Antipsychotic Drug Response Research Articles

Genome-wide methylation analysis of treatment resistant schizophrenia

Various studies have investigated the relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug response. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and treatment resistance schizophrenia. The primary aim of this pilot study is to investigate the association between treatment resistance status and genome-wide DNA methylation in schizophrenia patients. Treatment resistance status was determined for 109 patients with schizophrenia. Treatment resistance was the primary outcome variable in a model, including methylation status of white blood cells using the Illumina 450 array. The genome-wide DNA methylation levels in 109 Schizophrenia subjects did not show that DNA methylation sties were associated with resistance status. From our study, it is evident the importance of continuing to investigate the relationship between DNA methylation and antipsychotic response to personalize treatment in schizophrenia. Future studies require larger prescription databases to build on the results presented in this pilot study.

Association between neuropeptide Y gene polymorphism and antipsychotics effect.

The pathogenesis of schizophrenia is associated with neuropeptide Y (NPY) gene polymorphism to explore the relationship between rs16141, rs16145, and rs5573 polymorphisms in the NPY gene and antipsychotics response in the Chinese population. The unrelated 228 Chinese Han patients with schizophrenia were enrolled in the present study. Genotypisation within NPY gene was performed using the KASP genotyping assays. Before treatment and on the weekends of the 2nd, 4th, and 8th weeks after treatment, the medication status of the patients was recorded and the positive and negative syndrome scale (PANSS) was used to evaluate the clinical effect. A reduction in total PANSS scores ≥50% were classified as good responders, while others were poor responders. We evaluated the association between NPY gene and antipsychotic efficacy by comparing allele and genotype distribution, correlation analysis, linkage imbalance, and five genetic models between the two groups. No significant associations were found in the rs16141, rs16145, and rs5573 of NPY and antipsychotic treatment response (all p > 0.05). There was no significant relationship between the three SNPs polymorphisms in the NPY gene and the changes of positive, negative and general psychopathology subscales scores at each stage (all p > 0.05). The distribution of genotype and allele frequencies of locus rs16141 was not statistically difference between good responders and poor responders (genotype: χ2 =4.088, p=0.043, p-correction = 0.129; allele: χ2 = 4.088, p = 0.027, p-correction = 0.081). The allele distribution of rs5573 was significantly different between groups, yet the difference was disappeared after correcting (χ2 = 4.136, p = 0.042, p-correction =0.126). The distribution frequencies of TA/TG and GG haplotypes constituted by rs16141 and rs5573 showed no statistical difference between the two groups (p > 0.05). In recessive inheritance mode, NPYrs5573 was found to be associated with antipsychotic drug response (G/G vs. A/A +A/G: p = 0.028, AIC = 197.2, BIC = 210.9). This study didn't found association between polymorphisms in the NPY gene locus (rs16141, rs16145, and rs5573) and the response to antipsychotics after Bonferroni correction. The polymorphism of NPY gene and the efficacy of antipsychotic drugs in patients with schizophrenia need further study.

Correlation between telomere length and efficacy of oral and long-acting injectable antipsychotics on severity and cognitive impairment of schizophrenia

Objective To study the correlation between telomere length (TL) and long-acting injectable (LAI) and oral atypical antipsychotic (OAA) efficacy on schizophrenia (SCZ) severity and cognitive impairment. Methods Sixty Schizophrenia patients of 18–50 years and of either sex were included in a 12-week study. Thirty patients were recruited in each group, LAI and OAA. Positive and Negative Syndrome Scale (PANSS) and National Institute of Mental Health and Neuro-Sciences (NIMHANS) neuropsychological battery tests were evaluated at baseline and 12 weeks. TL was estimated at baseline. Results Both groups showed a significant improvement in PANSS and NIMHANS battery test scores after treatment (p < 0.001) within the group, though not between the groups. Mean TL at baseline was 407.58 ± 143.93 and 443.40 ± 178.46 in LAI and OAA groups respectively. A significant negative correlation (r = −0.28, p = 0.03) of TL was seen with the mean change in negative PANSS score after treatment. Conclusions LAI antipsychotics are similar to OAA in decreasing the disorder severity and improving the cognitive impairment in schizophrenia. Also, patients who have shorter TL show greater improvement in the negative PANSS score. Hence, TL holds the potential of predicting antipsychotic drug response in schizophrenia patients. KEY POINTS Long-acting injectable antipsychotic was comparable to oral atypical antipsychotics in bringing out improvement in disorder severity, cognitive functions over 12 weeks. Shorter telomere length has been found to be associated with a greater response in negative symptoms of schizophrenia.

The Pharmacodynamics of Antipsychotic Drugs in Women and Men.

Background: Animal and human experiments have confirmed sex differences in the expression of hepatic enzymes that metabolize antipsychotic drugs and that may, in this way, be partly responsible for the clinical sex/gender differences observed in the efficacy and tolerability of antipsychotic treatment.Aim: The aim of this mini review is to synthesize the literature on the pharmacodynamics of male/female differential response to antipsychotic drugs.Method: Relevant search terms were used to search for pre-clinical and human trials and analysis of antipsychotic differential drug response and occurrence/severity of adverse effects in women and men.Results: The search found that sex influences drug response via the amount of a given drug that enters the brain and the number of neurotransmitter receptors to which it can bind. Consequently, sex partly determines the efficacy of a specific drug and its liability to induce unwanted effects. There are other factors that can overshadow or enhance the dimorphic effect of sex, for instance, the host's age, hormonal status, diet and life style as well as the molecular structure of the drug and its dose, and the method of its administration. Most of all, the host's individual genetics affects each step of a drug's pharmacodynamics.Conclusion: On average, women's psychotic symptoms respond to antipsychotic drugs at doses lower than men's. This means that many women may be de facto overdosed and, thus, experience unnecessary adverse effects. That being said, factors such as genetics and age probably determine drug response and tolerability to a greater degree than do biological sex or gender social roles.

Schizophrenia Psychosis in Women

A first step towards personalized medicine is to consider whether, for some disorders, the safest and most effective treatment of women needs to differ from standard guideline recommendations developed on the basis of clinical trials conducted, for the most part, in men. A second step is to consider how women’s reproductive stages—pre-pubertal years, menstrual phases, pregnancy trimesters, lactation and postpartum periods, menopausal and postmenopausal/aging status—affect the optimal choice of treatment. This review focuses on these two steps in the treatment of psychosis, specifically schizophrenia. It discusses genetics, precursors and symptoms of schizophrenia, reproductive and associated ethical issues, antipsychotic drug response and adverse effects, substance abuse, victimization and perpetration of violence, and issues of immigration and of co-morbidity. The conclusions, while often based on clinical experience and theoretical considerations rather than strictly on the evidence of randomized controlled trials, are that clinical recommendations need to consider clinical and role differences that exist between men and women and make appropriate correction for age and reproductive status.

M199. COPY NUMBER VARIANCE (CNV) ANALYSIS TO DETERMINE OPTIMAL ANTIPSYCHOTIC DOSAGE IN SCHIZOPHRENIA: A PILOT STUDY

BackgroundThe relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug response has been thoroughly investigated and analyzed. However, from a pharmacokinetic standpoint, few studies have explored the relationship between Copy number variants (CNV) and antipsychotic dosage. The aim of the present study is to test the association between antipsychotic dosage and CNV in schizophrenia (SCZ) patients.MethodsThe current dosage of antipsychotic medications was collected from 263 schizophrenia patients. The dosage was standardized using three different methods: chlorpromazine equivalent(CPZe), defined daily dose (DDD), and percentage of maximum dose (PM %). The patients were then genotyped using the Illumina HumanOmni2.5–8 BeadChip Kit.ResultsThe CNV analysis did not show that CNVs are associated with dosage variation for CPZe, PM %, and DDD.DiscussionIn this pilot sample, we investigated for the first time CNVs and standardized antipsychotic dosage. The relationship between CNV and optimal antipsychotic dosage has far reaching clinical implications. Further analysis is required that utilitze large prescription databases to build on the results presented in this pilot study.

The ANKS1B gene and its associated phenotypes: focus on CNS drug response.

The ANKS1Bgene was a top finding in genome-wide association studies (GWAS)of antipsychotic drug response. Subsequent GWAS findings for ANKS1B include cognitive ability, educational attainment, body mass index, response to corticosteroids and drug dependence. We review current human association evidence for ANKS1B, in addition to functional studies that include two published mouse knockouts. The several GWAS findings in humans indicate that phenotypically relevant variation is segregating at the ANKS1B locus. ANKS1B shows strong plausibility for involvement in CNS drug response because it encodes a postsynaptic effector protein that mediates long-term changes to neuronal biology. Forthcoming data from large biobanks should further delineate the role of ANKS1B in CNS drug response.

T175. The Effects of Lorazepam on Resting-State Functional Connectivity

Benzodiazepines, such as lorazepam, are commonly used to treat anxiety. The pharmacological mechanism of action of benzodiazepines is well understood; however, it remains unclear which neural networks and systems are involved during resting-state functional connectivity. The objective of this study is to investigate the effects of lorazepam administration (12 hours or less prior to rsMRI) compared to non-lorazepam during the resting state in patients with psychosis. We focused our analyses on the effects of lorazepam on corticostriatal connectivity, as we have previously demonstrated that a specific pattern of striatal connectivity, the striatal connectivity index (SCI; Sarpal et al., 2016), was related to antipsychotic drug response.

M81 - SCHIZOPHRENIA POLYGENIC RISK SCORE PREDICTS ANTIPSYCHOTIC TREATMENT RESPONSE IN PATIENTS WITH FIRST EPISODE PSYCHOSIS

Background The genetic basis of antipsychotic drug efficacy is likely polygenic in nature. Genetic risks of schizophrenia may also be related to antipsychotic drug response. The Psychiatric Genomics Consortium (PGC) Genome-Wide Association Study (GWAS) provided evidence of association with schizophrenia risk for many Single Nucleotide Polymorphism (SNP) across the genome. We examined whether Polygenic Risk Scores (PRS) based on the PGC GWAS are predictive of antipsychotic efficacy in four cohorts of patients with first episode psychosis (total n=510): 1) Zucker Hillside Hospital First Episode schizophrenia trial (ZHH-FE), 2) European First Episode Schizophrenia Trial (EUFEST), 3) Spanish First Episode Psychosis study (SFEP), and 4) the clinical trial as part of the Center for Intervention Development and Applied Research at ZHH (CIDAR). Methods The discovery cohort was the ZHH-FE with 77 patients (mixed ethnicity) randomized to risperidone or olanzapine. Three replication cohorts were: 1) EUFEST with 141 patients (all Caucasian) randomized to five antipsychotics; 2) SFEP with 192 patients (all Caucasian) on various antipsychotics; and 3) CIDAR with 100 patients (mixed ethnicity) randomized to risperidone or aripiprazole. Genotyping was performed using the Illumina Omni-1Quad (EUFEST and ZHH-FE) or Illumina Infinium HumanOmniExpressExome platform (CIDAR and SFEP). SNP imputation was conducted with IMPUTE2 against the full 1000 Genomes v3 reference panel. PRS was computed based on the results of the PGC GWAS using PRSice software for the discovery cohort with thresholds at PT Results Hierarchical linear regression was performed on the 3-month symptom score with the PRS as the predictor while controlling for age, sex, and baseline symptom score. Genomic principal component scores were also covaried to control for population stratification for ZHH-FE and CIDAR. In the ZHH-FE cohort, higher PRS at the thresholds of PT Discussion These findings suggest that polygenic risk scores for schizophrenia may also be related to antipsychotic drug response. Patients with higher polygenic risk scores tended to have less improvement with antipsychotic drug treatment. Further analysis is needed to elucidate a more refined genomic profile for antipsychotic drug response.

Effect of Damaging Rare Mutations in Synapse-Related Gene Sets on Response to Short-term Antipsychotic Medication in Chinese Patients With Schizophrenia

The underlying mechanism for individual differences in patient response to antipsychotic medication remains unknown. To discover genes and gene sets harboring rare variants associated with short-term antipsychotic medication efficacy. In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, and December 31, 2011, 3023 patients recruited in China of Chinese Han descent with schizophrenia with total Positive and Negative Syndrome Scale (PANSS) score ≥ 60 received a 6-week treatment of antipsychotic medications randomly chosen from 5 atypical and 2 typical antipsychotic medications. Whole-exome sequencing (WES) was performed in 316 participants (grouped into those with the best response [n=156] and those who had no response [n=160] to the antipsychotic medication prescribed), according to the total PANSS score reduction rate after 6 weeks of treatment. Validation was performed using targeted sequencing in an independent sample of 1920 patients. Data analyses was performed between March 15, 2016, and March 1, 2017. Drug efficacy at week 6 was assessed according to the change in PANSS scores from baseline. Extremely good and extremely poor responders were selected for an initial WES association study, from which a subset of genes showing putative association was selected for independent replication with a targeted sequencing approach. Of the 3023 patients (1549 [51.24%] female and 1474 [48.8%] male; mean [SD] age, 31.2 [7.9] years), 2336 (77.3%) were eligible for genetic analysis. After quality-control exclusions, 316 patients (10.5%) were included for WES and 1920 (63.5%) were included for replication. In the WES discovery stage, 2 gene sets (reduced NMDA [N-methyl-D-aspartate]-mediated synaptic currents and reduced AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]-mediated synaptic currents) were found to be enriched with rare damaging variants in the nonresponder group, suggesting the involvement of these gene sets in antipsychotic medication efficacy. Reduced NMDA-mediated synaptic currents gene set was further replicated in an independent sample using targeting sequencing. No statistically significant differences in antipsychotic drug response were found among the patients who received different antipsychotic drugs. Genetic variation in glutamatergic or NMDA neurotransmission is implicated in short-term antipsychotic medication efficacy; WES may have utility in the study of rare genetic variation in pharmacogenetics. Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934.

Recent Progress in Pharmacogenomics of Antipsychotic Drug Response.

Pharmacogenomics (PGx) of antipsychotic drug response is an active area of research in the past few years. We reviewed recent PGx studies with an emphasis of development of new methodologies and new research directions. Traditional candidate gene approach continues to generate evidence to support the associations of antipsychotic response with genes coding for drug targets such as DRD2. Genome-wide association studies have found a few novel genes that may be associated with drug efficacy and adverse events. Recent application of polygenic risk score makes it possible to combine many genetic variants to predict clinical response. Finally, epigenetic research including DNA methylation is emerging and promises new findings that potentially can be applied in clinical practice. New methodologies may advance PGx closer to clinical application. Multiple genes and epigenomic markers can be used in prediction of clinical phenotypes.

Pharmacogenomics of Antipsychotic Drugs

Pharmacogenomic research of antipsychotic drug (APD) response continued to produce interesting findings in the past few years. Several genetic markers have been shown to be reliably associated with APD responses including efficacy and drug-induced adverse reactions. For APD treatment response, DRD2 has been shown to predict symptom reduction and APD efficacy. For APD-induced weight gain, a recent meta-analysis supports the associations with HTR2C and MC4R variants, as well as several other genetic markers. For clozapine-induced agranulocytosis, an independent sample has confirmed the association with HLA-DQB1. In addition, a multi-marker combination approach has been studied to increase the predictive power for APD response. However, these markers’ sensitivity and specificity are not high enough to be used in routine clinical practice. They may have some value in certain situations such as treatment refractory cases, and they need to be used in conjunction with other clinical predictors. Due to the polygenetic nature of drug response, the new polygenetic risk score method appears promising in combining many genetic markers in predicting clinical response. The current review focused on pharmacodynamic genes (i.e., drug target), and did not touch upon pharmacokinetic genes such as cytochrome P450 genes (e.g., CYP2D6), which have been shown to influence APD response especially adverse reactions. Future research should use a multi-marker approach to combine both pharmacodynamic and pharmacokinetic genes, as well as known clinical factors, to increase the predictive power for APD clinical response.

Effect of Disrupted-in-Schizophrenia 1 gene on treatment response in patients with a first episode of psychosis

IntroductionThere is substantial evidence suggesting that individual variability in antipsychotic treatment response could be genetically determined. Disrupted-in-Schizophrenia 1 (DISC1) gene has been previously associated to the illness and to treatment response in a sample of patients suffering from psychosis. However, there is a lack of studies on the effect of DISC1 on treatment response in samples of first episode psychosis.ObjectivesThe aim of this study was to explore the relation between variations in DISC1 gene and treatment response to antipsychotics in a sample of drug-naïve patients with a first episode of psychosis.MethodsTwo hundred and twenty Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys), rs6675281 (Leu607Phe) and rs1000731. Early (6 weeks) response to antipsychotic treatment was assessed with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. Other clinical and socio-demographic variables were recorded to eliminate potential confounding effects.ResultsWe found a significant association between rs1000731 and treatment response. Thus, those patients homozygous for the G allele of rs1000731 were more frequently non-responders, measured with SANS, after 6 weeks of treatment, than those carrying the A allele (X2 = 4.019; P = 0.032). Moreover, when analysing the clinical improvement longitudinally, we observed that those patients carrying the A allele for the rs1000731 presented a greater improvement in positive symptoms dimension (F = 8.905; P = 0.003).ConclusionsOur results suggest a minor contribution to antipsychotic drug response of genetic alterations in the DISC1 gene.Disclosure of interestThe authors have not supplied their declaration of competing interest.

BDNF Val66Met and clinical response to antipsychotic drugs: A systematic review and meta-analysis

BackgroundThe polymorphic brain-derived neurotrophic factor (BDNF) gene has been postulated to be involved in inter-individual variability response to antipsychotic drugs. PurposeTo perform a qualitative and quantitative synthesis of studies evaluating the influence of BDNF genetic variation on clinical response to antipsychotics. MethodsThe review protocol was published in the PROSPERO database (Reg. no CRD42015024614). A comprehensive search was performed through PubMed, Web of Knowledge and Cochrane databases up to July 2015. The methodological quality of identified studies was assessed using the MINORS criteria. Publication bias was estimated and potential sources of heterogeneity were investigated via meta-regression, subgroup and sensitivity analyses. ResultsNine studies including a total of 2461 antipsychotic-treated patients fulfilled inclusion criteria for meta-analysis of BDNF Val66Met. Using the random-effects model, the pooled results showed no significant association with antipsychotic response for the dominant (Met carriers vs Val/Val, OR: 0.93, 95% CI: 0.72–1.19, P=0.55), codominant (Met/Met vs Val/Val, OR: 0.82, 95% CI: 0.59–1.15, P=0.25), recessive (Met/Met vs Val carriers, OR: 0.81, 95% CI 0.60–1.10, P=0.18) or the allelic contrast (Met vs Val, OR: 0.92, 95% CI 0.76–1.10, P=0.34). Visual inspection of funnel plots and further evaluation with Egger's test did not suggest evidence of publication bias. Despite lack of significant heterogeneity in most comparisons, no evidence of association also emerged in the subgroup and sensitivity analyses conducted. ConclusionThe present meta-analysis excludes a clinically relevant effect of BDNF Val66Met on antipsychotic drug response per se. Nevertheless, further investigation is still needed to clarify in well-designed, large sample-based studies, the impact of BDNF haplotypes containing the Val66Met polymorphism.

Pharmacogenetics of antipsychotic drug response

Pharmacogenetics of antipsychotic drug response

Identification of Candidate Single-Nucleotide Polymorphisms in NRXN1 Related to Antipsychotic Treatment Response in Patients with Schizophrenia

Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs.

Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia

ObjectiveAntipsychotic drugs are the mainstay of treatment for schizophrenia. However, a substantial proportion of patients are poorly responsive or resistant to first-line treatments, and clozapine treatment is often indicated. Therefore, we and others have used clozapine treatment as a proxy phenotype for antipsychotic treatment resistance in pharmacogenetic studies. In the present study, we utilized this phenotype to test previously-identified candidate genes for antipsychotic treatment response. MethodWe assessed 89 Caucasian schizophrenia patients clinically assigned to clozapine treatment versus 190 Caucasian patients that were not selected for clozapine treatment. We conducted gene-based association tests on a set of 74 relevant candidate genes nominated in the CATIE pharmacogenetic study (Need et al., 2009), using the GATES procedure (Li et al., 2011). ResultsAfter correcting for multiple testing in the gene-based association test, the gene for brain derived neurotrophic factor (BDNF) was significantly associated with treatment resistance. The top single nucleotide polymorphisms (SNPs) in BDNF included rs11030104 (OR=2.57), rs10501087 (OR=2.19) and rs6265 (Val66Met) (OR=2.08). These SNPs appear to be in high linkage disequilibrium with each other. ConclusionBDNF appears to have a strong association with antipsychotic treatment resistance. Future studies are needed to replicate this finding and further elucidate the biological pathways underlying the association between BDNF and antipsychotic drug response.

Clinical response to antipsychotic drug treatment: Association study of polymorphisms in six candidate genes

Pharmacogenetic studies have demonstrated significant associations between several candidate genes (DRD2, DRD3, 5HTR2A and 5HTR2C, COMT and MTHFR) and antipsychotic drug response. The present study investigates the effect of nine polymorphisms in these genes for an association with antipsychotic treatment response. 329 Caucasian patients with a non-affective psychotic disorder using antipsychotics were included. All patients participated in the longitudinal GROUP-study in The Netherlands. We genotyped 9 SNPs in 6 candidate genes (DRD2: TaqI_A, -141C; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser; COMT: Val158Met; MTHFR: 677-C/T) using standard protocols. Polymorphisms were based on previous studies showing associations with positive symptoms treatment response. The Clinical Global Impression - Improvement (CGI-I) scale was used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used for association analyses. Ninety percent of the patients used second generation antipsychotics, with olanzapine (28%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value 0.034) and 677-C/T of MTHFR (P value 0.019) were tested statistically significant. Gly-carriers and T-carriers, respectively, showed more clinical improvement on the CGI-I. The other polymorphisms did not show a statistically significant association (P values>0.10). In conclusion, we replicated two out of nine of the previously reported associations between polymorphisms and treatment response. The direction and magnitude of the associations presented here in DRD3 (Ser9Gly) and MTHFR (677-C/T) are in line with previous association studies in Caucasian patients. These polymorphisms may be of value for predicting clinical response.

Evidence for a SULT4A1 Haplotype Correlating with Baseline Psychopathology and Atypical Antipsychotic Response

This study evaluated the impact of SULT4A1 gene variation on psychopathology and antipsychotic drug response in Caucasian subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and a replication sample. SULT4A1 haplotypes were determined using SNP data. The relationship to baseline psychopathology was evaluated using linear regression of Positive and Negative Syndrome Scale (PANSS) total score. Drug response was evaluated using Mixed Model Repeat Measures (MMRM) for change in PANSS. For the CATIE sample, patients carrying a haplotype designated SULT4A1-1(+) displayed higher baseline PANSS (p = 0.03) and, when treated with olanzapine, demonstrated a significant interaction with time (p = 0.009) in the MMRM. SULT4A1-1(+) patients treated with olanzapine displayed improved response compared with SULT4A1-1(-) patients treated with olanzapine (p = 0.008) or to SULT4A1-1(+) patients treated with risperidone (p = 0.006). In the replication sample, SULT4A1-1(+) patients treated with olanzapine demonstrated greater improvement than SULT4A1-1(-) patients treated with olanzapine (p = 0.05) or than SULT4A1-1(+) patients treated with risperidone (p = 0.05). If validated, determination of SULT4A1-1 haplotype status might be useful for identifying patients who show an enhanced response to long-term olanzapine treatment. Original submitted 6 October 2010; Revision submitted 9 December 2010.

Magnetic Resonance Imaging Predictors of Treatment Response in First-Episode Schizophrenia

Identifying neurobiological predictors of response to antipsychotics in patients with schizophrenia is a critical goal of translational psychiatry. Few studies, however, have investigated the relationship between indices of brain structure and treatment response in the context of a controlled clinical trial. In this study, we sought to identify magnetic resonance (MR) imaging measures of the brain that predict treatment response in patients experiencing a first-episode of schizophrenia. Structural MR imaging scans were acquired in 39 patients experiencing a first-episode of schizophrenia with minimal or no prior exposure to antipsychotics participating in a double-blind 16-week clinical trial comparing the efficacy of risperidone vs olanzapine. Twenty-five patients were classified as responders by meeting operationally defined treatment response criteria on 2 consecutive study visits. Fourteen patients never responded to antipsychotic medication at any point during the clinical trial. MR imaging scans were also acquired in 45 age- and sex-matched healthy volunteers. Cortical pattern matching methods were used to compare cortical thickness and asymmetry measures among groups. Statistical mapping results, confirmed by permutation testing, indicated that responders had greater cortical thickness in occipital regions and greater frontal cortical asymmetry compared with nonresponders. Moreover, among responders, greater thickness in temporal regions was associated with less time to respond. Our findings are consistent with the hypothesis that plasticity and cortical thickness may be more preserved in responders and that MR imaging may assist in the prediction of antipsychotic drug response in patients experiencing a first-episode of schizophrenia.