Psychotic experiences and negative symptoms from adolescence to emerging adulthood: developmental trajectories and associations with polygenic scores and childhood characteristics.

BACKGROUND: Psychotic experiences and negative symptoms (PENS) are common in non-clinical populations. PENS are associated with adverse outcomes, particularly when they persist. Little is known about the trajectories of PENS dimensions in young people, nor about the precursory factors associated with these trajectories. METHODS: We conducted growth mixture modelling of paranoia, hallucinations, and negative symptoms across ages 16, 17, and 22 in a community sample (N = 12 049-12 652). We then described the emergent trajectory classes through their associations with genome-wide polygenic scores (GPS) for psychiatric and educational phenotypes, and earlier childhood characteristics. RESULTS: Three trajectory classes emerged for paranoia, two for hallucinations, and two for negative symptoms. Across PENS, GPS for clinical help-seeking, major depressive disorder, and attention deficit hyperactivity disorder were associated with increased odds of being in the most elevated trajectory class (OR 1.07-1.23). Lower education GPS was associated with the most elevated trajectory class for hallucinations and negative symptoms (OR 0.77-0.91). Conversely for paranoia, higher education GPS was associated with the most elevated trajectory class (OR 1.25). Trajectory class associations were not significant for schizophrenia, obsessive-compulsive disorder, bipolar disorder, or anorexia GPS. Emotional/behaviour problems and life events in childhood were associated with increased odds of being in the most elevated trajectory class across PENS. CONCLUSIONS: Our results suggest latent heterogeneity in the development of paranoia, hallucinations, and negative symptoms in young people that is associated with specific polygenic scores and childhood characteristics.

In memory of Professor Iain Wilkinson: cognitive and neuroimaging endophenotypes in a consanguineous schizophrenia multiplex family.

BACKGROUND: Schizophrenia endophenotypes may help elucidate functional effects of genetic risk variants in multiply affected consanguineous families that segregate recessive risk alleles of large effect size. We studied the association between a schizophrenia risk locus involving a 6.1Mb homozygous region on chromosome 13q22-31 in a consanguineous multiplex family and cognitive functioning, haemodynamic response and white matter integrity using neuroimaging. METHODS: We performed CANTAB neuropsychological testing on four affected family members (all homozygous for the risk locus), ten unaffected family members (seven homozygous and three heterozygous) and ten healthy volunteers, and tested neuronal responses on fMRI during an n-back working memory task, and white matter integrity on diffusion tensor imaging (DTI) on four affected and six unaffected family members (four homozygous and two heterozygous) and three healthy volunteers. For cognitive comparisons we used a linear mixed model (Kruskal-Wallis) test, followed by posthoc Dunn's pairwise tests with a Bonferroni adjustment. For fMRI analysis, we counted voxels exceeding the p < 0.05 corrected threshold. DTI analysis was observational. RESULTS: Family members with schizophrenia and unaffected family members homozygous for the risk haplotype showed attention (p < 0.01) and working memory deficits (p < 0.01) compared with healthy controls; a neural activation laterality bias towards the right prefrontal cortex (voxels reaching p < 0.05, corrected) and observed lower fractional anisotropy in the anterior cingulate cortex and left dorsolateral prefrontal cortex. CONCLUSIONS: In this family, homozygosity at the 13q risk locus was associated with impaired cognition, white matter integrity, and altered laterality of neural activation.

Daily use of high-potency cannabis is associated with more positive symptoms in first-episode psychosis patients: the EU-GEI case-control study.

BACKGROUND: Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients. METHOD: We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses. RESULTS: In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14-0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = -0.22; 95% CI -0.37 to -0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use. CONCLUSIONS: Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

A twin study exploring the association between childhood emotional and behaviour problems and specific psychotic experiences in a community sample of adolescents.

BACKGROUND: Childhood emotional and behaviour problems are antecedents for later psychopathology. This study investigated genetic and environmental influences shaping the longitudinal association between childhood emotional and behaviour problems and specific PEs. METHOD: In a community-based twin sample, parents reported on emotional and behaviour problems when twins were ages 7 and 12 years. At age 16 years, specific PEs were measured using self-reports and parent reports. Structural equation model-fitting was conducted. RESULTS: Childhood emotional and behaviour problems were significantly associated with paranoia, cognitive disorganisation and parent-rated negative symptoms in adolescence (mean r = .15-.38), and to a lesser extent with hallucinations, grandiosity and anhedonia (mean r = .04-.12). Genetic influences on childhood emotional and behaviour problems explained significant proportions of variance in adolescent paranoia (4%), cognitive disorganisation (8%) and parent-rated negative symptoms (3%). Unique environmental influences on childhood emotional and behaviour problems explained ≤1% of variance in PEs. Common environmental influences were only relevant for the relationship between childhood emotional and behaviour problems and parent-rated negative symptoms (explaining 28% of variance) and are partly due to correlated rater effects. CONCLUSIONS: Childhood emotional and behaviour problems are significantly, if weakly, associated with adolescent PEs. These associations are driven in part by common genetic influences underlying both emotional and behaviour problems and PEs. However, psychotic experiences in adolescence are largely influenced by genetic and environmental factors that are independent of general childhood emotional and behaviour problems, suggesting they are not merely an extension of childhood emotional and behaviour problems.

Associations between risk factors for schizophrenia and concordance in four monozygotic twin samples.

Concordance for schizophrenia is high in monozygotic twins but the extent to which concordance varies according to the presence of other schizophrenia risk factors is not well established. We aimed to investigate this in systematically ascertained twin samples. DSM-III-R/DSM-IV diagnoses were made from original data or published case histories from four systematically ascertained monozygotic twin samples. Probandwise concordance for schizophrenia was calculated according to the presence of psychotic disorder in first-degree relatives, birth order, gender, and age-at-onset. Logistic regression analysis was also performed to adjust for potential confounders. Psychotic disorder in parents and earlier age-at-onset were significantly associated with higher probandwise concordance for schizophrenia, including after adjustment for potential confounders. For example, when no parents had a psychotic disorder concordance was 34/88 (38.6%) versus 10/16 (62.5%) when one parent was affected; and for age-at-onset <23 years concordance was 25/46 (54.3%), declining to 13/44 (29.5%) for age-at-onset >30 years. These results are consistent with psychotic disorder in parents and age-at-onset being markers of the level of familial liability to schizophrenia and these factors may be useful in genetic counseling of monozygotic twins and in identifying and managing those at particularly high risk, if these findings are further replicated.

Genome-wide analysis of adolescent psychotic-like experiences shows genetic overlap with psychiatric disorders.

This study aimed to test for overlap in genetic influences between psychotic-like experience traits shown by adolescents in the community, and clinically-recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic-like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self- and parent-ratings in three European community samples aged 15-19 years (Final N incl. siblings = 6,297-10,098). A mega-genome-wide association study (mega-GWAS) for each psychotic-like experience domain was performed. Single nucleotide polymorphism (SNP)-heritability of each psychotic-like experience domain was estimated using genomic-relatedness-based restricted maximum-likelihood (GREML) and linkage disequilibrium- (LD-) score regression. Genetic overlap between specific psychotic-like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD-score regression. GREML returned SNP-heritability estimates of 3-9% for psychotic-like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent-rated Negative Symptoms). Mega-GWAS analysis identified one genome-wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic-like experience trait domains (Paranoia and Hallucinations only in non-zero scorers). The major depression PRS significantly predicted Anhedonia and Parent-rated Negative Symptoms in adolescence. Psychotic-like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically-recognized psychiatric disorders, specifically schizophrenia and major depression.

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. SLEs might act as an environmental risk factor, but may also share a genetic propensity with psychotic experiences. AIMS: To estimate the extent to which genetic and environmental factors influence the relationship between SLEs and psychotic experiences. METHOD: Self- and parent reports from a community-based twin sample (4830 16-year-old pairs) were analysed using structural equation model fitting. RESULTS: SLEs correlated with positive psychotic experiences (r = 0.12-0.14, all P<0.001). Modest heritability was shown for psychotic experiences (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. CONCLUSIONS: Further to dependent SLEs being an environmental risk factor, individuals may have an underlying genetic propensity increasing their risk of dependent SLEs and positive psychotic experiences.

Homozygous single base deletion in TUSC3 causes intellectual disability with developmental delay in an Omani family.

Intellectual disability (ID) is the term used to describe a diverse group of neurological conditions with congenital or juvenile onset, characterized by an IQ score of less than 70 and difficulties associated with limitations in cognitive function and adaptive behavior. The condition can be inherited or caused by environmental factors. The genetic forms are heterogeneous, with mutations in over 500 known genes shown to cause the disorder. We report a consanguineous Omani family in which multiple individuals have ID and developmental delay together with some variably present features including short stature, microcephaly, moderate facial dysmorphism, and congenital malformations of the toes or hands. Homozygosity mapping combined with whole exome next generation sequencing identified a novel homozygous single base pair deletion in TUSC3, c.222delA, p.R74 fs. The mutation segregates with the disease phenotype in a recessive manner and is absent in 60,706 unrelated individuals from various disease-specific and population genetic studies. TUSC3 mutations have been previously identified as causing either syndromic or non-syndromic ID in patients from France, Italy, Iran and Pakistan. This paper supports the previous clinical descriptions of the condition caused by TUSC3 mutations and describes the seventh family with mutations in this gene, thus contributing to the genetic spectrum of mutations. This is the first report of a family from the Arabian peninsula with this form of ID. © 2016 Wiley Periodicals, Inc.

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.

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.

Proportion of Antipsychotics with CYP2D6 Pharmacogenetic (PGx) Associations Prescribed in an Early Intervention in Psychosis (EIP) Cohort: A Cross-Sectional Study.

BACKGROUND: Prescribing drugs for psychosis (antipsychotics) is challenging due to high rates of poor treatment outcomes, which are in part explained by an individual's genetics. Pharmacogenomic (PGx) testing can help clinicians tailor the choice or dose of psychosis drugs to an individual's genetics, particularly psychosis drugs with known variable response due to CYP2D6 gene variants ('CYP2D6-PGx antipsychotics'). AIMS: This study aims to investigate differences between demographic groups prescribed 'CYP2D6-PGx antipsychotics' and estimate the proportion of patients eligible for PGx testing based on current pharmacogenomics guidance. METHODS: A cross-sectional study took place extracting data from 243 patients' medical records to explore psychosis drug prescribing, including drug transitions. Demographic data such as age, sex, ethnicity, and clinical sub-team were collected and summarised. Descriptive statistics explored the proportion of 'CYP2D6-PGx antipsychotic' prescribing and the nature of transitions. We used logistic regression analysis to investigate associations between demographic variables and prescription of 'CYP2D6-PGx antipsychotic' versus 'non-CYP2D6-PGx antipsychotic'. RESULTS: Two-thirds (164) of patients had been prescribed a 'CYP2D6-PGx antipsychotic' (aripiprazole, risperidone, haloperidol or zuclopenthixol). Over a fifth (23%) of patients would have met the suggested criteria for PGx testing, following two psychosis drug trials. There were no statistically significant differences between age, sex, or ethnicity in the likelihood of being prescribed a 'CYP2D6-PGx antipsychotic'. CONCLUSIONS: This study demonstrated high rates of prescribing 'CYP2D6-PGx-antipsychotics' in an EIP cohort, providing a rationale for further exploration of how PGx testing can be implemented in EIP services to personalise the prescribing of drugs for psychosis.

Genetic and Phenotypic Features of Schizophrenia in the UK Biobank.

Importance: Large-scale biobanks provide important opportunities for mental health research, but selection biases raise questions regarding the comparability of individuals with those in clinical research settings. Objective: To compare the genetic liability to psychiatric disorders in individuals with schizophrenia in the UK Biobank with individuals in the Psychiatric Genomics Consortium (PGC) and to compare genetic liability and phenotypic features with participants recruited from clinical settings. Design, Setting, and Participants: This cross-sectional study included participants from the population-based UK Biobank and schizophrenia samples recruited from clinical settings (CLOZUK, CardiffCOGS, Cardiff F-Series, and Cardiff Affected Sib-Pairs). Data were collected between January 1993 and July 2021. Data analysis was conducted between July 2021 and June 2023. Main Outcomes and Measures: A genome-wide association study of UK Biobank schizophrenia case-control status was conducted, and the results were compared with those from the PGC via genetic correlations. To test for differences with the clinical samples, polygenic risk scores (PRS) were calculated for schizophrenia, bipolar disorder, depression, and intelligence using PRS-CS. PRS and phenotypic comparisons were conducted using pairwise logistic regressions. The proportions of individuals with copy number variants associated with schizophrenia were compared using Firth logistic regression. Results: The sample of 517 375 participants included 1438 UK Biobank participants with schizophrenia (550 [38.2%] female; mean [SD] age, 54.7 [8.3] years), 499 475 UK Biobank controls (271 884 [54.4%] female; mean [SD] age, 56.5 [8.1] years), and 4 schizophrenia research samples (4758 [28.9%] female; mean [SD] age, 38.2 [21.0] years). Liability to schizophrenia in UK Biobank was highly correlated with the latest genome-wide association study from the PGC (genetic correlation, 0.98; SE, 0.18) and showed the expected patterns of correlations with other psychiatric disorders. The schizophrenia PRS explained 6.8% of the variance in liability for schizophrenia case status in UK Biobank. UK Biobank participants with schizophrenia had significantly lower schizophrenia PRS than 3 of the clinically ascertained samples and significantly lower rates of schizophrenia-associated copy number variants than the CLOZUK sample. UK Biobank participants with schizophrenia had higher educational attainment and employment rates than the clinically ascertained schizophrenia samples, lower rates of smoking, and a later age of onset of psychosis. Conclusions and Relevance: Individuals with schizophrenia in the UK Biobank, and likely other volunteer-based biobanks, represent those less severely affected. Their inclusion in wider studies should enhance the representation of the full spectrum of illness severity.

Genetic and Geographical Associations With Six Dimensions of Psychotic Experiences in Adolesence.

BACKGROUND AND HYPOTHESIS: Large-scale epidemiological and genetic research have shown that psychotic experiences in the community are risk factors for adverse physical and psychiatric outcomes. We investigated the associations of six types of specific psychotic experiences and negative symptoms assessed in mid-adolescence with well-established environmental and genetic risk factors for psychosis. STUDY DESIGN: Fourteen polygenic risk scores (PRS) and nine geographical environmental variables from 3590 participants of the Twins Early Development Study (mean age 16) were associated with paranoia, hallucinations, cognitive disorganization, grandiosity, anhedonia, and negative symptoms scales. The predictors were modeled using LASSO regularization separately (Genetic and Environmental models) and jointly (GE model). STUDY RESULTS: In joint GE models, we found significant genetic associations of negative symptoms with educational attainment PRS (ß = -.07; 95% CI = -0.12 to -0.04); cognitive disorganization with neuroticism PRS (ß = .05; 95% CI = 0.03-0.08); paranoia with MDD (ß = .07; 95% CI = 0.04-0.1), BMI (ß = .05; 95% CI = 0.02-0.08), and neuroticism PRS (ß = .05; 95% CI = 0.02-0.08). From the environmental measures only family SES (ß = -.07, 95% CI = -0.10 to -0.03) and regional education levels (ß = -.06; 95% CI = -0.09 to -0.02) were associated with negative symptoms. CONCLUSIONS: Our findings advance understanding of how genetic propensity for psychiatric, cognitive, and anthropometric traits, as well as environmental factors, together play a role in creating vulnerability for specific psychotic experiences and negative symptoms in mid-adolescence.

Specificity of polygenic signatures across symptom dimensions in bipolar disorder: an analysis of UK Bipolar Disorder Research Network data.

BACKGROUND: Current definitions and clinical heterogeneity in bipolar disorder are major concerns as they obstruct aetiological research and impede drug development. Therefore, stratification of bipolar disorder is a high priority. To inform stratification, our analysis aimed to examine the patterns and relationships between polygenic liability for bipolar disorder, major depressive disorder (MDD), and schizophrenia with multidimensional symptom representations of bipolar disorder. METHODS: In this analysis, data from the UK Bipolar Disorder Research Network (BDRN) were assessed with the Operational Checklist for Psychotic Disorders. Individuals with bipolar disorder as defined in DSM-IV, of European ancestry (self-reported), aged 18 years or older at time of interview, living in the UK, and registered with the BDRN were eligible for inclusion. Psychopathological variables obtained via interview by trained research psychologists or psychiatrists and psychiatric case notes were used to identify statistically distinct symptom dimensions, calibrated with exploratory factor analysis and validated with confirmatory factor analysis (CFA). CFA was extended to include three polygenic risk scores (PRSs) indexing liability for bipolar disorder, MDD, and schizophrenia in a multiple indicator multiple cause (MIMIC) structural equation model to estimate PRS relationships with symptom dimensions. FINDINGS: Of 4198 individuals potentially eligible for inclusion, 4148 (2804 [67·6%] female individuals and 1344 [32·4%] male individuals) with a mean age at interview of 45 years (SD 12·03) were available for analysis. Three reliable dimensions (mania, depression, and psychosis) were identified. The MIMIC model fitted the data well (root mean square error of approximation 0·021, 90% CI 0·019-0·023; comparative fit index 0·99) and suggests statistically distinct symptom dimensions also have distinct polygenic profiles. The PRS for MDD was strongly associated with the depression dimension (standardised ß 0·125, 95% CI 0·080-0·171) and the PRS for schizophrenia was strongly associated with the psychosis dimension (0·108, 0·082-0·175). For the mania dimension, the PRS for bipolar disorder was weakly associated (0·050, 0·002-0·097). INTERPRETATION: Our findings support the hypothesis that genetic heterogeneity underpins clinical heterogeneity, suggesting that different symptom dimensions within bipolar disorder have partly distinct causes. Furthermore, our results suggest that a specific symptom dimension has a similar cause regardless of the primary psychiatric diagnosis, supporting the use of symptom dimensions in precision psychiatry. FUNDING: Wellcome Trust and UK Medical Research Council.

First-Episode Psychosis Patients Who Deteriorated in the Premorbid Period Do Not Have Higher Polygenic Risk Scores Than Others: A Cluster Analysis of EU-GEI Data.

Cluster studies identified a subgroup of patients with psychosis whose premorbid adjustment deteriorates before the onset, which may reflect variation in genetic influence. However, other studies reported a complex relationship between distinctive patterns of cannabis use and cognitive and premorbid impairment that is worthy of consideration. We examined whether: (1) premorbid social functioning (PSF) and premorbid academic functioning (PAF) in childhood and adolescence and current intellectual quotient (IQ) define different clusters in 802 first-episode of psychosis (FEP) patients; resulting clusters vary in (2) polygenic risk scores (PRSs) for schizophrenia (SCZ_PRS), bipolar disorder (BD_PRS), major depression (MD_PRS), and IQ (IQ_PRS), and (3) patterns of cannabis use, compared to 1,263 population-based controls. Four transdiagnostic clusters emerged (BIC = 2268.5): (1) high-cognitive-functioning (n = 205), with the highest IQ (Mean = 106.1, 95% CI: 104.3, 107.9) and PAF, but low PSF. (2) Low-cognitive-functioning (n = 223), with the lowest IQ (Mean = 73.9, 95% CI: 72.2, 75.7) and PAF, but normal PSF. (3) Intermediate (n = 224) (Mean_IQ = 80.8, 95% CI: 79.1, 82.5) with low-improving PAF and PSF. 4) Deteriorating (n = 150) (Mean_IQ = 80.6, 95% CI: 78.5, 82.7), with normal-deteriorating PAF and PSF. The PRSs explained 7.9% of between-group membership. FEP had higher SCZ_PRS than controls [F(4,1319) = 20.4, P < .001]. Among the clusters, the deteriorating group had lower SCZ_PRS and was likelier to have used high-potency cannabis daily. Patients with FEP clustered according to their premorbid and cognitive abilities. Pronounced premorbid deterioration was not typical of most FEP, including those more strongly predisposed to schizophrenia, but appeared in a cluster with a history of high-potency cannabis use.

A twin study of schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes.

The nosological status of schizoaffective disorders remains controversial. Twin studies are potentially valuable for investigating relationships between schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes, but no such study has yet been reported. We ascertained 224 probandwise twin pairs [106 monozygotic (MZ), 118 same-sex dizygotic (DZ)], where probands had psychotic or manic symptoms, from the Maudsley Twin Register in London (1948-1993). We investigated Research Diagnostic Criteria schizoaffective-mania, schizoaffective-depression, schizophrenia, mania and depressive psychosis primarily using a non-hierarchical classification, and additionally using hierarchical and data-derived classifications, and a classification featuring broad schizophrenic and manic syndromes without separate schizoaffective syndromes. We investigated inter-rater reliability and co-occurrence of syndromes within twin probands and twin pairs. The schizoaffective syndromes showed only moderate inter-rater reliability. There was general significant co-occurrence between syndromes within twin probands and MZ pairs, and a trend for schizoaffective-mania and mania to have the greatest co-occurrence. Schizoaffective syndromes in MZ probands were associated with relatively high risk of a psychotic syndrome occurring in their co-twins. The classification of broad schizophrenic and manic syndromes without separate schizoaffective syndromes showed improved inter-rater reliability, but high genetic and environmental correlations between the two broad syndromes. The results are consistent with regarding schizoaffective-mania as due to co-occurring elevated liability to schizophrenia, mania, and depression; and schizoaffective-depression as due to co-occurring elevated liability to schizophrenia and depression, but with less elevation of liability to mania. If in due course schizoaffective syndromes show satisfactory inter-rater reliability and some specific etiological factors they could alternatively be regarded as partly independent disorders.

Heritability estimates for psychotic symptom dimensions in twins with psychotic disorders.

Factor analysis of psychotic symptoms frequently results in positive, negative, and disorganized dimensions, but heritability estimates have not yet been reported. Symptom dimensions are usually only measured in individuals with psychotic disorders. Here, it is valuable to assess influences acting via liability to psychosis and independent modifying effects. We estimated heritability for psychotic symptom dimensions, taking account of these issues. Two-hundred-and-twenty-four probandwise twin pairs (106 monozygotic, 118 same-sex dizygotic), where probands had psychoses, were ascertained from the Maudsley Twin Register in London (1948-1993). Lifetime history of DSM-III-R psychotic disorder and psychotic symptom dimensions was assessed from clinical records and research interviews and rated using the Operational Criteria Checklist. Estimates of heritability and environmental components of variance in liability were made with structural equation modeling using a causal-contingent common pathway model adapted for ascertainment from a clinical register. Significant heritability was found for DSM-III-R psychotic disorder (h² = 90%, 95%CI 68-94%) and the disorganized symptom dimension (h² = 84%, 95%CI 18-93%). The heritability for the disorganized dimension remained significant when influences acting through liability to psychosis were set to zero, suggesting that some influences on disorganization are modifying factors independent of psychosis liability. However, the relative extent of modifying factors versus influences acting through psychosis liability could not be clearly determined. To our knowledge, this study provides the first formal evidence of substantive heritability for the disorganized symptom dimension, and suggests that genetic loci influencing disorganization in individuals with psychoses are in some cases different from loci that influence risk of psychotic disorders themselves.

Phenotype evaluation and genomewide linkage study of clinical variables in schizophrenia.

Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.

Psychotic-Like Experiences in Adolescence Occurring in Combination or Isolation: Associations with Schizophrenia Risk Factors.

OBJECTIVES: Individual adolescent psychotic-like experiences (PLEs) are associated with schizophrenia risk factors. As DSM-5 schizophrenia requires the co-occurrence of at least two psychotic symptoms, we investigated whether co-occurring adolescent PLEs have stronger associations with schizophrenia risk factors, lower quality of life and functioning, and have higher heritability, than individual PLEs. METHODS: Participants were 9646 16-year-old twins from the longitudinal Twins Early Development Study. We investigated co-occurrence of high questionnaire scores for three PLE combinations: (1) paranoia and hallucinations; (2) paranoia or hallucinations, and cognitive disorganization; and (3) paranoia or hallucinations, and negative symptoms, and their associations with 11 schizophrenia-relevant variables by regression analysis and structural equation twin modeling. RESULTS: Against expectation, none of the co-occurring PLEs had the nominally strongest associations significantly more often than individual PLEs. Co-occurring PLEs had the strongest associations with bullying victimization, cannabis use and lower life satisfaction, but individual PLEs had the strongest associations with cognitive function variables. Obstetric complications were most associated with negative symptoms. Secondary analysis revealed that co-occurrence of cognitive disorganization and negative symptoms had the nominally strongest associations with most schizophrenia-relevant variables overall and relatively high heritability (67%). CONCLUSIONS: Focusing on co-occurrence enhances some individual PLE associations but obscures others. The combination of subjective cognitive disorganization plus observed negative symptoms showed a broad range of enhanced associations with schizophrenia-relevant variables. Future research could investigate associations with other risk factors and the ability of this PLE combination to predict onset of schizophrenia.

Culturally adapted psychotherapies for depressed adults: A systematic review and meta-analysis.

BACKGROUND: There is current debate about the effectiveness and generalizability of evidence-based psychological therapies in treatment of depression for diverse ethno-cultural groups. This has led to increasing interest in culturally adapted psychotherapies (CAPs). METHODS: Studies on CAPs for face-to-face treatment of depressed adults were identified using nine electronic database searches. Data on the process of adaptation was analysed using thematic analysis and treatment efficacy was assessed through meta-analysis of Randomized Controlled Trials. RESULTS: Fifteen studies were included in the review, of which eight were included in a meta-analysis. Cognitive Behavioural Therapy and Behavioural Activation were commonly selected approaches for CAPs, mainly based on their strong evidence base for effectiveness. Twelve studies reported the adaptation process that follows all or some phases recommended by the Medical Research Council Framework for developing complex interventions. A meta-analysis of 16 RCTs, which included eight studies from the current review and eight studies from an earlier review (Chowdhary et al. (2014), demonstrated a statistically significant benefit in favour of CAPs, reducing symptom burden [standardized mean difference -0.63, 95% confidence interval -0.87 to -0.39]. Subgroup analysis showed a larger effect when the intervention was for the majority ethnic group in a population, rather than a minority group. LIMITATIONS: Some studies did not report all relevant information, and in the subgroup analysis only three studies were of minority groups. CONCLUSIONS: CAPs were confirmed to be more efficacious than control treatments. This supports the continued development and evaluation of culturally adapted psychotherapies for depression.