Toward Constructing an Endophenotype Strategy for Bipolar Disorders

The catechol-O-methyltransferase (COMT) Val158Met polymorphism is hypothesized to affect executive function in patient and control populations. Studies inconsistently report better performance on the Wisconsin Card Sort Test (WCST) in individuals with one or more Met alleles. We conducted a meta-analysis of studies published until August 2006 that reported WCST perseverative errors from healthy volunteers or patients with schizophrenia-spectrum disorders. Twelve studies met inclusion criteria (total n=1910) providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d=0.29; 95% confidence interval (CI) 0.02–0.55; P=0.03), but this was not supported in the patient sample (d=−0.07; 95% CI −0.40 to 0.26; P=0.68). Post hoc analyses suggested that Val and Met alleles are codominant in their effects on cognition. Effect size was greater in studies published at an earlier date and may also be larger in non-Caucasian samples. Gender did not affect the results. There was no evidence of publication bias. We conclude that there is small but significant relationship between Val158Met genotype and executive function in healthy individuals but not in schizophrenia.

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls.

A large number of candidate gene studies for aggression and violence have been conducted. Successful identification of associations between genetic markers and aggression would contribute to understanding the neurobiology of antisocial behavior and potentially provide useful tools for risk prediction and therapeutic targets for high-risk groups of patients and offenders. We systematically reviewed the literature and assessed the evidence on genetic association studies of aggression and related outcomes in order to provide a field synopsis. We searched PubMed and Huge Navigator databases and sought additional data through reviewing reference lists and correspondence with investigators. Genetic association studies were included if outcome data on aggression or violent behavior either as a binary outcome or as a quantitative trait were provided. From 1331 potentially relevant investigations, 185 studies constituting 277 independent associations on 31 genes fulfilled the predetermined selection criteria. Data from variants investigated in three or more samples were combined in meta-analyses and potential sources of heterogeneity were investigated using subgroup analyses. In the primary analyses, which used relaxed inclusion criteria, we found no association between any polymorphism analyzed and aggression at the 5% level of significance. Subgroup analyses, including by severity of outcome, age group, characteristics of the sample and ethnicity, did not demonstrate any consistent findings. Current evidence does not support the use of such genes to predict dangerousness or as markers for therapeutic interventions.

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Systematic meta-analyses and field synopsis of genetic association studies of violence and aggression

Effects of COMT polymorphisms on brain function and behavior in health and disease

Schizophrenia elevates the risk for aggressive behavior and violent crime, and different approaches have been used to manage this problem. The results of such treatments vary. One reason for this variation is that aggressive behavior in schizophrenia is heterogeneous in origin. This heterogeneity has usually not been accounted for in treatment trials nor is it adequately appreciated in routine clinical treatment planning. Here, we review pathways that may lead to the development of aggressive behavior in patients with schizophrenia and discuss their impact on treatment. Elements in these pathways include predisposing factors such as genotype and prenatal toxic effects, development of psychotic symptoms and neurocognitive impairments, substance abuse, nonadherence to treatment, childhood maltreatment, conduct disorder, comorbid antisocial personality disorder/psychopathy, and stressful experiences in adult life. Clinicians’ knowledge of the patient’s historical trajectory along these pathways may inform the choice of optimal treatment of aggressive behavior. Clozapine has superior antiaggressive activity in comparison with other antipsychotics and with all other pharmacological treatments. It is usually effective when aggressive behavior is related to psychotic symptoms. However, in many patients, aggression is at least partly based on other factors such as comorbid substance use disorder, comorbid antisocial personality disorder/psychopathy, or current stress. These conditions which are sometimes underdiagnosed in clinical practice must be addressed by appropriate adjunctive psychosocial approaches or other treatments. Treatment adherence has a crucial role in the prevention of aggressive behavior in schizophrenia patients.

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Pathways to Aggression in Schizophrenia Affect Results of Treatment

Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.

Susan J. Jones

Papers

Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia