Deconstructing the genetic architecture of treatment-resistant schizophrenia in East Asian ancestry.

BACKGROUND: Treatment-resistant schizophrenia (TRS) affects a substantial proportion of patients who do not respond adequately to antipsychotic medications, yet the underlying biological mechanism remains poorly understood. This study investigates the link between the genetic predisposition to schizophrenia and TRS. METHODS: 857 individuals diagnosed with schizophrenia were divided into TRS (n = 142) and non-TRS (n = 715) based on well-defined TRS criteria. Polygenic risk scores (PRS) were calculated using schizophrenia genome-wide association summary statistics from East-Asian and European ancestry populations. PRS was estimated using both P-value thresholding and Bayesian framework methods. Logistic regression analyses were performed to differentiate between TRS and non-TRS individuals. RESULTS: The schizophrenia PRS derived from the East-Asian training dataset effectively distinguished between TRS and non-TRS individuals (R2 = 0.029, p = 4.86 ×10-5, pT = 0.1, OR = 1.52, 95% CI = 1.242-1.861), with higher PRS values observed in the TRS group. Similar PRS analysis was conducted based on the European ancestry GWAS summary statistics, but we found superior prediction based on the East-Asian ancestry discovery data. CONCLUSION: This study reveals an association between common risk variants for schizophrenia and TRS status, suggesting that the genetic burden of schizophrenia may partly contribute to treatment resistance in individuals with schizophrenia. These findings propose the potential use of genetic risk factors for early TRS identification and timely access to clozapine. However, the ancestral background of the discovery sample is crucial for successfully implementing PRS in clinical settings.

Impact of Cognitive Impairments on Health-Related Quality of Life in Schizophrenia.

The impact of cognitive impairments on the health-related quality of life (HRQoL) in individuals with schizophrenia is unclear. The aim of this study was to examine the association between cognitive impairments and HRQoL in individuals with schizophrenia. A total of 609 individuals with schizophrenia were assessed on the Positive and Negative Syndrome Scale (PANSS) and a neurocognitive battery which comprised of the Wechsler Abbreviated Scale of Intelligence matrix reasoning, the Benton Judgment of Line Orientation Test, Continuous Performance Tests-Identical Pairs, and the Brief Assessment of Cognition in Schizophrenia. A cognitive factor g was derived from the neurocognitive battery. EuroQol five-dimensional (EQ-5D-5L) utility scores were derived from PANSS scores via a previously validated algorithm and used as a measure of HRQoL. Hierarchical multiple regression was conducted to examine the association between cognitive factor g and the EQ-5D-5L. Cognitive factor g (ß = 0.189, t = 4.956, p < 0.001) was found to be significantly associated with EQ-5D-5L scores. Age (ß = -0.258, t = -6.776, p < 0.001), sex (ß = 0.081, t = 2.117, p = 0.035), and being employed (ß = 0.091, t = 2.317, p = 0.021) were also significant predictors of EQ-5D-5L. Our results add to the extant literature on the burden cognitive impairments exact in individuals with schizophrenia. More research is needed to develop effective interventions for cognitive impairments in schizophrenia.

Social skills, negative symptoms and real-world functioning in individuals at ultra-high risk of psychosis.

BACKGROUND: Impairment in real-world social functioning is observed in individuals at Ultra-High Risk (UHR) of psychosis. Both social skills and negative symptoms appear to influence real-world functioning. This study aims to examine the psychometric properties of a social skills measure, the High-Risk Social Challenge task (HiSoC), and evaluate the relationship between social skills, negative symptoms, and real-world functioning in UHR individuals. METHODS: HiSoC data was analysed in 87 UHR individuals and 358 healthy controls. Exploratory factor analysis (EFA) was used to evaluate the factor structure of the HiSoC task. Convergent and divergent validity were assessed. Negative symptoms were assessed on the Positive and Negative Syndrome Scale (PANSS) and real-world functioning was indexed by the Global Assessment of Functioning (GAF). Commonality analysis was used to partition unique and shared variance of HiSoC and negative symptoms with real-world functioning. RESULTS: EFA yielded a three-factor structure of HiSoC consisting of Affect, Odd behaviour and language, and Social-interpersonal. The HiSoC task discriminated UHR and healthy controls (p < 0.001, Cohen's d = 0.437-0.598). Commonality analysis revealed that the unique variance of the social amotivation subdomain of negative symptoms was the strongest predictor of GAF (p < .001, R2 = .480). Shared variance of 3.7% between HiSoC Social-interpersonal and social amotivation was observed in relation to functioning. CONCLUSION: The HiSoC is a psychometrically valid task that is sensitive to identify social skill deficits in UHR. While social skills are related to functioning, experiential negative symptoms appear to be an important target for improving real-world functional outcomes.

Comparative study of emotion recognition and theory of mind between major depressive disorder and schizophrenia.

BACKGROUND: Social cognition as a transdiagnostic construct between major depressive disorder (MDD) and schizophrenia (SCZ) is not well understood. This may be attributed to the variability of social cognitive measures indexing the same construct. This study aims to compare emotion recognition and theory of mind domains, known to be impaired in SCZ, between MDD and SCZ. METHODS: Three groups of participants (NTotal = 150) were enrolled in this study: MDD (n = 51), SCZ (n = 50) and healthy controls (HC; n = 49). Emotion recognition was assessed on the Bell Lysaker Emotion Recognition Task (BLERT) and Penn Emotion Recognition Task (ER40); theory of mind was measured on The Awareness of Social Inference Test (TASIT). Mixed ANCOVAs were utilised to compare social cognitive performance across the groups. RESULTS: SCZ performed poorer in all 3 social cognition tasks compared to both MDD and HC. No statistically significant difference in social cognitive performance was observed between MDD and HC. CONCLUSIONS: This study serves as an effort towards employing the same standardised social cognitive measures for direct comparison of performance patterns across diagnostic groups. Future work is needed to extend this in larger samples of different illness severity and diagnostic categories.

Genome wide study of tardive dyskinesia in schizophrenia.

Tardive dyskinesia (TD) is a severe condition characterized by repetitive involuntary movement of orofacial regions and extremities. Patients treated with antipsychotics typically present with TD symptomatology. Here, we conducted the largest GWAS of TD to date, by meta-analyzing samples of East-Asian, European, and African American ancestry, followed by analyses of biological pathways and polygenic risk with related phenotypes. We identified a novel locus and three suggestive loci, implicating immune-related pathways. Through integrating trans-ethnic fine mapping, we identified putative credible causal variants for three of the loci. Post-hoc analysis revealed that SNPs harbored in TNFRSF1B and CALCOCO1 independently conferred three-fold increase in TD risk, beyond clinical risk factors like Age of onset and Duration of illness to schizophrenia. Further work is necessary to replicate loci that are reported in the study and evaluate the polygenic architecture underlying TD.

Large-scale evaluation of the Positive and Negative Syndrome Scale (PANSS) symptom architecture in schizophrenia.

Although the Positive and Negative Syndrome Scale (PANSS) is widely utilized in schizophrenia research, variability in specific item loading exist, hindering reproducibility and generalizability of findings across schizophrenia samples. We aim to establish a common PANSS factor structure from a large multi-ethnic sample and validate it against a meta-analysis of existing PANSS models. Schizophrenia participants (N = 3511) included in the current study were part of the Singapore Translational and Clinical Research Program (STCRP) and the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE). Exploratory Factor Analysis (EFA) was conducted to identify the factor structure of PANSS and validated with a meta-analysis (N = 16,171) of existing PANSS models. Temporal stability of the PANSS model and generalizability to individuals at ultra-high risk (UHR) of psychosis were evaluated. A five-factor solution best fit the PANSS data. These were the i) Positive, ii) Negative, iii) Cognitive/disorganization, iv) Depression/anxiety and v) Hostility factors. Convergence of PANSS symptom architecture between EFA model and meta-analysis was observed. Modest longitudinal reliability was observed. The schizophrenia derived PANSS factor model fit the UHR population, but not vice versa. We found that two other domains, Social Amotivation (SA) and Diminished Expression (DE), were nested within the negative symptoms factor. Here, we report one of the largest transethnic factorial structures of PANSS symptom domains (N = 19,682). Evidence reported here serves as crucial consolidation of a common PANSS structure that could aid in furthering our understanding of schizophrenia.

Cognitive Subtyping in Schizophrenia: A Latent Profile Analysis.

Cognitive dysfunction is a core feature of schizophrenia. The subtyping of cognitive performance in schizophrenia may aid the refinement of disease heterogeneity. The literature on cognitive subtyping in schizophrenia, however, is limited by variable methodologies and neuropsychological tasks, lack of validation, and paucity of studies examining longitudinal stability of profiles. It is also unclear if cognitive profiles represent a single linear severity continuum or unique cognitive subtypes. Cognitive performance measured with the Brief Assessment of Cognition in Schizophrenia was analyzed in schizophrenia patients (n = 767). Healthy controls (n = 1012) were included as reference group. Latent profile analysis was performed in a schizophrenia discovery cohort (n = 659) and replicated in an independent cohort (n = 108). Longitudinal stability of cognitive profiles was evaluated with latent transition analysis in a 10-week follow-up cohort. Confirmatory factor analysis (CFA) was carried out to investigate if cognitive profiles represent a unidimensional structure. A 4-profile solution was obtained from the discovery cohort and replicated in an independent cohort. It comprised of a "less-impaired" cognitive subtype, 2 subtypes with "intermediate cognitive impairment" differentiated by executive function performance, and a "globally impaired" cognitive subtype. This solution showed relative stability across time. CFA revealed that cognitive profiles are better explained by distinct meaningful profiles than a severity linear continuum. Associations between profiles and negative symptoms were observed. The subtyping of schizophrenia patients based on cognitive performance and its associations with symptomatology may aid phenotype refinement, mapping of specific biological mechanisms, and tailored clinical treatments.

Genetic liability in individuals at ultra-high risk of psychosis: A comparison study of 9 psychiatric traits.

Individuals at ultra-high risk (UHR) of psychosis are characterised by the emergence of attenuated psychotic symptoms and deterioration in functioning. In view of the high non-psychotic comorbidity and low rates of transition to psychosis, the specificity of the UHR status has been called into question. This study aims to (i) investigate if the UHR construct is associated with the genetic liability of schizophrenia or other psychiatric conditions; (ii) examine the ability of polygenic risk scores (PRS) to discriminate healthy controls from UHR, remission and conversion status. PRS was calculated for 210 youths (nUHR = 102, nControl = 108) recruited as part of the Longitudinal Youth at Risk Study (LYRIKS) using nine psychiatric traits derived from twelve large-scale psychiatric genome-wide association studies as discovery datasets. PRS was also examined to discriminate UHR-Healthy control status, and healthy controls from UHR remission and conversion status. Result indicated that schizophrenia PRS appears to best index the genetic liability of UHR, while trend level associations were observed for depression and cross-disorder PRS. Schizophrenia PRS discriminated healthy controls from UHR (R2 = 7.9%, p = 2.59 x 10-3, OR = 1.82), healthy controls from non-remitters (R2 = 8.1%, p = 4.90 x 10-4, OR = 1.90), and converters (R2 = 7.6%, p = 1.61 x 10-3, OR = 1.82), with modest predictive ability. A trend gradient increase in schizophrenia PRS was observed across categories. The association between schizophrenia PRS and UHR status supports the hypothesis that the schizophrenia polygenic liability indexes the risk for developing psychosis.

Evaluation of social cognitive measures in an Asian schizophrenia sample.

BACKGROUND: Converging evidence has indicated that deficits in social cognition may manifest as poor functioning; therefore, social cognition has emerged as an important research area and treatment target. However, few studies have examined the psychometrics of multiple social cognition measures in an Asian population. This study aims to evaluate the psychometrics of measures indexing the four core social cognition domains. METHODS: Schizophrenia outpatients (n = 116) and healthy controls (n = 73) completed a battery of nine social cognitive measures, twice, four weeks apart. Psychometric properties were examined via test-retest reliability, internal consistency, utility as a repeated measure, time administration, and tolerability. Logistic regression was performed to identify psychometrically sound tasks that best discriminated case-control status. PCA was conducted to explore social cognition dimensional structure. RESULTS: The Bell Lysaker Emotion Recognition Task (BLERT), Penn Emotion Recognition Task (ER40), and The Awareness of Social Inference Test, branch III (TASIT-3) showed strongest psychometrics. The Ambiguous Intentions and Hostility Questionnaire, Hostility Bias subscale (AIHQ-HB) showed slightly weaker properties, requiring further evaluation. The Hinting task, Mini Profile of Nonverbal Sensitivity (MiniPONS), Relationships Across Domains (RAD), Internal Personal and Situational Attributions Questionnaire (IPSAQ), and Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) showed poorer psychometrics in our sample. PCA revealed a two-factor solution comprising social cognition skills and attributional style/bias. CONCLUSION: Here, we examined the psychometric properties of a comprehensive social cognition battery based on the SCOPE study in an Asian schizophrenia population. Continued evaluation and standardization of social cognitive measures are needed to refine our understanding of this construct in schizophrenia.

Factor structure of the positive and negative syndrome scale (PANSS) in people at ultra high risk (UHR) for psychosis.

INTRODUCTION: The Positive and Negative Syndrome Scale (PANSS), a comprehensive psychopathology assessment scale used in the evaluation of psychopathology in schizophrenia, is also often used in the Ultra-High-Risk (UHR) population. This paper examined the dimensional structure of the PANSS in a UHR sample. METHODS: A total of 168 individuals assessed to be at UHR for psychosis on the Comprehensive Assessment of At-Risk Mental States (CAARMS) were evaluated on the PANSS, Calgary Depression Scale for Schizophrenia (CDSS), Beck Anxiety Inventory (BAI), Brief Assessment of Cognition in Schizophrenia (BACS), and Global Assessment of Functioning (GAF). Exploratory factor analysis (EFA) of the PANSS was performed to identify the factorial structure. Convergent validity was explored with the CAARMS, CDSS, BAI and BACS. RESULTS: EFA of the PANSS yielded five symptom factors - Positive, Negative, Cognition/Disorganization, Anxiety/Depression, and Hostility. This 5-factor solution showed good convergent validity with the CAARMS composite score, CDSS, BAI, and BACS. Positive, Negative and Anxiety/Depression factors were associated with functioning. CONCLUSION: The reported PANSS factor structure may serve to improve the understanding and measurement of clinical symptom dimensions manifested in people with UHR for future research and clinical setting.

A Systematic Review of the Effectiveness of Medical Cannabis for Psychiatric, Movement and Neurodegenerative Disorders.

The discovery of endocannabinoid's role within the central nervous system and its potential therapeutic benefits have brought forth rising interest in the use of cannabis for medical purposes. The present review aimed to synthesize and evaluate the available evidences on the efficacy of cannabis and its derivatives for psychiatric, neurodegenerative and movement disorders. A systematic search of randomized controlled trials of cannabis and its derivatives were conducted via databases (PubMed, Embase and the Cochrane Central Register of Controlled Trials). A total of 24 reports that evaluated the use of medical cannabis for Alzheimer's disease, anorexia nervosa, anxiety, dementia, dystonia, Huntington's disease, Parkinson's disease, post-traumatic stress disorder (PTSD), psychosis and Tourette syndrome were included in this review. Trial quality was assessed with the Cochrane risk of bias tool. There is a lack of evidence on the therapeutic effects of cannabinoids for amyotrophic lateral sclerosis and dystonia. Although trials with positive findings were identified for anorexia nervosa, anxiety, PTSD, psychotic symptoms, agitation in Alzheimer's disease and dementia, Huntington's disease, and Tourette syndrome, and dyskinesia in Parkinson's disease, definitive conclusion on its efficacy could not be drawn. Evaluation of these low-quality trials, as rated on the Cochrane risk of bias tools, was challenged by methodological issues such as inadequate description of allocation concealment, blinding and underpowered sample size. More adequately powered controlled trials that examine the long and short term efficacy, safety and tolerability of cannabis for medical use, and the mechanisms underpinning the therapeutic potential are warranted.