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Objectives: To examine the combined effect of the BDNF Val66Met (rs6265) polymorphism and BDNF DNA methylation on transcriptional regulation of the BDNF gene., Methods: DNA methylation profiles were generated for CpG sites proximal to Val66Met, within BDNF promoter I and exon V for prefrontal cortex samples from 25 schizophrenia and 25 control subjects. Val66Met genotypes and BDNF mRNA expression data were generated by transcriptome sequencing. Expression, methylation and genotype data were correlated and examined for association with schizophrenia., Results: There was 43% more of the BDNF V-VIII-IX transcript in schizophrenia samples. BDNF mRNA expression and DNA methylation of seven CpG sites were not associated with schizophrenia after accounting for age and PMI effects. BDNF mRNA expression and DNA methylation were not altered by Val66Met after accounting for age and PMI effects. DNA methylation of one CpG site had a marginally significant positive correlation with mRNA expression in schizophrenia subjects., Conclusions: Schizophrenia risk was not associated with differential BDNF mRNA expression and DNA methylation. A larger age-matched cohort with comprehensive clinical history is required to accurately identify the effects of genotype, mRNA expression and DNA methylation on schizophrenia risk.

Background: Due to the heterogeneous nature of schizophrenia, understanding the genetic risk for the disease is a complex task. Gene expression studies have proven to be more reliable than association studies as they are consistently replicated in a tissue specific manner., Methods: Using RNA-Seq we analysed gene expression in the frontal cortex of 24 individuals with schizophrenia and 25 unaffected controls., Results: We identified 1146 genes that were differentially expressed in schizophrenia, approximately 60% of which were up-regulated and 366 of 1146 (32%) also have aberrant DNA methylation (p=2.46×10 -39 ). The differentially expressed genes were significantly overrepresented in several pathways including inflammatory (p=8.7×10 -3 ) and nitric oxide pathways (p=9.2×10 -4 ). Moreover, these genes were significantly enriched for those with a druggable genome (p=0.04). We identified a number of genes that are significantly up-regulated in schizophrenia as confirmed in other gene expression studies using different brain tissues. Of the 349 genes associated with schizophrenia from the Psychiatric Genomics Consortium we identified 16 genes that are significant from our list of differentially expressed genes., Conclusions: Our results identified biological functional genes that are differentially expressed in schizophrenia. A subset of these genes are clinically proven drug targets. We also found a strong pattern of differentially expressed immune response genes that may reflect an underlying defect in schizophrenia., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Background: Schizophrenia is a clinically heterogeneous disorder and may be explained by its complex genetic architecture. Many schizophrenia susceptibility genes were identified but the picture remains unclear due to inconsistent or contradictory genetic association studies. This confusion may, in part, be because symptoms result from the combined interaction of many genes and these interacting genes are associated with specific sub-phenotypes of schizophrenia rather than schizophrenia as a whole. This study investigates the relationship between schizophrenia susceptibility genes and schizophrenia sub-phenotypes by identifying multiple gene variant interactions., Materials and Methods: Fifty SNPs from 21 genes were genotyped in 235 Australian participants with schizophrenia screened for various phenotypes. Schizophrenia participants were grouped into relevant phenotype clusters using cluster analysis and normalized phenotype cluster scores were calculated for each patient. The relationship between genotypes and normalized phenotype cluster scores were analyzed by linear regression analysis., Results: Three phenotype clusters were identified. There was some overlap in symptoms between phenotype clusters, particularly for depression. However, cluster 1 appears to be characterized by speech disorder and affective behavior symptoms, cluster 2 has predominantly hallucination symptoms and cluster 3 has mainly delusion symptoms. Interaction of five SNPs was found to have an effect on cluster 1 symptoms; ten SNPs on cluster 2 symptoms; and eight SNPs on cluster 3 symptoms., Conclusion: The interaction of specific susceptibility genes is likely to lead to specific clinical sub-phenotypes of schizophrenia. Larger patient cohorts with more extensive clinical data will improve the detection of gene interactions and the resultant schizophrenia clinical phenotypes., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Objective: Type 2 diabetes is commonly found in schizophrenia and is an important contributor to mortality and morbidity in this condition. Dopamine has been implicated in the aetiology of both diabetes and schizophrenia. It is possible that both disorders share a common genetic susceptibility., Methods: In a cross-sectional study, we examined 2 dopamine D2 receptor (DRD2) single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia (C939 T, rs6275 and C957 T, rs6277) along with fasting blood glucose and body mass index (BMI) in 207 antipsychotic-treated patients with schizophrenia. All participants met DSM-IV criteria for schizophrenia, and those with other psychiatric disorders were excluded. Analysis of covariance was used to compare fasting glucose results by DRD2 genotypes, after controlling for known confounds. For significant associations, follow-up Bonferroni post hoc tests examined differences in fasting glucose levels between genotypes. Specific comparisons were also made using analysis of variance and chi-square (Fisher's exact test)., Results: The 2 DRD2 risk genotypes were associated with significant increases in blood glucose, after controlling for BMI, age, sex, dosage and type of antipsychotic medication, number of hospitalisations, and negative symptoms (rs6275, F(2, 182) = 5.901, P = 0.003; rs6277 SNP, F(2, 178) = 3.483, P = 0.033)., Conclusions: These findings support the involvement of DRD2 not only in schizophrenia but also in elevated levels of blood glucose commonly found in antipsychotic-treated patients with schizophrenia. Our data support the notion that diabetes may not merely be a comorbid condition but could be fundamentally associated with the pathogenesis of schizophrenia itself., (© The Author(s) 2016.)

Background: The nitric oxide synthase 1 adaptor protein gene (NOS1AP) has previously been recognised as a schizophrenia susceptibility gene due to its role in glutamate neurotransmission. The gene is believed to inhibit nitric oxide (NO) production activated by the N-methyl-d-aspartate (NMDA) receptor and reduced NO levels have been observed in schizophrenia patients. However, association studies investigating NOS1AP and schizophrenia have produced inconsistent results, most likely because schizophrenia is a clinically heterogeneous disorder. This study aims to investigate the association between NOS1AP variants and defined depression phenotypes of schizophrenia., Methods: Nine NOS1AP SNPs, rs1415259, rs1415263, rs1858232, rs386231, rs4531275, rs4656355, rs4657178, rs6683968 and rs6704393 were genotyped in 235 schizophrenia subjects screened for various phenotypes of depression., Result: One NOS1AP SNP (rs1858232) was associated with the broad diagnosis of schizophrenia and eight SNPs were associated with depression related phenotypes within schizophrenia. The rs1415259 SNP showed strong association with sleep dysregulation phenotypes of depression., Conclusion: Results suggest that NOS1AP variants are associated with various forms of depression in schizophrenia and are more prevalent in males., Limitation: Schizophrenia is a clinically heterogeneous disease that can vary greatly between different ethnic and geographic populations so our observations should be viewed with caution until they are independently replicated, particularly in larger patient cohorts., (Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.)

Aims: The functional BDNF single nucleotide polymorphism (SNP) rs6265 has been associated with many disorders including schizophrenia and alcohol dependence. However, studies have been inconsistent, reporting both positive and negative associations. Comorbid alcohol dependence has a high prevalence in schizophrenia so we investigated the role of rs6265 in alcohol dependence in Australian populations of schizophrenia and alcohol-dependent patients., Methods: Two BDNF SNPs rs6265 and a nearby SNP rs7103411 were genotyped in a total of 848 individuals. These included a schizophrenia group (n = 157) and a second schizophrenia replication group (n = 235), an alcohol-dependent group (n = 231) that had no schizophrenia diagnosis and a group of healthy controls (n = 225)., Results: Allelic association between rs7103411 and comorbid alcohol dependence was identified (P = 0.044) in the primary schizophrenia sample. In the replication study, we were able to detect allelic associations between both BDNF SNPs and comorbid alcohol dependence (rs6265, P = 0.006; rs7103411, P = 0.014). Moreover, we detected association between both SNPs and risk-taking behaviour after drinking (rs6265, P = 0.005; rs7103411, P = 0.009) and we detected strong association between both SNPs and alcohol dependence in males (rs6265, P = 0.009; rs7103411, P = 0.013) while females showed association with multiple behavioural measures reflecting repetitive alcohol consumption. Haplotype analysis revealed the rs6265-rs7103411 A/C haplotype is associated with comorbid alcohol dependence (P = 0.002). When these SNPs were tested in the non-schizophrenia alcohol-dependent group we were unable to detect association., Conclusion: We conclude that these BDNF SNPs play a role in development of comorbid alcohol dependence in schizophrenia while our data do not indicate that they play a role in alcohol-dependent patients who do not have schizophrenia., (© The Author 2014. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain, which is known to be important in the etiology of schizophrenia. It is, therefore, not surprising that most antipsychotic medication acts on DRD2. DRD2 is widely expressed in the brain; levels are reduced in the brains of patients with schizophrenia, and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility., Methods: To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single-nucleotide polymorphisms (SNPs) in DRD2 by using a multiplex mass spectrometry method. SNPs were chosen by using a haplotype block-based gene-tagging approach; so, the entire DRD2 gene was represented., Results: One polymorphism, rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. Individuals carrying the genetic variation were more than twice as likely to have schizophrenia compared with controls., Conclusions: Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor of age of onset.

Despite considerable recent interest in the issue of comorbid substance use disorders in people with serious mental illness, there remains a need to refine approaches to screening. This paper describes the development and testing of a new screen for substance-related comorbidity, the 12-item DrugCheck Problem List (PL). Exploratory factor analysis with inpatient samples suggested a single-factor structure, although confirmatory factor analysis in a further sample found similar fit from a two-factor model. Sensitivity and specificity in detecting DSM-IV substance use disorders were both high and comparable to performances of the Severity of Dependence Scale and Alcohol Use Disorders Identification Test (Australian version). The list of problem areas provided by the PL has utility in driving further assessment and treatment planning, and offers suggested foci for motivational interviewing. While further testing is indicated, these data provide strong initial support for its use., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Smoking rate is disproportionately high among patients with schizophrenia, resulting in significant morbidity and mortality. However, cigarette smoking has been reported to have beneficial effects on negative symptoms, extrapyramidal symptoms, cognitive functioning and mood symptoms. Therefore, smoking cessation may worsen disability in schizophrenia. The association between smoking and these key clinical parameters was examined. Additionally, severity of smoking across four different antipsychotic treatment groups was explored., Method: One hundred and forty-six patients with schizophrenia were assessed for smoking using expired carbon monoxide and smoking history. They were administered the Positive and Negative Symptom Scale, The Extrapyramidal Symptom Rating Scale, the Barnes Akathisia Rating Scale, Reitans Trail-making Test (A and B) and General Health Questionnaire-28., Results: There was no difference in the chlorpromazine equivalent dose of any of the medications studied. Atypical agents were associated with significantly lower levels of smoking when compared with typical medications. There was no difference in smoking severity between the individual atypical medications examined. Similarly, there were no significant differences between smoking and non-smoking groups with regard to Positive and Negative Symptom Scale, Extrapyramidal Symptom Rating Scale, Trail-making Test and General Health Questionnaire-28. However, there was a significant difference between these groups with the smoking group demonstrating less akathisia., Conclusions: Smoking is not associated with positive, negative cognitive and mood symptoms in schizophrenia. Smoking is associated with lower levels of antipsychotic induced akathisia. Clinicians should not be discouraged from helping patients stop smoking for fear of worsening symptoms. However, akathisia may emerge upon cessation of smoking. Switching patients from typical to atypical antipsychotics may assist patients with schizophrenia to give up smoking.

The T allele of the human dopamine D2 receptor (DRD2) gene C957T polymorphism is associated with reduced mRNA translation and stability. This results in decreased dopamine induced DRD2 upregulation and decreased in vivo D2 dopamine binding. Conversely, the C allele of the C957T polymorphism is not associated with such changes in mRNA leading to increased DRD2 expression. PET and postmortem binding studies show that schizophrenia is often associated with increased DRD2 availability. We report that on the basis of comparing the frequencies of the C/C and T/T genotypes of 153 patients with schizophrenia and 148 controls that schizophrenia is associated with the C/C genotype. The C957T shows a population attributable risk for schizophrenia of 24% and an attributable risk in those with schizophrenia of 42%. Increased expression of D2 receptors associated with the C allele is likely to be important in the underlying pathophysiology of at least some forms of schizophrenia. Enhanced understanding of schizophrenia afforded by this finding may lead to advances in treatment and prevention.

Background: Hyperprolactinaemia induced by D(2) dopamine receptor antagonist antipsychotic medication can result in significant health problems., Aims: To examine the role of DRD2 polymorphism on prolactin levels in patients treated with antipsychotic medication., Method: Antipsychotic drugs with different degrees of D(2) receptor binding were given to 144 patients with schizophrenia. Serum prolactin levels were obtained and Taq1A DRD2 alleles were determined., Results: Prolactin levels increased across medication groups reflecting increasingly tight D(2) receptor binding (clozapine, olanzapine, typical antipsychotics and risperidone). In the combined medication group, patients with the DRD2(*)A1allele had 40% higher prolactin levels than patients without this allele. In patients treated with clozapine (the loosest D(2) receptor binding agent), patients with the DRD2(*)A1allele had prolactin levels twice those of patients without this allele., Conclusions: Patients with the DRD2A1 allele receiving antipsychotic medications had higher prolactin levels and were overrepresented among those with hyperprolactinaemia, suggesting greater functional D(2) receptor binding in this group.

Serotonin receptor 2A (HTR2A) is an important signalling factor implicated in cognitive functions and known to be associated with schizophrenia. The biological significance of HTR2A in schizophrenia remains unclear as molecular analyses including genetic association, mRNA expression and methylation studies have reported inconsistent results. In this study, we examine HTR2A expression and methylation and the interaction with HTR2A polymorphisms to identify their biological significance in schizophrenia. Subjects included 25 schizophrenia and 25 control post-mortem brain samples. Genotype and mRNA data was generated by transcriptome sequencing. DNA methylation profiles were generated for CpG sites within promoter-exon I region. Expression, genotype and methylation data were examined for association with schizophrenia. HTR2A mRNA levels were reduced by 14% (p = 0.006) in schizophrenia compared to controls. Three CpG sites were hypermethylated in schizophrenia (cg5 p = 0.028, cg7 p = 0.021, cg10 p = 0.017) and HTR2A polymorphisms rs6314 (p = 0.008) and rs6313 (p = 0.026) showed genetic association with schizophrenia. Differential DNA methylation was associated with rs6314 and rs6313. There was a strong correlation between HTR2A DNA methylation and mRNA expression. The results were nominally significant but did not survive the rigorous Benjamini-Hochberg correction for multiple testing. Differential HTR2A expression in schizophrenia in our study may be the result of the combined effect of multiple differentially methylated CpG sites. Epigenetic HTR2A regulation may alter brain function, which contributes to the development of schizophrenia. [ABSTRACT FROM AUTHOR]

Family members living with a relative diagnosed with schizophrenia have reported challenges and traumatic stressors, as well as perceived benefits and personal growth. This study explored factors associated with posttraumatic growth (PTG) within such families. Personality, stress, coping, social support, and PTG were assessed in 110 family members. Results revealed that a multiplicative mediational path model with social support and emotional or instrumental coping strategies as multi-mediators had a significant indirect effect on the relationship between extraversion and PTG. Clinically relevant concepts that map onto the multi-mediator model are discussed, and these findings are translated into clinical practice to facilitate naturally occurring PTG processes. [ABSTRACT FROM AUTHOR]

Hyperprolactinaemia in antipsychotic treated patients with schizophrenia is a consequence of D2 receptor (DRD2) blockade. Alcohol use disorder is commonly comorbid with schizophrenia and low availability of striatal DRD2 may predispose individuals to alcohol use. In this pilot study we investigated whether hyperprolactinaemia secondary to pharmacological DRD2 blockade was associated with alcohol use disorder in 219 (178 males and 41 females) patients with schizophrenia. Serum prolactin determinations were made in patients diagnosed with schizophrenia and maintained on antipsychotic agents. Clinical assessment included demographics, family history and administration of the AUDIT (Alcohol Use Disorders Identification Test). Higher AUDIT scores were associated with prolactin-raising antipsychotic medication (n = 106) compared with prolactin-sparing medication (n = 113). Risperidone (n = 63) treated patients had higher AUDIT scores and prolactin levels than those on other atypical antipsychotics (n = 113). Across the entire sample, patients with a prolactin greater than 800 mIU/L had higher AUDIT scores and were more likely to exceed the cut-off score for harmful and hazardous alcohol use. These differences were not explained by potential confounds related to clinical features and demographics, comorbidity or medication side-effects. These data suggest that by lowering dosage, or switching to another antipsychotic agent, the risk for alcohol use disorder in those with schizophrenia may be reduced. This hypothesis requires testing using a prospective methodology. [ABSTRACT FROM PUBLISHER]

Background: Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimer's disease and Post Traumatic Stress Disorder (PTSD). A single nucleotide polymorphism (SNP) (957C>T) and a deletion polymorphism (-141delC) in the DRD2 gene and a SNP (Taq1A) in a gene directly downstream of DRD2 have all been implicated in dopamine functioning in the brain. Methods: To test the importance of these three polymorphisms in PTSD susceptibility, a genetic screen was performed in 127 war veterans diagnosed with PTSD and 228 control individuals without a history of PTSD. Results: No significant association was found between PTSD and the Taq1A or -141delC polymorphisms. However, a significant association was observed with PTSD and the 957C>T polymorphism. PTSD individuals were more likely to carry the C allele compared to the controls (P=0.021). Conclusions: Our findings suggest that the 957C>T polymorphism in the DRD2 gene is one of the genetic factors for susceptibility to PTSD. Depression Anxiety, 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The authors comments on the paper "Towards an Integrated Approach to a Family Intervention for Co-Occurring Substance Abuse and Schizophrenia," by R. Sheils and T. Rolfe in the 2000 issue of the "Australian and New Zealand Journal of Family Therapy." The authors note that Sheils and Rolfe tend to understate the positive contribution that families can and do make for their relatives. They also cite several specific points by Sheils and Rolfe with which they have taken issue.

Abstract: Background: Factors associated with cannabis use among people with psychosis are not well understood. Aims: To examine whether people with psychosis and age-matched controls modified cannabis use in response to recent experiences. Method: This study predicted 4 weeks of cannabis use prospectively, using expectancies derived from recent occasions of use. Results: People with psychosis used cannabis less frequently than controls, but had more cannabis-related problems. More negative cannabis expectancies resulted in less frequent cannabis use over Follow-up. The psychosis group was more likely to moderate cannabis use after negative effects than controls. Conclusions: Results offer optimism about abilities of people with psychosis to moderate cannabis use in the short term. [Copyright &y& Elsevier]