Max Lam

Impact of psychiatric comorbidity in individuals at Ultra High Risk of psychosis — Findings from the Longitudinal Youth at Risk Study (LYRIKS)

Recent studies have reported a high prevalence of psychiatric comorbidities in Ultra High Risk (UHR) for psychosis populations. This study examined the prevalence of comorbidity and its impact on symptoms, functioning, cognition and transition to psychosis in the Longitudinal Youth at Risk Study (LYRIKS) sample. The Comprehensive Assessment of At-Risk Mental State (CAARMS) was used to identify UHR individuals and 163 participants were included in the study. Comorbid disorders were identified using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders. Participants were evaluated on the CAARMS, Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, Beck Anxiety Inventory, Global Assessment of Functioning and Brief Assessment of Cognition in Schizophrenia. Clinical, functioning and cognitive characteristics by lifetime and current comorbidity groups were compared using multivariate tests. Independent predictors of comorbidity were identified through logistic regression. Chi-squared tests were used to compare comorbidity rates between those who had developed psychosis at one year and those who had not. We found that 131 UHR participants (80.4%) had a lifetime comorbidity while 82 (50.3%) had a current comorbidity with depressive disorders being the most common. UHR individuals with comorbidity had more severe symptoms, higher distress and lower functioning with no differences in general cognition. Lower functioning was associated with current comorbidity. Eleven participants (6.7%) had developed psychosis after one year and there were no differences in the comorbidity rates between those who developed psychosis and those who did not. Psychiatric comorbidities in the UHR group are associated with adverse clinical outcomes and warrant closer attention.

The Longitudinal Youth at Risk Study (LYRIKS) — An Asian UHR perspective

Numerous studies have been published on the psychosis prodrome and have explored a wide array of its many aspects. However, the set of risk factors identified by these various efforts is not homogenous across studies. This could be due to unique population factors or relatively small sample sizes. Only few studies were conducted on Asian populations, whose socio-cultural characteristics differ - in some cases remarkably - from those in western populations. Singapore is a highly dense city-state in South-east Asia, with low rates of substance abuse. The Longitudinal Youth at Risk Study (LYRIKS) commenced in Singapore in 2008, designed to comprehensively assess a group of ultra high risk (UHR) individuals and identify clinical, social, neuropsychological and biological risk factors unique to the local population. 173 UHR individuals were recruited from this single-site study over 4 years. Here, we detail aspects of the study methodology and report on the baseline social and clinical characteristics of the sample population. 78% of the UHR sample suffered from a psychiatric disorder, with Major Depressive Disorder present in more than half of the sample. The mean Global Assessment of Functioning (GAF) score was 57.4, which indicated a moderate level of impairment. Although the recruited sample did not differ significantly by social and clinical characteristics when compared to previously published reports, the conversion rate to psychosis was 3.5% (n=6) at 6 months. Follow-up measures are currently underway to assess longitudinal incidence of psychosis and impact of risk factors on cognition, functioning and remission.

Body mass index, obesity, and psychopathology in patients with schizophrenia.

Abstract A number of studies have reported that patients with schizophrenia have a higher body mass index (BMI) than the general population. Few Asian studies have examined BMI in patients with schizophrenia. The aims of the current study were to evaluate the distribution of BMI and prevalence of obesity in a large sample of Chinese patients with schizophrenia (n = 973) and to examine the sociodemographic and clinical correlates of overweight (BMI ≥25 kg/m2) and obesity (BMI ≥30 kg/m2). There was a preponderance of patients who were overweight (58.7%) and obese (73.6%) as compared with control subjects. Regression modeling of clinical and symptom factors in schizophrenia patients revealed that females were almost twice as likely to be obese compared with males and patients with comorbid medical conditions were more likely to be obese compared with those who did not have a comorbid medical condition (odds ratio, 1.6). Those prescribed typical antipsychotic medications were 1.7 times more likely to be obese, whereas individuals prescribed with both typical and atypical antipsychotic medications were 2.2 times more likely to be obese as compared with those prescribed atypical antipsychotics. A significant predictor interaction for obesity was observed between sex and typical antipsychotics, sex and comorbid medical conditions, and years of education and comorbid medical conditions. The higher prevalence of obesity in patients with schizophrenia is a matter of clinical and public health concern; interventions to reduce weight to healthy levels would result in both improved health and quality of life among patients with schizophrenia.

Unraveling the relationship between obesity, schizophrenia and cognition

INTRODUCTION Previous studies investigating the relationship between obesity and cognition as well as gender differences in these relationships reported equivocal results. Here, we examined age, years of education, schizophrenia, and gender differences which might affect the relationship between obesity and cognition. METHODS 1012 healthy controls and 707 participants with schizophrenia were recruited. Information on body mass index (BMI) was obtained and a neurocognitive battery was administered. Structural equation modeling (SEM) was performed to examine the relationship between BMI, schizophrenia, cognition and its covariates. RESULTS No significant direct effect of BMI on cognition was found when cognition was regressed on age, years of education, diagnosis of schizophrenia and BMI. Instead, two SEM models indicated that indirect effects between BMI and cognition exist. The indirect effect of BMI on cognition through schizophrenia was present in both genders, while the indirect effect of cognition on BMI through schizophrenia was only found in females. BMI affecting cognition through age, years of education and schizophrenia appears to be the most plausible model that explains the data. This indirect effect was larger in females and was masked by diagnosis of schizophrenia. CONCLUSION With increased rates of obesity in schizophrenia, it is important to highlight the potentially deleterious effect of obesity on cognition. BMI could be used as a candidate risk marker to identify people at higher risk of cognitive deficits, and as an intervention target for modifications of cognitive outcomes.

Formulation of the age-education index: measuring age and education effects in neuropsychological performance

The complex interplay of education, age, and cognitive performance on various neuropsychological tests is examined in the current study. New education indices were formulated and further investigated to reveal how age and education variances work together to account for performance on neuropsychological tests. Participants were 830 English-speaking ethnic Chinese. Neuropsychological measures such as Verbal Memory, Digit Sequencing, Token Motor Task, Semantic Fluency, Symbol Coding, Tower of London, Judgment of Line Orientation, and Matrix Reasoning of the Wechsler Adult Intelligence Scale were administered. Education was measured by total years of education and adjusted years of education, as well as ratios of both measures with age. Age and education were associated with neuropsychological performance. Adjusted years of education was associated with fluency and higher cognitive processes, while the ratio between adjusted years of education and age was associated with tasks implicating working memory. Changes in education modalities implicated tasks requiring language abilities. Education and age represent key neurodevelopmental milestones. In light of our findings, special consideration should to be given when neuropsychological assessments are carried out in cross-cultural contexts and in societies where educational systems and pedagogy tend to be complex.

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.Gene discovery and polygenic predictions from a genome-wide association study of educational attainment in 1.1 million individuals.

Heritability of Neuropsychological Measures in Schizophrenia and Nonpsychiatric Populations: A Systematic Review and Meta-analysis

Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%-67%), Verbal Ability (43%-72%), Visuospatial Ability (20%-80%), and Attention/Processing Speed (28%-74%), while the lowest heritability was observed for Executive Function (20%-40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average rg = -.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population.

Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function

Importance Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. Objective To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Design, Setting, and Participants Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888). Main Outcomes and Measures Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Results Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 × 10−7), general cognitive function (z score, –4.43; P = 9.42 × 10−6), and verbal-numerical reasoning (z score, –5.43; P = 5.64 × 10−8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. Conclusions and Relevance The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

Refining the latent structure of neuropsychological performance in schizophrenia.

BACKGROUND Elucidating the cognitive architecture of schizophrenia promises to advance understanding of the clinical and biological substrates of the illness. Traditional cross-sectional neuropsychological approaches differentiate impaired from normal cognitive abilities but are limited in their ability to determine latent substructure. The current study examined the latent architecture of abnormal cognition in schizophrenia via a systematic approach. METHOD Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were carried out on a large neuropsychological dataset including the Brief Assessment of Cognition in Schizophrenia, Continuous Performance Test, Wisconsin Card Sorting Test, Benton Judgment of Line Orientation Test, and Wechsler Abbreviated Scale of Intelligence matrix reasoning derived from 1012 English-speaking ethnic Chinese healthy controls and 707 schizophrenia cases recruited from in- and out-patient clinics. RESULTS An initial six-factor model fit cognitive data in healthy and schizophrenia subjects. Further modeling, which accounted for methodological variance between tests, resulted in a three-factor model of executive functioning, vigilance/speed of processing and memory that appeared to best discriminate schizophrenia cases from controls. Factor analytic-derived g estimands and conventionally calculated g showed similar case-control discrimination. However, agreement analysis suggested systematic differences between both g indices. CONCLUSIONS Factor structures derived in the current study were broadly similar to those reported previously. However, factor structures between schizophrenia subjects and healthy controls were different. Roles of factor analytic-derived g estimands and conventional composite score g were further discussed. Cognitive structures underlying cognitive deficits in schizophrenia may prove useful for interrogating biological substrates and enriching effect sizes for subsequent work.

Asymmetry of lexico-semantic processing in schizophrenia changes with disease progression

BACKGROUND Are anomalies of cerebral asymmetry integral to the disease process? Here, we examined the influence of age, chronicity and age of onset of illness in 34 patients with early onset schizophrenia and 20 controls in relation to structural asymmetries of the temporal lobe and performance asymmetries on a semantic language lexical decision task. METHODS Volumetric MRI and a novel divided visual field probe of lateralised lexico-semantic language were assessed in patients with early onset schizophrenia (EOS) and controls. Novel ratios of age-illness overlap and directional asymmetry were developed in order to examine the association of chronicity factors to asymmetry. RESULTS Loss of laterality on the lexical decision task and discordant structural asymmetry were correlated with duration of illness but were not seen in younger, less chronic patients. Reduced lateral processing speed, and discordant structural asymmetry were associated with greater proportion of lifetime schizophrenia. CONCLUSION Although the conclusions are limited by the cross sectional nature of the study, anomalies of cerebral asymmetry in early onset patients may be an index of disease progression, and reflect directly on the disease process.