M. Aurora Falcone

Confirmation that the AKT1 (rs2494732) Genotype Influences the Risk of Psychosis in Cannabis Users

BACKGROUND Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect. METHODS In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis. RESULTS The rs2494732 locus was not associated with an increased risk of a psychotic disorder, with lifetime cannabis use, or with frequency of use. We did, however, find that the effect of lifetime cannabis use on risk of psychosis was significantly influenced by the rs2494732 locus (likelihood ratio statistic for the interaction = 8.54; p = .014). Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio = 2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers. Moreover, the interaction between the rs2494732 genotype and frequency of use was also significant at the 5% level (likelihood ratio = 13.39; p = .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio = 7.23 [95% confidence interval: 1.37, 38.12]). CONCLUSIONS Our findings provide strong support for the initial report that genetic variation at rs2494732 of AKT1 influences the risk of developing a psychotic disorder in cannabis users.

Brain derived neurotropic factor (BDNF) is associated with childhood abuse but not cognitive domains in first episode psychosis

BACKGROUND The Brain-derived Neurotrophic Factor (BDNF) modulates cognitive processes and is associated with increased risk of schizophrenia. Childhood trauma (CT) is frequent in patients with psychosis and severely affects course and outcome. AIMS We investigated the hypothesis that BDNF is associated with both CT and cognitive deficits in a sample of first-episode psychosis (FEP) cases and unaffected controls. METHOD Participants with FEP and healthy controls were recruited between August 2008 and July 2011 from South London, UK. Childhood traumatic events were detected using the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). Neuropsychological data were also collected. BDNF plasma levels were measured from fasting blood samples. RESULTS Data were available on 87 FEP patients and 152 controls. Our results showed a significant effect of separation (F=5.5; df=1,115; p=.02), physical (F=4.7; df=1, 118; p=.03) and sexual abuse (F=5.4; df=1,117; p=.02) on BDNF levels with lower levels among those who experienced the traumatic event compared to those who did not. Physical abuse predicted lower plasma levels of BDNF (β=-.30; p=.03) whereas sexual and/or physical abuse showed a trend (β=-.26; p=.06) in FEP patients but not in unaffected controls. No association between BDNF plasma levels and cognitive functions was found among patients with FEP and controls. CONCLUSION Our findings suggest the possible involvement of BDNF in the onset of first-episode psychosis in individuals exposed to early trauma and propose BDNF as a potential clinical biomarker to detect the detrimental effects of CT on human brain plasticity.

Failure to find association between childhood abuse and cognition in first-episode psychosis patients

This study investigated the relationship between severe childhood abuse and cognitive functions in first-episode psychosis patients and geographically-matched controls. Reports of any abuse were associated with lower scores in the executive function domain in the control group. However, in contrast with our hypothesis, no relationships were found amongst cases.

Jumping to conclusions and the persistence of delusional beliefs in first episode psychosis.

BACKGROUND Cognitive biases may contribute to delusion persistence. We tested this in a longitudinal study of first episode psychosis (FEP). METHODS 34 FEP patients completed assessments of delusions and Jumping to Conclusions (JTC) at baseline and 12-month follow-up. RESULTS JTC was associated with baseline delusion severity (t(32)=2.7, p=0.01). Baseline delusions persisted at follow-up for 8/20 participants (40%), who all jumped to conclusions (8/8, 100%), compared to half of those with no or changeable delusions (14/26, 54%; χ(2) (df=1)=5.7, p=0.03; Phi=0.4). CONCLUSION Findings implicate cognitive biases in delusion persistence, and support the potential to reduce delusions through reasoning-focused interventions.

Attrition and Rape Case Characteristics A Profile and Comparison of Female Sex Workers and Non-Sex Workers

The attrition of rape cases from the criminal justice system (CJS) remains high and there is a paucity of research in relation to marginalized groups. Sex workers (SWs) are vulnerable to sexual violence due to the nature of their work. They are also unlikely to report such violence to police for a range of reasons. Two stages of research sought to describe the victim, perpetrator, and offense characteristics of SW rape and to examine the attrition of these cases. All rapes and attempted rapes (N = 1,146) reported to police in a large city in the South West of England over a 21-year period were examined; 67 cases involved SWs. Data were extracted from police files in line with the variables of interest. Secondary analysis of the total number of SW rapes (n = 67) resulted in a profile of these cases. A matched pairs study revealed significant differences in victim, perpetrator, and assault characteristics between SW (n = 62) and non-sex-worker (NSW) samples (n = 62). Although no significant difference was found in terms of attrition from the CJS, SW cases were observed to secure more convictions for rape than NSW cases. The implications of the findings for practice and future research are discussed.

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project

BACKGROUND Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. CONCLUSIONS The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.

Cognitive impairment and subjective time in schizophrenics

Background: The large variation in individual clinical responses to antipsychotic treatment hampers the management of psychotic disorders. Genetic factors are considered a main cause of this variation. Pharmacogenetics studies have demonstrated significant associations between several candidate genes (a.o. D2, D3, 5HTR2A and 5HTR2C, GRM3, COMT and MTHFR) and the response to antipsychotic drugs. The present study investigates the effect of 12 polymorphisms for an association with antipsychotic treatment response in patients with a psychotic disorder. Methods: 335 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 12 SNPs in 7 candidate genes (DRD2: TaqI-A, TaqI-D, -141-C, C957T; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser, -759-T/C; COMT: Val108/158Met; MTHFR: 677-C/T, GRM3: rs274622) using standard protocols. Polymorphisms were based on previous studies showing associations with treatment response. The Clinical Global Impression- Schizophrenia scale was cross-sectionally used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used to test for an association between polymorphisms and improvement in positive symptoms. All polymorphisms were tested in an additive model, with minor allele dose as the dependent variable. Results: Ninety percent of the patients used atypical antipsychotics, with olanzapine (31%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value .029) and 677-C/T of MTHFR (P value .029) were tested significant. Gly carriers and T-carriers, respectively, showed better clinical improvement on the positive scale. All other polymorphisms did not show any association with treatment response (all P values >.10). Conclusion: We were able to replicate only two of the previously reported associations between polymorphisms and treatment response. Heterogeneity in patient samples and outcome variables as well as publication bias and false positive findings may all play a role in lack of replication, found in our study, as in others. The direction of the associations presented here in D3 (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.