYP2D6polymorphismonhaloperidol pharmacokinet-ics and on the outcome of haloperidol treatment. Clin. Pharmacol. Ther. 72 (4), 438–452.

Brosen, K., 2004. Pharmacogenetic and Pharmacogenomics. 2004 International Unionof Basic and Clinical Pharmacology, Irvine, CA. (Chapter 4).

Cascorbi, I., 2003. Pharmacogenetics of cytochrome p4502D6: genetic background andclinical implication. Eur. J. Clin. Investig. 33 (Suppl. 2), 17–22.

Cha, D.S., McIntyre, R.S., 2012. Treatment-emergent adverse events associated withatypical antipsychotics. Expert. Opin. Pharmacother. 13 (11), 1587–1598.

Chong, S.A., 1997. Tardive dyskinesia in CYP2D6polymorphism inChinese. Br. J. Psychiatry171, 586.

Clozapine package insert, 2010. East Hanover, NJ: Novartis Pharmaceuticals Corporation.Cooper, T.B., Kelly, R.G., 1979. GLC analysis of loxapine, amoxapine, and their metabo-

lites in serum and urine. J. Pharm. Sci. 68 (2), 216–219.

Crews, K.R., Hicks, J.K., Pui, C.H., Relling, M.V., Evans, W.E., 2012. Pharmacogenomicsand individualized medicine: translating science into practice. Clin. Pharmacol.Ther. 92 (4), 467–475.

Dahl, M.L., Ekqvist, B., Widen, J., Bertilsson, L., 1991. Disposition of the neurolepticzuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquinein humans. Acta Psychiatr. Scand. 84 (1), 99–102.

Dahl, M.L., Llerena, A., Bondesson, U., Lindstrom, L., Bertilsson, L., 1994. Dispositionof clozapine in man: lack of association with debrisoquine and S-mephenytoinhydroxylation polymorphisms. Br. J. Clin. Pharmacol. 37 (1), 71–74.

Dahl-Puustinen, M.L., Liden, A., Alm, C., Nordin, C., Bertilsson, L., 1989. Dispositionof perphenazine is related to polymorphic debrisoquin hydroxylation in humanbeings. Clin. Pharmacol. Ther. 46 (1), 78–81.

de Leon, J., Susce, M.T., Pan, R.M., Fairchild, M., Koch, W.H., Wedlund, P.J., 2005a. TheCYP2D6 poor metabolizer phenotype may be associated with risperidone adversedrug reactions and discontinuation. J. Clin. Psychiatry 66 (1), 15–27.

de Leon, J., Susce, M.T., Pan, R.M., Koch, W.H., Wedlund, P.J., 2005b. Polymorphicvariations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine D2 and D3 recep-tors and their association with tardive dyskinesia in severe mental illness. J. Clin.Psychopharmacol. 25 (5), 448–456.

de Leon, J., Susce, M.T., Murray-Carmichael, E., 2006. The AmpliChip CYP450genotyping test: Integrating a new clinical tool. Mol. Diagn. Ther. 10 (3), 135–151.

de Leon, J., Sandson, N.B., Cozza, K.L., 2008. A preliminary attempt to personalize risper-idone dosing using drug–drug interactions and genetics: part II. Psychosomatics 49(4), 347–361.

Desai, M., Tanus-Santos, J.E., Li, L., Gorski, J.C., Arefayene, M., Liu, Y., Desta, Z., Flockhart,D.A., 2003. Pharmacokinetics and QT interval pharmacodynamics of oral haloperidolin poor and extensive metabolizers of CYP2D6. Pharmacogenomics J. 3 (2), 105–113.

Dettling, M., Sachse, C., Brockmoller, J., Schley, J., Muller-Oerlinghausen, B., Pickersgill,I., Rolfs, A., Schaub, R.T., Schmider, J., 2000a. Long-term therapeutic drug monitor-ing of clozapine and metabolites in psychiatric in- and outpatients. Psychopharma-cology (Berl) 152 (1), 80–86.

Dettling, M., Sachse, C., Muller-Oerlinghausen, B., Roots, I., Brockmoller, J., Rolfs, A.,Cascorbi, I., 2000b. Clozapine-induced agranulocytosis and hereditary polymor-phisms of clozapine metabolizing enzymes: no association with myeloperoxidaseand cytochrome P4502D6. Pharmacopsychiatry 33 (6), 218–220.

Dorado, P., Penas, L.E.M., de la Rubia, A.A,.L.L., 2009. Relevance of CYP2D6–1584C N Gpolymorphism for thioridazine:mesoridazine plasma concentration ratio in psy-chiatric patients. Pharmacogenomics 10 (7), 1083–1089.

Eap, C.B., Guentert, T.W., Schaublin-Loidl, M., Stabl, M., Koeb, L., Powell, K., Baumann, P.,1996. Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thi-oridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizersof dextromethorphan and mephenytoin. Clin. Pharmacol. Ther. 59 (3), 322–331.

Eiermann, B., Engel, G., Johansson, I., Zanger, U.M., Bertilsson, L., 1997. The involvementof CYP1A2 and CYP3A4 in the metabolism of clozapine. Br. J. Clin. Pharmacol. 44 (5),439–446.

Elens, L., Bouamar, R., Hesselink, D.A., Haufroid, V., van Gelder, T., van Schaik, R.H., 2012.The new CYP3A4 intron 6 C N T polymorphism (CYP3A4*22) is associatedwith an in-creased risk of delayed graft function and worse renal function in cyclosporine-treated kidney transplant patients. Pharmacogenet. Genomics 22 (5), 373–380.

Ellingrod, V.L., Miller, D., Schultz, S.K., Wehring, H., Arndt, S., 2002a. CYP2D6 poly-morphisms and atypical antipsychotic weight gain. Psychiatr. Genet. 12 (1),55–58.

Ellingrod, V.L., Schultz, S.K., Arndt, S., 2002b. Abnormal movements and tardive dyski-nesia in smokers and nonsmokers with schizophrenia genotyped for cytochromeP450 2D6. Pharmacotherapy 22 (11), 1416–1419.

Fang, J., McKay, G., Song, J., Remillrd, A., Li, X., Midha, K., 2001. In vitro characterizationof the metabolism of haloperidol using recombinant cytochrome p450 enzymesand human liver microsomes. Drug Metab. Dispos. 29 (12), 1638–1643.

Fleeman, N., Dundar, Y., Dickson, R., Jorgensen, A., Pushpakom, S., McLeod, C.,Pirmohamed, M., Walley, T., 2011. Cytochrome P450 testing for prescribing anti-psychotics in adults with schizophrenia: systematic review and meta-analyses.Pharmacogenomics J. 11 (1), 1–14.

Fraguas, D., Kirchoff, D., 2006. Pharmacogenetics of antipsychotic-induced weight gain.Med. Sci. Monit. 12 (5), LE6–LE7.

Frueh, F.W., Amur, S., Mummaneni, P., Epstein, R.S., Aubert, R.E., DeLuca, T.M.,Verbrugge, R.R., Burckart, G.J., Lesko, L.J., 2008. Pharmacogenomic biomarker infor-mation in drug labels approved by the United States food and drug administration:prevalence of related drug use. Pharmacotherapy 28 (8), 992–998.

Fu, Y., Fan, C.H., Deng, H.H., Hu, S.H., Lv, D.P., Li, L.H.,Wang, J.J., Lu, X.Q., 2006. Association ofCYP2D6 and CYP1A2 gene polymorphism with tardive dyskinesia in Chinese schizo-phrenic patients. Acta Pharmacol. Sin. 27 (3), 328–332.

Gaedigk, A., Bradford, L.D., Marcucci, K.A., Leeder, J.S., 2002. Unique CYP2D6 activity distri-bution and genotype–phenotype discordance in black Americans. Clin. Pharmacol.Ther. 72 (1), 76–89.

Glazer, W.M., 1999. Does loxapine have “atypical” properties? Clinical evidence. J. Clin.Psychiatry 60 (Suppl. 10), 42–46.

Grimm, S.W., Richtand, N.M., Winter, H.R., Stams, K.R., Reele, S.B., 2006. Effects ofcytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapinepharmacokinetics. Br. J. Clin. Pharmacol. 61 (1), 58–69.

Grossman, I., Sullivan, P.F., Walley, N., Liu, Y., Dawson, J.R., Gumbs, C., Gaedigk, A.,Leeder, J.S., McEvoy, J.P., Weale, M.E., Goldstein, D.B., 2008. Genetic determinantsof variable metabolism have little impact on the clinical use of leading antipsy-chotics in the CATIE study. Genet. Med. 10 (10), 720–729.

Hagg, S., Spigset, O., Lakso, H.A., Dahlqvist, R., 2001. Olanzapine disposition in humansis unrelated to CYP1A2 and CYP2D6 phenotypes. Eur. J. Clin. Pharmacol. 57 (6–7),493–497.

12 D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

Hamelin, B.A., Dorson, P.G., Pabis, D., Still, D., Bouchard, R.H., Pourcher, E., Rail, J.,Turgeon, J., Crismon, M.L., 1999. CYP2D6 mutations and therapeutic outcome inschizophrenic patients. Pharmacotherapy 19 (9), 1057–1063.

Hartung, B., Wada, M., Laux, G., Leucht, S., 2005. Perphenazine for schizophrenia.Cochrane Database Syst. Rev. (1), CD003443.

Hendset, M., Hermann, M., Lunde, H., Refsum, H., Molden, E., 2007. Impact of theCYP2D6 genotype on steady-state serum concentrations of aripiprazole anddehydroaripiprazole. Eur. J. Clin. Pharmacol. 63 (12), 1147–1151.

Huang, M.L., Van Peer, A., Woestenborghs, R., De Coster, R., Heykants, J., Jansen, A.A.,Zylicz, Z., Visscher, H.W., Jonkman, J.H., 1993. Pharmacokinetics of the novel anti-psychotic agent risperidone and the prolactin response in healthy subjects. Clin.Pharmacol. Ther. 54 (3), 257–268.

Iloperidone package insert, 2012. East Hanover, NJ: Novartis PharmaceuticalsCorporation.

Inada, T., Senoo, H., Iijima, Y., Yamauchi, T., Yagi, G., 2003. Cytochrome P450 II D6 genepolymorphisms and the neuroleptic-induced extrapyramidal symptoms in Japa-nese schizophrenic patients. Psychiatr. Genet. 13 (3), 163–168.

Ingelman-Sundberg, M., 2004. Human drug metabolising cytochrome P450 enzymes:properties and polymorphisms. Naunyn-Schmiedebergs Arch. Pharmacol. 369(1), 89–104.

Jaanson, P., Marandi, T., Kiivet, R.A., Vasar, V., Vaan, S., Svensson, J.O., Dahl, M.L., 2002.Maintenance therapy with zuclopenthixol decanoate: associations betweenplasma concentrations, neurological side effects and CYP2D6 genotype. Psycho-pharmacology (Berl) 162 (1), 67–73.

Jerling, M., Dahl, M.L., Aberg-Wistedt, A., Liljenberg, B., Landell, N.E., Bertilsson, L.,Sjoqvist, F., 1996. The CYP2D6 genotype predicts the oral clearance of the neurolepticagents perphenazine and zuclopenthixol. Clin. Pharmacol. Ther. 59 (4), 423–428.

Jurgens, G., Rasmussen, H.B., Werge, T., Dalhoff, K., Nordentoft, M., Andersen, S.E., 2012.Does the medication pattern reflect the CYP2D6 genotype in patients with diagno-ses within the schizophrenic spectrum? J. Clin. Psychopharmacol. 32 (1), 100–105.

Kakihara, S., Yoshimura, R., Shinkai, K., Matsumoto, C., Goto, M., Kaji, K., Yamada, Y.,Ueda, N., Ohmori, O., Nakamura, J., 2005. Prediction of response to risperidonetreatment with respect to plasma concencentrations of risperidone, catecholaminemetabolites, and polymorphism of cytochrome P450 2D6. Int. Clin. Psychopharmacol.20 (2), 71–78.

Kapitany, T., Meszaros, K., Lenzinger, E., Schindler, S.D., Barnas, C., Fuchs, K., Sieghart, W.,Aschauer, H.N., Kasper, S., 1998. Genetic polymorphisms for drug metabolism(CYP2D6) and tardive dyskinesia in schizophrenia. Schizophr. Res. 32 (2), 101–106.

Kassahun, K., Mattiuz, E., Nyhart Jr., E., Obermeyer, B., Gillespie, T., Murphy, A.,Goodwin, R.M., Tupper, D., Callaghan, J.T., Lemberger, L., 1997. Disposition and bio-transformation of the antipsychotic agent olanzapine in humans. Drug Metab.Dispos. 25 (1), 81–93.

Kim, E., Yu, K.S., Cho, J.Y., Shin, Y.W., Yoo, S.Y., Kim, Y.Y., Jang, I.J., Shin, S.G., Kwon, J.S., 2006.Effects of DRD2 and CYP2D6 genotypes on delta EEG power response to aripiprazolein healthy male volunteers: a preliminary study. Hum. Psychopharmacol. 21 (8),519–528.

Kohlrausch, F.B., Gama, C.S., Lobato, M.I., Belmonte-de-Abreu, P., Callegari-Jacques, S.M.,Gesteira, A., Barros, F., Carracedo, A., Hutz, M.H., 2008. Naturalistic pharmacogeneticstudy of treatment resistance to typical neuroleptics in European–Brazilian schizo-phrenics. Pharmacogenet. Genomics 18 (7), 599–609.

Kohnke, M.D., Griese, E.U., Stosser, D., Gaertner, I., Barth, G., 2002. Cytochrome P4502D6 deficiency and its clinical relevance in a patient treated with risperidone.Pharmacopsychiatry 35 (3), 116–118.

Kootstra-Ros, J.E., Smallegoor, W., van der Weide, J., 2005. The cytochrome P450CYP1A2 genetic polymorphisms *1F and *1D do not affect clozapine clearance ina group of schizophrenic patients. Ann. Clin. Biochem. 42 (Pt 3), 216–219.

Kubo, M., Koue, T., Inaba, A., Takeda, H., Maune, H., Fukuda, T., Azuma, J., 2005. Influenceof itraconazole co-administration and CYP2D6 genotype on the pharmacokinetics ofthe new antipsychotic ARIPIPRAZOLE. Drug Metab. Pharmacokinet. 20 (1), 55–64.

Kubo, M., Koue, T., Maune, H., Fukuda, T., Azuma, J., 2007. Pharmacokinetics ofaripiprazole, a new antipsychotic, following oral dosing in healthy adult Japanesevolunteers: influence of CYP2D6 polymorphism. Drug Metab. Pharmacokinet. 22(5), 358–366.

Kurose, K., Sugiyama, E., Saito, Y., 2012. Population differences in major functionalpolymorphisms of pharmacokinetics/pharmacodynamics-related genes in EasternAsians and Europeans: implications in the clinical trials for novel drug develop-ment. Drug Metab. Pharmacokinet. 27 (1), 9–54.

Kwon, J.S., Jang, J.H., Kang, D.H., Yoo, S.Y., Kim, Y.K., Cho, S.J., 2009. Long-term efficacyand safety of aripiprazole in patients with schizophrenia, schizophreniform disorder,or schizoaffective disorder: 26-week prospective study. Psychiatry Clin. Neurosci. 63(1), 73–81.

Laika, B., Leucht, S., Heres, S., Steimer, W., 2009. Intermediate metabolizer: increasedside effects in psychoactive drug therapy. The key to cost-effectiveness of pretreat-ment CYP2D6 screening? Pharmacogenomics J. 9 (6), 395–403.

Laika, B., Leucht, S., Heres, S., Schneider, H., Steimer, W., 2010. Pharmacogenetics andolanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influencetherapeutic outcome. Pharmacogenomics J. 10 (1), 20–29.

Lam, L.C., Garcia-Barcelo, M.M., Ungvari, G.S., Tang, W.K., Lam, V.K., Kwong, S.L., Lau,B.S., Kwong, P.P., Waye, M.M., Chiu, H.F., 2001. Cytochrome P450 2D6 genotypingand association with tardive dyskinesia in Chinese schizophrenic patients.Pharmacopsychiatry 34 (6), 238–241.

Lamba, J.K., Lin, Y.S., Schuetz, E.G., Thummel, K.E., 2012. Genetic contribution to variablehuman CYP3A-mediated metabolism. Adv. Drug Deliv. Rev. 54 (10), 1271–1294.

Lane, H.Y., Liu, Y.C., Huang, C.L., Chang, Y.C.,Wu, P.L., Lu, C.T., Chang,W.H., 2006. Risperidone-relatedweight gain: genetic and nongenetic predictors. J. Clin. Psychopharmacol. 26 (2),128–134.

Lee, S.J., Bell, D.A., Coulter, S.J., Ghanayem, B., Goldstein, J.A., 2005. RecombinantCYP3A4*17 is defective in metabolizing the hypertensive drug nifedipine, and theCYP3A4*17 allele may occur on the same chromosome as CYP3A5*3, representing anew putative defective CYP3A haplotype. J. Pharmacol. Exp. Ther. 313 (1), 302–309.

Lett, T.A., Wallace, T.J., Chowdhury, N.I., Tiwari, A.K., Kennedy, J.L., Muller, D.J., 2012.Pharmacogenetics of antipsychotic-induced weight gain: review and clinical impli-cations. Mol. Psychiatry 17 (3), 242–266.

Lingjaerde, O., Ahlfors, U.G., Bech, P., Dencker, S.J., Elgen, K., 1987. The UKU side effectrating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr.Scand. Suppl. 334, 1–100.

Linnet, K., Wiborg, O., 1996a. Influence of Cyp2D6 genetic polymorphism on ratios ofsteady-state serum concentration to dose of the neuroleptic zuclopenthixol. Ther.Drug Monit. 18 (6), 629–634.

Linnet, K., Wiborg, O., 1996b. Steady-state serum concentrations of the neurolepticperphenazine in relation to CYP2D6 genetic polymorphism. Clin. Pharmacol.Ther. 60 (1), 41–47.

Liou, Y.J., Wang, Y.C., Bai, Y.M., Lin, C.C., Yu, S.C., Liao, D.L., Lin, M.W., Chen, J.Y., Lai, I.C.,2004. Cytochrome P-450 2D6*10 C188T polymorphism is associated withantipsychotic-induced persistent tardive dyskinesia in Chinese schizophrenicpatients. Neuropsychobiology 49 (4), 167–173.

Llerena, A., Alm, C., Dahl, M.L., Ekqvist, B., Bertilsson, L., 1992a. Haloperidol disposition isdependent on debrisoquine hydroxylation phenotype. Ther. Drug Monit. 14 (2),92–97.

Llerena, A., Dahl, M.L., Ekqvist, B., Bertilsson, L., 1992b. Haloperidol disposition isdependent on the debrisoquine hydroxylation phenotype: increased plasma levelsof the reduced metabolite in poor metabolizers. Ther. Drug Monit. 14 (3), 261–264.

Llerena, A., Berecz, R., Dorado, P., de la Rubia, A., 2004a. QTc interval, CYP2D6 andCYP2C9 genotypes and risperidone plasma concentrations. J. Psychopharmacol.18 (2), 189–193.

Llerena, A., de la Rubia, A., Berecz, R., Dorado, P., 2004b. Relationship between haloper-idol plasma concentration, debrisoquine metabolic ratio, CYP2D6 and CYP2C9genotypes in psychiatric patients. Pharmacopsychiatry 37 (2), 69–73.

Lohmann, P.L., Bagli, M., Krauss, H., Muller, D.J., Schulze, T.G., Fangerau, H., Ludwig, M.,Barkow, K., Held, T., Heun, R., Maier, W., Rietschel, M., Rao, M.L., 2003. CYP2D6 poly-morphism and tardive dyskinesia in schizophrenic patients. Pharmacopsychiatry 36(2), 73–78.

Lovlie, R., Daly, A.K., Matre, G.E., Molven, A., Steen, V.M., 2001. Polymorphisms in CYP2D6duplication-negative individuals with the ultrarapid metabolizer phenotype: a rolefor the CYP2D6*35 allele in ultrarapid metabolism? Pharmacogenetics 11 (1), 45–55.

Luo, J.P., Vashishtha, S.C., Hawes, E.M., McKay, G., Midha, K.K., Fang, J., 2011. In vitroidentification of the human cytochrome p450 enzymes involved in the oxidativemetabolism of loxapine. Biopharm. Drug Dispos. 32 (7), 398–407.

Lurasidone package insert, 2012. Marlborough, MA: Sunovion Pharmaceuticals Inc.Mark, T.L., 2010. For what diagnoses are psychotropic medications being prescribed?:

a nationally representative survey of physicians. CNS Drugs 24 (4), 319–326.McCullough, K.B., Formea, C.M., Berg, K.D., Burzynski, J.A., Cunningham, J.L., Ou, N.N., Rudis,

M.I., Stollings, J.L., Nicholson, W.T., 2011. Assessment of the pharmacogenomics edu-cational needs of pharmacists. Am. J. Pharm. Educ. 75 (3), 51.

McEvoy, J.P., Lieberman, J.A., Stroup, T.S., Davis, S.M., Meltzer, H.Y., Rosenheck, R.A.,Swartz, M.S., Perkins, D.O., Keefe, R.S., Davis, C.E., Severe, J., Hsiao, J.K., 2006. Effec-tiveness of clozapine versus olanzapine, quetiapine, and risperidone in patientswith chronic schizophrenia who did not respond to prior atypical antipsychotictreatment. Am. J. Psychiatry 163 (4), 600–610.

McGraw, J., Waller, D., 2012. Cytochrome P450 variations in different ethnic popula-tions. Expert Opin. Drug Metab. Toxicol. 8 (3), 371–382.

Megens, A.A., Awouters, F.H., Schotte, A., Meert, T.F., Dugovic, C., Niemegeers, C.J.,Leysen, J.E., 1994. Survey on the pharmacodynamics of the new antipsychotic ris-peridone. Psychopharmacology (Berl) 114 (1), 9–23.

Melkersson, K.I., Scordo, M.G., Gunes, A., Dahl, M.L., 2007. Impact of CYP1A2 and CYP2D6polymorphisms on drug metabolism and on insulin and lipid elevations and insulinresistance in clozapine-treated patients. J. Clin. Psychiatry 68 (5), 697–704.

Mendoza, R., Wan, Y.J., Poland, R.E., Smith, M., Zheng, Y., Berman, N., Lin, K.M., 2001.CYP2D6 polymorphism in a Mexican American population. Clin. Pharmacol. Ther.70 (6), 552–560.

Miceli, J.J., Anziano, R.J., Robarge, L., Hansen, R.A., Laurent, A., 2000a. The effect ofcarbamazepine on the steady-state pharmacokinetics of ziprasidone in healthyvolunteers. Br. J. Clin. Pharmacol. 49 (Suppl. 1), 65S–70S.

Miceli, J.J., Smith, M., Robarge, L., Morse, T., Laurent, A., 2000b. The effects of ketocona-zole on ziprasidone pharmacokinetics — a placebo-controlled crossover study inhealthy volunteers. Br. J. Clin. Pharmacol. 49 (Suppl. 1), 71S–76S.

Mihara, K., Suzuki, A., Kondo, T., Yasui, N., Furukori, H., Nagashima, U., Otani, K., Kaneko,S., Inoue, Y., 1999. Effects of the CYP2D6*10 allele on the steady-state plasma con-centrations of haloperidol and reduced haloperidol in Japanese patients withschizophrenia. Clin. Pharmacol. Ther. 65 (3), 291–294.

Mihara, K., Kondo, T., Yasui-Furukori, N., Suzuki, A., Ishida, M., Ono, S., Kubota, T., Iga, T.,Takarada, Y., de Vries, R., Kaneko, S., 2003. Effects of various CYP2D6 genotypeson the steady-state plasma concentrations of risperidone and its active metabolite,9-hydroxyrisperidone, in Japanese patients with schizophrenia. Ther. Drug Monit.25 (3), 287–293.

Miyazaki, M., Nakamura, K., Fujita, Y., Guengerich, F.P., Horiuchi, R., Yamamoto, K.,2008. Defective activity of recombinant cytochromes P450 3A4.2 and 3A4.16 in ox-idation of midazolam, nifedipine, and testosterone. Drug Metab. Dispos. 36 (11),2287–2291.

Mrazek, D.A., Lerman, C., 2011. Facilitating clinical implementation of pharmacogenomics.JAMA 306 (3), 304–305.

13D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

Muller, D.J., Brandl, E.J., Hwang, R., Tiwari, A.K., Sturgess, J.E., Zai, C.C., Lieberman, J.A.,Kennedy, J.L., Richter, M.A., 2012. The AmpliChip(R) CYP450 test and response totreatment in schizophrenia and obsessive compulsive disorder: a pilot study andfocus on cases with abnormal CYP2D6 drug metabolism. Genet. Test. Mol. Biomark.16 (8), 897–903.

Nikoloff, D., Shim, J.C., Fairchild, M., Patten, N., Fijal, B.A., Koch, W.H., MacPherson, A.,Flockhart, D., Yoon, Y.R., Yoon, J.S., Kim, Y.H., Shin, J.G., 2002. Association betweenCYP2D6 genotype and tardivedyskinesia in Korean schizophrenics. PharmacogenomicsJ. 2 (6), 400–407.

Nozawa, M., Ohnuma, T., Matsubara, Y., Sakai, Y., Hatano, T., Hanzawa, R., Shibata, N.,Arai, H., 2008. The relationship between the response of clinical symptomsand plasma olanzapine concentration, based on pharmacogenetics: Juntendo Uni-versity Schizophrenia Projects (JUSP). Ther. Drug Monit. 30 (1), 35–40.

Ohara, K., Tanabu, S., Yoshida, K., Ishibashi, K., Ikemoto, K., Shibuya, H., 2003. Ef-fects of smoking and cytochrome P450 2D6*10 allele on the plasma haloperi-dol concentration/dose ratio. Prog. Neuropsychopharmacol. Biol. Psychiatry27 (6), 945–949.

Ohmori, O., Suzuki, T., Kojima, H., Shinkai, T., Terao, T., Mita, T., Abe, K., 1998. Tardivedyskinesia and debrisoquine 4-hydroxylase (CYP2D6) genotype in Japaneseschizophrenics. Schizophr. Res. 32 (2), 107–113.

Ohmori, O., Kojima, H., Shinkai, T., Terao, T., Suzuki, T., Abe, K., 1999. Genetic associa-tion analysis between CYP2D6*2 allele and tardive dyskinesia in schizophrenicpatients. Psychiatry Res. 87 (2–3), 239–244.

Ohnuma, T., Shibata, N., Matsubara, Y., Arai, H., 2003. Haloperidol plasma concentrationin Japanese psychiatric subjects with gene duplication of CYP2D6. Br. J. Clin.Pharmacol. 56 (3), 315–320.

Olanzapine package insert, 2009. Indianapolis, IN: Eli Lilly and Company.Olesen, O.V., Linnet, K., 2000. Identification of the human cytochrome P450 isoforms medi-

ating in vitro N-dealkylation of perphenazine. Br. J. Clin. Pharmacol. 50 (6), 563–571.Oosterhuis, M., Van De Kraats, G., Tenback, D., 2007. Safety of aripiprazole: high serum

levels in a CYP2D6 mutated patient. Am. J. Psychiatry 164 (1), 175.Ozdemir, V., Kalow, W., Tang, B.K., Paterson, A.D., Walker, S.E., Endrenyi, L., Kashuba,

A.D., 2000. Evaluation of the genetic component of variability in CYP3A4 activity:a repeated drug administration method. Pharmacogenetics 10 (5), 373–388.

Ozdemir, V., Bertilsson, L., Miura, J., Carpenter, E., Reist, C., Harper, P., Widen, J.,Svensson, J.O., Albers, L.J., Kennedy, J.L., Endrenyi, L., Kalow, W., 2007. CYP2D6 ge-notype in relation to perphenazine concentration and pituitary pharmacodynamictissue sensitivity in Asians: CYP2D6-serotonin–dopamine crosstalk revisited.Pharmacogenet. Genomics 17 (5), 339–347.

Pan, L., Vander Stichele, R., Rosseel, M.T., Berlo, J.A., De Schepper, N., Belpaire, F.M.,1999. Effects of smoking, CYP2D6 genotype, and concomitant drug intake on thesteady state plasma concentrations of haloperidol and reduced haloperidol inschizophrenic inpatients. Ther. Drug Monit. 21 (5), 489–497.

Panagiotidis, G., Arthur, H.W., Lindh, J.D., Dahl, M.L., Sjoqvist, F., 2007. Depot haloperi-dol treatment in outpatients with schizophrenia on monotherapy: impact ofCYP2D6 polymorphism on pharmacokinetics and treatment outcome. Ther. DrugMonit. 29 (4), 417–422.

Park, J.Y., Shon, J.H., Kim, K.A., Jung, H.J., Shim, J.C., Yoon, Y.R., Cha, I.J., Shin, J.G., 2006.Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on thepharmacokinetics and pharmacodynamics of haloperidol in healthy subjects.J. Clin. Psychopharmacol. 26 (2), 135–142.

Patsopoulos, N.A., Ntzani, E.E., Zintzaras, E., Ioannidis, J.P., 2005. CYP2D6 polymor-phisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis.Pharmacogenet. Genomics 15 (3), 151–158.

Plesnicar, B.K., Zalar, B., Breskvar, K., Dolzan, V., 2006. The influence of the CYP2D6 poly-morphism on psychopathological and extrapyramidal symptoms in the patients onlong-term antipsychotic treatment. J. Psychopharmacol. 20 (6), 829–833.

Prakash, C., Kamel, A., Gummerus, J., Wilner, K., 1997. Metabolism and excretion of anew antipsychotic drug, ziprasidone, in humans. Drug Metab. Dispos. 25 (7),863–872.

Richelson, E., Souder, T., 2000. Binding of antipsychotic drugs to human brain receptorsfocus on newer generation compounds. Life Sci. 68 (1), 29–39.

Riedel, M., Schwarz, M.J., Strassnig, M., Spellmann, I., Muller-Arends, A., Weber, K.,Zach, J., Muller, N., Moller, H.J., 2005. Risperidone plasma levels, clinical responseand side-effects. Eur. Arch. Psychiatry Clin. Neurosci. 255 (4), 261–268.

Roh, H.K., Chung, J.Y., Oh, D.Y., Park, C.S., Svensson, J.O., Dahl, M.L., Bertilsson, L., 2001.Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but nothigh doses of haloperidol in Korean schizophrenic patients. Br. J. Clin. Pharmacol. 52(3), 265–271.

Rostami-Hodjegan, A., Amin, A.M., Spencer, E.P., Lennard, M.S., Tucker, G.T., Flanagan, R.J.,2004. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasmaclozapine concentrations: a predictive model and nomograms to aid clozapine doseadjustment and to assess compliance in individual patients. J. Clin. Psychopharmacol.24 (1), 70–78.

Sajjad, S.H., 1997. CYP2D6 genotype and tardive dyskinesia. Br. J. Psychiatry 170, 580.Saphris package insert, 2013. Whitehouse Station. NJ: Merck & Co., Inc.Schnoll, R.A., Shields, A.E., 2011. Physician barriers to incorporating pharmacogenetic

treatment strategies for nicotine dependence into clinical practice. Clin. Pharmacol.Ther. 89 (3), 345–347.

Schotte, A., Janssen, P.F., Gommeren, W., Luyten, W.H., Van Gompel, P., Lesage, A.S., DeLoore, K., Leysen, J.E., 1996. Risperidone compared with new and reference antipsy-chotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 124(1–2), 57–73.

Scordo, M.G., Spina, E., Facciola, G., Avenoso, A., Johansson, I., Dahl, M.L., 1999.Cytochrome P450 2D6 genotype and steady state plasma levels of risperidoneand 9-hydroxyrisperidone. Psychopharmacology (Berl) 147 (3), 300–305.

Scordo, M.G., Spina, E., Romeo, P., Dahl, M.L., Bertilsson, L., Johansson, I., Sjoqvist, F.,2000. CYP2D6 genotype and antipsychotic-induced extrapyramidal side effects inschizophrenic patients. Eur. J. Clin. Pharmacol. 56 (9–10), 679–683.

Sheehan, J.J., Sliwa, J.K., Amatniek, J.C., Grinspan, A., Canuso, C.M., 2010. Atypical anti-psychotic metabolism and excretion. Curr. Drug Metab. 11 (6), 516–525.

Sheffield, L.J., Phillimore, H.E., 2009. Clinical use of pharmacogenomic tests in 2009.Clin. Biochem. Rev. 30 (2), 55–65.

Shi, Y., Li, Y., Tang, J., Zhang, J., Zou, Y., Cai, B., Wang, L., 2012. Influence of CYP3A4,CYP3A5 and MDR-1 polymorphisms on tacrolimus pharmacokinetics and earlyrenal dysfunction in liver transplant recipients. Gene 510 (2), 226–231.

Shimoda, K., Morita, S., Yokono, A., Someya, T., Hirokane, G., Sunahara, N., Takahashi, S.,2000. CYP2D6*10 alleles are not the determinant of the plasma haloperidolconcentrations in Asian patients. Ther. Drug Monit. 22 (4), 392–396.

Sistonen, J., Fuselli, S., Palo, J.U., Chauhan, N., Padh, H., Sajantila, A., 2009. Pharmacogeneticvariation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales.Pharmacogenet. Genomics 19 (2), 170–179.

Someya, T., Shimoda, K., Suzuki, Y., Sato, S., Kawashima, Y., Hirokane, G., Morita, S.,Yokono, A., Takahashi, S., 2003. Effect of CYP2D6 genotypes on the metabolism ofhaloperidol in a Japanese psychiatric population. Neuropsychopharmacology 28(8), 1501–1505.

Spyker, D.A., Munzar, P., Cassella, J.V., 2010. Pharmacokinetics of loxapine following in-halation of a thermally generated aerosol in healthy volunteers. J. Clin. Pharmacol.50 (2), 169–179.

Stephan, P.L., Jaquenoud Sirot, E., Mueller, B., Eap, C.B., Baumann, P., 2006. Adverse drugreactions following nonresponse in a depressed patient with CYP2D6 deficiencyand low CYP 3A4/5 activity. Pharmacopsychiatry 39 (4), 150–152.

Stroup, T.S., 2007. Heterogeneity of treatment effects in schizophrenia. Am. J. Med. 120(4 Suppl. 1), S26–S31.

Sunwoo, Y.E., Ryu, J., Jung, H., Kang, W., Liu, K., Yoon, Y., Lee, S., Shin, J., 2004. Disposi-tion of chlorpromazine in Korean healthy subjects with CYP2D6 wild type and*10B mutation. Clin. Pharmacol. Therap. 75 (2), P9 [Abstract].

Suzuki, A., Otani, K., Mihara, K., Yasui, N., Kaneko, S., Inoue, Y., Hayashi, K., 1997. Effectsof the CYP2D6 genotype on the steady-state plasma concentrations of haloperidoland reduced haloperidol in Japanese schizophrenic patients. Pharmacogenetics 7(5), 415–418.

Suzuki, T., Mihara, K., Nakamura, A., Nagai, G., Kagawa, S., Nemoto, K., Ohta, I., Arakaki, H.,Uno, T., Kondo, T., 2011. Effects of the CYP2D6*10 allele on the steady-state plasmaconcentrations of aripiprazole and its active metabolite, dehydroaripiprazole, inJapanese patients with schizophrenia. Ther. Drug Monit. 33 (1), 21–24.

Swen, J.J., Nijenhuis, M., de Boer, A., Grandia, L., Maitland-van der Zee, A.H., Mulder, H.,Rongen, G.A., van Schaik, R.H., Schalekamp, T., Touw, D.J., van derWeide, J.,Wilffert, B.,Deneer, V.H., Guchelaar, H.J., 2011. Pharmacogenetics: from bench to byte — an up-date of guidelines. Clin. Pharmacol. Ther. 89 (5), 662–673.

Teutsch, S.M., Bradley, L.A., Palomaki, G.E., Haddow, J.E., Piper, M., Calonge, N., Dotson, W.D.,Douglas, M.P., Berg, A.O., 2009. The Evaluation of Genomic Applications in Practice andPrevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet. Med. 11(1), 3–14.

Thanacoody, R.H., Daly, A.K., Reilly, J.G., Ferrier, I.N., Thomas, S.H., 2007. Factors affectingdrug concentrations and QT interval during thioridazine therapy. Clin. Pharmacol.Ther. 82 (5), 555–565.

Thomas, P., Srivastava, V., Singh, A., Mathur, P., Nimgaonkar, V.L., Lerer, B., Thelma, B.K.,Deshpande, S.N., 2008. Correlates of response to Olanzapine in a North IndianSchizophrenia sample. Psychiatry Res. 161 (3), 275–283.

Tiwari, A.K., Deshpande, S.N., Rao, A.R., Bhatia, T., Lerer, B., Nimgaonkar, V.L., Thelma,B.K., 2005. Genetic susceptibility to tardive dyskinesia in chronic schizophreniasubjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms.Schizophr. Res. 75 (1), 21–26.

US Food and Drug Administration, 2009. Drug Approval Package. Iloperidone (Availableat: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022192s000TOC.cfm.Accessed August 11, 2012).

US Food and Drug Administration, 2012. Table of Pharmacogeneomic Biomarkers inDrug Labels. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm (Accessed July 9, 2012).

van der Weide, J., van Baalen-Benedek, E.H., Kootstra-Ros, J.E., 2005. Metabolic ratios ofpsychotropics as indication of cytochrome P450 2D6/2C19 genotype. Ther. DrugMonit. 27 (4), 478–483.

Vogel, F., 1959. Moderne probleme der humangenetik. [German]. Ergeb. Inn. Med.Kinderheilkd 12, 52–125.

von Bahr, C., Movin, G., Nordin, C., Liden, A., Hammarlund-Udenaes, M., Hedberg, A.,Ring, H., Sjoqvist, F., 1991. Plasma levels of thioridazine and metabolites areinfluenced by the debrisoquin hydroxylation phenotype. Clin. Pharmacol. Ther.49 (3), 234–240.

Westlind-Johnsson, A., Hermann, R., Huennemeyer, A., Hauns, B., Lahu, G., Nassr, N.,Zech, K., Ingelman-Sundberg, M., von Richter, O., 2006. Identification and charac-terization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity.Clin. Pharmacol. Ther. 79 (4), 339–349.

Williams, J.A., Ring, B.J., Cantrell, V.E., Jones, D.R., Eckstein, J., Ruterbories, K., Hamman,M.A., Hall, S.D., Wrighton, S.A., 2002. Comparative metabolic capabilities ofCYP3A4, CYP3A5, and CYP3A7. Drug Metab. Dispos. 30 (8), 883–891.

Winter, H.R., Earley, W.R., Hamer-Maansson, J.E., Davis, P.C., Smith, M.A., 2008. Steady-state pharmacokinetic, safety, and tolerability profiles of quetiapine, norquetiapine,and other quetiapinemetabolites in pediatric and adult patients with psychotic disor-ders. J. Child Adolesc. Psychopharmacol. 18 (1), 81–98.

Wojcikowski, J., Maurel, P., Daniel, W.A., 2006. Characterization of human cytochromep450 enzymes involved in the metabolism of the piperidine-type phenothiazineneuroleptic thioridazine. Drug Metab. Dispos. 34 (3), 471–476.

14 D. Ravyn et al. / Schizophrenia Research 149 (2013) 1–14

Yasui-Furukori, N., Kondo, T., Suzuki, A., Mihara, K., Tokinaga, N., Inoue, Y., Otani, K.,Kaneko, S., 2001. Effect of the CYP2D6 genotype on prolactin concentration in schizo-phrenic patients treated with haloperidol. Schizophr. Res. 52 (1–2), 139–142.

Yoshii, K., Kobayashi, K., Tsumuji, M., Tani, M., Shimada, N., Chiba, K., 2000. Identifica-tion of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlor-promazine by human liver microsomes. Life Sci. 67 (2), 175–184.

Young, D., Midha, K.K., Fossler, M.J., Hawes, E.M., Hubbard, J.W., McKay, G., Korchinski,E.D., 1993. Effect of quinidine on the interconversion kinetics between haloperidoland reduced haloperidol in humans: implications for the involvement of cyto-chrome P450IID6. Eur. J. Clin. Pharmacol. 44 (5), 433–438.

Zahari, Z., Salleh, M.R., Teh, L.K., Ismail, R., 2009. Influence of CYP2D6 polymorphismson symptomatology and side-effects of patients with schizophrenia in Malaysia.Malays. J. Med. Sci. 16 (3), 12–20.

Zanger, U.M., Turpeinen, M., Klein, K., Schwab, M., 2008. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal.Bioanal. Chem. 392 (6), 1093–1108.

Zhang, J.P., Malhotra, A.K., 2011. Pharmacogenetics and antipsychotics: therapeutic ef-ficacy and side effects prediction. Expert Opin. Drug Metab. Toxicol. 7 (1), 9–37.

Zhou, S.F., 2009. Polymorphism of human cytochrome P450 2D6 and its clinical signif-icance: part II. Clin. Pharmacokinet. 48 (12), 761–804.

Zink, M., Englisch, S., Meyer-Lindenberg, A., 2010. Polypharmacy in schizophrenia.Curr. Opin. Psychiatry 23 (2), 103–111.

Ziprasidone package insert, 2012. New York, NY: Pfizer Inc.Zochowska, D., Wyzgal, J., Paczek, L., 2012. Impact of CYP3A4*1B and CYP3A5*3 poly-

morphisms on the pharmacokinetics of cyclosporine and sirolimus in renal trans-plant recipients. Ann. Transplant. 17 (3), 36–44.

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具