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Generalized anxiety disorder (GAD) is a prevalent and chronic mental disorder that elicits widespread functional impairment. Given the high degree of non-response/partial response among patients with GAD to available pharmacological treatments, there is a strong need for novel approaches that can optimize outcomes, and lead to medications that are safer and more effective. Although investigations have identified interesting targets predicting treatment response through pharmacogenetics (PGx), pharmaco-epigenetics, and neuroimaging methods, these studies are often solitary, not replicated, and carry several limitations. This review provides an overview of the current status of GAD genetics and PGx and presents potential strategies to improve treatment response by combining better phenotyping with PGx and improved analytical methods. These strategies carry the dual benefit of delivering data on biomarkers of treatment response as well as pointing to disease mechanisms through the biology of the markers associated with response. Overall, these efforts can serve to identify clinical, genetic, and epigenetic factors that can be incorporated into a pharmaco(epi)genetic test that may ultimately improve treatment response and reduce the socioeconomic burden of GAD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose of Review: This review highlights recent advances in the investigation of genetic factors for antipsychotic response and side effects., Recent Findings: Antipsychotics prescribed to treat psychotic symptoms are variable in efficacy and propensity for causing side effects. The major side effects include tardive dyskinesia, antipsychotic-induced weight gain (AIWG), and clozapine-induced agranulocytosis (CIA). Several promising associations of polymorphisms in genes including HSPG2, CNR1, and DPP6 with tardive dyskinesia have been reported. In particular, a functional genetic polymorphism in SLC18A2, which is a target of recently approved tardive dyskinesia medication valbenazine, was associated with tardive dyskinesia. Similarly, several consistent findings primarily from genes modulating energy homeostasis have also been reported (e.g. MC4R, HTR2C). CIA has been consistently associated with polymorphisms in the HLA genes (HLA-DQB1 and HLA-B). The association findings between glutamate system genes and antipsychotic response require additional replications., Summary: The findings to date are promising and provide us a better understanding of the development of side effects and response to antipsychotics. However, more comprehensive investigations in large, well characterized samples will bring us closer to clinically actionable findings.

Objective: Pharmacotherapy is one of the primary treatments for psychiatric disorders. Given the variation in individual response, a more personalized approach is needed. This paper will discuss methods for user-friendly referrals, recruitment criteria, data storage and dissemination, biological sample and clinical questionnaire collection, and advertising., Methods: The Individualized Medicine: Pharmacogenetics Assessment and Clinical Treatment (IMPACT) study is one of the first to use pharmacogenetic testing on a large scale in psychiatry as a tool to predict individual drug response and tolerability. As IMPACT's eligibility criteria includes all diagnoses and comorbidities, the participant population will reflect the diversity amongst mental health consumers. IMPACT's innovative study design will demonstrate the utility of this testing within the health care system., Results: IMPACT has successfully implemented pharmacogenetic testing on a relatively large scale, and in both tertiary level and primary care settings. It represents a novel approach to psychiatric care and from its initial stages the design has evolved to accommodate the nature and needs of the health care community., Conclusion: It is anticipated that IMPACT will continue to demonstrate the feasibility of pharmacogenetic testing and facilitate its introduction and implementation in routine healthcare practice., (Copyright © 2017. Published by Elsevier Ltd.)

Genetic variation in cytochrome enzymes is known to affect drug metabolism and influence treatment response. Recently, the rs472660 variant in CYP3A43 has been associated with olanzapine response and clearance. In this study, we investigated the impact of rs472660 and the putatively functional marker rs680055 on antipsychotic response. We genotyped the rs472660 and rs680055 single nucleotide polymorphisms (SNPs) in N = 152 schizophrenia patients of European descent collected at two sample sites who were predominately treated with second generation antipsychotics for up to 6 months. Treatment response was assessed prospectively using Brief Psychiatric Rating Scale (BPRS) scores. Statistical analysis was performed using Chi square and analysis of covariance. The rs680055 SNP was significantly associated with treatment response. Carriers of the minor allele had significantly lower BPRS scores at study end (p = 5.9 × 10(-4)) with 8 % of the variance being explained by rs680055 genotype. Post hoc analyses revealed that this effect was present in both samples and in both genders. The rs472660 SNP was also associated with response (p = 0.027); however, this finding was not significant after multiple test correction. This is the first evidence that the rs680055 missense mutation influences antipsychotic response. Although our finding for rs472660 was only a non-significant trend after correction, our results still support the notion that this SNP may play a role in antipsychotic response. Despite the fact that the functional role of CYP3A43 in antipsychotic metabolism is not fully understood yet, our study provides an important contribution to understanding genetic factors of antipsychotic response.

Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future.

We currently rely on large randomized controlled trials and meta-analyses to make clinical decisions; this places us at a risk of discarding subgroup or individually specific treatment options owing to their failure to prove efficacious across entire populations. There is a new era emerging in personalized medicine that will focus on individual differences that are not evident phenomenologically. Much research is directed towards identifying genes, endophenotypes, and biomarkers of disease that will facilitate diagnosis and predict treatment outcome. We are at the threshold of being able to predict treatment response, primarily through genetics and neuroimaging. In this review we discuss the most promising markers of treatment response and adverse effects emerging from the areas of pharmacogenetics and neuroimaging in depression and schizophrenia.

Manifestation of tardive dyskinesia (TD) among schizophrenia subjects on long-term antipsychotic treatment with typical drugs has been a clinical concern. Despite its association with extrapyramidal symptoms, typical drugs are still routinely prescribed globally though marginally superior atypical drugs have long been available. The genetic component in the etiology of TD is well documented. Search for these determinants has led to a few consensus associations of CYP2D6 *10, CYP1A2*1F, DRD2 Taq1A (rs1800497), DRD3 Ser9Gly (rs6280) and MnSOD Ala9Val (rs4880) variants with TD. However, translation of these observations into the clinic has not been achieved so far. This review discusses the salient features of TD etiopathology, current status of TD genetics, interactions between genetic and nongenetic factors, some major drawbacks, challenges and expected focus in TD research over the next decade, with emphasis on pharmacogenetics.

Background: Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with unclear pathogenesis. CYP2D6 is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. Materials & methods: We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n = 198, of which 82 had TD). Results: TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. Conclusion: Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.

Tardive dyskinesia (TD) is a movement disorder that may occur after extended use of antipsychotic medications. The etiopathophysiology is unclear; however, genetic factors play an important role. The Perlecan (HSPG2) gene was found to be significantly associated with TD in Japanese schizophrenia patients, and this association was subsequently replicated by an independent research group. To add to the evidence for this gene in TD, we conducted a meta-analysis specific to the relationship of HSPG2 rs2445142 with TD occurrence, while also adding our unpublished genotype data. Overall, we found a significant association of the G allele with TD occurrence (p = 0.0001); however, much of the effect appeared to originate from the discovery dataset. Nonetheless, most study samples exhibit the same trend of association with TD for the G allele. Our findings encourage further genetic and molecular studies of HSPG2 in TD.

Altered glutamate neurotransmission is implicated in the etiology of schizophrenia (SCZ) and the pharmacogenetics of response to clozapine (CLZ), which is the drug of choice for treatment-resistant SCZ. Response to antipsychotic therapy is highly variable, although twin studies suggest a genetic component. We investigated the association of 10 glutamate system gene variants with CLZ response using standard genotyping procedures. GRM2 (rs4067 and rs2518461), SLC1A2 (rs4354668, rs4534557, and rs2901534), SLC6A9 (rs12037805, rs1978195, and rs16831558), GRIA1 (rs2195450), and GAD1 (rs3749034) were typed in 163 European SCZ/schizoaffective disorder patients deemed resistant or intolerant to previous pharmacotherapy. Response was assessed following 6 months of CLZ monotherapy using change in Brief Psychiatric Rating Scale (BPRS) scores. Categorical and continuous response variables were analyzed using χ2 tests and analysis of covariance, respectively. We report no significant associations following correction for multiple testing. Prior to correction, nominally significant associations were observed for SLC6A9, SLC1A2, GRM2, and GRIA1. Most notably, CC homozygotes of rs16831558 located in the glycine transporter 1 gene (SLC6A9) exhibited an allele dose-dependent improvement in positive symptoms compared to T allele carriers (puncorrected = 0.008, pcorrected = 0.08). To clarify the role of SLC6A9 in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.

Objectives: The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia‐associated HLA‐region single‐nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. Methods: The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. Results: The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. Conclusion: Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD. [ABSTRACT FROM AUTHOR]

BACKGROUND: The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response. METHODS: Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each studys original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed-effects model. RESULTS: Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02-1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024-0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11-2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65). CONCLUSIONS: Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for atypical antipsychotics.

Genetic influences on acute responses to psychoactive drugs may contribute to individual variability in addiction risk. ABCB1 is a human gene that encodes P-glycoprotein, an ATP-dependent efflux pump that may influence the pharmacokinetics of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. Using data from 48 young adults (aged 19–25 years) reporting 1–4 days of cannabis use per week who completed a placebo-controlled human laboratory experiment, we tested the hypothesis that the rs2235048 polymorphism of ABCB1 would influence acute responses to smoked cannabis. C-allele carriers reported on average greater frequency of weekly cannabis use compared to the TT genotype carriers (TC/CC mean ± SEM = 2.74 ± 0.14, TT = 1.85 ± 0.24, p = 0.004). After smoking a single cannabis cigarette to their desired high, C-allele carriers had higher area-under-the-curve (AUC) of both THC metabolites (11-OH-THC TC/CC = 7.18 ± 9.64, TT = 3.28 ± 3.40, p = 0.05; THC-COOH TC/CC = 95.21 ± 116.12, TT = 45.92 ± 42.38, p = 0.043), and these results were impact by self-reported ethnicity. There were no significant differences in self-reported subjective drug effects except for a greater AUC of visual analogue scale rating of drug liking (TC/CC = 35,398.33 ± 37,233.72, TT = 15,895.56 ± 13,200.68, p = 0.017). Our preliminary findings suggest that further work in a larger sample should investigate whether human ABCB1 influences cannabis-related phenotypes and plays a role in the risk of developing a cannabis use disorder. [ABSTRACT FROM AUTHOR]

Tardive dyskinesia (TD) is a potentially irreversible movement disorder observed following long‐term antipsychotic exposure. Its cause is unknown; however, a genetic component has been supported by studies of affected families. Dysbindin‐1, encoded by the dystrobrevin‐binding protein 1 DTNBP1 gene, has been associated with schizophrenia and is potentially involved in dopamine neurotransmission through its regulation of dopamine release and dopamine D2 receptor recycling, making it a candidate for investigation in TD. We investigated common variants across the DTNBP1 gene in our schizophrenia/patients with schizoaffective disorder of European ancestry. We found a number of DTNBP1 three‐marker haplotypes to be associated with TD occurrence and TD severity (p < 0.05). These preliminary findings, if replicated in larger independent samples, would suggest that drugs targeting dysbindin‐1 may be an option in the prevention and treatment of TD. [ABSTRACT FROM AUTHOR]

Tardive dyskinesia (TD) is a movement disorder that may develop in schizophrenia patients being treated long-term with antipsychotic medication. TD interferes with voluntary movements and leads to stigma, and can be associated with treatment non-adherence. The etiology of TD is unclear, but it appears to have a genetic component. There is emerging evidence of immune dysregulation in TD. In the current study, we set out to investigate the complex schizophrenia-associated complement component 4 (C4) gene for possible association with TD occurrence and TD severity as assessed by the Abnormal Involuntary Movement Scale (AIMS) in a sample of 129 schizophrenia patients of European ancestry. We have genotyped the copy numbers of long and short forms of C4 A and C4 B gene variants in 129 European ancestry patients with schizophrenia or schizoaffective disorder. We did not find predicted C4 A or C4 B expression to be nominally associated with TD risk or severity. However, we found the number of copies of C4 BL to be nominally associated with TD severity (p = 0.020). [ABSTRACT FROM AUTHOR]

Objectives: Tardive dyskinesia (TD) is a movement disorder that may develop as a side effect of antipsychotic medication. The aetiology underlying TD is unclear, but a number of mechanisms have been proposed. Methods: We investigated single-nucleotide polymorphisms (SNPs) in the genes coding for neuregulin-1 and erbB-4 receptor in our sample of 153 European schizophrenia patients for possible association with TD. Results: We found the ERBB4 rs839523 CC genotype to be associated with risk for TD occurrence and increased severity as measured by the Abnormal Involuntary Movement Scale (AIMS) (P = .003). Conclusions: This study supports a role for the neuregulin signalling pathway in TD, although independent replications are warranted. [ABSTRACT FROM AUTHOR]

Highlights • Nine single-nucleotide polymorphisms (SNPs) in the Disrupted in Schizophrenia 1 (DISC1) gene was investigated for possible association with TD. • The tested DISC1 SNPs were not significant associated with TD. • The DISC1 rs11122359 may be interacting with the vesicular monoamine transporter 2 (VMAT2/ SLC18A2) rs363224 in TD. Abstract Tardive dyskinesia (TD) is an involuntary movement disorder that occurs in ∼20% of patients after extended antipsychotic use. Its pathophysiology is unclear; however, familial patterns and gene association studies indicate an inherited component to risk. The disrupted in schizophrenia 1 (DISC1) gene was selected for analysis because it interacts with and regulates two important proteins involved in antipsychotic medication action: the dopamine D2 receptor and the cAMP phosphodiesterase type IVB (PDE4B). The D2 receptor is the obligate target of all existing antipsychotic medications, and PDE4B hydrolyzes cAMP, a core signaling molecule activated by agonist binding to the D2 receptor. Notably, PDE4B inhibitors such as rolipram have been shown to reduce TD-like behaviours in animal models. Nine single-nucleotide polymorphisms (SNPs) in the DISC1 gene were investigated in a sample of 193 chronic schizophrenia patients for association with the presence and severity of TD, with age and sex as additional variables. TD severity was measured using the Abnormal Involuntary Movement Scale (AIMS). Two DISC1 SNPs were associated with TD severity (uncorrected p < 0.05), but these findings did not survive correction for multiple testing. This preliminary investigation suggests that DISC1 gene variants do not affect risk for TD or severity. [ABSTRACT FROM AUTHOR]

Tardive dyskinesia (TD) is a movement disorder that may occur after extended use of antipsychotic medications. The etiopathophysiology is unclear; however, genetic factors play an important role. The Perlecan (HSPG2) gene was found to be significantly associated with TD in Japanese schizophrenia patients, and this association was subsequently replicated by an independent research group. To add to the evidence for this gene in TD, we conducted a meta-analysis specific to the relationship of HSPG2 rs2445142 with TD occurrence, while also adding our unpublished genotype data. Overall, we found a significant association of the G allele with TD occurrence (p = 0.0001); however, much of the effect appeared to originate from the discovery dataset. Nonetheless, most study samples exhibit the same trend of association with TD for the G allele. Our findings encourage further genetic and molecular studies of HSPG2 in TD. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: A recent genome‐wide association study (GWAS) in obsessive–compulsive disorder (OCD) reported a significant marker in the dispatched homolog 1 (Drosophila) gene (DISP1 gene) associated with serotonin reuptake inhibitor (SRI) antidepressant response (Qin et al., ). DISP1 has never been examined before in terms of association with SRI response until this GWAS. We attempt to replicate the GWAS finding by investigating the association of the DISP1 rs17162912 polymorphism with SRI response in our sample of 112 European Caucasian OCD patients. Methods: Patients were previously treated naturalistically with up to 6 different SRIs sequentially, including 5 selective SRIs (fluoxetine, fluvoxamine, sertraline, paroxetine, and citalopram) and 1 SRI (clomipramine). Each medication trial was evaluated retrospectively for response and was rated categorically as either responder or nonresponder using the Clinical Global Impression–Improvement scale. Fisher's exact test was used to investigate the relationship between the DISP1 rs17162912 genotype distribution and SRI response. Results: We did not observe a significant association between rs17162912 and SRI response (p = .32). Conclusion: This replication study did not support the role of DISP1 in predicting SRI response in OCD; however, methodological differences between the original GWAS and our study, as well as limited power and low minor allele frequency, may have hindered replication. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia (SCZ) is a chronic severe neuropsychiatric disorder, where pharmacological treatment has been hindered by adverse effects, including antipsychoticinduced weight gain (AIWG) and related complications. Genetic studies have been exploring the appetite regulation and energy homeostasis pathways in AIWG with some promising leads. The serotonin system has been shown to participate in these pathways. Methods: In the current study, we examined single nucleotide polymorphisms across the serotonin receptor genes HTR3A and HTR3B. Prospective weight change was assessed for a total of 149 SCZ patients of European ancestry. Results: We did not find the tested HTR3A or HTR3B gene markers to be associated with AIWG in our sample. Conclusion: Our preliminary findings suggest that these receptors may not play a major role in predicting AIWG. [ABSTRACT FROM AUTHOR]

Objectives: Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms (SNPs) in orexin receptors 1 and 2 (HCRTR1 and HCRTR2) for association with AIWG.Methods: Schizophrenia or schizoaffective disorder subjects (n = 218), treated mostly with clozapine and olanzapine for up to 14 weeks, were included. Replication was conducted in a subset of CATIE samples (n = 122) treated with either olanzapine or risperidone for up to 190 days. Association between SNPs and AIWG was assessed using analysis of covariance (ANCOVA) with baseline weight and duration of treatment as covariates.Results: Several SNPs in HCRTR2 were nominally associated with AIWG in patients of European ancestry treated with either clozapine or olanzapine (P<0.05). In the replication analysis two SNPs rs3134701 (P = 0.043) and rs12662510 (P = 0.012) were nominally associated with AIWG. None of the SNPs in HCRTR1 were associated with AIWG.Conclusion: This study provides preliminary evidence supporting the role of HCRTR2 in AIWG. However, these results need to be confirmed in large study samples. [ABSTRACT FROM PUBLISHER]

Objective Approximately 30% of patients with schizophrenia fail to respond to antipsychotic therapy and are classified as having treatment-resistant schizophrenia. Clozapine is the most efficacious drug for treatment-resistant schizophrenia and may deliver superior therapeutic effects partly by modulating glutamate neurotransmission. Response to clozapine is highly variable and may depend on genetic factors as indicated by twin studies. We investigated eight polymorphisms in the N-methyl- d-aspartate glutamate receptor subunit gene GRIN2B with response to clozapine. Methods GRIN2B variants were genotyped using standard TaqMan procedures in 175 European patients with schizophrenia deemed resistant or intolerant to treatment. Response was assessed using change in Brief Psychiatric Rating Scale scores following six months of clozapine therapy. Categorical and continuous response was assessed using chi-squared test and analysis of covariance, respectively. Results No associations were observed between the variants and response to clozapine. A-allele carriers of rs1072388 responded marginally better to clozapine therapy than GG-homozygotes; however, the difference was not statistically significant ( p = 0.067, uncorrected). Conclusions Our findings do not support a role for these GRIN2B variants in altering response to clozapine in our sample. Investigation of additional glutamate variants in clozapine response is warranted. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim: The recent Psychiatric Genomics Consortium genome-wide association study identified an SNP, rs2514218, located 47kb upstream of the DRD2 gene to be associated with risk for schizophrenia (p = 2.75e-11). Since all antipsychotics bind to dopamine D2 receptors, we examined rs2514218 in relation to response to antipsychotic treatment. Patients & methods: We investigated the SNP in relation to treatment response in a prospective study consisting of 208 patients (151 Caucasians, 42 African-Americans and 15 others) treated with clozapine for 6 months. Results: rs2514218 was associated with total score change in the brief psychiatric rating scale under an additive model (pcorr= 0.033). Conclusion: Our finding provides evidence for rs2514218 association with antipsychotic response, but further replication is required before firm conclusions can be drawn. [ABSTRACT FROM AUTHOR]

Antipsychotics frequently cause changes in glucose metabolism followed by development of weight gain and/or diabetes. Recent findings from our group indicated an influence of glucose-related genes on this serious side effect. With this study, we aimed to extend previous research and performed a comprehensive study on the peroxisome proliferator-activated receptor gamma (PPARG) and the adiponectin (ADIPOQ) genes. In 216 schizophrenic patients receiving antipsychotics for up to 14 weeks, we investigated single-nucleotide polymorphisms in or near PPARG (N=24) and ADIPOQ (N=18). Statistical analysis was done using ANCOVA in SPSS. Haplotype analysis was performed in UNPHASED 3.1.4 and Haploview 4.2. None of the PPARG or ADIPOQ variants showed significant association with antipsychotic-induced weight gain in our combined sample or in a refined subsample of patients of European ancestry treated with clozapine or olanzapine after correction for multiple testing. Similarly, no haplotype association could withstand multiple test correction. Although we could not find a significant influence of ADIPOQ and PPARG on antipsychotic-induced weight gain, our comprehensive examination of these two genes contributes to understanding the biology of this serious side effect. More research on glucose metabolism genes is warranted to elucidate their role in metabolic changes during antipsychotic treatment. [ABSTRACT FROM AUTHOR]

Objective Antipsychotics are effective in treating schizophrenia symptoms. However, the use of clozapine and olanzapine in particular are associated with significant weight gain. Mouse and human studies suggest that the protein kinase cAMP-dependent regulatory type II beta ( PRKAR2B) gene may be involved in energy metabolism, and there is evidence that it is associated with clozapine's effects on triglyceride levels. We aimed at assessing PRKAR2B's role in antipsychotic-induced weight gain in schizophrenia patients. Methods DNA samples from adult schizophrenia or schizoaffective disorder patients of mixed ancestry were genotyped, and weight gain was assessed. We analyzed 16 tag single-nucleotide polymorphisms across the PRKAR2B gene in a Caucasian subset treated either with clozapine or olanzapine ( N = 99). Linear regression based on an additive model was performed with the inclusion of relevant covariates. Results Normalized per cent weight change was analyzed, revealing that patients with the minor allele at rs9656135 had a mean weight increase of 4.1%, whereas patients without this allele had an increase of 3.4%. This association is not significant after correcting for multiple testing. Conclusions Because of limited power, PRKAR2B's role in antipsychotic-induced weight gain is unclear, but biological evidence suggests that PRKAR2B may be involved. Further research in larger sample sizes is warranted. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives: Genetic variation in the fat mass- and obesity-associated gene (FTO) has been associated with obesity in the general population. In this study we have investigated these variants for association with antipsychotic-induced weight gain (AIWG). Methods: A total of 218 patients with chronic schizophrenia or schizoaffective disorder treated mostly with clozapine or olanzapine for up to 14 weeks were included in the study. We analyzed 4 polymorphisms in intron 1 of the FTO gene (rs1421085, rs8050136, rs9939609, rs9930506) for association with AIWG using ANCOVA. Results: No statistically significant associations were observed between the single nucleotide polymorphisms and AIWG. However, patients homozygous for the A-allele of rs9939609 gained numerically higher weight than the other genotypic groups (AA: 5.26 ± 6.7%; TA: 4.66 ± 5.6%; TT: 4.21 ± 5.3%). Conclusion: Our current observations suggest that the FTO gene variants investigated may not play a major role in AIWG. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD. [Copyright &y& Elsevier]

Background Previous studies have shown that antipsychotics with high propensity for antipsychotic-induced weight gain (AIWG) influence glucose transporter type 4 (GLUT4) mediated glucose intake. Variation in the gene encoding TBC1 domain family member 1 (TBC1D1), a Rab-GTPase activating protein regulating GLUT4 trafficking, has been associated with obesity. Therefore, we investigated the impact of TBC1D1 polymorphisms on AIWG. Methods We analyzed rs9852 and rs35859249 in TBC1D1 in 195 schizophrenia subjects treated mostly with clozapine or olanzapine for up to 14 weeks. Association was tested using analysis of variance and analysis of covariance with change (%) from baseline weight as the dependent variable. Results Analysis of covariance showed a non-significant trend for lower weight gain in carriers of the T-allele of rs9852 than in C-allele homozygotes ( p = 0.063). This effect was more pronounced in the subgroup of patients treated with clozapine or olanzapine ( p = 0.024). For rs35859249, no significant association with AIWG could be detected. Conclusions This is the first study examining the association between TBC1D1 and AIWG. The moderate association of rs9852, located in the 3′UTR near a miRNA binding site, indicates an influence of TBC1D1 on AIWG. Further investigations remain necessary to elucidate the role of this gene in AIWG. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: This study aimed to: 1) replicate previously reported associations between dopamine D4 receptor gene (DRD4) polymorphisms and antipsychotic (AP) response in a clozapine (CLZ) response sample; and 2) explore possible associations of polymorphisms across dopamine D5 receptor gene (DRD5) as well as other DRD4 regions. Methods: DRD4 exon III 48-bp, intron I (G)n, and 120-bp repeat polymorphisms, and three DRD4 single nucleotide polymorphisms (SNPs); and DRD5 (CA/CT/GT)n microsatellite and four DRD5 SNPs were assessed using standard genotyping and statistical procedures. Results: We report evidence, which does not survive correction for multiple testing, supporting previous DRD4 findings. Findings of interest include the 120-bp 1-copy allele, intron I (G)n 142-bp/140-bp genotype, and exon III 4R allele with CLZ response. All DRD5 tests were negative. Conclusions: Overall, these results suggest a possible minor contribution of DRD4 variants, but not DRD5 variants, towards the AP/CLZ response phenotype. [Copyright &y& Elsevier]

Abstract: Neurexin-1 (NRXN1) modulates recruitment of NMDA receptors. Furthermore, clozapine reduces hyperactivity of NMDA receptors. Thus, regulation of the NRXN1 gene may mediate the efficacy of clozapine at reducing cortical hyperactivity. We examined the putative functional SNP, rs1045881, for association with schizophrenia, and the potential role of this SNP in clozapine response. The rs1045881 variant was not significantly associated with schizophrenia (N=302 case–control pairs), but with clozapine response (N=163; p=0.030). Baseline and BPRS scores after six months revealed a trend for rs1045881 genotype by treatment interaction (p=0.079). In the post hoc analysis, a significant association between BPRS negative symptoms score and genotype was observed (p=0.033). These results suggest that the rs1045881 NRXN1 polymorphism may influence clozapine response. [Copyright &y& Elsevier]

Tardive dyskinesia (TD) is a severe and potentially irreversible motor side effect linked to long-term antipsychotic exposure. Changes in dopamine neurotransmission have been implicated in the etiology of TD, and catechol- O-methyl-transferase (COMT) is an enzyme that metabolizes dopamine. Objectives. We investigated five single-nucleotide polymorphisms in addition to the functional Val158Met variant spanning the COMT gene for association with TD. Methods. We analyzed the six COMT single-nucleotide polymorphisms in a sample of schizophrenia/schizoaffective disorder patients ( n=226; 196 Caucasians and 30 African Americans). Results. We found a significant association between the marker rs165599 in the 3′ untranslated region of COMT and TD (AA versus G-carrier: ORAA=2.22, 95% CI:1.23–4.03; P=0.007). The association appeared to be originating from males. We did not find a significant association of the other five tested polymorphisms with TD in our samples. We performed a sex-stratified meta-analysis across all of the published studies ( n=6 plus our own data) of COMT and TD, and found an association between ValVal genotype and TD in females (ORValVal=1.63, 95% CI: 1.09–2.45; P=0.019) but not in males. Conclusions. Overall, our results suggest that the COMT gene may have a minor but consistent role in TD, although sex-stratified studies with additional markers in larger clinical samples should be performed. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Tardive dyskinesia (TD) is a potentially irreversible side effect of antipsychotic medication treatment that occurs in approximately 25% of chronically treated schizophrenia patients. Oxidative stress has been one of the proposed mechanisms influencing TD risk. originally reported a significant association between TD and the NADPH quinine oxidoreductase 1 (NQO1) gene Pro187Ser (C609T, rs1800566) polymorphism in Korean schizophrenia patients; however, subsequent studies have not consistently replicated these findings. Similarly, Hori et al. (2000) reported an association between TD and the Manganese superoxide dismutase SOD2 (MnSOD) gene Ala9Val (rs4880) polymorphism in a Japanese sample, but most research groups failed to replicate their positive findings. Aims: We investigated the role of the NQO1 polymorphism Pro187Ser and SOD2 (Ala9Val) in a group of well-characterized schizophrenia patients (N =223) assessed for TD. We also performed a meta-analysis of all the previously published TD studies, including data from our sample, on these polymorphisms, Pro187Ser (N =5 studies) and Ala9Val (N =9 studies). Results: We did not observe a significant association of the Pro187Ser or Ala9Val polymorphism with TD occurrence or AIMS scores in our Caucasian and African American samples when analyzed independently. Meta-analysis did not reveal a significant association of the Pro187Ser/Ala9Val alleles or genotypes with TD occurrence. Conclusions: Neither the NQO1 Pro187Ser nor the SOD2 Ala9Val appear to play a major role in TD risk, although additional polymorphisms should be tested before the role of NQO1 and SOD2 in TD can be completely excluded. [Copyright &y& Elsevier]

Abstract: Tardive dyskinesia (TD) is a neuroleptic-induced movement disorder. Its pathophysiology is unclear. The most consistent genetic findings have shown an association with the Ser9Gly polymorphism of the DRD3 gene. However, only few polymorphisms within DRD3 has been tested, and a comprehensive examination of DRD3 in TD is still lacking. Further, brain-derived neurotrophic factor (BDNF), a neuronal growth and survival peptide, regulates DRD3 expression and may be involved in the neuronal degeneration observed in TD. In the present study, we investigated 15 tag DRD3 polymorphisms and four tag BDNF polymorphisms for association with TD in our sample of Caucasian schizophrenia patients (N =171). While BDNF markers showed no association, a haplotype containing rs3732782, rs905568, and rs7620754 in the 5′ region of DRD3 was associated with TD diagnosis (p[10,000 permutations]=0.007). We also found evidence of interaction between BDNF and DRD3 polymorphisms. Further studies are needed to confirm these findings. [Copyright &y& Elsevier]

Abstract: Tardive dyskinesia is a severe debilitating movement disorder characterized by choreoathetotic movements developing in one-fifth of the patients with schizophrenia. In this study we have investigated the significance of CYP3A4*1B and CYP2D6*4 polymorphisms in TD susceptibility among chronic schizophrenia patients (n=335) from north India. Tardive dyskinesia was diagnosed in ∼29% (96/335) of these patients. No significant association of either of the two SNPs with TD (CYP3A4*1B χ2=0. 308, df=1, p=0.579; CYP2D6*4 χ2=0.006, df=1, p=0.935) was observed. However a trend towards increased severity of TD in patients heterozygous for the CYP2D6*4 mutation was observed. [Copyright &y& Elsevier]

Antidepressant-induced mania (AIM) is a side effect of antidepressant treatment that is characterized by mania or hypomania after the start of medication. It is likely polygenic, but its genetic component remains largely unexplored. We aim to conduct the first genome-wide association study of AIM in 814 bipolar disorder patients of European ancestry. We report no significant findings from our single-marker or gene-based analyses. Our polygenic risk score analyses also did not yield significant results with bipolar disorder, antidepressant response, or lithium response. Our suggestive findings on the hypothalamic-pituitary-adrenal axis and the opioid system in AIM require independent replications. • We report the first genome-wide association study of antidepressant-induced mania. • We report no significant single-markers or genes in 814 bipolar disorder patients. • Suggestive findings will need replications in larger well-characterized samples. [ABSTRACT FROM AUTHOR]

Individuals carrying genetic variants that result in non-extensive CYP2D6 and CYP2C19 enzyme activity seem to be more prone to non-response and side-effects of psychotropic medications. Therefore, tailoring prescriptions using genetic information may improve patient outcomes. This study examined treatment outcome in psychiatric care after CYP2D6 and CYP2C19 genetic information was provided to patients and physicians. CYP2D6 and CYP2C19 genotyping, assessment of side effects and medical histories were obtained from 80 subjects who were prescribed either antidepressant or antipsychotic medications. Our measure of outcome was mainly physicians' opinions however UKU side effects scores were also used. For CYP2D6, we calculated an activity score based on genotype and psychiatric medications. Correlation analysis was performed for CYP2D6 activity scores and UKU scores. Overall, we received supportive responses from physicians who enrolled patients in our study. Notably, while almost every fourth physician reported improvement in patient outcome, not a single physician indicated that their patient's symptoms worsened after they had used a pharmacogenetic report to guide treatment. We did not observe statistically significant differences in side effects. Overall, our results suggest improved patient outcome following pharmacogenetic testing; nonetheless, more research is required to assess the exact benefit of pharmacogenetics in clinical practice. • This study assessed treatment outcome in psychiatric practice following pharmacogenetic testing for CYP2D6 and CYP2C19. • Outcome was measured by physicians' opinions of their patients' outcome following treatment changes. • Our secondary measure of clinical outcome was based on differences in side effect scores across metabolic activity groups. • Nearly one in four psychiatrists reported some degree of clinical improvement in their patient's outcome. • Not a single physician stated that their patient's clinical condition worsened. [ABSTRACT FROM AUTHOR]

Tardive dyskinesia (TD) is a potentially irreversible and often debilitating movement disorder secondary to chronic use of dopamine receptor blocking medications. Genetic factors have been implicated in the etiology of TD. We therefore have reviewed the most promising genes associated with TD, including DRD2 , DRD3 , VMAT2 , HSPG2 , HTR2A , HTR2C , and SOD2 . In addition, we present evidence supporting a role for these genes from preclinical models of TD. The current understanding of the etiogenesis of TD is discussed in the light of the recent approvals of valbenazine and deutetrabenazine, VMAT2 inhibitors, for treating TD. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex psychiatric disorder where genetic, epigenetic, and environmental factors play a role in disease onset, course of illness, and treatment outcome. Pharmaco(epi)genetic research presents an important opportunity to improve patient care through prediction of medication side effects and response. In this narrative review, we discuss the current state of research and important progress of both genetic and epigenetic factors involved in antipsychotic response, over the past five years. The review is largely focused on the following frequently prescribed antipsychotics: olanzapine, risperidone, aripiprazole, and clozapine. Several consistent pharmacogenetic findings have emerged, in particular pharmacokinetic genes (primarily cytochrome P450 enzymes) and pharmacodynamic genes involving dopamine, serotonin, and glutamate neurotransmission. In addition to studies analysing DNA sequence variants, there are also several pharmacoepigenetic studies of antipsychotic response that have focused on the measurement of DNA methylation. Although pharmacoepigenetics is still in its infancy, consideration of both genetic and epigenetic factors contributing to antipsychotic response and side effects no doubt will be increasingly important in personalized medicine. We provide recommendations for next steps in research and clinical evaluation. [ABSTRACT FROM AUTHOR]

Pharmacogenetics seeks to improve patient drug response and decrease side effects by personalizing prescriptions using genetic information. Since 2012, by one estimate, the number of patients who have had pharmacogenetic testing has doubled and this number is expected to double again by 2015. Given the increasing evidence for genetic influences on treatment response, we deemed it important to study physicians' opinions of pharmacogenetic testing. Surveys were completed by 168 Canadian physicians who had ordered at least one pharmacogenetic test (in particular for CYP2D6 or CYP2C19) for the prescription of psychiatric medication. Our results indicated that 80% of respondents believe genetic testing would become common standard in psychiatric drug treatment and 76% of respondents reported satisfactory or higher than satisfactory understanding of the pharmacogenetic report provided. Significantly more male physicians believed they had a higher understanding of the pharmacogenetic report compared to female physicians. To our knowledge, this is the only study that has assessed physicians' opinions of pharmacogenetic testing for psychotropic medication after they had received a pharmacogenetic report. Our results demonstrate a positive opinion of physicians on pharmacogenetics and indicate great potential for future clinical application. [ABSTRACT FROM AUTHOR]

Abstract: Background: Brain-derived neurotrophic factor (BDNF) has extensive effects on the nervous system including cell survival, differentiation, neuronal growth and maintenance, as well as cell death. Moreover, it promotes synaptic plasticity and interacts with dopaminergic and serotonergic neurons, suggesting an important role on the alteration of brain function with antipsychotic medications and induced weight gain in schizophrenia patients. The differential effects of BDNF gene variants could lead to changes in brain circuitry that would in turn cause variable response to antipsychotic medication. Therefore, we hypothesized that genetic variation in this candidate gene helps in explaining the inter-individual variation observed in antipsychotic drug treatment with respect to response and induced weight gain. Method: We examined four single-nucleotide polymorphisms across the BDNF gene, including Val66Met (rs6265). Prospective BPRS change scores and weight change after six weeks were obtained from a total of 257 schizophrenia patients of European ancestry. Results: The markers rs11030104 and Val66Met were associated with antipsychotic response (P =0.04; 0.007, respectively). On the other hand, marker rs1519480 was associated with weight gain (P =0.04). Moreover, a two-marker haplotype across rs6265 and rs1519480 was associated with weight change (P =0.001). Results with Val66Met in response, and results with rs6265-rs1519480 haplotypes remained significant at the modified Bonferroni corrected alpha of 0.017. Conclusion: BDNF genetic variants might play an important role in predicting antipsychotic response and antipsychotic-induced weight gain. However, replication in larger and independent samples is required. [Copyright &y& Elsevier]