Catechol-O-methyltransferase and the clinical features of psychosis

A functional polymorphism (Val-158-Met) at the Catechol-O-methyltransferase (COMT) locus has been identified as a potential etiological factor in schizophrenia. Yet the association has not been convincingly replicated across independent samples. We hypothesized that phenotypic heterogeneity might be diluting the COMT effect. To clarify the putative association, we performed an exploratory analysis to test for association between COMT and five psychosis symptom scales. These were derived through factor analysis of the Operational Criteria Checklist for Psychiatric Illness. Our sample was the Irish Study of High Density Schizophrenia Families, a large collection consisting of 268 multiplex families. This sample has previously shown a small but significant effect of the COMT Val allele in conferring risk for schizophrenia. We tested for preferential transmission of COMT alleles from parent to affected offspring (n = 749) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression). Significant overtransmission of the Val allele was found for mania (P <0.05) and depression (P = 0.01) scales. Examination of odds ratios (ORs) revealed a heterogeneous effect of COMT, whereby it had no effect on Negative Symptoms, but largest impact on Depression (OR = 1.4). These results suggest a modest affective vulnerability conferred by this allele in psychosis, but will require replication.

Paranoia and self-concepts in psychosis: A systematic review of the literature.

The purpose of the present study was to review systematically, research exploring the relationship between self-concepts and paranoia in psychosis. A literature search was performed by two independent raters in relevant databases (MedLine, PsychInfo and Web of Science) and articles meeting the inclusion criteria were cross-referenced. Following scrutiny according to inclusion criteria, 18 studies were selected for review. A narrative synthesis of findings, in which methodological variability is discussed, is presented relative to three key areas: the nature of the relationship between paranoia and self-concepts; the association between paranoia and discrepancies in self-concepts; the nature of the relationship between paranoia and self-concepts when other, dimensional aspects of these constructs are taken into account. The systematic literature review indicated relatively consistent findings, that paranoia is associated with more negative self-concepts when measured cross-sectionally. Results are somewhat more mixed in regards to research on paranoia and self-concept discrepancies. Studies investigating dimensional aspects of self-concepts and paranoia yield findings of particular interest, especially in regards to the association indicated between instability of self-concepts and paranoia. Limitations in research and of the present systematic review are discussed. Clinical and theoretical implications of findings are outlined and possible directions for future research are suggested.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=0.052) and UK bipolar disorder case-control cohorts (P=0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11,707 cases and 10 carriers in 21,204 controls (meta-analysis CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

Exposure to Political Violence in Northern Ireland and Outcome of First Episode Psychosis

The impact of political violence on individuals presenting with an episode of first episode psychosis has not been examined. Individuals were assessed for exposure to political violence in Northern Ireland (the “Troubles”) by asking for a response to 2 questions: one asked about the impact of violence “on your area”; the second about the impact of violence “on you or your family’s life.” The participants were separated into 2 groups (high and low impact) for each question. Symptom profiles and rates of substance misuse were compared across the groups at baseline and at 3-year follow up. Of the 178 individuals included in the study 66 (37.1%) reported a high impact of the “Troubles” on their life and 81 (45.5%) a high impact of the “Troubles” on their area. There were no significant differences in symptom profile or rates of substance misuse between high and low groups at presentation. At 3-year follow-up high impact of the “Troubles” on life was associated with higher Positive and Negative Symptom Scale (PANSS) Total (P = .01), PANSS-Positive (P < .05), and PANSS-General (P < .01) scores and lower global assessment of functioning disability (P < .05) scores, after adjusting for confounding factors. Impact of the “Troubles” on area was not associated with differences in symptom outcomes. This finding adds to the evidence that outcomes in psychosis are significantly impacted by environmental factors and suggests that greater attention should be paid to therapeutic strategies designed to address the impact of trauma.

Enquiring about traumatic experiences in psychosis: A comparison of case notes and self-report questionnaires

Purpose: Studies have found an association between a history of trauma and the presence of psychotic symptoms. Despite the research evidence it appears to be the case that many clinicians are not routinely asking about traumatic experiences. This study aims to ascertain the level of agreement between rates of self-reported trauma and that which is recorded in case notes.

Methods: The study population was drawn from all individuals with a confirmed diagnosis of psychosis, residing within a defined catchment area. Rates of childhood trauma, lifetime trauma and trauma related to the Troubles in Northern Ireland recorded in participants’ case notes were compared to their responses on self-report questionnaires: THQ, CTQ and TREQ.

Results: Relatively high levels of trauma were reported by participants on the self-report measures that were administered. The rates of trauma recorded in case note records were similar to that found in other studies. Also in line with other research were poor levels of agreement between self-report and case note data.

Conclusion: High levels of lifetime, childhood and trauma related to the Troubles in Northern Ireland were found when the individuals in the sample were directly assessed for the purposes of this study. In contrast much lower rates were recorded in patient notes on routine clinical assessment. The results suggest that clinicians do not routinely enquire about trauma histories with this population and as a result, case notes underestimate trauma prevalence.