Molecular Psychiatry (2012) 17, 242–266 & 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12 www.nature.com/mp EXPERT REVIEW Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications TAP Lett, TJM Wallace, NI Chowdhury, AK Tiwari, JL Kennedy1 and DJ Mu¨ller1 Neurogenetics Section, Centre for and Mental Health, Toronto, ON, Canada

Second-generation antipsychotics (SGAs), such as , clozapine and olanzapine, are the most common treatments for . SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin are among the most promising, and new evidence suggests that the DRD2, TNF, SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1, MDR1, ADRA1A and INSIG2. More research is required before genetically informed, personalized can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application. Molecular Psychiatry (2012) 17, 242–266; doi:10.1038/mp.2011.109; published online 6 September 2011 Keywords: antipsychotics; ; personalized medicine; pharmacogenetics; schizophrenia; weight gain

Introduction clozapine, many SGAs have been developed, such as olanzapine and risperidone, although among SGAs, The introduction of in the 1950s only clozapine shows an increased of provided the first effective pharmacological treatment treatment compared with FGAs.3 Unfortunately, most of schizophrenia (SCZ), and established antipsycho- SGAs, in particular clozapine and olanzapine, have tics as the primary intervention of many psychiatric been linked to substantial drug-induced weight gain, disorders. Numerous typical antipsychotics or first- which confers risks of metabolic syndrome, diabetes generation antipsychotics (FGAs) were subsequently mellitus type II and cardiovascular disease4–6 developed, and collectively demonstrated successful (Figure 1). Furthermore, antipsychotic-induced treatment of psychotic symptoms, in particular weight gain (AIWG) has consistently been associated delusions and hallucinations. The benefits of FGAs with elevation of liver enzymes, suggesting that were offset by the common occurrence of elevated antipsychotics may be involved in hepatocyte prolactin and extrapyramidal symptoms (EPS), such damage.7 SCZ patients have a 20% shorter lifespan as Parkinsonism and tardive dyskinesia. These med- compared with the general population, with cardio- ications were also severely limited by their inability vascular disease being the leading cause of death.8 to treat the full range of SCZ symptoms. In the Moreover, Goff et al.9 reported a quadrupled increased early 1970s, clozapine was introduced as the first incidence of diabetes (13 vs 3%) and double incidence atypical antipsychotic or second-generation antipsy- of (27 vs 17%) in the CATIE (Clinical chotic (SGA), which marked a significant advantage Antipsychotic Trials of Intervention Effectiveness) over typical in its decreased risks of sample when compared with age-, race- and gender- causing neurological side effects, and increased 1,2 match controls from NHANES III (National Health and efficacy of treatment. Since the introduction of Nutrition Examination Survey III). In addition to the health risks of weight gain, social stigmatization of Correspondence: Dr DJ Mu¨ ller, Pharmacogenetics Research weight gain and obesity are major factors contributing Clinic, Centre for Addiction and Mental Health, 250 College to patient non-compliance4,10 (Figure 1). Street, R 30 Toronto, ON M5T 1R8, Canada. E-mail: [email protected] 1These are co-senior authors. Typical and atypical antipsychotics Received 5 April 2011; revised 11 July 2011; accepted 29 July In general, most SGAs use a ‘pharmacological shot- 2011; published online 6 September 2011 gun’ approach with strong affinity for the serotonin Pharmacogenetics of AIWG TAP Lett et al 243 a Biocomputational Screening Training of Cost Regulatory Ethical Analysis Effectiveness Caregivers Effectiveness Oversight

Personalized Medicine b Personal Risks Hypertension Social Challenges Cardiovascular Disease Healthcare Costs Metabolic Syndrome Antipsychotic-Induced Stigmatization Liver Damage Weight Gain Interpersonal Type-II Diabetes Relationships Non-Compliance

c

Environmental Personal Secondary Energy Lipid Pharmacokinetcs Drug Targets Factors Characteristics Signaling Homeostasis Metabolism

Epigenetics (?) Demographics CYP2D6 HTR2C SNAP-25 LEP/LEPR SREB Sedentary Lifestyles Co-Morbidities MDR1 ADRA1A NPY/NPY5R TNF Co- DRD2 MC4R APOC3/APOA5 Poor Eating Habits CNR1 LPL Poverty Smoking

Figure 1 Factors and outcomes relating to antipsychotic-induced weight gain and personalized medicine. (a) The future of ‘personalized medicine’ in psychiatry requires consideration of pharmacogenetic screening and personal variables that may influence drug response for each individual antipsychotic used by each patient. Additional factors influence the efficacy of individualized DNA pharmacogenetic tests including genetic screens with sufficient sensitivity and specificity, biocomputational analysis to build an algorithm incorporating genetic and non-genetic factors (for example, neuro-fuzzy modeling), ethical challenges such as genetic discrimination due to the pleiotropic effects of variants, as well as education of physicians and caregivers to communicate genetic findings. (b) Antipsychotic-induced weight gain leads to cardiovascular disease, type II diabetes, hypertension and metabolic syndrome costs. Weight gain is also a leading factor in patient non-compliance, a major risk factor for relapse and rehospitalization. Finally, weight gain can cause stigmatization and difficulties in interpersonal relationships that may further alienate SCZ patients. (c) Both genetic (for example, CYP2D6, HTR2C and LEP genes) and non-genetic (co-medication, sedentary lifestyle and socio-demographic) factors may influence treatment-induced weight gain, including possible epigenetic factors.

5-HT2 with concomitant affinities for dopa- minergic, muscarinic, histaminergic and adrenergic receptors.11 In contrast, FGAs are generally more specific, and bind with greater affinity to the D2 receptor. It should be noted that there are exceptions to this generalization as a class of FGAs called phenothiazines (for example, chlorpro- mazine) have a more diverse binding profile, whereas SGAs such as risperidone and have high D2 and D3 antagonism.12 Although SGAs have preferential action on 5-HT2 receptors, the rapid dissociation of most SGAs from the D2 receptor has been suggested to account for the atypicality.13,14 SGAs constitute a major improvement in the avoid- ance of extrapyramidal symptoms through reduced D2 receptor occupancy.15 Unfortunately, side effects such as weight gain and impaired glucose tolerance/ lipid abnormalities are observed.4 However, the risk Figure 2 Meta-analyses values for mean and 95% con- of weight gain is variable among SGAs (Figure 2). The fidence interval of weight change after FDA-approved antipsychotic treatment (up to 12 weeks). Sources of mechanism of drug-induced weight gain is mostly information: Parsons et al.160 (olanzapine, risperidone, unclear; receptor-binding profiles of these have ziprasidone, haloperidol and placebo), Allison et al.161 been implicated. For instance, the SGA amisulpride is (clozapine, thioridazine, chlorpromazine, fluphenazine) a pure D2/D3 antagonist that and Marder et al.162 (aripiprazole). 95% Confidence interval correlates with lower metabolic risks; moreover, both is unavailable for aripiprazole.

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 244 the serotonin 5-HT2c-and the histamine H1-blocking treatment and in the prevalence of side effects. The activity have been associated with increased risk majority of atypical antipsychotics are metabolized by of metabolic abnormalities.13 phase I cytochrome P450 (CYP450) isoenzymes.4 Pharmacokinetic studies have hypothesized that poor Genetic factors CYP450 activity could be associated with increased Genetic factors are among the strongest risk factors serum levels of antipsychotics that may lead to influencing AIWG.4 For example, a recent twin increased weight gain. Cytochrome P450 2D6 and sibling study found AIWG to be heritable (CYP2D6) is responsible for the metabolism of (h2 =0.6–0.8).16 An understanding of the genetic factors risperidone; thus, polymorphisms in this gene may involved in AIWG could allow for tailored treatment be associated with weight gain. The CYP2D6 gene is for at-risk individuals. However, the literature on the highly polymorphic with > 90 reported allelic genetic contribution to metabolic side effects induced variants.18 In risperidone-treated patients, T-allele by antipsychotics has presented inconsistencies. carriers of the 188C/T variant (CYP2D6*10) were Similar to other complex phenotypes, AIWG is likely reported to have significantly lowered CYP2D6 to be polygenic with each polymorphism making a activity. Furthermore, the effect was largest among minor contribution to the overall phenotype. Further- homozygote carriers.19 The 188T allele of CYP2D6 more, risk factors may vary between antipsychotic was significantly associated with AIWG in a study of medications. Nevertheless, numerous compelling Han Chinese SCZ patients undergoing risperidone genes have come to the forefront, such as HTR2C, treatment.20 leptin and DRD2, and new susceptibility genes are More recently, the MDR1 gene has been a target being discovered as techniques for studying pharma- of pharmacokinetic studies. MDR1 encodes for cogenetics become more sophisticated. p-glycoprotein. P-glycoprotein is an ATP-dependent efflux pump that is expressed at blood-tissue barriers and tissues involved in normal excretory function.21 Methods It limits the absorption of orally administered drugs, We reviewed published association studies in AIWG promotes drug elimination into bile and urine, as well from December 2006 to date, using the Medline as limits transport to various tissues.22 The T alleles database (http://www.ncbi.nlm.nih.gov/pubmed/) and of the C2677T and C3435T polymorphisms were ISI web of knowledge (http://apps.isiknowledge. significantly associated with weight gain in risper- com; for review of studies before 2006, see Mu¨ller idone- and olanzapine-treated women (P = 0.015 and and Kennedy4 and Mu¨ller et al.5). Earlier studies P = 0.031, respectively).22 In contrast, an earlier study were cited when they were important in the context yielded no significant results, although the smaller of newer findings. The following search terms sample size of this study may not have had sufficient were included: antipsychotic, neuroleptics, body statistical power to detect an association (Table 2).23 weight, weight gain, obesity, overweight, metabolic The notion that variation in drug-metabolizing syndrome, BMI, therapeutic outcome, side effects, enzyme activity and neural transporters may have a gene, genetics, pharmacogenetics and the name of role in AIWG is intriguing, especially with regard to each active antipsychotic medication together with personalized medicine. Thus far, the pharmacokinetic weight gain, gene and other keywords. Conference genes have been suggested to be simpler traits than abstracts were excluded, except for one important genes involved in .24,25 However, finding from the study by Lencz et al.17 In our it remains unclear whether plasma concentrations comprehensive review, all studies were considered of SGAs correlate with weight gain. Randomized regardless of differences with respect to ethnicities, age controlled trials generally fail to demonstrate any groups, diagnostic criteria and experimental designs. relationship between weight gain risk and dose for The majority of studied individuals were affected by clozapine, olanzapine and risperidone.26 Conversely, SCZ or schizoaffective disorders with some studies quetiapine dosage may be connected to both fre- also including healthy controls, first-episode psycho- quency and magnitude of weight gain, and results sis, bipolar disorders and pediatric psychiatric from long-term trials of risperidone are controver- patients. Multiple study design modalities were sial.26 considered including candidate gene, tag-single nu- The extent to which pharmacokinetic genes may cleotide polymorphism (SNP) analysis, cross-sectional predict AIWG or its efficacy is still largely undeter- design, case and control and -wide association mined. A recent outcome from the CATIE study study (GWAS), in addition to variable length of study. suggests that genetic determinates of variable drug Meta-analyses and studies combining previous inves- metabolism (CYP450, MDR1, flavin-containing mono- tigations were considered as interim summaries of oxygenase 3) have little impact on the clinical use of previous works. In total, 49 studies were selected for antipsychotic medication.27 Epigenetic and micro- this review (Table 1). RNA-dependent control of pharmacokinetic genes would provide another layer of informa- Pharmacokinetic studies tion. The major drug-metabolizing enzyme of olanza- The role of and plasma drug levels pine and clozapine, CYP1A2, has been shown to have has been emphasized in the efficacy of antipsychotic the expected inverse correlation between DNA

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 245 Table 1 Summary of genes reviewed for this article with SNPs of high interest.

Gene Gene name Location SNPs of interesta symbol

ADIPOQ Adiponectin, C1Q and collagen domain containing 3q27 ADRA1A Adrenergic, a-1A-, receptor 8p21.2 ADRA2A Adrenergic, a-2A-, receptor 10q24-q26 rs1800544 (a, m) ADRb3 Adrenergic, b-3, receptor 8p12 rs4993 (a, m) AMPK 50 Adenosine monophosphate-activated kinase Multiple subunits PRKAA1: rs10074991 (a) APOA1 Apolipoprotein A-I 11q23-q24 APOA2 Apolipoprotein A-II 1q21-q23 APOA4 Apolipoprotein A-IV 11q23 APOA5 Apolipoprotein A-V 11q23 APOB Apolipoprotein B (including Ag(x) antigen) 2p24-p23 APOC3 Apolipoprotein C-III 11q23.1-q23.2 APOE Apolipoprotein E 19q13.2 BDNF Brain-derived neurotrophic factor 11p13 rs6265 (a, m, f) CNR1 1 6q14-q15 rs806378 (a, f) CL ATP citrate lyase 17q21.2 CYP2D6 Cytochrome P450, family 2, subfamily D, polypeptide 6 22q13.1 DRD1 5q35.1 DRD2 11q23 rs4436578 (a); rs1799732 (a, f); rs1079598 (a); rs1800497 (a, m); rs6277 (a, f) DRD3 3q13.3 DRD4 11p15.5 DRD5 4p16.1 FAAH Fatty acid amide hydrolase 1p35-p34 rs324420 (a, f) FABP3 Fatty acid binding protein 3, muscle and heart 1p33-p32 (mammary-derived growth inhibitor) FTO Fat mass and obesity associated 16q12.2 rs9939609 (m) GAL Galanin prepropeptide 11q13.3 GHRL Ghrelin/obestatin prepropeptide 3p26-p25 GNB3 Guanine nucleotide-binding protein (G protein), 12p13 b-polypeptide 3 HRH1 H1 3p25 HRH2 Histamine receptor H2 5q35.2 HRH3 Histamine receptor H3 20q13.33 HTR1A 5-Hydroxytryptamine (serotonin) receptor 1A 5q11.2-q13 HTR2A 5-Hydroxytryptamine (serotonin) receptor 2A 13q14-q21 rs6313 (a, f) HTR2C 5-Hydroxytryptamine (serotonin) receptor 2C Xq24 rs3813929 (a, m, f) HTR6 Serotonin receptor 6 1p36-p35 INSIG1 Insulin-induced gene 1 7q36 INSIG2 Insulin-induced gene 2 2q14.2 LEP Leptin 7q31.3 rs7799039 (a, m, f) LEPR 1Leptin receptor 1p31 rs1137101 (a,m, f); rs817983 (a, f) LPL Lipoprotein lipase 8p22 MC4R 18q22 rs17782313 (m) MDR1 Multidrug resistance protein 1 (ABCB1: ATP-binding 7q21.12 rs1045642 (f, m); cassette sub-family B member 1) rs2032582 (f, m) MTHFR Methylenetetrahydrofolate reductase 1p36.3 NPY Nuropeptide Y 7p15.1 NPY5R Y5 4q31-q32 PMCH Pro-melanin-concentrating hormone 12q23.2 rs7973796 (a, m) PON1 Paraoxonase 1 7q21.3 PPARG Peroxisome proliferator-activated receptor-g 3p25 rs1801282 (m, f); rs121909244 (m, f); rs3856806 (m, f); rs1800571 (m, f) SCAP SREBF chaperone 3p21.31 SCARB1 Scavenger receptor class B, member 1 12q24.31 SCARB2 Scavenger receptor class B, member 2 4q21.1

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 246 Table 1 Continued

Gene Gene name Location SNPs of interesta symbol

SH2B1 Src 2 16p11.2 SNAP-25 Synaptosomal-associated protein, 25kDa 20p12-p11.2 SREBF1 Sterol regulatory element-binding factor 1 17p11.2 SREBF2 Sterol regulatory element-binding transcription factor 2 22q13 SLC6A4 Solute carrier family 6 ( transporter, 17q11.2 serotonin), member 4 Tag lipase Tri-acylglycerol lipase (PNPLA3: patatin-like 22q13.31 Phospholipase domain containing 3) TNF Tumor necrosis factor-a 6p21.3 rs1800629 (m, f) TNFRSFA Tumor necrosis factor receptor superfamily, member 1A 12p13.2 TNFRSF1B Tumor necrosis factor receptor superfamily, member 1B 1p36.22

Abbreviation: SNP, single nucleotide polymorphism. aSNPs of high interest include either replication in independent samples, associations with metabolic dysregulation including metabolic syndrome, hypercholesterinemia etc. or SNPS of functional relevance or combination of ‘a’, ‘m’ and ‘f’. (a = association with AIWG; m = association with metabolism dysregulation; f = functional significance).

and CYP1A2 mRNA.28 Thus, epigenetic rs3813929 decreases transcriptional activity.41,42 How- and genetic analyses of CYP1A2 may give a more ever, a subsequent study by McCarthy et al.43 failed to detailed picture of the potential relationship between replicate these earlier findings, and a more recent antipsychotic metabolism and weight gain. However, paper by Hill and Reynolds44 found the T allele to the field of is in its infancy with reduce promoter activity. Thus, the true effects of this its focus almost entirely on cancer treatments. polymorphism and transcriptional activity have to be In conclusion, there is a paucity of research relating further elaborated as these conflicting results are to pharmacokinetic genes and AIWG. Further mole- likely due to different cell lines and variable promoter cular genetic analyses of pharmacokinetic genes such examined. It remains unclear how recep- as the CYP450 and MDR1 genes are warranted tor expression is related to AIWG. Nonetheless, we to understand the clinical utility of these genes in believe it is interesting that functional studies have the development of a more personalized therapy. been conducted, and that despite conflicting findings, some significant results have been obtained. Further- more, it is unclear to which extent these cell lines can Pharmacodynamics be used to explain the variable expression of HTR2C Monoamine influence on homeostatic balance in different regions of the brain, and the role of RNA editing (see below). It is also important to note that Serotonin system. The serotonin system has been the the rs3813929 variant may have less importance in focus of numerous studies as SGAs that are associated African-American populations because of the lower with the highest risk of weight gain strongly minor allele frequency (Hapmap release no. 27:45 antagonize serotonin (5-HT) receptors. Serotonin African ancestry in Southwest USA (ASW) T-allele receptors are strong targets of SGAs as revealed by frequency = 0.035). Nonetheless, the rs3813929 pro- neuroimaging studies that showed high occupancy of moter polymorphism has been the most heavily 29 5-HT2 receptors by SGAs. Moreover, genetic variants studied variant, and may provide the best evidence in the 5-HT2 receptor genes have been strongly linked for AIWG. An additional variant in the HTR2C gene, to response to clozapine and risperidone.20,22,30–39 In the rs6318 (Cys23Ser) SNP may disrupt a disulfide addition, 5-HT receptors influence central pathways bridge, which suggests functional significance.46 affecting satiety and hunger. The 5-HT , Since 2006, 15 studies of 12 polymorphisms in four d-fenfluramine, is a potent appetite suppressant. 5-HT receptor genes (namely HTR1A, HTR2A, HTR2C Moreover, both animal and human studies report and HTR6) have been reported.32,33 The rs3813929 strong evidence that 5-HT levels and pro-satiety variant of HTR2C was reported to be associated with signaling are positively correlated.40 weight gain in five studies;20,34,37,47,48 however, Of the serotonin receptor genes, the HTR2C has six additional studies have not been able to associate been the most extensively studied gene in AIWG. the variant with change in body mass.22,30,35,38,39,49 An The rs3813929 (C/T) promoter SNP (À759C/T) of the additional promoter variant in the HTR2C gene, X-linked HTR2C gene is one of the most consistent rs518147 (À697C/G)47 and the combined haplo- markers associated with AIWG. The rs3813929 var- type (c.1-11429(GT)n 13 repeat (13R), À759C/T and iant is likely to have functional significance; however, 401C > G) were associated with the risk of obesity and interpretation of the functional activity is difficult. metabolic syndrome.32,33 However, studies of rs6318 Two studies have reported that the C allele of have yielded inconclusive38 or negative20,30,31,34,36

Molecular Psychiatry Table 2 Summary of gene association studies in antipsychotic-induced weight gain

Gene Polymorphismsa Observation period Medication Sample Main findings

ADIPOQ 276G/T 8–24 Weeks olanzapine SCZ: 164 Japanese Not significant38 ADIPOQ Tag-SNPs (12) 12 Weeks clozapine (98 patients with SCZ: 160 German rs17300539 associated with BMI change in clozapine previous SGAs exposure) therapy (allelic: P = 0.001; genotypic: P = 0.0009)86 ADRA1A Tag-SNP (44) > 2 Years mostly SGA SCZ: 394 Chinese Numerous SNPs located in the promoter and intron regions associated changes in BMI (P < 0.05)80 ADRA1A rs922733; rs2644627; 10.8 Months SGA 427 European Americans Not significant78 rs1383914 ADRA1A Arg492Cys < 42 Days risperidone SCZ: 123 Han Chinese Not significant20 ADRA2A rs1800544 (À1291G/C) 6–14 Weeks olanzapine (20) SCZ or SA: 129 European-Americans: C allele carriers gained more clozapine (85) European American (64) weight (P = 0.013). African-Americans: not significant81 risperidone (13) African American (54) haloperidol (11) Other (11) ADRA2A rs1800544 (À1291G/C) 4 Weeks olanzapine Psychotic or mood disorder: Not significant48 124 (German Caucasian) ADRA2A rs1800544 (À1291G/C) > 3 Months olanzapine SCZ: 62 Korean G allele associated with significant ( > 10%) weight gain (P = 0.013)79 ADRB3 64Try/Arg 8–24 Weeks olanzapine SCZ: 164 Japanese Arg/Arg genotype associated with increase BMI vs Try/Arg þ Try/Try (P = 0.024)38 AMPK Tag-SNPs from PKAA1/2, 12 Weeks clozapine (98 patients with SCZ:160 German PRKAA1 (rs10074991) significant with weight gain PRKAB1 and PRKAG1/2/3 previous SGAs exposure) (allelic: P = 0.011; genotypic: P = 0.004)86

subunits Lett TAP AIWG of Pharmacogenetics APOA1 rs5070 Cross-sectional study olanzapine (67) 168 Mostly European Not significant115 rs4225 risperidone (101) American

APOA2 rs5085 Cross-sectional study olanzapine (67) 168 Mostly European Not significant115 al et risperidone (101) American APOA4 rs5092 Cross-sectional study olanzapine (67) 168 Mostly European rs5092 associated with weight profile in olanzapine rs675 risperidone (101) American patients (P = 0.0116)115 APOB rs3791981 Cross-sectional study olanzapine (67) 168 Mostly European Not significant115 rs1801701 risperidone (101) American rs676210 APOE rs405509 Cross-sectional study olanzapine (67) 168 Mostly European rs7412 associated with weight gain in olanzapine patients rs439401 risperidone (101) American (P = 0.0056)115 rs446037 rs7412 rs429358 BDNF rs6265 (66Val/Met) > 10 Years treatment clozapine (98) SCZ: 196 Met/Met had lower weight gain than Val carriers risperidone (36) Control: 50 (P = 0.01). Genotype effect significant in males alone perphenazine (20) Chinese (P = 0.004) but not females131 haloperidol (19) chlorpromazine (14) fluphenazine and oeua Psychiatry Molecular trifluperazine (9) BDNF rs6265 (66Val/Met) < 42 Days risperidone SCZ: 123 Han Chinese 66Met/Met genotype had lower weight gain than 66Val/ Val (P = 0.02)20 247 248 oeua Psychiatry Molecular

Table 2 Continued

Gene Polymorphismsa Observation period Medication Sample Main findings

CNR1 Tag-SNPs (20) 6 Weeks clozapine (101) SCZ or SA: 183 European-American: T-allele carriers of rs806378 gained olanzapine (34) European American (117) more weight (P = 0.008). T allele acts as a binding site for haloperidole (12) African (55) transcription factor arylhydrocarbon receptor translocator risperidone (36) (ARNT)139 CNR1 rs1049353 (1359G/A) 24 Weeks clozapine (25) Mostly SCZ: 83. Controls: Not significant140 olanzapine (22) 80. European American. risperidone (14) quetiapine (6) aripiprazole (6) haloperidol (10) CL rs2304497 6 Weeks olanzapine SCZ SA: 130 Not significant144 Controls: 50 (Indian) CYP2D6 188C/T (CYP2D6*10) < 42 Days risperidone SCZ: 123 Han Chinese C/C genotype associated with lower body weight than variants C/T (P = 0.004) and T/T (P = 0.04)20 AIWG of Pharmacogenetics DRD1 À800T/C < 42 Days risperidone SCZ: 123 Han Chinese Not significant20 48A/G DRD2 Tag-SNPs (13) 48.2±27.8 Months clozapine (239) SCZ: 479 Chinese C allele of rs4436578 is associated with weight gain 57

olanzapine (70) (P = 0.003, OR = 3.36 (1.62–7.00)) Lett TAP risperidone (170) DRD2 311Ser/Cys < 42 Days risperidone SCZ: 123 Han Chinese Not significant20

DRD2 rs1799732 (À141C Ins/Del) Longitudinal study (10 olanzapine (26) SCZ (first episode): 58 Deletion carriers gained more weight over time al et 62 measurements over 16 risperidone (32) African American (40%) (F10,242 = 2.11, P = 0.024) weeks) European American (28%) Hispanic (19%) Other (13%) DRD3 38Ala/Thr < 42 Days risperidone SCZ: 123 Han Chinese Not significant20 9Ser/Gly DRD4 VNTR polymorphism 4 Weeks SGA or FGA SCZ or SA (mostly) 102 Longer allele carriers gained more weight than did short European American; allele homozygotes (P = 0.003)36 antipsychotic naive DRD1 to 36 Tag-SNPs 6 Weeks clozapine or olanzapine (132) SCZ SA: 206 DRD2: rs1079598 associated with weight gain (P = 0.03). DRD5 VNTR polymorphism other (48) (European: 139, African rs6277 (957C/T) associated with weight gain in (DRD4) American: 56) Europeans (P < 0.05). TaqIA A1 (T) allele associated in Europeans on clozapine and olanzapine (OR 2.18 95% CI 1.00–4.75)63 FAAH 129Pro/Thr 8–24 Weeks olanzapine SCZ: 164 Japanese Not significant38 FAAH rs324420 (385C/A) 24 Weeks clozapine (25) Mostly SCZ: 83. Controls: 80. Significant allele (385C; P = 0.002) and genotype (CC vs A olanzapine (22) European American carriers; P = 0.004) association140 risperidone (14) quetiapine (6) aripiprazole (6) haloperidol (10) FABP3 Tag-SNPs (7) 12 Weeks clozapine (98 patients with SCZ:160 German Not significant86 previous SGAs exposure) FTO rs9939609 12 Weeks clozapine (98 patients with SCZ:160 German Not significant86 previous SGA exposure) Table 2 Continued

Gene Polymorphismsa Observation period Medication Sample Main findings

FTO rs9939609 Prospective study; various medications 165 First-episode psychosis Not significant152 1 year GAL rs694066 Cross-sectional study olanzapine (67) 168 Mostly European Not significant115 risperidone (101) American GHRL 72Leu/Met 8–24 Weeks olanzapine SCZ: 164 Japanese Not significant38 GHRL rs26312 Cross-sectional study olanzapine (67) 168 Mostly European Not significant115 risperidone (101) American GNB3 rs5443 (825C/T) > 3 Months olanzapine SCZ: 79 Korean Not significant98 GNB3 rs5443 (825C/T) 8–24 Weeks olanzapine SCZ: 164 Japanese T allele associated with weight gain (P = 0.043)38 GNB3 rs5443 (825C/T) 4 Weeks olanzapine (124) Psychotic or mood disorder: Not significant48 124 (German Caucasian) GNB3 rs5443 (825C/T) 2–6 Weeks olanzapine SCZ: 42 Caucasian Not significant97 HRH1 449Leu/Ser 8–24 Weeks olanzapine SCZ: 164 Japanese Monomorphic38 HRH2 À1018 G/A 8–24 Weeks olanzapine SCZ: 164 Japanese Not significant38 HRH3 332Ser/Ser 8–24 Weeks olanzapine SCZ: 164 Japanese Not significant38 HTR1A 272Gly/Asp < 42 Days risperidone SCZ: 123 Han Chinese Not significant20 HTR2A rs6311(À1438A/G) > 6 Months olanzapine (28) SCZ or SA: 46 European 2 (À1438A, 102T, and 452His) had rs6313 (102T/C) clozapine (18) significantly higher C levels compared with rs6314 (452His/Try) haplotype 3 (À1438A, 102T, and 452Tyr) carriers in the

olanzapine group (P = 0.034) and in the overall study Lett TAP AIWG of Pharmacogenetics population (P = 0.019)31 HTR2A rs6313 (102T/C) 8–24 Weeks olanzapine SCZ: 164 Japanese 102T/C associated with weight gain (P = 0.0078)38 HTR2A rs6313 (102T/C) < 42 Days risperidone SCZ: 123 Han Chinese T102C: C/C genotype less weight gain than T/T al et rs6314 (452His/Try) (P < 0.0001) 452 His/Tyr: not significant20 HTR2C rs6318 (Cys23Ser) 6 Weeks clozapine (24) SCZ or SA: 128 Significant association: rs498207A (P = 0.0049). Nominal rs498207 olanzapine (33) European (118) association: rs3813928G (P = 0.038), rs3813929C rs3813928 risperidone (8) Turkish (10) (P = 0.04)34 rs3813929 (À759C/T) amisulpride (2) quitiapine (2) mixed (52) HTR2C rs3813929 (À759C/T) 6 Weeks olanzapine SCZ: 107 Polish (36 drug- À759T and –697C had a protective effect for weight gain rs518147(À697G/C) naive patients) (P = 0.0006, P = 0.002)47 HTR2C rs3813929 (À759C/T) > 6 Months olanzapine (28) SCZ or SA: 46 European Olanzapine: haplotype (À759C, À697C, and 23Ser) had rs518147(À697G/C) clozapine (18) American higher BMI (P = 0.029) and C peptide levels (P = 0.029). rs6318 (Cys23Ser) Clozapine: haplotype (À759C, À697G, and 23Cys) was higher among obese patients (P = 0.015)31 HTR2C rs3813929 (À759C/T) > 3 Months olanzapine SCZ: 74 Korean Not significant35 HTR2C rs3813929 (À759C/T) 4 Weeks FGAs, SGAs SCZ: 84 Korean 759T protective against weight gain (P = 0.030)37 oeua Psychiatry Molecular HTR2C rs6318 (Cys23Ser) 8–24 Weeks olanzapine SCZ: 164 Japanese 23Ser þ 64Arg/Arg (ADRB3) predicted weight gain rs3813929 (À759C/T) (P < 0.0001). À759C/T: not significant38 HTR2C rs3813929 (À759C/T) 4 Months risperidone (47) SCZ: 108 Croatian females Not significant22 olanzapine (61) 249 250 oeua Psychiatry Molecular

Table 2 Continued

Gene Polymorphismsa Observation period Medication Sample Main findings

HTR2C rs6318 (Cys23Ser) 4 Weeks SGA or FGA SCZ or SA (mostly) 102 Not significant36 European American; antipsychotic naive HTR2C rs6318 (Cys23Ser) Average 11.2 weeks clozapine (92) SCZ: 139 African American Not significant30 rs3813929 (À759C/T) (6–14) haloperidol (13) (GT)12–18/(CT) 4–5 olazapine (21) risperidone (13) HTR2C rs6318 (Cys23Ser) < 42 Days risperidone SCZ: 123 Han Chinese À759T protective against weight gain (P = 0.04). rs3813929 (À759C/T) Cys23Ser was non-significant20 HTR2C c.1–11429 (GT)n > 3 Months clozapine (44) SCZ:79, SA: 33 Other:15 Haplotype (c.1-142948(GT)13 repeat, À759C, À697C, –997G/A olanzapine (40) (mostly European American) 401C) associated with obesity risk (OR 3.71, 95% rs3813929 (À759C/T) risperidone (26) CI 1.24–11.12). 401C associated with obesity (OR 2.80, 32 rs518147 (À697G/C) other (16) CI: 1.03–7.62) AIWG of Pharmacogenetics 401:C > G HTR2C c.1-142948(GT)n > 3 Months clozapine (78) SCZ or SA: 112 (mostly À697G/C, rs1414334:C > G associated with higher risk of –997 G/A olanzapine (71) European American) metabolic syndrome. (P < 0.05)33 rs3813929 (À759C/T) risperidone (63) rs518147 (À697G/C) other (59) Lett TAP rs1414334:C > G HTR2C c.1-142948(GT)n > 3 Months risperidone (39) Cases: 164 Irish descent (SCZ: c.1-142948(GT)n 13 repeat and rs1414334C: associated –997 G/A clozapine (37) 70, SA: 28, other: 114) with metabolic syndrome in pooled (OR 2.35; CI 1.19– al et rs3813929 (À759C/T) olanzapine (35) 4.62)50 rs518147 (À697G/C) typical AS (31) rs1414334:C > G HTR2C rs3813929 (À759C/T) clozapine (21) SCZ: 134 Not significant39 olanzapine (31) risperidone (16) other (27) none (2) HTR2C rs3813929 (À759C/T) Variable (mostly > 1 clozapine (68) Psychotic: 89; mood: 21; other Not significant49 year) olanzapine (54) disorder: 23 risperidone (30) aripiprazole (23) quetiapine (23) HTR2C rs3813929 (À759C/T) 4 Weeks olanzapine (124) Psychotic or mood disorder: Change in BMI and weight associated with olanzapine 124 (German Caucasian) treatment (P = 0.009; P = 0.008)48 HTR6 267T/C < 42 Days risperidone SCZ: 123 Han Chinese C allele predicted higher weight gain (P = 0.02)20 HTR6 267T/C 8–24 Weeks olanzapine SCZ: 164 Japanese Not significant38 INSIG1 Tag-SNPs 12 Weeks FGA (98) SCZ 160 German rs13223383 associated with weight gain (P = 0.005)142 SGA (26) both (36) INSIG2 rs17587100 6 Weeks clozapine (24) SCZ: 128 Not significant34 rs10490624 olanzapine (33) Mostly European American rs17047764 risperidone (8) rs7566605 amisulpride (2) quitiapine (2) combination (52) Table 2 Continued

Gene Polymorphismsa Observation period Medication Sample Main findings

INSIG2 rs17587100; rs10490624 < 14 Weeks clozapine (96) SCZ or SA: 154 Not significant143 rs17047764; rs7566605 olanzapine (34) haloperidol (12) risperidone (12) INSIG2 Tag-SNPs 12 Weeks FGA (98) SCZ 160 German 3 SNPs (rs17587100, rs10490624, rs17047764) associated SGA (26) with weight gain (P = 0.0003–0.00007)142 mixed (36) LEP rs7799039 (À2548A/G) 1 Year risperidone 74 Mostly European American A-allele carriers showed a steeper rate of increase in children (7–17years) weight and BMI (P < 0.03)113 LEP rs7799039 (À2548A/G) 10 Weeks risperidone; chlorpromazine SCZ: 84 Han Chinese rs7799039 associated with weight gain (P = 0.045)111 LEP rs7799039 (À2548A/G) > 3 Months olanzapine SCZ: 98 Korean AG genotype gained significantly more than AA (P = 0.029)109 LEP rs7799039 (À2548A/G) > 2 Years clozapine SCZ: 102 Han Chinese AG genotype associated with increases BMI (P = 0.014). The association was observed in males (P = 0.003) but not females (P = 0.26)110 LEP rs7799039 (À2548A/G) 6 Weeks olanzapine SCZ: 37 European American Patients carrying 2584G or 223Rallele had a significant increase BMI increase (P = 0.049)114 LEP rs7799039 (À2548A/G) > 3 Months clozapine (71) 200 Dutch Full sample: Not significant. GG genotype is associated olanzapine (68) SCZ: 139 with obesity in males. AA genotype significant in risperidone (57) SA: 43 females112 other (4) Other: 18 Males:134 Lett TAP AIWG of Pharmacogenetics Females: 66 LEP rs7799039 (À2548A/G) Prospective study; 1 various medications 165 First-episode psychosis Not significant152 year al et LEP rs7799039 (À2548A/G) Variable (mostly > 1 clozapine (68) Disorders: psychotic (89); Not significant49 year) olanzapine (54) mood (21); other (23) risperidone (30) aripiprazole (23) quetiapine (23) LEP 6 SNPs 6 Week olanzapine SCZ SA: 130. controls: 50 Not significant144 (Indian) LEPR rs1137101 (223Q /R) 6 Weeks olanzapine SCZ: 37 European Americans Patients carrying 2584G or 223R allele had a significant increase BMI increase (P = 0.049)114 LEPR rs1137101 (223Q /R) > 3 Months clozapine (71) 200 Dutch Full sample: Not significant. 233RR associated with olanzapine (68) SCZ: 139 obesity in males. 233QQ significant in females112 risperidone (57) SA: 43 other (4) Other: 18 Males:134 Females: 66 LEPR rs1137101 (223Q /R) Variable (mostly > 1 clozapine (68) Disorders: psychotic (89); Not significant49

oeua Psychiatry Molecular year) olanzapine (54) mood (21); other (23) risperidone (30) aripiprazole (23) quetiapine (23) 251 252 oeua Psychiatry Molecular

Table 2 Continued

Gene Polymorphismsa Observation period Medication Sample Main findings

LEPR rs1137101 (223Q /R) Prospective study; 1 various medications 165 First-episode psychosis Not significant152 year LEPR rs7602 Cross-sectional study olanzapine (67) 168 Mostly European rs817983 associated with weight profile in risperidone rs1171276 risperidone (101) American patients (P = 0.001)115 rs8179183 LPL 5 SNPs 6 Weeks olanzapine SCZ SA: 130 Not significant144 Controls: 50 (Indian) MC4R Tag-SNPs < 12 Weeks cohort 1: quetiapine (36) Cohort 1: A marker in the SNP in the 30 region demonstrated risperidone (135) Drug-naive youths (4–19 significant recessive effects in all three cohorts. aripiprazole (41) years) European American Cohort 1: P = 2.8 Â 10À7 olanzapine (45) (131) Cohort 2: P = 0.00014 cohort 2: Non-refractory African American (70) Cohort 3: P = 0.007

patients receiving clozapine Other (69) AIWG of Pharmacogenetics cohort 3: Naturalistic Study Cohort 2: SCZ: 73 European (up to 12 drugs) American, Cohort 3: SCZ: 40 MDR1 2677C/T; 3435C/T 4 Months risperidone (61) SCZ: 108 Croatian females 3435T and 2677T alleles associated with weight gain olanzapine (47) (P = 0.015, P = 0.031)22 Lett TAP MDR1 1236C/T; 2677G/A; 6 Weeks olanzapine SCZ: 41 mostly European Not significant23 2435C/T American tal et MTHFR 677C/T; 1298A/C 12 Months clozapine (11) 58 Mostly European American 677T allele carriers had 3.6-fold increase in risk of olanzapine (8) metabolic syndrome (P = 0.02). 1298A/C did not risperidone (8) significantly contribute to the model163 quetapine (6) haloperidol (4) aripirozole (4) ziprasidone (2) polytherapy (16) NPY rs1468271 Cross-sectional study olanzapine (67) 168 Mostly European Not significant115 risperidone (101) American NPY5R rs6837793 Cross-sectional study olanzapine (67) 168 Mostly European rs6837793 associated with weight profile in the rs11100494 risperidone (101) American risperidone group (P = 0.0024)115 PMCH rs7973796; rs11111201 Mean 20.5 months olanzapine SCZ: 300, control: 150 French rs7973796 ( þ 201A/G): (0.23–120) Canadian Associated with BMI change (P = 0.025) rs11111201: Not significant136 PON1 rs705381 Cross-sectional study olanzapine (67) 168 Mostly European rs705381 associated with weight profile in risperidone rs662 risperidone (101) American patients (P = 0.0012)115 rs3917550 PPARG rs1801282 (12Pro/Ala) 2 Months olanzapine SCZ: 95 Turkish Ala/Pro significantly increase in weight over the Pro/Pro genotype (P = 0.016)164 SCAP Tag-SNPs (3) 12 Weeks FGA (98) SCZ: 160 German rs12490383 (281C/T) marginally associated with weight SGA (26) gain (P = 0.01)142 both (36) SCARB1 rs1084677 Cross-sectional study olanzapine (67) 168 Mostly European rs4765626 associated with weight profile in olanzapine rs4765623 risperidone (101) American (P = 0.015)115 Table 2 Continued

Gene Polymorphismsa Observation period Medication Sample Main findings

SCARB2 rs3853188 Cross-sectional study olanzapine (67) 168 Mostly European rs3853188 is nominally associated with weight profile in rs894251 risperidone (101) American risperidone patients (P = 0.0224)115 SH2B1 rs7498665 Prospective study; various medications 165 First-episode psychosis Not significant152 1 year SNAP-25 401C/T; 1065T/G; 8–24 Weeks olanzapine SCZ: 164 Japanese in-patients Not significant38 1069T/C SNAP-25 Mn1I, TaiI, DdelI > 5 Weeks risperidone; olanzapine; SCZ: 162 DdelI: TT protective against weight gain (P = 0.031)104 quetiapine; amisulpride; Control: 312. sertidole Mostly German SREBF1 Tag-SNPs (4) 12 Weeks FGA (98) SCZ 160 German Not significant142 SGA (26) both (36) SREBF2 Tag-SNPs (3) 12 Weeks FGA (98) SCZ 160 German rs4822064 ( þ 301C/G) was nominally associated with SGA (26) weight gain (P = 0.04)142 both (36) SLC6A4 SERTin2 (VNTR 9R/10R or 3 Months olanzapine SCZ: 94 Croatian females SERTin2: not significant. SERTPR : S allele and SS 12R) genotype was associated with higher weight gain in SERTPR (L/S) baseline non-obese subjects (P = 0.021)165 Tag lipase rs2915748 6 Weeks olanzapine SCZ, SA: 130 Not significant144 rs2234972 Controls: 50 (Indian)

TNF rs1800629 (À308G/A) 8 Years (monthly clozapine SCZ: 55 À308GG genotype is associated with more weight gain Lett TAP AIWG of Pharmacogenetics weight assessment) than A allele carriers (P = 0.0084)149 TNF rs1800629 (À308G/A) 8–24 Weeks olanzapine SCZ: 164 Japanese À308G/A: minor allele frequency < 5-857C/T: Not 38

–857C/T significant al et TNF rs1800629 (À308G/A) 3-Week, 6-week and 6- clozapine SCZ: 247 A weight gain trend was observed for G carriers after 6 month observation European American (160) months (P = 0.091)148 periods African American (73) Other (12) TNFRSFA 36A/G 8–24 Weeks olanzapine SCZ: 164 Japanese Not significant38 TNFRSFB 196Met/Arg 8–24 Weeks olanzapine SCZ: 164 Japanese Minor allele frequency < 538

Abbreviations: BMI, body mass index; CI, confidence interval; FGA, first-generation antipsychotic; OR, odds ratio; SA, schizoaffective disorder; SCZ, schizophrenia; SGA, second-generation antipsychotic; SNP, single nucleotide polymorphism; VNTR, variable-number tandem repeat. aOlder studies used positional or other designations for polymorphisms. Where available, we added rs numbers from dbSNP. oeua Psychiatry Molecular 253 Pharmacogenetics of AIWG TAP Lett et al 254 results in six studies (Table 2). Finally, in a study of clinically significant risk for weight gain.30,53,54 In a 112 European Americans replicated in 165 European meta-analysis, De Luca et al.30 reported a slight Americans, the rs1414334C allele of the HTR2C gene association of rs3813929 with weight gain, and was associated with the risk of metabolic syndrome however noted significant heterogeneity across sam- in patients taking clozapine (odds ratio (OR) 9.20, ples. A more recent meta-analysis of 10 independent confidence interval 1.95–43.45) and risperidone (OR studies confirmed this association.54 The positive 5.35, confidence interval 1.26–22.83).50 The 102T/C result for the 102T/C polymorphism of the HTR2A polymorphism of the HTR2A gene was significantly gene suggests that additional 5-HT receptors can be associated with weight gain in patients receiving involved in weight gain. These promising findings olanzapine and risperidone treatment in Japanese and should serve as a stimulus for future research, Han Chinese samples (P < 0.0001 and P = 0.0049, especially with the advent of new research techniques respectively).20,38 A haplotype-type analysis in a and decreasing cost of analysis. limited sample size (N = 46, White Europeans) re- ported association between C peptide levels and The dopamine system. The role of dopamine in À1438A, À102T and 452His haplotypes, but not a mediating antipsychotic response is well documen- change in body mass index (BMI), suggesting that ted. Accumulating evidence suggests that targeting of further research is required to establish the potential dopamine by all antipsychotic medications is role of HTR2A in AIWG (Table 2).31 Finally, a single associated with amelioration of positive symptoms. variant of the HTR1A gene was negative in a Han Positron emission tomography studies reveal that a Chinese population (Table 2).20 minimal occupancy of 60% of striatal dopamine D2 The negative findings for the HTR2C receptor gene receptors is required for clinical response, whereas were in studies with patients undergoing extensive blockade > 80% may be the main cause of EPS.15,55 previous treatment, which may explain the incon- However, striatal dopamine D2 receptor availability sistencies across results. The association between was found to be significantly lower in obese rs3813929 and AIWG tended to be significant in individuals compared with controls.56 Furthermore, studies with short treatment duration ( < 3 months), disruption in the dopamine D2 receptor gene (DRD2) and less or not significant in long-term studies was reported to be associated with obesity.4,5 ( > 3 months; Table 3). Furthermore, in studies of Dopamine modulates motivation and central European-American patients treated predominantly reward circuitry, and thus, deficiency in dopamine with clozapine or olanzapine, a significant associa- transmission through dopamine antagonism may tion was reported, although the association was not perpetuate increased eating to compensate from a observed in an Asian or an African-American popula- blunted reward circuitry. Although dopamine anta- tion. The negative finding in African Americans gonisms are such an integral part of antipsychotic may be expected due to the lack of variation of the efficacy, only recently has evidence emerged that rs3813929 SNP in that population. There may be the dopamine system may be involved in weight gain an additional level of control of the HTR2C that side effects. could explain the lack of association in European Initial analyses by Lane et al.20 of five polymorph- Americans and Asians. The HTR2C gene has a ism in the D1, D2 and D3 dopamine receptor genes unique feature in that RNA editing may dynamically (DRD1, DRD2, DRD3) were unsuccessful in discover- regulate receptor activity,51 and that this pattern ing an association between risperidone and AIWG of editing is altered in animals treated with anti- (Table 2). In contrast, recent studies using tag-SNPs psychotics.52 have implicated variants for DRD2 and variable- Taken together, meta-analyses have repeatedly number tandem repeats (VNTRs) of the dopamine reaffirmed that the C allele of this SNP poses a receptor D4 (DRD4) in AIWG. In a long-term study by

Table 3 HTR2C receptor variants, À759C/T and Cys23Ser, association with SGA-induced weight gain

Variant White Asian African American

þÀþÀþÀ

À759C/T (rs3813929) 34 (ST)a22(LT) 37 (ST, DN) 35 (LT)a30(ST)a 47 (ST)a49(LT) 20 (ST) 38 (LT)a 48 (ST, DN)a Cys23Ser (rs6318) 36 (ST) 38 (LT)a20(ST) 30 (ST)sa

Abbreviations: DN, mostly or all antipsychotic naive; LT, long term ( > 3 months); SGA, second-generation antipsychotic; ST, short term ( < 3months). þ or À = Significant or non-significant association with SGA-induced weight gain, respectively. aThese denote patients treated with solely or mostly olanzapine or clozapine.

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 255 Hong et al.,57 tag-SNP analysis of the DRD2 gene neurotransmission should be examined. For example, found that the C allele of rs4436578 was strongly the functional VNTR variant of the dopamine trans- associated with weight gain (P = 0.003, OR = 3.36 porter gene (DAT1) has been associated with response (1.62–7.00)) in 479 Chinese SCZ patients undergoing to the dopamine receptor agonist methyphenidate,74 clozapine, olanzapine and risperidone treatment. but not in antipsychotic efficacy.75 The DAT1 VNTR is The À141C Ins/Del (rs1799732) has previously been also associated with appetite suppression and binge associated with decreased efficacy of antipsychotic eating.76 Taken together, these findings lend strong treatment58,59 and may alter D2 receptor density;60,61 rationale that DAT1 may be involved in AIWG, however, the direction change in density remains regardless of the lack of association with antipsycho- controversial. Thus, it remains difficult to interpret tic response. In general, we expect that the dopamine the biological significance at the present time. system will have a greater role in AIWG than early One recent longitudinal study of first-episode SCZ studies have suggested. reported that rs1799732 was associated with more weight gain (P = 0.024),62 and further examination of The adrenergic system. Most antipsychotics have this variant is warranted to confirm this result. relatively strong affinities for a1- and a2-adrenergic Furthermore, our group examined 36 tag-SNPs and 1 receptors. The adrenergic system is hypothesized VNTR spanning 5 dopamine receptors (DRD1–DRD5) to affect cognition and emotion, although very few in 206 chronic SCZ or schizoaffective disorder pharmacogenetic studies have reported any genetic patients.63 The DRD2 rs1079598 marker was asso- variation that contributes to treatment response.77 ciated with weight gain (P = 0.03). When stratifying However, adrenergic receptors are expressed according to ethnicity and antipsychotics (that is, ubiquitously in the body, and there is a strong Europeans treated with clozapine or olanzapine), evidence indicating that the ratio of a2- to b3- associations were observed in three DRD2 SNPs: adrenergic receptors in the adipose tissue influences rs6277 (957C/T), rs10779598 and rs1800497 (Taq1A). obesity through adipocyte hyperplasia.20,78 The This is consistent with a previous association contribution of the adrenergic system to AIWG has between rs1800497 and obesity.64,65 Moreover, the previously been understudied, although more recent association of the rs6277 marker is particularly findings suggest a greater role. interesting because the rs6277T allele is associated The ADRA1A gene was non-significant in two with decreased striatal D2 affinity in vivo, and in vitro independent studies of four polymorphisms in analysis revealed decreases in mRNA stability and Caucasian and Han Chinese populations.79 However, half-life.66,67 Our group also observed the rs6277C Liu et al.80 used tagging SNPs to strongly characterize allele to be associated with an increased risk of the ADRA1A gene and demonstrated that numerous tardive dyskinesia.68 Therefore, the rs6277 poly- variants were associated with SGA-induced weight morphism could have a broader association with gain in a long-term, prospective study of 394 Chinese antipsychotic tolerance, whereas the rs6277C allele SCZ patients. This tag-SNP analysis showed evidence carriers may be exposed to higher risk of adverse that the majority of significantly associated SNPs events. were located in the promoter and intron regions, and The expression of the dopamine D4 receptor is that the effect was enhanced in females. Positive elevated in patients suffering from SCZ,69 and D4 results have also been observed in ADRA2A and receptors are more strongly targeted by clozapine.70 ADRB3 genes. Park et al.79 reported that the C-allele The hypofunctional 7-repeat (7R) allele of DRD4 exon carrier of the À1291G/C (rs1800544) polymorphism 3 VNTR has been associated with maximal BMI in of ADRA2A gained significantly more weight in bulimia nervosa.71–73 Our group did not find a olanzapine-treated Korean patients (P = 0.013). significant association with weight gain;63 however, Furthermore, our group found that in mostly cloza- a prospective study by Popp et al.36 of 102 anti- pine- or olanzapine-treated SCZ patients, rs1800544 psychotic-naive, European-American inpatients, did was significantly associated with European Ameri- discover that 7R carriers conferred greater weight gain cans (P = 0.013), but not in African American (P = 0.003). The role of the 7R allele as a potential risk patients81 (Table 2). The involvement of the 64 marker for antipsychotic-naive patients awaits repli- Try/Arg SNP (rs4993) of the ADRB3 gene in obesity, cation and should be an interesting avenue diabetes and hypertension has been well documen- for future research. ted;82 however, only a single study had significantly In summary, previous findings in the dopaminergic associated rs4993 and BMI in Japanese SCZ patients system have only recently received more attention (P = 0.024).38 and warrants further investigation. The future direc- In general, the adrenergic system has been com- tion of research should be directed towards: (1) paratively understudied, and the role of adrenergic confirming these novel findings, (2) receptors in AIWG is unclear. All of the preceding studies to examine the functional significance (such ADR genes have been implicated in obesity and as the rs4436578 and rs1079598 variants of DRD2) AIWG. This is in accordance with other obesity- and (3) examining other genes involved in dopamine related genes like the leptin and melanocortin 4 signal transmission. These initial findings strongly receptor genes (Table 2). However, unlike other suggest that other genes related to dopamine strongly associated obesity-associated genes (for

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 256 example, FTO), the protein products of these genes associated with weight gain in an Asian olanzapine- are directly or indirectly affected by antipsychotic treated population (P = 0.043);38 however, negative actions. Thus, study of these obesity- and antipsycho- results were reported in two studies with smaller tic-related genes are paramount to understand AIWG, sample sizes (Table 2).97,98 The apparent association whereas genetic variation in other obesity-related between the 825C/T SNP and metabolic side effects genes may best explain baseline weight profiles. The suggests that further analysis with an increased sample tag-SNPs analysis of the ADRA1A gene and positive size for the GNB3 gene is justified, with more detailed findings in the ADRA2A and ADRB3 genes suggests analysis of other regions of the gene. that all of these genes increase liability for AIWG; nonetheless, further study is required to confirm their Synaptic signaling. The synaptosomal-associated risk profiles. For instance, the ADRA2A and ADRB3 protein of 25kDa (SNAP-25) is one of the three genes have only been studied in clozapine- or involved in forming the soluble N-ethyl- olanzapine-treated populations; hence the effect is maleimide-sensitive protein receptor (SNARE). undetermined on antipsychotics with a smaller SNAREs form a complex that functions in vesicle weight profile. Moreover, the effect of the ADR genes trafficking at the presynaptic membrane, thereby in AIWG is unclear across different ethnicities as the modulating the release of .99 majority of the studies were performed in Asian SNAP-25 is expressed in the islet of Langerhans populations. (pancreatic b-cells) and is involved in insulin release.100,101 Furthermore, SNAP-25 is located in The histamine system. The histaminergic system has insulin-responsive tissues and therefore may affect an important role in reducing food intake and energy lipolysis.102 As intercellular signaling has an intricate regulation through histamine-induced activation of link to the homeostatsis of hunger/satiety, six gene the histamine receptors. For example, the of variants in the SNAP-25 gene have been analyzed in antipsychotic medications in blocking the histamine-1 three studies. (H1) receptor has been reported to correlate with In an initial study of the SNAP-25 gene by our their tendency to stimulate weight gain,83 and group, two polymorphisms, rs3746544 (MnlI T/G) deletions of the histamine-1 receptor gene abolish and rs8636 (TaiI T/C), were associated with both weight gain in SGA-treated mice.84 Furthermore, H1 antipsychotic drug response and drug-induced receptor , such as olanzapine, activate weight gain; however, the rs1051312 (Ddel T/C) hypothalamic AMP-activated protein kinase SNAP-25 polymorphism was not significant.103 Musil (AMPK1) that has been linked to the regulation of et al.104 reported an association between rs3746544 food intake, and reverse the actions of the and rs8636 and serum triglyceride levels. The anorexigenic hormone leptin.85 Therefore, histamine rs1051312 polymorphism was associated with may have been considered a compelling candidate for increased in BMI after 5 weeks of SGA treatment. treatment-emergent weight gain; however, only one The fact that the results of SNAP-25 polymorphisms study has examined histamine receptors 1, 2 and 3 are only partially replicated may be due ethnicity obtaining negative findings (Table 2), although their and shorter observation time in the latter study. In sample size was limited.38 Steen and colleagues86 addition, three other polymorphisms (401C/T, 1065T/ examined the five-receptor subunits of AMPK using G and 1069T/C) were not significant in a Japanese tag-SNPs. Of the markers examined, only the sample, and 401C/T was monomorphic.38 However, rs10074991 polymorphism of the PRKAA1 subunit this study was the first examination of SNAP-25 (AMPK) was associated with weight gain (Table 2). markers in an Asian population. The histaminergic system has not yet been exhaus- SNAP-25 polymorphisms may well impact weight tively studied, and despite negative findings of the gain and potentially the development of metabolic histamine receptors, this remains an interesting avenue syndrome during antipsychotic treatment. This for future research. In particular, the downstream potential impact is further supported by the indepen- signaling pathway of histamine receptors seems to be dent findings of the role of SNAP-25 in pancreatic an appealing candidate for future research. insulin release and peripheral insulin sensitivity. Further studies are required in larger samples that Secondary effects of antipsychotic medication are prospectively analyzed to elucidate the exact The G-protein system. Monoamine receptors (for role of rs3746544, rs8636 and rs1051312 markers in example, serotonin and dopamine receptors) signal to weight gain and dyslipidemia. effector proteins through intracellular heterotrimeric G-protein subunits (a, b, g). The G-protein beta-3 Appetite regulators subunit (GNB3) gene has been previously associated Leptin. Leptin is a peptide hormone secreted with hypertension and obesity.87–94 In addition, the exclusively by the adipose tissue that acts at the 825C/T splice variant of GNB3 (rs5443)88 was a level of the by binding to its rece- successful predictor of weight reduction in patients ptor, and activating secondary signals. These undergoing sibutramine therapy.95,96 Three studies secondary signals inhibit food intake and increase have investigated the relationship between GNB3 energy expenditure.105 High serum leptin inhibits 825C/T SNP and AIWG. The 825T allele was neuropeptide Y (NPY) mRNA expression,105 and

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 257 stimulates the release of a-melanocyte-stimulating weight gain in European males and the AA genotype hormone (a-MCH).106 This effect leads to appetite in females, suggesting a potential sex-specific effect suppression, energy storage and insulin secretion (Table 2). In an analysis of risperidone-treated (Figure 3). Therefore, the gene encoding the leptin adolescents (7–17-years old), Calarge et al.113 found protein and its receptor has generated interest in the A allele to be associated with a steeper increase in pharmacogenetic studies of AIWG. BMI z-scores. The disparity between these studies The rs7799039 (À2548A/G) promoter variant of remains unclear, but could be explained by different leptin is proximal to a binding site for the transcrip- risk factors involved in AIWG between adults and tional factor SP1. The transcriptional , children or ethnicity differences. nucleolin, can bind to SP1 or its consensus site.107 The rs1137101 (223Gln/Arg) polymorphism of the Thus, the presence of the A/A or A/G genotype leptin receptor (LEPR) gene has also been studied. corresponded with high and intermediate leptin The presence of the 223Arg allele has been associated mRNA expressions, respectively, whereas the G/G with lower obesity risk in risperidone-treated adoles- homozygote expressed low mRNA levels.107,108 Three cents.112 One small study which measured olanzapine studies examining Asian populations found the plasma levels in 37 European-American patients variant allele (G) or genotype (GA) to be associated found that carrying the 223Arg or À2548G alleles with AIWG.109–111 Zhang et al.110 reported in further conferred risk of weight gain only in the subgroup analysis that this association was significant in males of patients with high olanzapine plasma levels.114 but not in females. Similarly, Gregoor et al.112 found In a cross-sectional study using a physiogenomic the GG genotype to be significantly associated with approach, Ruan˜ o et al.115 reported the rs817983

Figure 3 Schematic representation of the leptin–melanocortin system. Higher amounts of adipose tissue lead to increased level of leptin in fat tissue. Leptin stimulates POMC neurons in the arcuate nucleus of the hypothalamus. POMC is post-translationally cleaved to produce a-MSH. The a-MSH binds to MC4R. Stimulation of MC4R results in an upregulation of downstream effectors such as BDNF, leading to anorexigenic results such as decreased food intake and increased energy expenditure. Simultaneously, leptin inhibits another population of neurons in the arcuate nucleus that produce orexigenic hormones (AgRP and NPY). The AgRP acts as an MC4R antagonist, stimulating downstream orexigenic effectors. a-MSH, a-melanocytes-stimulating hormone; AgRP, agouti-related peptide; BDNF, brain-derived neurotrophic factor; CART, cocaine and -regulated transcript; GHSR, growth hormone secretagogue receptor; LEPR, leptin receptor; MC3R, 3; MC4R, melanocortin 4 receptor; NPY, neuropeptide Y; NPY1R, neuropeptide Y1 receptor; NPY5R, neuropeptide Y5 receptor; POMC, pro-opiomelanocortin.

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 258 (656N/K) SNP of LEPR to be associated with weight indicate that BDNF regulates energy expenditure.126 gain resulting from risperidone but not from olanza- The functional 66Val/Met polymorphism (rs6265) has pine treatment (P = 0.001). been extensively studied for association with mental In summary, the leptin system has not yet been illness and cognitive function.127 However, recent investigated exhaustively; however, several positive candidate gene studies have suggested a role in eating findings in the functional promoter À2548A/G poly- behavior128 and BMI,129 and the association between morphism of the leptin gene, as well as 223Gln/Arg rs6265 and BMI has been replicated in a GWAS polymorphisms in its receptor, should act as incen- (P = 5.1 Â 10À10; effect size = 4.58±0.73).130 Therefore, tive for future research. the BDNF gene has been shown to be associated with psychiatric disorders, altered by antipsychotic The melancortin-4 receptor. The melanocortin-4 treatment and influence weight gain, thereby making receptor (MC4R) is a seven-transmembrane G BDNF an ideal candidate for pharmacogenetic protein-coupled receptor expressed in the central research on AIWG. nervous system, primarily in the hypothalamus. However, only two groups have investigated this MC4R is a key regulator of the leptinergic control of functional variant for association with AIWG in energy homeostasis.116 For example, MC4R activa- Chinese populations. The 66Met/Met genotype was tion of downstream effectors such as brain-derived associated with lower weight gain in Chinese neurotrophic factor (BDNF) results in decreased food SCZ patients (P = 0.02).20 This finding was replicated intake and increased energy expenditure (Figure 3). in a subsequent study, however, only in males Heterozygous coding mutations in MC4R are (P = 0.01).131 Taken together, BDNF has been under- implicated in 0.5–6.3% in severe or early-onset obese studied to date, and future study would benefit from populations, making it the most frequent cause of further examination of the BNDF gene in more ethnic monogenic forms of human obesity.117–119 A common groups and more variants. For example, the rs925946 genetic variant located 188 kb downstream of the SNP has also been strongly associated with weigh MC4R gene (rs17782313) has been associated with gain and change in BMI (P = 8.5 Â 10À10; effect increased fat mass, weight and risk of obesity.120,121 size = 3.85±0.63).130 Furthermore, rs17782313 has been associated with higher intake of total energy and dietary fat, Neuropeptide Y. Neuropeptide Y is a peptide resulting in greater long-term weight change in a neurotransmitter secreted by the hypothalamus healthy population. Recently, a GWAS of AIWG in a for regulation of appetite and energy expenditure drug-naive pediatric population identified one highly (Figure 3). NPY agonists such as dexamethasone have significant marker that overlaps the region previously been reported to increase food intake in . identified by a large-scale GWAS of obesity Moreover, blockage of the Y1 and Y5 NPY receptors (P = 2.8 Â 10À7, N = 270; Table 2). Our group subse- decreases food intake through inhibition of NPY.132 quently replicated this finding in two independent Given that the NPY and its receptors have an intimate samples consisting of adults receiving SGA treatment role in energy homeostasis, Ruan˜ o et al.,115 studied (P = 1.4 Â 10À4, N = 73; P = 0.007, N = 40; Table 2). polymorphisms in the NPY gene (rs1468271) and Furthermore, each replication showed the same in the NPY5R gene (rs6837793, rs11100494). It was directions of risk alleles and genotypes for weight reported that rs6837793 was associated with gain (risk allele homozygotes conferred B9kg of weight gain in risperidone- (P = 0.0024) but not in weight gain vs 4 kg in heterozygotes and non-risk olanzapine-treated patients (Table 2). Although allele carriers). The two consecutive replications of preliminary, these findings seem interesting and this marker and the similar distribution of weight should be addressed in further research. gain is highly indicative of a true association with AIWG.14 Pro-melanin-concentrating hormone. The pro-melanin- This ‘high-interest’ finding implicates the MC4R concentrating hormone (PMCH) gene encodes the gene region in AIWG, and further investigations are precursor to a-MCH. Animal studies have reported necessary to fully characterize the contribution of that the PMCH protein regulates food intake and energy MC4R (as well as potential unidentified genes) in this homeostasis,133 and PMCH knockout mice were found region of this SNP. In addition, this region may to be hypophagic.134 Results from linkage study of contain previously undiscovered non-coding RNA obesity as a potential secondary effect of antipsychotics that post-transcriptionally regulate MC4R expression point to 12q24, including the PMCH or in guiding RNA modification.122 gene.135 A long-term follow-up case–control study in the same sample reported the rs7973796G allele of the Brain-derived neurotrophic factor. BDNF regulates PMCH gene to be associated with increased BMI survival and development of neurons, with impor- compared with controls (P = 0.025).136 Subsequent tant effects on neurogenesis and plasticity.123 Neuro- studies are required to verify the association between developmental models of SCZ implicate reduced the PMCH gene and AIWG. BDNF levels in the , and BDNF levels seem to be altered by the use of Ghrelin. Ghrelin is a gastric hormone with a potent antipsychotics,124,125 and also numerous studies orexigenic effect; that is, it mediates perception of

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 259 hunger and/or appetite for meal initiation through dyslipidemia and weight gain.4 Clozapine and receptors in the hypothalamus (Figure 3). Atypical chlorpromazine have been shown to be the strongest antipsychotic medications have been found to activators of sterol regulatory element-binding protein decrease morning fasting ghrelin levels in the first transcription activators, whereas ziprasidone had 2 weeks of treatment, but to increase ghrelin levels in a minimal effect.141 Le Hellard et al.142 used a longer treatment durations.106 Two studies have functional convergent genomic approach to reported negative results with two independent investigate the role of five genes involved in the variants in the ghrelin gene, although their relatively sterol regulatory element-binding protein activation small sample sizes and poor coverage of the of fatty acids and cholesterol production (SREBF1, genetic variability in this gene does not negate its SREBF2, SCAP, INSIG1 and INSIG2). The 201G/T potential role in antipsychotic-induced weight gain (rs13223383) polymorphism of the INSIG1 gene (Table 2).38,115 was associated with weight gain (P = 0.005), and a strong association between clozapine and the INSIG2 Endocannabinoids. The endocannabinoid system gene was found for three tag-SNPs (rs17587100, modulates energy balance by tonically reinforcing rs17047764 and rs889904; P = 0.0003–0.00007).142 motivation to find and consume food, and transiently However, two subsequent studies in more hetero- regulating orexigenic and anorexic mediators in the geneous populations on mixed medications were not hypothalamus.137 Cannabinoid receptor 1 (CNR1) able to replicate these results34,143 (Table 2). The agonists increase food intake and body weight, mixed findings in the INSIG2 gene may be due to whereas antagonists lead to weight loss.138 On the limited power in the latter two studies; therefore, basis of these findings, our group analyzed tag-SNPs further replication studies are necessary to covering the CNR1 gene and found the rs806378T understand the influence of INSIG2 in AIWG. allele to be associated with SGA-induced weight gain in European Americans (n = 117; P = 0.008), but not in High-density and low-density lipoprotein African Americans (n = 55).139 We then conducted pathways. Patients receiving atypical antipsychotic electrophoretic mobility shift assays showing treatment are known to be at greater risk for elevations that the presence of the T allele created a binding in serum triglycerides and glucose. Apolipoproteins site for the transcription factor arylhydrocarbon are proteins that bind to lipids to facilitate receptor translocator (ARNT), implying functional their transport and regulate their metabolism. In a significance. ARNT forms heterodimers with another study of the contrasting mechanism of olanzapine- transcription factor SIM1 that has been associated and risperidone-mediated weight gain, olanzapine with monogenic forms of obesity, and is essential was associated with lipid dysregulation. The for differentiation of paraventricular nucleus in apolipoprotein E (APOE) gene is essential for normal the hypothalamus. Another study investigating the catabolism of low-density lipoprotein. The rs7412 synonymous polymorphism rs1049353 was (176Arg/Cys; e2 allele) marker of APOE was found to negative140 (Table 2). be associated with weight gain induced by olanzapine Two studies have also investigated the endo- (P = 0.0056; OR = 1.42).115 Two genes involved in high- cannabinoid-degrading enzyme, FAAH (fatty acid density lipoprotein modulation were also found to amide hydrolase). The 129Pro/Thr polymorphism be associated with olanzapine-induced weight gain: (rs324420) was not significant in an Asian popula- apolipoprotein A IV (APOA4), and the scavenger tion.38 In contrast, genotype and allele associations receptor class B, member 1 (SCARB1)(P = 0.0116, were reported for rs324420 (P = 0.004 and P = 0.002, OR = 1.17; P = 0.015, OR = 1.05, respectively). A signi- respectively) in European Americans,140 suggesting ficant association was observed for the paraoxoase 1 that the FAAH gene may predispose patients to (PON1) gene in risperidone-treated patients and a clinically significant SGA-induced weight gain. nominal association scavenger receptor class B, In summary, the endocannabinoid system is a novel member 2 (SCARB2)(P = 0.0012, OR = 0.85; P = 0.0224, and promising candidate in explaining antipsychotic- OR = 1.38, respectively).115 Another study of 154 SCZ induced weight gain. Our findings in the CNR1 patients from Northern India found a significant gene are especially interesting as the gene was well haplotype associated with olanzapine-induced weight covered by tag-SNPs, and a possible functional gain of the lipoprotein lipase gene (rs285C-rs320T- significance was demonstrated for the rs806378T rs326-A-rs328C-rs4922115G: P = 0.005, OR = 2.26 (1.26– allele. Results in the FAAH gene are suggestive of an 4.05), but no SNP alone was associated with weight association with weight gain. However, the positive gain.144 No other significant associations were found finding was conducted in a small number of patients, in the lipid metabolism genes examined (Table 2). and all of the above observations need to be replicated The reported findings in the low- and high-density in larger samples. lipoprotein pathways are intriguing, especially considering that the APOC3, APOA5 and LPL genes Lipid metabolism have been found to alter serum lipids in SCZ patients Cellular lipogenesis pathways. Antipsychotic- undergoing FGA or SGA treatment.145 Elevated induced stimulation of cellular lipogenesis has been triglycerides are a hallmark of pre-diabetes, and proposed as another possible explanation for further study of these pathways could elucidate the

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 260 relationship between AIWG and disorders such as review, we have reviewed a total of 58 susceptibility metabolic syndrome and diabetes mellitus type 2. genes. Several of these genes have shown promising results in initial and replication studies. Tumor necrosis factor alpha. Tumor necrosis factor The promoter polymorphism of rs3813929 (À759 C/ alpha (TNFa) is a proinflammatory cytokine T) in the HTR2C gene and the rs7799039 (À2548G/A) with endocrine function that has been associated of the leptin gene are the most consistently associated with adipogenesis, obesity, insulin resistance and variants with AIWG. This trend is concurrent with lipid metabolism.4 Moreover, elevated levels of TNFa previous reviews,4,6 and meta-analyses in the HTR2C have been associated with clozapine treatment, gene.54,153 The three negative findings in the HTR2C making TNF a reasonable candidate gene.146,147 In an gene (À759C/T) that were published more recently initial study in our group, the rs1800629 (À308A/G) were long-term studies in which patients had pre- promoter polymorphism of TNF was negative148 viously undergone extensive antipsychotic treatment. (Table 2). However, positive signals were observed Thus, HTR2C may be more likely to be involved in the in 55 clozapine-treated patients in an 8-year longitud initial side effects of antipsychotic treatment. inal study (P = 0.0084).149 An additional marker in The rs7799039 promoter variant of the leptin gene the gene encoding TNFa receptor 1A was not was implicated in AIWG in every recent study we significant.38 examined. However, there are conflicting results on Investigations of rs1800629 and other polymorph- whether the G or A allele confers susceptibility. isms are required to determine the influence of Zhang et al.110 reported significant association of the TNF in antipsychotic-induced weight gain, especially G allele in the male, but not in the female subgroup, regarding potential long-term effects. and Gregoor et al.112 observed that the G allele was associated with the occurrence of obesity in males, Genome-wide association studies whereas the A allele was associated in females, GWAS in AIWG. Only one GWAS was published on inferring a potential sex-specific interaction. More- metabolic side effects of antipsychotic medication. over, Calarge et al.113 found the A allele to be Adkins et al.150 reported some promising findings in associated with increased BMI in adolescents, sug- the CATIE sample. The most interesting finding was a gesting a possible effect of age or early onset. significant association between an SNP in the MEIS2 The disparity between these groups could be gene (Meis homeobox 2) and waist and hip circum- explained by different risk factors between genders ference under risperidone treatment. However, no and age, and replication is needed to investigate polymorphisms reached genome-wide significance these effects. for changes in BMI. There has also been progress in finding numerous novel variants. Previous investigations of the DRD2 GWAS in obesity. Recently, GWASs in obesity have gene have been negative; however, it is important to implicated numerous gene variants with changes note that these investigations did not cover the gene in BMI and weight gain. Markers within or close to using tag-SNPs. Two studies using tag-SNPs had SH2B adapter protein 1 (SH2B1) and fat mass and found two novel markers that were associated obesity-associated (FTO) genes have been strongly in Asian and European-American samples.57,63 Thus, associated with changes in body mass.130,151 GWASs DRD2 is one of the most promising genes and should in obesity have implicated numerous gene variants garner further research, including DNA sequencing. with changes in BMI and weight gain. Markers within Furthermore, novel susceptibility genes, such as or close to SH2B1 and FTO genes have been strongly CNR1, MC4R, NPY, ADRA2A and the INSIG2 genes associated with changes in body mass152 and FTO86,152 have also shown promising results that need to be genes not to be associated with AIWG (Table 2). replicated in further studies. Nonetheless, these genes represent interesting The mixed results in some of the pharmacogenetic candidates for future studies. studies are likely a reflection of limitations derived from biological complexity of AIWG, potential non- Discussion genetic confounders of AIWG and the design of candidate gene studies. It is likely that each risk Antipsychotic drugs are the primary treatment for allele contributes only a small proportion of the psychotic disorders and are widely prescribed to most variation predisposing an individual to treatment- schizophrenic patients, often lifelong. Despite their emergent side effects. Studies focusing on a few benefits in alleviating many symptoms of SCZ, AIWG polymorphisms in a single gene may not be able to is undoubtedly of major clinical concern for many detect an effect. In addition, environmental factors patients. Unfortunately, a single reliable predictor of that may be linked to AIWG are poorly understood weight gain has not been found. Pharmacogenetic and could potentially confound results. Patients with studies have begun to converge on several genetic premorbid weight below average BMI have been variants that are reproducibly associated with anti- reported to gain the most weight, whereas patients psychotic treatment-emergent weight gain. At the with above-average BMI at the start of antipsychotic time of the previous review by Mu¨ ller and Kennedy4 treatment have the least weight gain and this should in 2006, 18 candidate genes had been reported. In this be taken account in future studies.154 Other factors

Molecular Psychiatry Pharmacogenetics of AIWG TAP Lett et al 261 influencing AIWG include gender and age,154–156 as clinical environment remain, although first steps well as smoking, which may also further increase the have already been taken. risk for cardiovascular disease (for a detailed discus- Genetic screens with sufficient sensitivity and sion, see McCreadie157). Furthermore, to the best of specificity need to be developed. Recently, a DNA- our knowledge, no studies have examined epigenetic based screen was developed for clozapine-induced factors, such as methylation status or acetyla- agranulocytosis with high specificity (98%). How- tion, which can profoundly alter gene expression. ever, the sensitivity was below a threshold necessary Despite these limitations, new approaches are for clinically meaningful screens (20%).158 By con- beginning to be used to increase specificity and trast, there is a much greater understanding of the quality of results. Ruan˜ o et al.115 used a novel method genetic basis of AIWG indicating that screening of statistical analysis called physiogenomics to for weight gain side effects could achieve greater adequately handle comprehensive genomic data and sensitivity. These tests would also require insights enhance statistical power. Using this method, the into biocomputational analysis to build an algorithm authors elucidated an independent set of risk factors incorporating genetic and non-genetic factors. The for patients receiving different SGAs. Risperidone- neuro-fuzzy model, which incorporates artificial induced weight gain was associated with appetite neural networks and fuzzy logic, has recently been peptide genes (LEPR, NPRY5 and PON1). In contrast, used by Lan et al.159 in predicting 93% of SCZ olanzapine-induced weight gain was reported in the patients with weight gain under antipsychotic treat- genes involved in lipid metabolism (APO3, APOA4 ment. This model suggests that pharmacogenetic and SCARB1; Table 2). Le Hellard et al.142 used a testing is a feasible prediction tool for AIWG. functional convergent genomic approach in which The ethical challenges are another imminent factor the five genes in the lipid biosynthesis pathway were that needs to be addressed to avoid genetic discrimi- analyzed using tagging SNPs. This strategy allowed nation by health professionals, insurance companies for a detailed characterization of genomic function in and caregivers. For instance, the pleiotropic effect of the lipid biosynthesis pathway. Such methodology many gene variants will create particular challenges. may be used as a paradigm for future personalized The education of physicians and caregivers is also genetics screening algorithms. Liu et al.80 studied the necessary to provide guidelines on how to commu- ADRA1A gene exhaustively using tag-SNPs to dis- nicate genetic findings. cover that most SNPs that are associated with changes In conclusion, with economically feasible DNA in BMI are located in promoter and intron regions tests already available, pharmacogenetics holds sub- rather than missense mutations. The advantage of this stantial promise in predicting treatment emergence approach is better characterization of the full varia- side effects and advancing the field of personalized tion in a single gene. Our group139 performed tag-SNP medicine. Physicians currently prescribe medication analysis on the CNR1 gene. In addition, we used an based on the average properties of drugs in clinical electromobility shift assay to identify a transcription trials. Pharmacogenetics will provide rational treat- factor-binding site; thereby comprehensively studying ment based on matching antipsychotics to a patient’s the CNR1 gene, and providing functional relevance to DNA profile, thus, potentially providing effective the findings. GWAS in AIWG and in obesity can be treatment with minimal side effects to outliers and regarded as a complimentary approach to candidate mean responders to a given antipsychotic medication. gene studies, which may allow identifying novel With the culminating and continuing interest in candidates and chromosomal regions of interest. pharmacogenetic analysis of AIWG, we are confident GWASs on AIWG have generated first interesting that personalized pharmacotherapy preventative findings such as the MEIS and MC4R genes (Table 2). of iatrogenic metabolic side effects will be available The increase in sophistication of these studies in the coming years. provides a better understanding of how these genes relate to AIWG, thereby enhancing previous findings, Conflict of interest and overcoming limitations of traditional candidate genes studies. Therefore, these approaches are likely JLK has received a one time honorarium from Eli Lilly to set a new standard for future analysis. Corporation and has been a consultant to GSK, Sanofi-Aventis and Dainippon-Sumitomo. Clinical implications Given the findings to date, the increased conceptual Acknowledgments understanding of AIWG from past studies, and the novel developments in research strategies and tech- Grant supports to this study were provided as follows: niques, it could be argued that the personalized CIHR operating grant to DJM (Genetics of antipsycho- prescription based on genetic screening is very tics induced metabolic syndrome, MOP 89853); promising with application in the near future. Indeed, NARSAD 2009 Young Investigator Award to DJM, pharmacogenetics has arguably progressed faster in CIHR Michael Smith New Investigator Salary Prize for psychiatry than in any other field with the exception Research in Schizophrenia to DJM and OMHF New of perhaps oncology. Challenges to introducing Investigator Fellowship to DJM. We thank Jeffery individualized DNA pharmacogenetic tests in a Powers for graphical design consultation. AKT is a

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