Methylome-wide Association Study of Patients with Recent-onset Psychosis.

Objective: Dysregulation of gene expression through epigenetic mechanisms may have a vital role in the pathogenesis of schizophrenia (SZ). In this study, we investigated the association of altered methylation patterns with SZ symptoms and early trauma in patients and healthy controls. Methods: The present study was conducted to identify methylation changes in CpG sites in peripheral blood associated with recent-onset (RO) psychosis using methylome-wide analysis. Lifestyle factors, such as smoking, alcohol, exercise, and diet, were controlled. Results: We identified 2,912 differentially methylated CpG sites in patients with RO psychosis compared to controls. Most of the genes associated with the top 20 differentially methylated sites had not been reported in previous methylation studies and were involved in apoptosis, autophagy, axonal growth, neuroinflammation, protein folding, etc. The top 15 significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways included the oxytocin signaling pathway, long-term depression pathway, axon guidance, endometrial cancer, long-term potentiation, mitogen-activated protein kinase signaling pathway, and glutamatergic pathway, among others. In the patient group, significant associations of novel methylated genes with early trauma and psychopathology were observed. Conclusion: Our results suggest an association of differential DNA methylation with the pathophysiology of psychosis and early trauma. Blood DNA methylation signatures show promise as biomarkers of future psychosis.

Development of the Korea-Polyenvironmental Risk Score for Psychosis.

OBJECTIVE: Comprehensive understanding of polyenvironmental risk factors for the development of psychosis is important. Based on a review of related evidence, we developed the Korea Polyenvironmental Risk Score (K-PERS) for psychosis. We investigated whether the K-PERS can differentiate patients with schizophrenia spectrum disorders (SSDs) from healthy controls (HCs). METHODS: We reviewed existing tools for measuring polyenvironmental risk factors for psychosis, including the Maudsley Environmental Risk Score (ERS), polyenviromic risk score (PERS), and Psychosis Polyrisk Score (PPS). Using odds ratios and relative risks for Western studies and the "population proportion" (PP) of risk factors for Korean data, we developed the K-PERS, and compared the scores thereon between patients with SSDs and HCs. In addition, correlation was performed between the K-PERS and Positive and Negative Syndrome Scale (PANSS). RESULTS: We first constructed the "K-PERS-I," comprising five factors based on the PPS, and then the "K-PERS-II" comprising six factors based on the ERS. The instruments accurately predicted participants' status (case vs. control). In addition, the K-PERS-I and -II scores exhibited significant negative correlations with the negative symptom factor score of the PANSS. CONCLUSION: The K-PERS is the first comprehensive tool developed based on PP data obtained from Korean studies that measures polyenvironmental risk factors for psychosis. Using pilot data, the K-PERS predicted patient status (SSD vs. HC). Further research is warranted to examine the relationship of K-PERS scores with clinical outcomes of psychosis and schizophrenia.

Psychological factors intervening between childhood trauma and suicidality in first-episode psychosis.

Several studies have investigated childhood trauma (ChT) and suicidality in psychosis. However, psychological factors intervening between ChT and suicidality are not well understood. The aims of this study were to explore the roles of negative schema and rumination in the relationship between ChT and suicidality in first-episode psychosis (FEP). Participants were 306 patients with FEP who were enrolled in the Korean Early Psychosis Cohort Study, a prospective naturalistic observational cohort study. ChT, suicidality, negative schema, and rumination were evaluated using the Early Trauma Inventory Self Report-Short Form, Columbia Suicide Severity Rating Scale, Brief Core Schema Scale, and Brooding Scale. In addition, psychopathology and depression were evaluated. Structural equation model and a phantom approach were employed to analyze the pathway from ChT to suicidality. We found close associations between ChT, rumination, negative schema, and suicidality. Importantly, negative schema played a direct intervening role in the relationship between ChT and suicidality in patients with FEP. Our findings suggest that targeting negative schema in individuals with FEP exposed to ChT will be an effective strategy for reducing suicidality.

Effects of antipsychotics on rumination in patients with first-episode psychosis.

BACKGROUND: Rumination is a well-known risk factor for depression. It is also associated with negative and positive symptoms and suicidality in patients suffering from psychosis. However, no studies have addressed the effect of antipsychotics on rumination. METHODS: Using the Brooding Scale (BS), we investigated the effect of antipsychotics on rumination at the 6-month follow up in patients with first-episode psychosis (n = 257). The relationship between rumination and other clinical variables was explored by conducting a correlation analysis and structural equation modeling (SEM). The clinical characteristics and short-term outcomes were compared between high and low ruminators at 6 months. RESULTS: Significant reductions in rumination and various clinical variables were observed at the 6-month follow-up. A significant correlation was observed between rumination and the score on the positive subscale of the Positive and Negative Syndrome Scale (PANSS). A direct path between the PANSS score and rumination was identified by SEM. High ruminators had more severe psychopathology, experienced more childhood traumas, and took less exercise than low ruminators. The recovery rate at 6 months was higher in low ruminators than in high ruminators. CONCLUSIONS: Our findings suggest that antipsychotics are beneficial for reducing rumination in patients with first-episode psychosis. The outcomes at the 6-month follow-up were better in low ruminators than high ruminators.

Classification of schizophrenia and normal controls using 3D convolutional neural network and outcome visualization.

BACKGROUND: The recent deep learning-based studies on the classification of schizophrenia (SCZ) using MRI data rely on manual extraction of feature vector, which destroys the 3D structure of MRI data. In order to both identify SCZ and find relevant biomarkers, preserving the 3D structure in classification pipeline is critical. OBJECTIVES: The present study investigated whether the proposed 3D convolutional neural network (CNN) model produces higher accuracy compared to the support vector machine (SVM) and other 3D-CNN models in distinguishing individuals with SCZ spectrum disorders (SSDs) from healthy controls. We sought to construct saliency map using class saliency visualization (CSV) method. METHODS: Task-based fMRI data were obtained from 103 patients with SSDs and 41 normal controls. To preserve spatial locality, we used 3D activation map as input for the 3D convolutional autoencoder (3D-CAE)-based CNN model. Data on 62 patients with SSDs were used for unsupervised pretraining with 3D-CAE. Data on the remaining 41 patients and 41 normal controls were processed for training and testing with CNN. The performance of our model was analyzed and compared with SVM and other 3D-CNN models. The learned CNN model was visualized using CSV method. RESULTS: Using task-based fMRI data, our model achieved 84.15%∼84.43% classification accuracies, outperforming SVM and other 3D-CNN models. The inferior and middle temporal lobes were identified as key regions for classification. CONCLUSIONS: Our findings suggest that the proposed 3D-CAE-based CNN can classify patients with SSDs and controls with higher accuracy compared to other models. Visualization of salient regions provides important clinical information.

The Development of the Brooding Scale.

OBJECTIVE: The purpose of this study was to develop a Brooding Scale (BS) and to confirm its psychometric properties. METHODS: A preliminary questionnaire was developed based on a literature review and face-to-face interviews with healthy subjects. To evaluate reliability and construct validity, a 15-item BS was administered to 124 healthy subjects. Convergent validity was tested by assessing the relationship between the BS and the Ruminative Response Scale (RRS). Discriminant validity was confirmed in 58 patients with schizophrenia. RESULTS: The internal consistency for the BS was excellent. An exploratory factor analysis yielded two factors: the emotional (six items) and cognitive (five items) domains, which explained 33.83% and 23.69% of the variance, respectively. The BS total score and scores for factors 1 and 2 showed significant positive correlations with the RRS. The total score and sub-factor scores of the BS were significantly higher in patients with schizophrenia than in healthy subjects. CONCLUSION: The BS can be used as a reliable and valid tool to assess brooding in healthy adults. In addition, it had good discriminant validity for patients with schizophrenia.

Metabolite signature associated with stress susceptibility in socially defeated mice.

OBJECTIVE: Social defeat represents a naturalistic form of conditioned fear and is often used as an animal model of depression. The present study aimed to identify the neurochemicals in select brain regions of mice exposed to social defeat stress. METHODS: Adult C57BL/6N mice were subjected social defeat stress for 10 days. Using high-resolution magic angle spinning 1H nuclear magnetic resonance (HR-MAS 1H NMR), untargeted metabolomes were measured in the amygdala (AMY), dorsal hippocampus (dHIP), dorsal striatum (dST), and prefrontal cortex (PFC). RESULTS: We observed perturbations of glutamine in the AMY; glutamate in the dHIP; glycine and myo-inositol in the dST; and aspartate, choline, and phosphoethanolamine in the PFC of susceptible and/or unsusceptible groups compared to the control group. The susceptible and unsusceptible groups significantly differed with regard to three metabolites: glutamine, glycine, and choline. CONCLUSION: These findings suggest that social defeat stress induces disturbances in the metabolism of amino acids, lipids, and neurotransmitters in several brain areas. The resulting susceptibility-related metabolites may provide new insights into the pathophysiology underlying stress-related mental illness.