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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.

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.

Objective Childhood onset aggression can cause major suffering to affected families and is associated with many negative outcomes in the child's later life, including poor academic performance, adolescent delinquency, drug abuse, depression and antisocial personality disorder. Currently available prevention and intervention strategies have limited efficacy, but a better understanding of underlying genetic and neurobiological factors can lead to more effective prevention and treatment strategies, through genetic screening programs and novel therapies. Method This study examined the RS1 (n = 299 aggression, n = 192 controls) and RS3 (n = 291 aggression, n = 189 controls) microsatellite repeats within the promoter region of the vasopressin receptor 1A gene (AVPR1A) and their association with extreme childhood aggression, as assessed by the Child Behavior Checklist (CBCL), as well as the Teacher Report Form (TRF) and Youth Self Report (YSR). Binary logistic regression was used to model the relationship between microsatellite length and childhood aggression. Age and sex were used as covariates. Results Logistic regression revealed a nominally significant association between one specific RS3 repeat and non-aggressive status. No association was found for any of the RS1 repeats. In a separate model, grouping repeats into short and long, carriers of long RS3 repeats were nominally significantly associated with non-aggressive status. Conclusions These findings suggest a role for AVPR1A and its RS3 microsatellite in extreme childhood aggression and could lead to a better understanding of the biological pathways of aggressive behavior. However, independent replication and further research into the functionality of studied genetic variants is required.

Purposes/background Antidepressants (ADs) play a valuable role in treating the depressive episodes of bipolar disorder. However, 14% of these individuals taking ADs experience AD-associated mania (AAM) within a few weeks of starting treatment. Numerous studies have suggested potential clinical and genetic risk factors. We aimed to conduct a comprehensive systematic review and meta-analysis that integrates the past literature with the recent studies and identifies important predictors for AAM. Methods/procedures The review was limited to experimentally designed studies that contain the relevant search terms in PubMed and PsychInfo. After removing studies that were in discordance with our criteria, the review included 24 reports examining clinical risk factors and 10 investigating genetic risk factors. Our meta-analysis was conducted on 5 clinical risk factors, each of which had at least 4 articles with extractable data. Findings/results The only clinical factors in the literature that have been shown to be more indicative of AAM risk are AD monotherapy and tricyclic ADs. Among genetic factors, the serotonin transporter gene polymorphism may play a minor role in AAM. Our meta-analysis provided support for the number of prior depressive episodes. Implications/conclusion Prevention of AAM may be served by early detection of recurrent depression episodes. Further large-scale longitudinal studies are required to determine the underpinnings of AAM.

Antidepressant medications are the most common treatment for major depression and related disorders. Pharmacogenetic studies have demonstrated that response to these medications is associated with genetic variation. While these studies have been invaluable they have yet to explain why a significant number of patients do not respond to their initial medication. The epigenetic modification known as DNA methylation has recently been studied in the context of antidepressant treatment response. As such, the purpose of this article is to review the advances made in the relatively new field of pharmaco-epigenetics of antidepressant response. We included all published articles examining DNA methylation in association with antidepressant treatment response in Major Depressive Disorder from April 2006 to June 2016 using the PubMed, Medline, PsychInfo and Web of Science databases. At the present time, although original articles are limited, epigenetic modifications of SLC6A4, BDNF, and IL11 genes are showing promising results as biomarkers for prediction of antidepressant response. However, research methods and results are heterogeneous and additional studies are required before results are generalizable. At the end of this review we provide recommendations for study design and analytic approaches.

Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-α receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.

Background Obsessive-Compulsive Disorder (OCD) has a complex genetic component and may be preceded by environmental stressors. The spindle and kinetochore associated complex subunit 2 (SKA2) gene interacts with the glucocorticoid receptor and is implicated in mediating hypothalamic–pituitary-adrenal (HPA) axis function but has yet to be examined in OCD. We hypothesized that genetic and epigenetic variation of SKA2 may be involved in OCD disease risk and symptom severity. Methods OCD patients (n = 54) were rated for disease severity using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Genotyping of SKA2 rs7208505 was performed using Taqman TM, while DNA methylation levels were quantified using bisulfite pyrosequencing. OCD genotype frequencies were compared to the general population (n = 379, 1000 Genomes Project Consortium) using Pearson’s chi-square test. The relationships among the rs7208505 variant, methylation density, and symptom severity were modeled using linear regression. Results Genotype distributions significantly differed between OCD patients and the 1000 Genomes sample (χ2 (2, n = 433) = 8.66, p = 0.013). The odds of having OCD was 1.66 times more likely for individuals carrying a C allele (OR 1.66 [95% CI: 1.09–2.55]; p = 0 0.02). Specifically, the odds of having the CC genotype was 2.58 times more likely for OCD patients (OR 2.58 [95% CI: 1.23–5.23]; p = 0.007). When examining symptom severity there was no effect of genotype (p > 0.05). Finally, epigenetic variation was not significantly associated with symptom severity in our statistical models. Conclusions These results provide preliminary evidence that SKA2 genetic variation may be associated with OCD disease status, while no association was detected when examining symptom severity, or methylation density at this locus. The rs7208505 minor allele occurs more frequently in OCD patients than in the general population, suggesting that there is merit in pursing further studies of this marker in larger sample sizes.

Background The current process used to prescribe antidepressant medication is markedly inefficient, as more than 50% of treated patients fail to reach remission. Antidepressant treatment success has been associated with genetic variation, but studies are not well replicated and epigenetic mechanisms remain under investigated. DNA methylation may provide more information regarding antidepressant response and guide physicians in choosing the most effective medication for each patient. We investigated the influence of SLC6A4 methylation and 5-HTTLPR genotypes on antidepressant response in our sample. Methods A subset of depression patients with complete clinical data (European Caucasian, n=166), were selected from our discovery sample (IMPACT; N=8,000). Saliva samples were collected at enrollment and genetic testing was done of cytochrome P450 liver enzyme, 5HTTLPR and 5HT2A variants to guide clinical choice and dosage of psychotropic medications. As such, a significant component of our sample includes treatment refractory, as well as medication intolerant patients. DNA was bisulfite converted and methylation profiles were interrogated using the Infinium HumanMethylation450 Beadchip array. Nine CpG probes located across the SLC6A4 promoter region were selected, based on previous studies, to quantify methylation levels. Change in Beck Depression Inventory II (BDI-II) score was used to measure antidepressant response over eight weeks. The relationship among genotype, methylation levels, and antidepressant response was analysed using linear regression modeling. Results Increased methylation in the promoter region of the SLC6A4 gene was nominally associated with impaired response to antidepressants in our sample. The effect was driven by methylation site cg05016953, located in exon 1 A. Increased methylation level as measured by CpG cg05016953 was associated with less improvement in BDI-II score over eight weeks of antidepressant treatment (F(3,163)=6.14, puncorr=0.012). 5-HTTLPR genotype was not associated with SLC6A4 DNA methylation or antidepressant treatment response. Discussion An increase in SLC6A4 DNA methylation at cg05016953 may be associated impaired response to antidepressant medications in our sample. The SLC6A4 transcriptional control region contains a CpG island, previously shown to functionally influence mRNA levels depending on 5-HTTLPR genotypes. Typically, hypermethylation in promoter regions is associated with decreased gene expression. Theoretically, hypermethylation of the 5-HTT promoter would reduce the number of serotonin transporters, and reduce serotonin re-uptake, which in simple terms should improve response to SSRI treatment. Further pharmaco-epigenetic studies are required to elucidate the effect of DNA methylation changes on antidepressant response.

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.

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 study's 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. C.C.Z. is supported by the Brain and Behavior Research Foundation, American Foundation for Suicide Prevention and Eli Lilly. D.F. is supported by the Vanier Canada Graduate Scholarship. D.J.M. has been or is supported by the Canadian Institute of Health Research (CIHR) Operating Grant: “Genetics of antipsychotic-induced metabolic syndrome,” Michael Smith New Investigator Salary Prize for Research in Schizophrenia, NARSAD Independent Investigator Award by the Brain & Behavior Research Foundation, and Early Researcher Award from Ministry of Research and Innovation of Ontario. E.H. is supported by the Canada Graduate Scholarship. H.Y.M. has grant support from Sumitomo Dainippon, Sunovion, Boehringer Ingelheim, Eli Lilly, Janssen, Reviva, Alkermes, Auspex, and FORUM. J.A.L. has received research funding from Alkermes, Biomarin, EnVivo/Forum, Genentech, and Novartis. J.L.K. is supported the CIHR grant “Strategies for gene discovery in schizophrenia: subphenotypes, deep sequencing and interaction.” J.R.B. is supported by NIH grant MH083888. A.K.T. is supported by a NARSAD Young Investigator Award. J.S. is supported by a Pfizer independent grant. P.M. receives salary from Clinica Universidad de Navarra and has received research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health, and Astrazeneca. S.G. is supported by the Ningbo Medical Technology Project Fund (No. 2004050), the Natural Science Foundation of Ningbo (No. 2009A610186, No. 2013A610249), and the Zhejiang Provincial Medical and Health Project Fund (No. 2015127713). S.G.P. has received research support from Otsuka, Lundbeck, FORUM, and Alkermes.

Background Obsessive-Compulsive Disorder (OCD) has a strong genetic component, is highly comorbid with Major Depressive Disorder (MDD), and is often triggered by environmental stress. Epigenetic modifications are thought to play a significant role in complex psychiatric disorders and may impact the relationship between genes and the environment via the hypothalamic-pituitary-adrenal (HPA) axis. The SKA2 gene interacts with the glucocorticoid receptor, is implicated in mediating HPA axis function, but has yet to be examined in OCD. We hypothesized that genetic and epigenetic variation in SKA2 may play a role in OCD disease risk and symptom severity. Methods A sample of n=64 OCD patients, divided equally by presence/absence of comorbid MDD, and age and gender matched, were selected. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score was used to measure disease severity. Genotyping for the SKA2 rs7208505 marker was performed using the Taqman allele specific assay method and DNA methylation levels were quantified using bisulfite pyrosequencing. Methylation percentage was corrected for genotype using previously established methods. Genotypes for rs7208505 were compared to controls of European ancestry (n=365; 1000 Genomes Project Consortium) using Pearson’s chi-squared test. The relationship among the rs7208505 variant, methylation corrected, symptom severity, and MDD status was modeled using linear regression. Results The SKA2 rs7208505 genotype distributions significantly differed between OCD patients and controls (χ2=8.66, p=0.013). Genotypes were associated with symptom severity (p=0.011), in that patients with the CC genotype had lower Y-BOCS scores than the CT/TT genotypes. While OCD patients diagnosed with MDD had more severe Y-BOCS scores (p=0.023), neither genetic nor epigenetic variation of rs7208505 was associated with comorbid MDD status. Methylation corrected for genotype was not significant in the regression model (p>0.05). Discussion These results provide some evidence that SKA2 genetic variation may be associated with OCD risk and symptom severity. Methylation corrected for genotype was not associated with OCD symptom severity; however, patients with TT and CT genotypes had more severe Y-BOCS scores than the CC genotype carriers. Further work will include replication in larger samples and interrogating additional genetic and epigenetic variations in SKA2.

Background A recent genome-wide association study (GWAS) of antidepressant response in obsessive-compulsive disorder (OCD) reported a genome-wide significant marker in the dispatched homolog 1 (Drosophila) gene (DISP1). This gene encodes for a protein that is important for spinal cord development. Methods In this study, we attempted to replicate this finding by investigating the DISP1 rs17162912 polymorphism in 359 OCD patients with serotonin reuptake inhibitor (SRI: fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, and clomipramine) antidepressant response data. SRI response was defined categorically as responder ("very much" and "much" improved) and non-responder ("minimal" improvment, "no change", or "worse") using the Clinical Global Impression – Improvement (CGI-I) scale and Pearson chi-squared test was performed between the genotype distribution and SRI response status. Results We did not observe significant association between the DISP1 rs17162912 (P=0. 470) with SRI response. Discussion This study did not provide support for a role of the DISP1 rs17162912 in predicting SRI response in OCD patients. Future investigation of the region of DISP1 may provide further insight into whether it contributes to SRI response in patients with OCD. Financial Relationships I (or my spouse/partner) do have potential conflicts of interest to disclose.