CYP450 Pharmacogenetic treatment strategies for antipsychotics: A review of the evidence

Schizophrenia Research 149 (2013) 1–14

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Review

CYP450 Pharmacogenetic treatment strategies for antipsychotics: A review of the evidence Dana Ravyn a, Vipa Ravyn b, Robert Lowney a, Henry A. Nasrallah c,⁎ a b c

CMEology, West Hartford, CT, United States Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, CO, United States Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, United States

a r t i c l e

i n f o

Article history: Received 27 March 2013 Received in revised form 3 June 2013 Accepted 19 June 2013 Available online 17 July 2013 Keywords: Schizophrenia Antipsychotic Cytochrome Metabolism Pharmacogenetics

a b s t r a c t Although a number of first- and second-generation antipsychotics are available, achieving optimal therapeutic response for patients with schizophrenia can be challenging. The presence of polymorphic alleles for cytochrome P (CYP) 450 may result in lack of expression, altered levels of expression, or altered function of CYP450 enzymes. CYP2D6, CYP1A2, and CYP3A4/5 are major enzymes in the metabolism of antipsychotics and 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 relatively inexpensive. Evidence-based guidelines provide dose recommendations for some antipsychotics. To date few studies have demonstrated a significant association with genotype-guided antipsychotic use and clinical efficacy. However, many studies have been small, retrospective or cohort designs, and many have not been adequately powered. Numerous studies have shown a significant association between genotype and adverse effects, such as CYP2D6 polymorphisms and tardive dyskinesia. This review summarizes evidence for the role of CYP450 genetic variants in the response to antipsychotic medications and the clinical implications 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 visits in 2008 (Mark, 2010). There is significant interindividual variation in response to antipsychotics, much of which remains unexplained (Stroup, 2007). Antipsychotics are one of the most highly individualized classes of medications. Despite the fact that a number of firstand second-generation antipsychotics are available, achieving optimal therapeutic outcomes can be challenging for some individuals. The majority of patients with schizophrenia do not experience complete therapeutic benefit with antipsychotic therapy, which can lead to polypharmacy, a practice poorly supported by clinical evidence and associated with risk of adverse effects (McEvoy et al., 2006; Zink et al., 2010). Further, risk of discontinuation and relapse can result from treatment-limiting adverse effects and long-term side effects such as weight gain and metabolic syndrome (Cha and McIntyre, 2012).

⁎ Corresponding author at: Psychiatry & Neuroscience, University of Cincinnati College of Medicine, Department of Psychiatry and Behavioral Neuroscience, 260 Stetson Street, Suite 3200, Cincinnati, OH 45219, United States. Tel.: +1 513 558 4615; fax: +1 513 558 4616. E-mail address: [email protected] (H.A. Nasrallah). 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.06.035

Variability in response to antipsychotics can be influenced by an array of factors, including age, sex, ethnicity, nutritional status, smoking, and alcohol use. There is strong evidence for the role of genetic variability in individual responses to antipsychotic therapy. Advances in pharmacogenetic research have led to discovery of many polymorphisms strongly linked to the metabolism and pharmacodynamics of antipsychotic medications. The goal of clinical pharmacogenetics is to use individual-level genetic data to predict and optimize the response to antipsychotics while preventing or minimizing adverse events. Use of pharmacogenetics has demonstrated the ability to improve patient outcomes in many therapy areas, and is generally cost effective (Crews et al., 2012). Nevertheless, evidence-based guidelines for pharmacogenetics remain scarce, and there are numerous barriers to its clinical implementation (McCullough et al., 2011; Mrazek and Lerman, 2011; Schnoll and Shields, 2011). 1.1. Methods This review summarizes evidence for the role of genetic variants of CYP450 enzymes in the metabolism of antipsychotic medications and the clinical implications of pharmacogenetics of cytochrome P (CYP) enzymes in the management of patients receiving antipsychotics. A literature search was conducted to examine the impact of CYP450 variants on antipsychotic pharmacology and any known

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clinical outcomes. The search strategy [(pharmacogenetic* OR “cytochrome P*”) AND (antipsychotic* OR neuroleptic*)] was used to identify relevant literature in PubMed and OVID. The search was conducted for all articles from inception to April 30, 2013. Eligible studies included pharmacologic characteristics of antipsychotics relevant to CYP metabolism in vitro, in healthy volunteers, or in patients, or reports of efficacy or adverse effects that defined patients according to CYP genotype or phenotype. Relevant literature was used to identify any additional primary studies. Research abstracts, unpublished studies, articles with non-English abstracts, commentaries, letters to the editor, and editorials were excluded. As discussed in detail below, study quality was limited by small study size, poorly defined populations and ethnicity, and scarcity of outcomes studies. 2. Pharmacogenetic studies of antipsychotics 2.1. Overview The term pharmacogenetics was coined by Vogel in 1959, and refers to the interaction between an individual's genetics and his or her response to drugs, often on the basis of a single gene polymorphism (Vogel, 1959). In contrast, pharmacogenomics is a relatively recent term used in association with studies of the human genome and focuses on complex, multifactorial interactions. While pharmacogenetics seeks to individualize therapy, pharmacogenomics identifies targets for drugs, and characterizes drug responses in populations. Studies of the pharmacogenetics of antipsychotics evaluate the association between genetic variations with either the pharmacokinetics or pharmacodynamics of individual agents. In pharmacokinetic studies, pharmacogenetics aims to predict antipsychotic drug responses by identifying variants in genes associated with the metabolism of specific agents. Such genetic variations affecting metabolism may lead to alterations in the bioavailability of certain antipsychotics, resulting in loss of efficacy (decreased plasma levels) or increased toxicity (elevated plasma levels). In pharmacodynamic studies, pharmacogenetics evaluates the association of genetic polymorphisms in drug targets with therapeutic outcomes or adverse effects. These targets may be receptors postulated to have a role in the etiology of disease, targets in the mechanism of action of the therapeutic agent, transporters, or intermediates in signaling pathways involved in efficacy or side effects of the drug. 2.2. Pharmacogenetic testing Pharmacogenetic testing of drug metabolism consists of two approaches (Sheffield and Phillimore, 2009). Biochemical tests are used to evaluate the rate of metabolism by a patient after he or she takes a probe drug, which is a well characterized target of a recognized metabolic pathway. The excretion of the parent drug and its metabolite are then measured at regular intervals and a rate of metabolism calculated. The result is often referred to as an individual's phenotype, although the use of the term to describe functional aspects of drug metabolism differs from its connotation in genetics. Although the activity of a patient's metabolic enzymes can be measured directly, this is not practical, particularly for CYP450 enzymes, which would require a liver biopsy. The other approach to pharmacogenetics is the use of molecular genetic testing to characterize the alleles of a patient's gene related to metabolic enzymes, the drug target, or receptors. The genes of interest often have a number of alleles, and polymorphisms present in these alleles may result in lack of expression, altered levels of expression, or altered function.1 1 In this article, unitalicized capitals are used to indicate a protein and italicized capitals are used to indicate a gene. Alleles are indicated by an asterisk, followed by the allele number. In most cases, *1 represents the wild type; for example, CYP2C9 is the enzyme and CYP2CP*1 is the most common allele.

3. Pharmacokinetics and genetic variations in CYP450 enzymes Historically, pharmacogenetics has focused on drug metabolizing enzymes as a result of their wide variation in comparison to allelic polymorphisms of pharmacodynamic drug targets (Brosen, 2004). Further, outcomes of genetic variation are easier to measure because drug metabolism assays are standardized, and interpretation is relatively straightforward. For example, a low steady-state concentration indicates rapid metabolism and a high concentration indicates slow metabolism. Numerous enzymes associated with drug absorption and elimination have been the subject of pharmacogenetic studies, which are recommended or required by the US Food and Drug Administration (FDA) for certain therapies. The FDA requires information related to pharmacogenetic biomarkers in the labeling of over 100 drugs, 27 of which are for agents with a primary indication in psychiatry (US Food and Drug Administration, 2012). Association of an enzyme with metabolism of a drug is necessary but not sufficient justification for pharmacogenetic testing, as many drugs may be metabolized by alternative pathways. Further, pharmacogenetic results should be interpreted in context of the physician's knowledge of other factors that influence efficacy and toxicity of antipsychotic agents, such as comorbidities, adherence, body weight, and smoking (Rostami-Hodjegan et al., 2004). In addition to pharmacogenetic considerations, CYP isoforms can be induced and inhibited by certain drugs, which can substantially alter metabolism of other drugs through drug–drug interactions. Oral antipsychotics are substrates of CYP450 enzymes, which are crucial to their metabolism and elimination (Fig. 1). The efficacy and toxicity of antipsychotic agents is affected by factors that induce or inhibit CYP450 expression and function, such as drug–drug interactions. Additionally, the multiallelic nature of CYP450 enzyme genetics can result in various phenotypes. These polymorphisms reflect gene insertions and deletions, gene duplications, copy number variations, and single nucleotide polymorphisms (SNPs), which can lead to decreased or elevated metabolism. The resulting phenotypes associated with these genetic variants are usually classified as one of four groups: poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) or normal, and ultra-rapid metabolizers (UM) (Fig. 2) (van der Weide et al., 2005). The clinical consequences of variations in metabolism depend on whether the drug taken is pharmacologically active or is a prodrug that needs to be converted to an active metabolite. If the antipsychotic is pharmacologically active, the PM phenotype will result in increased plasma concentration. Many antipsychotics have a narrow therapeutic window and reduced metabolism can result in concentration-dependent adverse effects, as illustrated in Fig. 2 (van der Weide et al., 2005). Patients with the IM phenotype are also likely to have increased exposure to drugs compared with EMs. However, the degree to which plasma levels are elevated and their clinical significance is often unclear. The UM phenotype can result in subtherapeutic drug levels when conventional doses are administered as the antipsychotic will be metabolized before it has a pharmacologic effect. The PM is most extensively studied for antipsychotics, particularly in those agents with a narrow therapeutic index. UM phenotype is clinically significant because of its wide distribution (Sistonen et al., 2009). In contrast to pharmacologically active agents, a prodrug must be metabolized to an active form. For some antipsychotics, the parent drug and its metabolite will both have activity, and variations in metabolism can have complex outcomes. 3.1. CYP variations and dose recommendations The human CYP2D6 gene is polymorphic and the resulting CYP2D6 isozymes have significant implications in clinical medicine (Zhou, 2009). Of 121 drug labels that included pharmacogenetic information from 1945 to 2005, 35% pertained to CYP2D6 (Frueh et al., 2008). The majority of antipsychotics are metabolized primarily or secondarily by CYP2D6 (Fig. 1). Additionally, CYP2D6 variability is a significant

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

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

factor in the metabolism of many other psychiatric drugs. Significantly decreased capacity to metabolize CYP2D6 substrates occurs in about 8% of Caucasians, 3–8% of blacks and African Americans, and 6% of Asians (Cascorbi, 2003). The CYP2D6 UM phenotype has been observed in 1–10% of Caucasians, 0–2% of East Asians, 2% of blacks and African Americans, and 10–29% of North African/Middle Easterners and 1% of Mexicans (Lovlie et al., 2001; Mendoza et al., 2001; Gaedigk et al., 2002). The CYP1A2*1C (rs2069514) allele is associated with decreased inducibility and occurs in 21–27% of Asians, 7% of Africans, and 1–4% of Caucasians (McGraw and Waller, 2012). Ethnic differences in CYP3A4/5 activity may be explained by unidentified

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polymorphisms. CYP3A4*1B (rs2740574) has been associated with decreased metabolism in some studies, while others have shown it to be associated with increased metabolism, so its clinical relevance remains to be determined (Amirimani et al., 2003). The CYP3A4*20 (rs67666821) polymorphism, which results in a premature stop codon and lack of enzyme activity, is prevalent in 26% of African Americans, 22% of Asians, and 6% of Caucasians (McGraw and Waller, 2012). As Fig. 1 shows, numerous antipsychotics are metabolized primarily by both CYP2D6 and either CYP1A2 or CYP3A4. Other antipsychotic agents are primarily metabolized by CYP2D6 and secondarily by others like CYP3A4 and CYP1A2 or primarily by CYP3A4 or CYP1A2. CYP3A is the most abundant CYP450 enzyme in the liver and small intestine and the subfamily is involved in the metabolism of over 50% of prescription drugs (Williams et al., 2002). CYP3A4 and CYP3A5 share sequence homology and substrate specificity, and the large active sites contribute to their ability to accommodate myriad substrates (McGraw and Waller, 2012). There can be up to a 40-fold interindividual variation in CYP3A4 activity (Ingelman-Sundberg, 2004). The promiscuous and overlapping nature of CYP3A enzymes has made it challenging to identify phenotypic variants using substrate probes. However, identification of SNPs have revealed several polymorphisms with potential clinical implications. Several polymorphisms of CYP3A4 have been characterized, but most are low frequency and occur as heterozygotes with the wild type allele, while others have no demonstrable effect on substrate metabolism (Ozdemir et al., 2000). A SNP in the promoter region resulting in the CYP3A4*1B polymorphism is associated with increased promoter activity and a requirement for higher doses of cyclosporine in patients undergoing transplantation (Zochowska et al., 2012). Another polymorphism is CYP3A4*20, a SNP that results in a premature stop codon and loss of enzymatic activity, conferring intermediate metabolism phenotype in heterozygotes (Westlind-Johnsson et al., 2006). CYP3A4*22 (rs35599367) is a recently identified SNP in an intron of CYP3A4 that results in decreased expression (Elens et al., 2012). Some CYP3A4 polymorphisms have been associated with clinically significant findings related to patients receiving cyclosporine and tacrolimus (Shi et al., 2012; Zochowska et al., 2012). Unlike CYP2D6 and other CYP450 enzymes, there is no evidence for a CYP3A4 null allele (Lamba et al., 2012). Although commercial tests are

Fig. 2. Genetic mechanisms for CYP450 metabolic phenotypes and their pharmacokinetic implications (van der Weide et al., 2005).

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

Phenotype Clinical Relevance

Recommendations

Refs

Aripiprazole

PMa

Reduce to 67% of maximum dose

Hendset et al. (2007), Oosterhuis et al. (2007), Swen et al. (2011), Aripiprazole package insert (2012)

None

Kubo et al. (2005), Kim et al. (2006), Hendset et al. (2007), Kubo et al. (2007)

IMb

• 80% increase in aripiprazole exposure and 30% decrease in exposure to the active metabolite resulting in 60% higher exposure to the total active moieties • Elimination half life for aripiprazole is increased from 75 h to 146 h in PMs • Significant increase in aripiprazole exposure (27%) and total active moieties (15%) in patients Not determined No significant changes in steady state clozapine levels or norclozapine or clozapine response

Clozapine

UMc PM, IM, UM

Haloperidol

PM

Significantly increased plasma concentrations; PM phenotype associated with increased risk of EPS

Reduce dose by 50% or select alternative drug

IM

Significantly increased plasma concentrations associated with the IM phenotype

None

UM

Insufficient data to allow calculation of dose adjustment. Be alert to decreased haloperidol plasma concentration and adjust maintenance dose or select alternative drug. • Iloperidone and its primary metabolite (P88) Reduce dose by one-half have comparable activity; the second metabolite (P95) has a unique receptor profile • P95 is reduced from 48% of iloperidone exposure in EMs to 25% in PMs • P88 levels increase from 19% of iloperidone exposure in EMs to 34% in PMs Not determined None Not determined None CYP2D6 is a minor metabolic pathway; None olanzapine clearance is not reduced in subjects who are deficient in this enzyme Not determined None Not determined None Exposure is increased approximately 3-fold The US FDA recommends genetic testing prior and clearance decreased to initiation or restarting therapy

Iloperidone

PM

Olanzapine

IM UM PM

Perphenazine

IM UM PM

Risperidone

IM UM PM

Thioridazine

IM UM PM

IM UM

None None

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

Not determined Not determined • CYP2D6 PM patients experienced a higher incidence of adverse drug reactions, including lengthening of QTc interval and parkinsonism. • A case–control study found that CYP2D6 PMs had a three times higher odds (OR 3.4; 95% CI 1.5–8.0) of significant risperidone adverse drug reactions and a six-times higher odds of discontinuation (OR 6.0; 95% CI 1.4–25.4), compared with EMs. Not determined Not determined • In healthy volunteers, thioridazine plasma levels increased 4.5-fold; sum of thioridazine plus mesoridazine plus sulforidazine increased 1.4-fold • In patients with one or no CYPD6 alleles, plasma levels were increased 1.8-fold or 3.8-fold, respectively • A small study in patients (n = 9) with no functional CYP2D6 alleles found elevated plasma levels but no significant effect on QTc interval Not determined Patients with CYP2D6–1548C N G polymorphism had lower thioridazine: mesoridazine ratios than those homozygous for the CYP2D6–1548C allele.

None None Insufficient data to allow calculation of dose adjustment. Select alternative drug and be alert to adverse drug effects and adjust dose according to clinical response

None None Thioridazine is associated with risk of QTc interval prolongation in a dose-dependent manner. Therefore, thioridazine is contraindicated in combination with other drugs that reduce CYP2D6 activity or in patients known to have a genetic defect leading to reduced levels of CYP2D6 activity.

None Insufficient data to allow calculation of dose adjustment

Dahl et al. (1994), Arranz et al. (1995), Dettling et al. (2000a,b, 2001), Melkersson et al. (2007) 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) 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), Brockmoller et al. (2002), Panagiotidis et al. (2007)

Iloperidone package insert (2012)

Hagg et al. (2001), Nozawa et al. (2008), Thomas et al. (2008), Olanzapine package insert (2009)

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

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

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

Dorado et al. (2009)

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

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Table 1 (continued) Antipsychotics

Phenotype Clinical Relevance

Zuclopenthixol PM

IM

Recommendations

Steady state plasma levels were up to 1.9-fold Reduce dose by 50% or select alternative drug higher in healthy volunteers and up to 1.6-fold higher in patients Patients with CYP2D6*3 and *4 alleles had higher risk of neurologic adverse events with an OR of 1.7 for tardive dyskinesia and 2.3 for Parkinsonism Not determined Reduce dose by 25% or select alternative drug

UM

Insufficient data to allow calculation of dose adjustment. Select alternative drug and be alert to adverse drug effects and adjust dose according to clinical response

Refs Jerling et al. (1996), Linnet and Wiborg (1996a), Jaanson et al. (2002), Swen et al. (2011)

Jerling et al. (1996), Linnet and Wiborg (1996a), Jaanson et al. (2002) 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.

available to identify some variants of CYP3A4 associated with reduced activity, there are currently no recommendations on their use (Lee et al., 2005; Miyazaki et al., 2008; Zanger et al., 2008). Nevertheless, it is possible that as polymorphisms resulting in loss of function or decreased expression are characterized, they may be found to have clinical implications in dosing of antipsychotics for which CYP3A4 is a major route of metabolism, such as lurasidone, quetiapine, risperidol, and loxapine. This following section summarizes relevant studies of CYP metabolic variation in patients and healthy volunteers receiving antipsychotics. Knowledge of the pharmacology and clinical relevance of metabolic variations, as well as evidence-based dosing recommendations from expert panels and/or drug labeling, where available, is summarized in Table 1. 3.2. First generation antipsychotics 3.2.1. Chlorpromazine A prototype phenothiazine antipsychotic, chlorpromazine undergoes primary metabolism by both CYP2D6 and CYP1A2, to form more than 100 metabolites with widely varying pharmacologic properties. A study in Korea found that healthy volunteers who were heterozygous and homozygous for the *10 allele of CYP2D6 (rs1065852) had 1.3- and 1.7-fold higher chlorpromazine area under the curve (AUC), respectively (Yoshii et al., 2000; Sunwoo et al., 2004). 3.2.2. Haloperidol CYP3A4 is principally responsible for the metabolism of haloperidol (Fang et al., 2001). Although in vitro data suggest a minor role for CYP2D6 in haloperidol metabolism, studies in have shown a significant effect of CYP2D6 on pharmacokinetics of haloperidol plasma levels. These studies have consistently shown that patients and volunteers with CYP2D6 PM phenotype had higher serum concentrations and decreased 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 patients with schizophrenia in Sweden who received haloperidol decanoate depot treatments showed PMs had the highest dose-corrected plasma concentration and UMs had the lowest, with a sixfold difference (Panagiotidis et al., 2007). It is recommended that the haloperidol dose be reduced by 50% in PMs (Table 1) (Swen et al., 2011). 3.2.3. Loxapine A tricyclic typical antipsychotic, loxapine has a distinct pharmacologic profile, with a ratio of serotonin to dopamine receptor binding similar to atypicals (Glazer, 1999). Loxapine undergoes extensive metabolism to form various metabolites, including the antidepressant amoxapine. The

major products are hydroxylation to 8-OH loxapine by CYP1A2 and 7-OH loxapine by CYP2D6, formation of amoxapine by CYP3A4, and oxidation to loxapine N-oxide by CYP3A4 (Luo et al., 2011). Studies of oral loxapine in healthy volunteers showed that metabolites 8-OH loxapine and amoxapine were below the levels at which they would have pharmacologic activity while 7-OH loxapine levels were substantial at steady state (Cooper and Kelly, 1979). Inhaled dosing of loxapine aerosol is currently being investigated for treatment of acute agitation (Allen et al., 2011). In a study of healthy volunteers administered loxapine aerosol, peak plasma level concentrations of loxapine and its metabolites were similar to those observed after oral administration (Spyker et al., 2010). Notably, 7-OH loxapine has a 5-fold higher affinity for the dopamine D2 receptor than loxapine. The clinical implications of these observations for patients with CYP polymorphisms are not yet known. 3.2.4. Perphenazine Although 10–15 times more potent than chlorpromazine, perphenazine is associated with a high incidence of extrapyramidal adverse effects and tardive dyskinesia (Hartung et al., 2005). Perphenazine is extensively metabolized in the liver to a number of metabolites by sulfoxidation, hydroxylation, dealkylation, and glucuronidation. Perphenazine is primarily metabolized by CYP2D6 to 7-OH perphenazine, which has about 70% of the biologic activity of the parent drug (Olesen and Linnet, 2000). In healthy volunteers, administration of a single dose resulted in a 4-fold higher AUC of perphenazine in PMs, compared with EMs (Dahl-Puustinen et al., 1989). Similar results were observed in a study of healthy Chinese-Canadian males (Ozdemir et al., 2007). After a single dose of perphenazine, those who were homozygous for the CYP2D6*10 allele had a 2.9-fold higher AUC for perphenazine, compared with those who were homozygous for the wild type CYP2D6*1 allele (P b 0.001) (Ozdemir et al., 2007). A study of psychiatric inpatients in Denmark found PMs had a 2-fold increase in perphenazine steady state levels, compared with EMs (Linnet and Wiborg, 1996b). Another study of psychiatric patients in Sweden showed a 3-fold decrease in clearance of perphenazine in PMs (Jerling et al., 1996). The US FDA recommends genetic testing before initiating or restarting treatment with perphenazine. 3.2.5. Thioridazine CYP2D6 and CYP3A4 are responsible for conversion of thioridazine to mesoridazine, which is more active than the parent drug, and the subsequent formation of the metabolite sulforidazine, which has comparable activity to thioridazine (Eap et al., 1996; Berecz et al., 2003; Wojcikowski et al., 2006). A study of psychiatric patients in Spain

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with two active CYP2D6 alleles found that those with CYP2D6– 1584C N G polymorphism (rs1080985) were ultrarapid metabolizers and had lower plasma thioridazine:mesoridazine ratios than those homozygous for CYP2D6–1584C allele (Dorado et al., 2009). Among healthy volunteers, the plasma concentration of thioridazine following a single dose was increased 4.5-fold in PMs, compared with EMs, and the sum of levels of thioridazine plus mesoridazine plus sulforidazine were increased 1.4-fold (von Bahr et al., 1991). A study in Spain evaluated dose-corrected plasma concentrations in 76 psychiatric patients receiving thioridazine monotherapy (Berecz et al., 2003). In the presence of one or no active CYP2D6 alleles, plasma thioridazine concentrations were 1.8- and 3.8-fold higher (P b 0.01 for both), compared with two or more functional alleles. No significant differences in plasma levels of mesoridazine or sulforidazine were observed (Berecz et al., 2003). Another study in psychiatric patients receiving thioridazine found that those with no functional CYP2D6 alleles had significantly higher dose-adjusted plasma concentrations than those with ≥1 functional CYP2D6 allele (P = 0.017) (Thanacoody et al., 2007). There was no significant effect on QTc interval associated with CYP2D6 genotypes. Thioridazine is associated with risk of QTc interval prolongation in a dose-dependent manner. Therefore, thioridazine is contraindicated in combination with other drugs that reduce CYP2D6 activity or in patients known to have a genetic defect leading to reduced levels of CYP2D6 activity (Table 1). 3.2.6. Zuclopenthixol A thioxanthene derivative, zuclopenthixol is metabolized by sulfoxidation, N-dealkylation, and glucuronidation to form several metabolites, all of which are pharmacologically inactive (Dahl et al., 1991). CYP2D6 is mainly responsible for zuclopenthixol sulfoxidation and N-dealkylation. A study evaluated the cosegregation of zuclopenthixol clearance with debrisoquine hydroxylation in healthy volunteers (Dahl et al., 1991). Among PMs, exposure to zuclopenthixol was 1.9-fold higher, the half-life longer, and plasma clearance lower, compared with EMs. Among 36 patients with schizophrenia in Sweden, retrospective data from 113 therapeutic drug monitoring samples showed that, compared with CYP2D6 PM genotypes, those with homozygous or heterozygous EM genotypes had 2.2 or 1.5-fold higher clearance rates, respectively (Jerling et al., 1996). Another clinical study in 119 patients with schizophrenia in Denmark found that mean steady state plasma levels of zuclopenthixol were 60% higher in PMs, compared with EMs (P b 0.01) (Linnet and Wiborg, 1996a). A study evaluated 52 outpatients with schizophrenia in Estonia who were receiving zuclopenthixol decanoate maintenance dosages of 100 to 400 mg every 4 weeks (Jaanson et al., 2002). The study results showed that the median plasma concentrations of zuclopenthixol were 1.6- and 1.4-fold higher in PMs and heterozygous EMs, respectively, compared with homozygous EMs. Further, those with the CYP2D6*3 and *4 alleles (rs35742686 and rs3892097, respectively) had higher risk of neurological adverse events. Patients with at least one of these alleles in CYP2D6 had an odds ratio (OR) of 1.7 (95% confidence 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. Aripiprazole Aripiprazole is metabolized by CYP2D6 and CYP3A4 to its active metabolite dehydroaripiprazole (DARI), which has similar pharmacologic properties to the parent compound. Aripiprazole is the major moiety in systemic circulation, while DARI represents about 40% of aripiprazole exposure (Aripiprazole package insert, 2012). Patients with the CYP2D6 PM phenotype have an 80% increase in aripiprazole exposure and a 30% decrease in DARI exposure, resulting in a 60% higher exposure to the total active moieties; the elimination half life of aripiprazole and DARI increase 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 recommended that the dose in PMs be reduced to 67% of the maximum recommended daily dose (i.e., a reduction to 67% of the maximum daily dose of 30 mg would be approximately 20 mg) (Swen et al., 2011). The manufacturer recommends that the initial dose of aripiprazole be reduced by one half in PMs (Aripiprazole package insert, 2012). A study of 62 psychiatric patients in Norway retrospectively evaluated dose-adjusted serum concentrations of aripiprazole and DARI in patients with CYP2D6 genotypes *1/*1 (EM), *1/*3–6 (IM), *3–6/*3–6 (PM) (Hendset et al., 2007). For PMs vs EMs, the median serum concentration of aripiprazole was 1.7-fold higher (P b 0.01) and concentration of aripiprazole plus DARI was 1.5-fold higher (P b 0.05). Although increased serum levels in IMs vs. EMs were less pronounced, they were statistically significant for both aripiprazole (P b 0.05) and DARI (P b 0.05). Another study in 63 Japanese patients with schizophrenia prospectively evaluated the concentration/dose ratios of aripiprazole and DARI in those with CYP2D6 wild type or *10 alleles (Suzuki et al., 2011). CYP2D6*10 is associated with decreased activity, and is present in about 50% of the Asian population (Bertilsson et al., 2002). The concentration/dose ratios in patients with wild 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). These data demonstrate that the *10 alleles may lead to significantly elevated levels of aripiprazole and DARI in Asian patients, although the clinical significance is unknown. Although it is likely that concentrationdependent adverse events may occur more frequently in Asians with this phenotype, one prospective study in Korean patients found no significant difference with regard to ethnicity in response to aripiprazole (Kwon et al., 2009). 3.3.2. Asenapine Asenapine is sublingually administered and metabolized principally through direct glucuronidation by glucuronosyltransferases (UGT)1A4 and oxidation by CYP1A2. Notably, asenapine is a suicide substrate for CYP2D6. Administration could decrease the amount of CYP2D6 in PMs as well as EMs, with recovery to previous levels requiring days or weeks. Therefore, caution is advised when switching to or coadministering an antipsychotic or other agent metabolized by CYP2D6, particularly in PMs (Sunwoo et al., 2004; Saphris package insert, 2013). 3.3.3. Clozapine Clozapine is metabolized by CYP1A2, CYP2D6, and CYP3A4 (Eiermann et al., 1997; Clozapine package insert, 2010). CYP1A2 and CYP3A4 are involved in metabolism of clozapine to N-desmethylclozapine (norclozapine) and CYP3A4 is responsible for its oxidation to clozapine N-oxide. Norclozapine is active with partial agonism at D2/D3 receptors but lacks serotonin-reuptake activity. Although clozapine is a substrate for CYP2D6, studies in patients with schizophrenia found no significant influence of CYP2D6 PM and IM phenotypes on levels of clozapine or norclozapine (Dahl et al., 1994; Arranz et al., 1995; Dettling et al., 2000a,b; Melkersson et al., 2007). Another study in 108 patients found no difference in the distribution of PM and UM metabolism between patients with agranulocytosis and controls (Dettling et al., 2001). Evaluation of 58 patients with schizophrenia found CYP1A2*1F (rs762551), *1D (rs2069514), and *1C (rs35694136) allele frequencies of 67%, 6%, and 1%, respectively (Kootstra-Ros et al., 2005). No significant correlation was found between *1F, and *1C and clozapine plasma levels. The frequency of *1D was too low to draw any conclusions. 3.3.4. Iloperidone CYP2D6 catalyzes metabolism of iloperidone to P94, which is converted to the active metabolite P95 (Iloperidone package insert, 2012). Additionally, iloperidone undergoes interconversion to the active metabolite P88 and vice versa in the cytosol. In CYP2D6 PMs less iloperidone is metabolized and plasma levels of the P95 metabolite

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decrease (US Food and Drug Administration, 2009). The increased levels of the parent drug iloperidone results in more cytosolic conversion and higher levels of P88 (Table 1) (US Food and Drug Administration, 2009). Consequently, PMs have lower P95 levels and higher P88 levels relative to EMs (Fig. 3) (US Food and Drug Administration, 2009). 3.3.5. Lurasidone Lurasidone is metabolized by CYP3A4 to form two inactive metabolites and two active metabolites, ID14283 and ID14326, present in the plasma at 25% and 2% of the parent drug concentration, respectively (Lurasidone package insert, 2012). At the time this review was undertaken, there were no published cases or studies evaluating lurasidone in healthy persons or patients with CYP3A4 variants. 3.3.6. Olanzapine The major pathways for olanzapine metabolism are direct glucuronidation and CYP-mediated oxidation (Olanzapine package insert, 2009; Sheehan et al., 2010). The most important enzymes in olanzapine metabolism are uridine diphosphate (UDP) and UGTs (Kassahun et al., 1997). CYP1A2 and CYP2D6 catalyze metabolism of olanzapine, although CYP2D6 does not appear to have a major role in vivo as olanzapine levels are not significantly elevated in patients with deficient CYP2D6 activity (Olanzapine package insert, 2009). Studies of patients with schizophrenia in India and Japan found no significant correlation between CYP2D6 polymorphisms and olanzapine plasma levels (Nozawa et al., 2008; Thomas et al., 2008). A study of healthy volunteers in Sweden showed no significant differences in olanzapine pharmacokinetic parameters between EMs and PMs for either CYP1A2 or CYP2D6 (Hagg et al., 2001). A study of patients with schizophrenia receiving olanzapine found that the CYP1A2*1F/*1F genotype result in a 22% reduction of dose/ body-weight normalized olanzapine plasma concentrations compared with CYP1A2*1A carriers, after controlling for smoking and other inducers (Laika et al., 2010). Approximately 50% of patients with the CYP3A43 AA genotype (rs472660) have high clearance of olanzapine and subtherapeutic blood levels. The A allele is much more frequent in African Americans than Caucasians (67% vs. 14%), and patients with this the CYP3A43 genotype had more symptoms and were more likely to discontinue treatment (Bigos et al., 2011). 3.3.7. Paliperidone Although paliperidone is the active metabolite of risperidone (9-OH-risperidone), risperidone (see below) is metabolized by the liver whereas paliperidone is metabolized principally by the kidneys (de Leon et al., 2008). Therefore, paliperidone is a useful alternative

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for patients that have moderate to severe hepatic impairment or are taking medications that inhibit hepatic metabolism. 3.3.8. Quetiapine The major enzyme responsible for quetiapine metabolism is CYP3A4, and results in four metabolites: 7-hydroxyl, sulfoxide, N-desalkyl and O-desalkyl products (Grimm et al., 2006). N-desalkylquetiapine (norquetiapine) is metabolically active and is also eliminated by CYP3A4. However, the AUC of norquetiapine is only 27% of the AUC of quetiapine (Winter et al., 2008). The metabolite 7-hydroxyquetiapine is active and formed by CYP2D6, but is unlikely to be a significant consideration in metabolism because of its low plasma concentration (Bakken et al., 2009). In one case, a 47-year-old man with psychotic depression who experienced serious adverse drug reactions when treated with quetiapine and clomipramine was found to have very low CYP3A4/5 activity (Stephan et al., 2006). After discontinuation of quetiapine and reduction of the clomipramine dose, adverse reactions subsided with the exception of elevated liver enzymes. 3.3.9. Risperidone Risperidone is metabolized by CYP2D6 to 9-OH-risperidone (9-OHR) or paliperidone (de Leon et al., 2008). Early studies reported that risperidone and 9-OHR have equivalent pharmacodynamic activity (Megens et al., 1994). These data, which were the basis for drug labeling, were based on a study of a single risperidone dose in 11 healthy male volunteers, only 2 of whom were PMs (Huang et al., 1993). It was concluded on the basis of these data that CYP2D6 polymorphisms should have no substantial clinical implications for risperidone metabolism as decreased 9-OHR production would be compensated for by higher plasma levels of the parent drug, risperidone. Subsequently, studies found that CYP2D6 PM patients experienced a higher incidence of adverse drug reactions, including lengthening of QTc interval and parkinsonism (Bork et al., 1999; Kohnke et al., 2002; Llerena et al., 2004a; de Leon et al., 2005a). Although risperidone and 9-ROH have similar affinities for dopamine D2 receptor in the brain, they otherwise have distinct pharmacologic profiles that may explain the emergence of adverse effects in patients with higher plasma risperidone/9-OHR ratios. Compared to 9-OHR, the affinity of risperidone is 3.7, 10, and 6 times higher for the α1, α2, and 5-HT2A receptors, respectively (Schotte et al., 1996; Richelson and Souder, 2000). Elevated risperidone to 9-OHR ratios have been demonstrated to be associated with CYP2D6 polymorphisms among Italian patients with schizophrenia who were PMs or in heterozygous EMs, compared to homozygous EMs (Scordo et al., 1999). Other studies showed similar elevated ratios in Asian patients with schizophrenia who had recognized CYP2D6 PM alleles (Mihara et al., 1999; Roh et al., 2001; Mihara et al., 2003).

Fig. 3. Poor metabolizer phenotype both raises and lowers blood levels of active iloperidone metabolites. Iloperidone is metabolized to P95 by CYP2D6 and interconverted to P88 in the cytosol, both of which are active metabolites. In CYP2D6 PMs, plasma levels of the P95 metabolite decrease. The increased levels of the parent drug iloperidone results in more cytosolic conversion and higher levels of P88. As a result, PMs have lower P95 levels and higher P88 levels relative to EMs (US Food and Drug Administration, 2009).

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There is currently insufficient data to allow calculation of dose adjustment for PMs, IMs, or UMs receiving risperidone (Table 1). The use of conventional or microarray laboratory genotyping may be useful to identify patients with CYP2D6 polymorphisms. The clinical use of this test as it relates to risperidone therapy has been reviewed in detail by de Leon et al. (2006). Guidelines recommended that an alternative therapy be selected for patients with a relevant CYP2D6 phenotype or vigilance be used for adverse drug events and dosage adjusted to clinical response (Table 1) (Swen et al., 2011). 3.3.10. Ziprasidone Ziprasidone is extensively metabolized in the liver by aldehyde oxidase and CYP3A4 (Beedham et al., 2003). Approximately two-thirds of the initial metabolism of ziprasidone results from generation of S-methyldihydroziprasidone by aldehyde oxidase, and the remaining third results in ziprasidone sulfoxide. These metabolites undergo further degradation by CYP3A4 (Prakash et al., 1997). Although most of the metabolism of ziprasidone is carried out by aldehyde oxidase, drug-drug interactions resulting from coadministration of CYP3A4 inducers or inhibitors may still occur (Miceli et al., 2000a,b; Ziprasidone package 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; 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; 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 quality of these investigations varies widely and methodologies include retrospective and prospective open label studies as well as case–control studies. Most studies to date have been modest in size and there is a wide variation in the data reported with regard to genotyping procedures, population stratification in groups of mixed ethnicity, and whether populations were in Hardy–Weinberg equilibrium. A single-center study in Denmark investigated the association of CYP2D6 genotype with antipsychotic therapeutic and adverse effects in 576 hospitalized patients diagnosed with schizophrenia (Jurgens et al., 2012). Antipsychotic, adjuvant, and anticholinergic drug utilization was evaluated retrospectively as a surrogate measure of outcomes in genotyped patients. Results showed that PMs and UM received 626 and 550 median chlorpromazine equivalents (CPZEq), respectively, compared with 384 CPZEq. in EMs (P = 0.018). For CYP2D6-dependent antipsychotics alone, the difference was not statistically significant (P = 0.096). Although it may be expected that UMs would require higher doses of antipsychotics, it is unclear why PMs also received higher CPZEq. It is possible that adverse antipsychotic reactions that can resemble symptoms of schizophrenia led to increased doses in some patients (Lingjaerde et al., 1987). A cross-sectional study in Sweden evaluated outcomes associated with genetic variants of CYP2D6 in 116 outpatients (78% diagnoses with schizophrenia) receiving antipsychotic drugs (Alenius et al., 2008). Patients were genotyped and classified according to the CANSEPT method, which combines the Camberwell Assessment of Need (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 clinical needs (Group 2); those without significant side effects but with significant social or clinical needs (Group 3); and those with significant side effects and significant social or clinical needs (Group 4). There were more EMs in the groups without significant needs (67% in Groups 1 + 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 phenotypes with a significantly lower mean dose in PMs (2.4 mg) compared with the mean dose of others (4.5–5.8 mg) (P = 0.012). An open label study in Brazil evaluated CYP3A4/5 and CYP2D6 polymorphisms in 186 patients with schizophrenia receiving typical antipsychotics (Kohlrausch et al., 2008). Patients were separated into groups according to their response to therapy. The nonrefractory group (n = 65) consisted of those who had long-lasting response to treatment and the refractory, or treatment-resistant group had (n = 121) failed to respond to haloperidol or chlorpromazine for 12 weeks or thioridazine for 24 weeks, did not have appropriate behavior control, and showed continued symptoms. Patients underwent genotyping for nine polymorphisms in the CYP3A4 gene, one in the CYP3A5 gene and 24 polymorphisms in the CYP2D6 gene (Table 2). There was no statistically significant association between CYP2D6 genotype and treatment response. Notably, the study found that those with the CYP3A4*1A variant (wild type) had a three times greater odds of being refractory than those with the CYP3A4*1B polymorphism CYP3A4–392A N G (OR = 3.32, P = 0.014). Similar results were found when analyzing data from only those taking haloperidol, which is metabolized by CYP3A4. The phenotype associated with CYP3A4*1B occurs in about 4–5% of Caucasians and is associated with increased promoter activity resulting from reduced binding of a transcriptional repressor (Amirimani et al., 2003). Patients with low CYP3A5 expression (CYP3A5*3/CYP3A5*3) (rs776746) were also at a significantly 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 randomized study. A post hoc analysis examined the impact of 25 genetic variants of drug metabolizing enzymes among a subset of CATIE participants (n = 750) treated with olanzapine, quetiapine, risperidone, ziprasidone, and perphenazine (Grossman et al., 2008). The study included assessment of polymorphisms associated with CYP2D6, CYP1A2, CYP3A4, CYP3A5, and aldehyde oxidase 1 (AOX1). None of the variants tested showed a significant association with dosing, efficacy, overall tolerability, or tardive dyskinesia. 4.2. Adverse effects 4.2.1. Extrapyramidal symptoms Numerous studies have examined the relationship between CYP2D6 genotype and extrapyramidal symptoms (EPS) in patients with schizophrenia 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; Inada et 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 and found no significant association between tardive dyskinesia and CYP2D6 in overall populations (Fleeman et al., 2011). When the analysis was limited to prospective studies, there was a significant association between tardive dyskinesia and CYP2D6 homozygous mutant genotype compared to the wild type (OR = 2.08, 95% CI 1.21–3.57) or the homozygous mutant compared to the heterozygotes with one copy of the wild type allele (OR = 1.83, 95% CI 1.09–3.08) (Fleeman et al., 2011). Tardive dyskinesia was significantly more severe in patients with homozygous mutant CYP2D6 alleles compared with the homozygous wild type alleles. Patients with homozygous or heterozygous mutant CYP2D6 genotypes were significantly more likely to develop Parkinsonism (OR = 1.64, 95% CI 1.04–2.58), but genotype was not associated with severity. There was no significant association between acute dystonia or akathisia and CYP2D6 genotypes, although the number of patients in studies reporting these outcomes was small.

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Table 2 Studies of association between CYP2D6, CYP3A4, and CYP1A2 polymorphisms and clinical efficacy of antipsychotics in adult patients with schizophrenic spectrum disorders (Arranz et 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; Kohlrausch et 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

Arranz et al. (1995)

Haloperidol

Caucasian (172)

CYP2D6*1 to *15, *17

Haloperidol decanoate

Caucasian (26)

CYP2D6*3, *4, *5

Haloperidol or chlorpromazine

Brazilian (186)

Olanzapine

South Asian (130)

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 CYP2D6*4, CYP1A2*1C, *1F

No significant association with clinical efficacy Nonsignificant trend toward lower therapeutic efficacy with increasing number of active CYP2D6 genes No significant association with clinical efficacy No significant association between CYP2D6 and clinical efficacy CYP2A4*1B and CYP3A5*3 significantly associated with refractoriness to treatment

Thomas et al. (2008)

Olanzapine

Caucasian (124)

CYP1A2*1F

Risperidone

Caucasian (82)

CYP2D6*4, *6, *14

Risperidone

Asian (136)

CYP2D6*2, *10

Antipsychotics metabolized by CYP2D6 Typical antipsychotics

Caucasian (128)

CYP2D6*1, *3, *4, *5, *6, *7

Caucasian (308)

CYP2D6*3, *4, *5

Various antipsychotics

Caucasian (365)

CYP2D6*1, *2, *3, *4, *6 to *10, *41

Various antipsychotics

Asian (156)

CYP2D6*3, *4, *5, *6, *9, *10, *14, *17

Various antipsychotics

Caucasian (576)

CYP2D6*3, *4, *5, *6

Various antipsychotics

Caucasian (116)

CYP2D6*1 to *8

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 clinical efficacy No significant association with clinical efficacy No significant association with clinical efficacy No significant difference in clinical improvement No significant association with disease symptom severity More UM in the nonrefractory than refractory group (4.1% vs. 0.9%; P = 0.9) Clinical efficacy was lower in IMs receiving drugs metabolized by CYP2D6 than IMs receiving other medications (P = 0.017) UMs had significantly more severe negative symptoms (P = 0.001) No significant association with observable clinical impact in dosing or use of anticholinergic drugs More EM in nonrefractory than refractory group (67% vs. 46%; P = 0.02) No significant association with clinical efficacy

Brockmoller et al. (2002)

Panagiotidis et al. (2007) Kohlrausch et al. (2008)

Laika et al. (2010) Riedel et al. (2005) Kakihara et al. (2005) Hamelin et al. (1999) Aitchison et al. (1999) Laika et al. (2009)

Zahari et al. (2009) Jurgens et al. (2012)

Alenius et al. (2008) Muller et al. (2012)

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

A prospective study in 172 psychiatric inpatients evaluated the relationship between CYP2D6 phenotype and haloperidol adverse events (Brockmoller et al., 2002). PMs had significantly higher event rates of EPS than those with one or more active CYP2D6 genes (P = 0.02). The highest percentage of patients with grade 2 or 3 adverse effects were UMs (100%) and this group also experienced the smallest therapeutic improvement or a worsening of symptoms. Another study evaluated EPS in 26 outpatients with schizophrenia receiving depot haloperidol monotherapy (Panagiotidis et al., 2007). Although there was a significant association between haloperidol plasma concentration and the number of active CYP2D6 alleles, no relationship to treatment outcomes or EPS was observed. A case–control study found that CYP2D6 PMs had a significant three times higher odds of risperidone adverse drug reactions (OR 3.4, 95% CI 1.5–8.0) and a six-times higher odds of discontinuation (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 of tardive dyskinesia in association with CYP1A2*1F polymorphisms (Basile et al., 2000). Those with the C/C genotype for CYP1A2 were at significantly increased risk of tardive dyskinesia induced by typical antipsychotics, compared with those who were heterozygous or homozygous for the CYP1A2 A allele (P = 0.0007). 4.2.2. Weight gain The most common CYP2D6 polymorphism among Asians is CYP2D6*10, which occurs in up to 50% of various Asian subpopulations and results in an unstable enzyme and diminished activity (Kurose et

al., 2012). A study of 123 Chinese inpatients with schizophrenia receiving risperidone monotherapy found that those with homozygous wild type CYP2D6 alleles had significantly lower weight gain than those with the heterozygous (P b 0.004) or homozygous (P = 0.04) CYP2D6*10 polymorphisms (Lane et al., 2006). Another study in 11 patients with schizophrenia receiving olanzapine examined the relationship between CYP2D6 polymorphisms and weight gain. Genotype was significantly associated with body mass index change, with patients having a *1/*3 or *4 genotype experiencing a larger percent change in BMI, compared with those with the wild type (*1/*1) genotype (P b 0.001) (Ellingrod et al., 2002a). An open label prospective study investigated the association between weight gain and CYP1A2 and CYP2D6 genotype in 130 South Asian patients with schizophrenia or schizoaffective disorder (Thomas et al., 2008). No significant correlation was seen between weight gain and the presence of CYP2D6*4, CYP1A2*1C, or CYP1A2*1F. 5. Is CYP pharmacogenetics ready for clinical practice? Several laboratories offer Clinical Laboratory Improvement Amendments (CLIA)-approved CYP450 genotyping to identify known polymorphisms and these test results are currently being used in treatment decision making. In its Critical Path Initiative 2010, the US FDA emphasized the need to include pharmacogenetics language on product labeling where appropriate, and specific CYP450 pharmacogenetic recommendations can now be found on numerous package inserts (US Food and Drug Administration, 2012); however, the issue of whether to use pharmacogenetic testing to enhance outcomes in

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

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 of evidence” assessment (Teutsch et al., 2009).

patients receiving antipsychotics is complex. There is a plausible biologic rationale, accumulating evidence linking genetic variation with drug response, and availability of reliable laboratory tests (Mrazek and Lerman, 2011). Conversely, the lack of large, high-quality studies has hindered consensus and widespread evidence-based recommendations. The major question is whether there is sufficient evidence that pharmacogenetic testing improves efficacy or safety in specific settings, such as the use of antipsychotics in adult patients with schizophrenia. Given the urgency of implementation and the plethora of potentially confounding factors involved in drug metabolism, it is unlikely that randomized controlled trials will be conducted for every clinical application of pharmacogenetic testing desirable. Therefore, the level of evidence needed for clinical implementation is currently being debated. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the Pharmacogenomics Research Network has argued that, given biologic plausibility and evidence of a gene–drug association, noninferiority when compared with current standards of prescribing is an acceptable threshold (Altman, 2011). There are numerous resources clinicians may use to gather information on the strength of evidence related to pharmacogeneticbased dosing and treatment decisions, as well as specific dosing guidelines, some of which are summarized in this review. These include resources from CPIC, which provides peer-reviewed recommendations and drug/gene guidelines (Swen et al., 2011). The Pharmacogenomic Knowledge Base (PharmGKB), curates knowledge and evidence for the impact of specific genetic variations on drug metabolism (Altman, 2007). The Pharmacogenetic Research Network is funded by the National Institutes of Health and brings together numerous research initiatives. The Royal Dutch Association for the Advancement of Pharmacy has developed pharmacogenetics-based therapeutic dose recommendations based on the available evidence (Swen et al., 2011). The guidelines currently provide recommendations for over 50 drugs and 100 genotype/phenotype–drug combinations. Identified studies are graded for the quality of evidence and clinical relevance for the gene–drug interaction. Risk analysis is then used to develop recommendations for dose adjustments and therapeutic strategies, such as therapeutic drug monitoring, alternative drug selections, or warning for adverse events. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative, established by the Centers for Disease Control and Prevention (CDC), has created guidelines for evaluation and evidence-based application of genetic tests (Teutsch et al., 2009). The EGAPP provides an analytic framework for examining evidence related to pharmacogenetic testing. Fig. 4 illustrates a hypothetical application of this framework to the problem of genotype testing for antipsychotic use. This approach emphasizes the analytic validity (sensitivity and specificity of the genotype test), clinical validity (ability of the test to predict the association of genotype with the circulating levels or clinical response predicted by the genotype), and clinical utility (likelihood that use of the test to guide drug choice will improve outcomes). A recent meta analysis of CYP450 testing for prescribing antipsychotics in adults with schizophrenia found 41 of 2841 studies reported analytic validity, 47 of 2151 reported data on

clinical validity, and only 1 of 1234 reported clinical utility (Fleeman et al., 2011). 6. Conclusion The US FDA has increasingly required inclusion of pharmacogenetic information in product labeling, and provides guidance on incorporation of pharmacogenetic studies in drug development. Plasma levels— and potentially the efficacy and safety—of many antipsychotic drugs are influenced by known CYP450 genetic variants. CLIA-approved assays are available to test for these polymorphisms in patients and are relatively inexpensive. No randomized clinical trials have yet evaluated whether use of CYP450 genotyping in antipsychotic treatment decision making is associated with better treatment response or reduced likelihood of adverse events in adult psychiatric patients. Randomized trials are not only cost prohibitive, they may not be practical because some polymorphisms are too infrequent (Mrazek and Lerman, 2011). Additionally, given the current high predictive value of pharmacogenetic tests, it would not be ethical to randomize patients to treatments that are potentially toxic for known phenotypes. Most studies to date have been unable to provide sufficient evidence to support the use of CYP450 genotype testing to improve therapeutic efficacy in the use of antipsychotic medications and the clinical utility of this strategy has not been determined. The inability to conclusively demonstrate a therapeutic benefit of genotype testing may be limited by several factors, including: 1) retrospective or cross-sectional design, 2) inadequate statistical power from small study groups and/or infrequent 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 literature provides a consistent body of evidence supporting the use of genotypic testing to prevent adverse events in adults receiving some antipsychotics. The role of additional genetic variants beyond CYP450 in the therapeutic and adverse responses to antipsychotics is currently being evaluated, including those polymorphisms related to pharmacodynamic targets such as dopamine and serotonin receptors, and cellular transporters (Arranz et al., 2011; Zhang and Malhotra, 2011). These studies offer additional avenues to predict efficacy and may be useful to prevent adverse effects, including weight gain and EPS (Fraguas and Kirchoff, 2006; Lett et al., 2012). Guidelines provide an important resource for the clinical application of pharmacogenetics to antipsychotic use where sufficient evidence currently exists to make a recommendation. Although in many cases the evidence base clinical implementation of pharmacogenetics is sufficient, conclusive recommendations for routine use of pharmacogenetic testing to guide antipsychotic use in adults with schizophrenia awaits results of large prospective trials with generalizable results. Role of funding source There was no funding for this article. Contributors Contributors:

D. 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 interest Drs. 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. Acknowledgment There are no acknowledgments.

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