Genetic diversity fuels gene discovery for tobacco and alcohol use.

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

Associations between polygenic risk of substance use and use disorder and alcohol, cannabis, and nicotine use in adolescence and young adulthood in a longitudinal twin study.

BACKGROUND: Recent well-powered genome-wide association studies have enhanced prediction of substance use outcomes via polygenic scores (PGSs). Here, we test (1) whether these scores contribute to prediction over-and-above family history, (2) the extent to which PGS prediction reflects inherited genetic variation v. demography (population stratification and assortative mating) and indirect genetic effects of parents (genetic nurture), and (3) whether PGS prediction is mediated by behavioral disinhibition prior to substance use onset. METHODS: PGSs for alcohol, cannabis, and nicotine use/use disorder were calculated for Minnesota Twin Family Study participants (N = 2483, 1565 monozygotic/918 dizygotic). Twins' parents were assessed for histories of substance use disorder. Twins were assessed for behavioral disinhibition at age 11 and substance use from ages 14 to 24. PGS prediction of substance use was examined using linear mixed-effects, within-twin pair, and structural equation models. RESULTS: Nearly all PGS measures were associated with multiple types of substance use independently of family history. However, most within-pair PGS prediction estimates were substantially smaller than the corresponding between-pair estimates, suggesting that prediction is driven in part by demography and indirect genetic effects of parents. Path analyses indicated the effects of both PGSs and family history on substance use were mediated via disinhibition in preadolescence. CONCLUSIONS: PGSs capturing risk of substance use and use disorder can be combined with family history measures to augment prediction of substance use outcomes. Results highlight indirect sources of genetic associations and preadolescent elevations in behavioral disinhibition as two routes through which these scores may relate to substance use.

Genetic correlation, pleiotropy, and causal associations between substance use and psychiatric disorder.

BACKGROUND: Substance use occurs at a high rate in persons with a psychiatric disorder. Genetically informative studies have the potential to elucidate the etiology of these phenomena. Recent developments in genome-wide association studies (GWAS) allow new avenues of investigation. METHOD: Using results of GWAS meta-analyses, we performed a factor analysis of the genetic correlation structure, a genome-wide search of shared loci, and causally informative tests for six substance use phenotypes (four smoking, one alcohol, and one cannabis use) and five psychiatric disorders (ADHD, anorexia, depression, bipolar disorder, and schizophrenia). RESULTS: Two correlated externalizing and internalizing/psychosis factor were found, although model fit was beneath conventional standards. Of 458 loci reported in previous univariate GWAS of substance use and psychiatric disorders, about 50% (230 loci) were pleiotropic with additional 111 pleiotropic loci not reported from past GWAS. Of the 341 pleiotropic loci, 152 were associated with both substance use and psychiatric disorders, implicating neurodevelopment, cell morphogenesis, biological adhesion pathways, and enrichment in 13 different brain tissues. Seventy-five and 114 pleiotropic loci were specific to either psychiatric disorders or substance use phenotypes, implicating neuronal signaling pathway and clathrin-binding functions/structures, respectively. No consistent evidence for phenotypic causation was found across different Mendelian randomization methods. CONCLUSIONS: Genetic etiology of substance use and psychiatric disorders is highly pleiotropic and involves shared neurodevelopmental path, neurotransmission, and intracellular trafficking. In aggregate, the patterns are not consistent with vertical pleiotropy, more likely reflecting horizontal pleiotropy or more complex forms of phenotypic causation.

Personality Traits in Individuals with the Dual Diagnosis of Psychosis and Substance Use Disorders: A Comprehensive Review and Meta-Analysis.

OBJECTIVE: Substance abuse comorbidity is highly prevalent and is linked to detrimental outcomes in individuals with psychotic disorder, but the role of personality traits as the underlying mechanism is being increasingly underscored. This study aimed to profile temperamental risks of comorbid substance use disorder in psychotic disorders by performing meta-analyses on personality trait differences between psychotic disorders with comorbidity (dual diagnosis; DD) and without it (psychotic disorders; PSD). Methods: A systematic review of English articles using PubMed, MEDLINE, Scopus, Google Scholar, and ProQuest Dissertation and Theses. Only original empirical studies including participants with diagnosis of psychotic disorders based on structured diagnostic interviews, with and without substance use disorder evaluated with reliable and valid tests were included. Articles were independently extracted by two authors using predefined data fields, including study quality indicators. All pooled analyses were based on random-effect models. Thirteen studies (N = 885) met our inclusion criteria. All effect-size estimates were calculated based on means and standard deviations of included measures. Separate effect size estimates were obtained for four traits in the UPPS model (negative urgency, low premeditation, low perseverance, sensation seeking), four traits in the HS model (unconscientious disinhibition, negative affect, disagreeable disinhibition, positive affect) and trait anhedonia. Results: Negative urgency (four studies with 262 participants; ES = 0.59; 95% confidence interval [CI] [0.34, 0.84]), low premeditation (five studies with 349 participants; ES = 0.60; 95% CI [0.39, 0.80]), sensation seeking (seven studies with 550 participants; ES = 0.63; 95% CI [0.17, 1.09]) and unconscientious disinhibition (five studies with 291 participants; ES = 0.36; 95% CI [0.13, 0.59]) were elevated in DD than PSD. Heterogeneity of sensation seeking was significant (I2 = 86.2%). Conclusions: The findings of the current meta-analysis highlight a unique profile of impulsive and externalizing trait personality domains pertaining to DD. The study emphasizes the importance of emotion regulation interventions targeting impulsivity or negative affect (i.e. negative urgency, low premeditation) in substance abuse comorbidity patients.

Attention and memory bias to facial emotions underlying negative symptoms of schizophrenia.

INTRODUCTION: This study assessed bias in selective attention to facial emotions in negative symptoms of schizophrenia and its influence on subsequent memory for facial emotions. METHODS: Thirty people with schizophrenia who had high and low levels of negative symptoms (n = 15, respectively) and 21 healthy controls completed a visual probe detection task investigating selective attention bias (happy, sad, and angry faces randomly presented for 50, 500, or 1000 ms). A yes/no incidental facial memory task was then completed. Attention bias scores and recognition errors were calculated. RESULTS: Those with high negative symptoms exhibited reduced attention to emotional faces relative to neutral faces; those with low negative symptoms showed the opposite pattern when faces were presented for 500 ms regardless of the valence. Compared to healthy controls, those with high negative symptoms made more errors for happy faces in the memory task. Reduced attention to emotional faces in the probe detection task was significantly associated with less pleasure and motivation and more recognition errors for happy faces in schizophrenia group only. CONCLUSIONS: Attention bias away from emotional information relatively early in the attentional process and associated diminished positive memory may relate to pathological mechanisms for negative symptoms.

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Alcohol and nicotine polygenic scores are associated with the development of alcohol and nicotine use problems from adolescence to young adulthood.

BACKGROUND AND AIMS: Molecular genetic studies of alcohol and nicotine use have identified many genome-wide association study (GWAS) loci. We measured associations between drinking and smoking polygenic scores (PGS) and trajectories of alcohol and nicotine use outcomes from late childhood to early adulthood, substance-specific versus broader-liability PGS effects, and if PGS performance varied for consumption versus problematic substance use. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We fitted latent growth curve models with structured residuals to scores on measures of alcohol and nicotine use and problems from ages 14 to 34 years. We then estimated associations between the intercept (initial status) and slope (rate of change) parameters and PGSs for drinks per week (DPW), problematic alcohol use (PAU), cigarettes per day (CPD) and ever being a regular smoker (SMK), controlling for sex and genetic principal components. All data were analyzed in the United States. PGSs were calculated for participants of the Minnesota Twin Family Study (n = 3225) using results from the largest GWAS of alcohol and nicotine consumption and problematic use to date. FINDINGS: Each PGS was associated with trajectories of use for their respective substances [i.e. DPW (ßmean = 0.08; ßrange = 0.02-0.12) and PAU (ßmean = 0.12; ßrange = -0.02 to 0.31) for alcohol; CPD (ßmean = 0.08; ßrange = 0.04-0.14) and SMK (ßmean = 0.18; ßrange = 0.05-0.36) for nicotine]. The PAU and SMK PGSs also exhibited cross-substance associations (i.e. PAU for nicotine-specific intercepts and SMK for alcohol intercepts and slope). All identified SMK PGS effects remained as significant predictors of nicotine and alcohol trajectories (ßmean = 0.15; ßrange = 0.02-0.33), even after adjusting for the respective effects of all other PGSs. CONCLUSIONS: Substance use-related polygenic scores (PGSs) vary in the strength and generality versus specificity of their associations with substance use and problems over time. The regular smoking PGS appears to be a robust predictor of substance use trajectories and seems to measure both nicotine-specific and non-specific genetic liability for substance use, and potentially externalizing problems in general.

Rare genetic variants explain missing heritability in smoking.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

Adolescent cannabis use and adult psychoticism: A longitudinal co-twin control analysis using data from two cohorts.

Observational studies have repeatedly linked cannabis use and increased risk of psychosis. We sought to clarify whether this association reflects a causal effect of cannabis exposure or residual confounding. We analyzed data from two cohorts of twins who completed repeated, prospective measures of cannabis use (N = 1544) and cannabis use disorder symptoms (N = 1458) in adolescence and a dimensional measure of psychosis-proneness (the Personality Inventory for DSM-5 Psychoticism scale) in adulthood. Twins also provided molecular genetic data, which were used to estimate polygenic risk of schizophrenia. Both cumulative adolescent cannabis use and use disorder were associated with higher Psychoticism scores in adulthood. However, we found no evidence of an effect of cannabis on Psychoticism or any of its facets in co-twin control models that compared the greater-cannabis-using twin to the lesser-using co-twin. We also observed no evidence of a differential effect of cannabis on Psychoticism by polygenic risk of schizophrenia. Although cannabis use and disorder are consistently associated with increased risk of psychosis, the present results suggest this association is likely attributable to familial confounds rather than a causal effect of cannabis exposure. Efforts to reduce the prevalence and burden of psychotic illnesses thus may benefit from greater focus on other therapeutic targets. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cortical volume and 40-Hz auditory-steady-state responses in patients with schizophrenia and healthy controls.

BACKGROUND: Abnormalities in the 40-Hz auditory steady-state response (ASSR) of the gamma range have been reported in schizophrenia (SZ) and are regarded as important pathophysiological features. Many of the previous studies reported diminished gamma oscillations in SZ, although some studies reported increased spontaneous gamma oscillations. Furthermore, brain morphological correlates of the gamma band ASSR deficits have rarely examined. We investigated different measures of the 40-Hz ASSR and their association with brain volumes and psychological measures of SZ. METHODS: The 40-Hz ASSR was measured for 80 dB click sounds (1 ms, 500-ms trains at 40-Hz, with 3050 to 3500 inter-train interval) using electroencephalography with 64 electrodes in 33 patients with SZ (male: 16, female: 17 (age range: 21-60)) and 30 healthy controls (HCs) (male: 13, female: 17 (age range: 23-64)). Four gamma oscillation measures (evoked power, spontaneous oscillations (baseline and total power), and inter-trial phase coherence (ITC)) were assessed. The source activities of the ASSR were also analyzed. Brain volumes were assessed using high-resolution magnetic resonance imaging and voxel-based morphometry and superior temporal gyrus (STG) volume measures were obtained. RESULTS: Patients with SZ had larger total and evoked powers and higher ITC than HCs. Both groups showed significantly different association between mean evoked power and right STG volume. In HCs but not SZ, mean evoked power showed significant positive correlation with right STG volume. In addition, the two groups showed significantly different association between verbal fluency and mean evoked power. High evoked power was significantly correlated with poor verbal fluency in SZ. CONCLUSIONS: The current study found increased gamma oscillation in SZ and suggests significant involvement of the STG in gamma oscillations.

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

The Relationship between Childhood Trauma and Suicidal Ideation: Role of Maltreatment and Potential Mediators.

OBJECTIVE: Childhood trauma is recognized as an important risk factor in suicidal ideation, however it is not fully understood how the different types of childhood maltreatment influence suicidal ideation nor what variables mediate the relationship between childhood trauma and suicidal ideation. This study examined the path from childhood trauma to suicidal ideation, including potential mediators. METHODS: A sample of 211 healthy adults completed the Childhood Trauma Questionnaire (CTQ), Beck scale for Suicidal Ideation (BSI), Functional Social Support Questionnaire (FSSQ) and Hospital Anxiety and Depression Scale (HADS). Path analysis was used to investigate the relationship among study variables. RESULTS: Of the several types of childhood maltreatment we considered, only childhood sexual abuse directly predicted suicidal ideation (ß=0.215, p=0.001). Childhood physical abuse (ß=0.049, 95% confidence interval: 0.011-0.109) and childhood emotional abuse (ß=0.042, 95% confidence interval: 0.001-0.107) indirectly predicted suicidal ideation through their association with anxiety. Childhood neglect indirectly predicted suicidal ideation through association with perceived social support (ß=0.085, 95% confidence interval: 0.041-0.154). CONCLUSION: Our results confirmed that childhood sexual abuse is a strong predictor of suicidal ideation. Perceived social support mediated the relationship between suicidal ideation and neglect. Anxiety fully mediated the relationship between suicidal ideation and both physical abuse and emotional abuse. Interventions to reduce suicidal ideation among survivors of childhood trauma should focus on anxiety symptoms and attempt to increase their social support.

Informationally administered reward enhances intrinsic motivation in schizophrenia.

Even when individuals with schizophrenia have an intact ability to enjoy rewarding moments, the means to assist them to translate rewarding experiences into goal-directed behaviors is unclear. The present study sought to determine whether informationally administered rewards enhance intrinsic motivation to foster goal-directed behaviors in individuals with schizophrenia (SZ) and healthy controls (HCs). Eighty-four participants (SZ=43, HCs=41) were randomly assigned to conditions involving either a performance-contingent reward with an informationally administered reward or a task-contingent reward with no feedback. Participants were asked to play two cognitive games of equalized difficulty. Accuracy, self-reported intrinsic motivation, free-choice intrinsic motivation (i.e., game play during a free-choice observation period), and perceived competency were measured. Intrinsic motivation and perceived competency in the cognitive games were similar between the two participant groups. The informationally administered reward significantly enhanced self-reported intrinsic motivation and perceived competency in both the groups. The likelihood that individuals with schizophrenia would play the game during the free-choice observation period was four times greater in the informationally administered reward condition than that in the no-feedback condition. Our findings suggest that, in the context of cognitive remediation, individuals with schizophrenia would benefit from informationally administered rewards.

Validation of the Korean Version of the Clinical Assessment Interview for Negative Symptoms.

OBJECTIVE: Clinical Assessment Interview for Negative Symptoms (CAINS) has recently been developed to improve measurement of negative symptoms in schizophrenia. We performed a multi-center study to validate the Korean version of the CAINS (CAINS-K) and explore potential cultural variation. METHODS: One hundred eighty schizophrenia patients diverse in demographic and illness profile were recruited from four centers in Korea. Along with the CAINS-K, the Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Calgary Depression Scale for Schizophrenia (CDSS), a self-report measure of behavioral inhibition and activation (BIS/BAS) and neurocognitive tasks were administered to verify external validities. RESULTS: The CAINS-K showed high internal-consistency (0.92) and inter-rater reliability (0.77). Exploratory Factor Analysis replicated a two-factor structure of the original scale including motivation/pleasure and expression deficits dimensions. Korean patients tended to report lower pleasure compared to American patients in the prior study. The CAINS-K showed an adequate convergent validity with the SANS, negative symptoms of the BPRS, and BAS. A divergent validity was supported as the CAINS-K showed zero or only weak correlations with other symptoms of the BPRS, depression from the CDSS, and neurocognitive tasks. CONCLUSION: The CAINS-K demonstrated high internal consistency and adequate external validities, and is expected to promote studies on negative symptoms in Korean patients with schizophrenia.

Attentional processing of emotional faces in schizophrenia: Evidence from eye tracking.

Severe emotional disturbances such as anxiety and depression have been closely related to aberrant attentional processing of emotional stimuli. However, this has been little studied in schizophrenia, which is also characterized by marked emotional impairments such as heightened negative affect and anhedonia. In the current study, we investigated temporal dynamics of motivated attention to emotional stimuli in schizophrenia. For this purpose, we tracked eye movements of 22 individuals with schizophrenia or schizoaffective disorder (ISZs) and 19 healthy controls (HCs) to emotional (i.e., happy, sad, angry) and neutral face pairs presented either for 500 ms or 1,500 ms. Initial fixation direction and viewing time at 3 successive intervals (0-500, 500-1,000, 1,000-1,500 ms) were calculated. The results showed that both ISZs and HCs were more likely to orient initial fixations and exhibited longer viewing times to emotional than neutral faces. However, compared with HCs, ISZs allocated less attention to overall faces during the late stage (1,000-1,500 ms) when one of the paired faces displayed negative emotions. Furthermore, positive symptoms were highly associated with initial fixation avoidance to angry faces while depressive symptoms were related to later avoidance of angry faces. Both social amotivation and poor interpersonal functioning were closely related to diminished sustained attention to happy faces. This suggests that early attentional capture of emotional salience may be relatively preserved in schizophrenia, but the people with this disorder display an atypical late attentional process characterized by generalized attentional avoidance of negative stimuli. Of note, aberrant attentional processes of social threat and reward were closely associated with major symptoms and functioning in this disorder. (PsycINFO Database Record

A Two-Factor Model Better Explains Heterogeneity in Negative Symptoms: Evidence from the Positive and Negative Syndrome Scale.

Acknowledging separable factors underlying negative symptoms may lead to better understanding and treatment of negative symptoms in individuals with schizophrenia. The current study aimed to test whether the negative symptoms factor (NSF) of the Positive and Negative Syndrome Scale (PANSS) would be better represented by expressive and experiential deficit factors, rather than by a single factor model, using confirmatory factor analysis (CFA). Two hundred and twenty individuals with schizophrenia spectrum disorders completed the PANSS; subsamples additionally completed the Brief Negative Symptom Scale (BNSS) and the Motivation and Pleasure Scale-Self-Report (MAP-SR). CFA results indicated that the two-factor model fit the data better than the one-factor model; however, latent variables were closely correlated. The two-factor model's fit was significantly improved by accounting for correlated residuals between N2 (emotional withdrawal) and N6 (lack of spontaneity and flow of conversation), and between N4 (passive social withdrawal) and G16 (active social avoidance), possibly reflecting common method variance. The two NSF factors exhibited differential patterns of correlation with subdomains of the BNSS and MAP-SR. These results suggest that the PANSS NSF would be better represented by a two-factor model than by a single-factor one, and support the two-factor model's adequate criterion-related validity. Common method variance among several items may be a potential source of measurement error under a two-factor model of the PANSS NSF.

Measuring negative symptoms in patients with schizophrenia: reliability and validity of the Korean version of the Motivation and Pleasure Scale-Self-Report.

BACKGROUND: The Clinical Assessment Interview for Negative Symptoms (CAINS) is one of the validated interview measures of negative symptoms in psychotic disorders. The Motivation and Pleasure Scale-Self-Report (MPSR) is a self-report measure that assesses the motivation and pleasure domains of negative symptoms based on the CAINS. This study evaluated the reliability and validity of a Korean version of the MPSR. METHODS: A total of 139 patients with schizophrenia completed the MPSR, CAINS, Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scales, Calgary Depression Scale for Schizophrenia, and other measures of trait and cognitive function. RESULTS: The 15-item MPSR showed good internal consistency. In addition, it also had a good convergent validity with the Motivation and Pleasure subscale of the CAINS and the anhedonia/avolition subscale of the SANS. The scale was not associated with psychotic symptoms, agitation/mania, and depression/anxiety, and it showed good discriminant validity. MPSR scores were significantly correlated with Behavioral Activation System total score for trait measure. CONCLUSION: The Korean version of the MPSR is a notable self-report method for examining the severity of negative symptoms in schizophrenia.

Theory of mind in Koreans with schizophrenia: A meta-analysis.

Previous meta-analytic studies conducted in Western countries have consistently revealed impairments in theory of mind (ToM) in schizophrenia. However, there is no systematic meta-analytic review of ToM deficits in individuals with schizophrenia in non-Western countries. In addition, ToM impairments in individuals with schizophrenia have not been investigated in the distinctive domains (i.e., verbal vs. visual, or affective vs. cognitive). The current meta-analytic study systematically synthesized 13 studies comparing ToM performance of adults with schizophrenia (n=377) and that of healthy controls (n=386) in Korea. The results indicate that Koreans with schizophrenia showed overall large ToM impairments (d=-1.273) but intact performance in control tasks that require a similar amount of cognitive demand as ToM tasks do. Large impairments in affective and cognitive ToM (d=-1.445 and -1.202, respectively) and verbal and visual ToM (d=-1.239 and -1.221, respectively) were found in Koreans with schizophrenia. There were no differences in magnitude between affective and cognitive ToM or between verbal and visual ToM. These results suggest that Koreans with schizophrenia experience substantial impairments in various ToM domains. Comprehensive multi-modality-based assessment targeting various ToM domains should be considered for treatment planning of individuals with schizophrenia.