Heritability of Individual Psychotic Experiences Captured by Common Genetic Variants in a Community Sample of Adolescents.

Occurrence of psychotic experiences is common amongst adolescents in the general population. Twin studies suggest that a third to a half of variance in adolescent psychotic experiences is explained by genetic influences. Here we test the extent to which common genetic variants account for some of the twin-based heritability. Psychotic experiences were assessed with the Specific Psychotic Experiences Questionnaire in a community sample of 2152 16-year-olds. Self-reported measures of Paranoia, Hallucinations, Cognitive Disorganization, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms were obtained. Estimates of SNP heritability were derived and compared to the twin heritability estimates from the same sample. Three approaches to genome-wide restricted maximum likelihood (GREML) analyses were compared: (1) standard GREML performed on full genome-wide data; (2) GREML stratified by minor allele frequency (MAF); and (3) GREML performed on pruned data. The standard GREML revealed a significant SNP heritability of 20 % for Anhedonia (SE = 0.12; p < 0.046) and an estimate of 19 % for Cognitive Disorganization, which was close to significant (SE = 0.13; p < 0.059). Grandiosity and Paranoia showed modest SNP heritability estimates (17 %; SE = 0.13 and 14 %; SE = 0.13, respectively, both n.s.), and zero estimates were found for Hallucinations and Negative Symptoms. The estimates for Anhedonia, Cognitive Disorganization and Grandiosity accounted for approximately half the previously reported twin heritability. SNP heritability estimates from the MAF-stratified approach were mostly consistent with the standard estimates and offered additional information about the distribution of heritability across the MAF range of the SNPs. In contrast, the estimates derived from the pruned data were for the most part not consistent with the other two approaches. It is likely that the difference seen in the pruned estimates was driven by the loss of tagged causal variants, an issue fundamental to this approach. The current results suggest that common genetic variants play a role in the etiology of some adolescent psychotic experiences, however further research on larger samples is desired and the use of MAF-stratified approach recommended

Are genetic risk factors for psychosis also associated with dimension-specific psychotic experiences in adolescence?

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value=2.57x10-4) and rs9960767 (p-value=6.23x10-4). Replication in an independent sample of 16-year-olds (N=3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed

Association between stressful life events and psychotic experiences in adolescence: evidence for gene-environment correlations

- Background: Stressful life events (SLEs) are associated with psychotic experiences (PEs). SLEs might act as an environmental risk factor, but may also share a genetic propensity with PEs. - Aims: Estimate the extent to which genetic and environmental factors influence the relationship between SLEs and PEs. - Method: Self and parent-reports from a community-based twin sample (4,830 16-year-old pairs) were analysed using structural equation model-fitting. - Results: SLEs correlated with positive PEs (r = .12-.14, all p<. 001). Modest heritability was shown for PEs (25-57%) and dependent SLEs (32%). Genetic influences explained the majority of the modest covariation between dependent SLEs and paranoia and cognitive disorganisation (bivariate heritabilities = 74-86%). The relationship between SLEs and hallucinations and grandiosity was explained by both genetic and common environmental effects. - Conclusion: Further to dependent SLEs being an environmental risk factor, individuals may have an underlying genetic propensity increasing their risk of dependent SLEs and positive PEs

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies

Association of polymorphisms in HCN4 with mood disorders and obsessive compulsive disorder

Hyperpolarization activated cyclic nucleotide-gated (HCN) potassium channels are implicated in the control of neuronal excitability and are expressed widely in the brain. HCN4 is expressed in brain regions relevant to mood and anxiety disorders including specific thalamic nuclei, the basolateral amygdala, and the midbrain dopamine system. We therefore examined the association of HCN4 with a group of mood and anxiety disorders. We genotyped nine tag SNPs in the HCN4 gene using Sequenom iPLEX Gold technology in 285 Caucasian patients with DSM-IV mood disorders and/or obsessive compulsive disorder and 384 Caucasian controls. HCN4 polymorphisms were analyzed using single marker and haplotype-based association methods. Three SNPs showed nominal association in our population (rs12905211, rs3859014, rs498005). SNP rs12905211 maintained significance after Bonferroni correction, with allele T and haplotype CTC overrepresented in cases. These findings suggest HCN4 as a genetic susceptibility factor for mood and anxiety disorders; however, these results will require replication using a larger sample

‘Like I said about culture. You don't talk about mental health’: An interpretative phenomenological analysis of the experience of first-episode psychosis in South Asian individuals

Background There is strong evidence of inequalities in mental healthcare access, experiences and outcomes for service users belonging to Black and Asian Minority Ethnic groups experiencing psychosis. Clinicians and academics have speculated that cultural variation in conceptualisations of psychosis, alongside inequitable service provision may explain disparities. There is, however, a dearth of literature exploring this in a South Asian population, despite this ethnic group being the second largest in the United Kingdom. The present study aimed to explore how people from this minority group have experienced and made sense of first-episode psychosis (FEP). Methods A qualitative approach was used to explore the lived experience and sense-making of South Asian individuals experiencing FEP and accessing early intervention services. Eight people were interviewed using a semi-structured format. The data were analysed using Interpretative Phenomenological Analysis. Results Three superordinate themes were identified in the group analysis: (1) Disconnection from self and others (2) Doubt and dispute (3) Power and shame. Conclusions Distinctive ethnic, cultural and systemic influences were strongly evident in how people conceptualized their experiences, how they managed their sense-making and where they sought support. Experiences were discussed in the context of power and shame, and this research proposes that socio-cultural context and racialised discourses have an impact on self-concept, the experiences of help-seeking (formal and informal), and fundamentally how services help individuals from marginalized communities

Art therapy for people with dementia

Background: Art therapy is defined by the British Association of Art Therapists as: “a form of psychotherapy that uses art media as its primary mode of communication. Clients who are referred to an art therapist need not have experience or skill in art. The art therapist is not primarily concerned with making an aesthetic or diagnostic assessment of the client’s image. The overall aim of its practitioners is to enable a client to change and grow on a personal level through the use of art materials in a safe and facilitating environment”. Historically, drawings and paintings have been recognised as a useful part of therapeutic processes within psychiatric and psychological specialties, and this has been acknowledged within medical and neurology‐based disciplines. Arts‐based therapies are generally considered as interventions managing manifestations of dementia, as they may help to slow cognitive deterioration, address symptoms related to psychosocially challenging behaviours and improve quality of life. Objectives: To review the effects of art therapy as an adjunctive treatment for dementia compared with standard care and other non‐pharmacological interventions. Search methods: We identified trials from ALOIS ‐ the Cochrane Dementia and Cognitive Improvement Group’s Specialised Register ‐ on 12 May 2014, 20 March 2015, 15 January 2016, 4 November 2016, and 4 October 2017. We also handsearched the grey literature and contacted specialists in the field and authors of relevant reviews or studies to enquire about other sources of relevant information. Selection criteria: All randomised controlled trials examining art therapy as an intervention for dementia. Data collection and analysis: Two review authors independently extracted data. We examined scales measuring cognition, affect and emotional well‐being, social functioning, behaviour and quality of life. Main results: We found two studies that met the inclusion criteria, incorporating data on a total of 60 participants (from 88 randomised), in experimental groups (n = 29) and active control groups (n = 31). One study compared group art therapy with simple calculation activities over 12 weeks. The other study compared group art therapy with recreational activities over 40 weeks. It was not possible to pool the data for analysis from the included studies, due to heterogeneity in terms of differences in the interventions, control treatments and choice of outcome measures. In both studies there were no clear changes reported between the intervention group and the control group in the important outcome measures. According to GRADE ratings, we judged the quality of evidence for these outcome measures to be 'very low'. Authors' conclusions: There is insufficient evidence about the efficacy of art therapy for people with dementia. More adequately‐powered and high‐quality studies using relevant outcome measures are needed

Migration and Psychosis: Evidence from South Asian Communities in Bradford

Objective: To study the risk of psychosis in south Asian communities in Bradford and investigate the role of cannabis as a contributory factor. Study Design: Naturalistic studies based on electronic summary records. Place and Duration of Study: The studies were conducted at the Becklin Centre, St James's University Hospital, Leeds and the University of Leeds, School of Medicine from 2018 to 2020. Material and Method: A service evaluation and research project looking into the role of cannabis included 194 patients admitted to acute psychiatry wards at the Becklin Centre between 1st January 2016 and 30th November 2018. Epidemiological study used electronic summary records provided by the Bradford Early Intervention for Psychosis Service of 15-35-year old newly diagnosed cases with first episode psychosis in 2013-15 and local census data to calculate the risks ratios. Results: Compared with indigenous white population, Pakistanis in Bradford had significantly higher risk of psychosis (RR: 1.41, 95% CI 1.07, 1.85*). This trend was also seen in Bangladeshi community (RR 1.72, 95% CI 0.91, 3.28*). Indian community, on the other hand, experienced lower risk (RR 0.54, 95% CI 0.20, 1.27). Conclusion: We found increased risk of psychosis in Pakistani and Bangladeshi communities but not in Indian community

A proposal for reducing maximum target doses of drugs for psychosis: Reviewing dose–response literature

Background: Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects. Aims: This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit. Methods: We used data from two dose–response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D2 receptor occupancy to extrapolate our recommendations. Results: We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation. Conclusions: In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal