Risk and protective factors for severe mental disorders in Asia.

Among 369 diseases and injuries, the years lived with disability (YLDs) and disability-adjusted life-years (DALYs) rates for severe mental illnesses (SMIs) are within the top 20 %. Research on risk and protective factors for SMIs is critically important, as acting on modifiable factors may reduce their incidence or postpone their onset, while early detection of new cases enables prompt treatment and improves prognosis. However, as most of the studies on these factors are from Western countries, the findings are not generalizable across ethnic groups. This led us to conduct a systematic review of the risk and protective factors for SMIs identified in Asian studies. There were common factors in Asian and Western studies and unique factors in Asian studies. In-depth knowledge of these factors could help reduce disability, and the economic and emotional burden of SMIs. We hope that this review will inform future research and policy-making on mental health in Asian countries.

Effects of Social Defeat Stress on Microtubule Regulating Proteins and Tubulin Polymerization.

Objective: : Microtubule (MT) stability in neurons is vital for brain development; instability is associated with neuropsychiatric disorders. The present study examined the effects of social defeat stress (SDS) on MT-regulating proteins and tubulin polymerization. Methods: : After 10 days of SDS, defeated mice were separated into susceptible (Sus) and unsusceptible (Uns) groups based on their performance in a social avoidance test. Using extracted brain tissues, we measured the expression levels of α-tubulin, acetylated α-tubulin, tyrosinated α-tubulin, MT-associated protein-2 (MAP2), stathmin (STMN1), phospho stathmin serine 16 (p-STMN1 [Ser16]), phospho stathmin serine 25 (p-STMN1 [Ser25]), phospho stathmin serine 38 (p-STMN1 [Ser38]), stathmin2 (STMN2), phospho stathmin 2 serine 73 (p-STMN2 [Ser73]), 78-kDa glucose-regulated protein (GRP-78), and CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) using Western blot assay. The tubulin polymerization rate was also measured. Results: : We observed increased and decreased expression of acetylated and tyrosinated α-tubulin, respectively, decreased expression of p-STMN1 (Ser16) and increased expression of p-STMN1 (Ser25), p-STMN2 (Ser73) and GRP-78 and CHOP in the prefrontal cortex and/or hippocampus of defeated mice. A reduced tubulin polymerization rate was observed in the Sus group compared to the Uns and Con groups. Conclusion: : Our findings suggest that SDS has detrimental effects on MT stability, and a lower tubulin polymerization rate could be a molecular marker for susceptibility to SDS.

Altered thalamic volumes and functional connectivity in the recovered patients with psychosis.

BACKGROUND: Investigating neural correlates in recovered patients with psychosis is important in terms of identifying biological markers associated with recovery status or predicting a possible future relapse. We sought to examine thalamic nuclei volumes and thalamus-centered functional connectivity (FC) in recovered patients with psychosis who discontinued their medication. METHODS: Thirty patients with psychosis who satisfied the criteria for full recovery and 50 healthy controls (HC) matched for age, sex, and education underwent magnetic resonance imaging and clinical evaluation. The recovered patients were divided into the maintained and relapsed subjects according to their clinical status on the follow-ups. Thalamic nuclei volumes and thalamus-centered FC were measured between the recovered patients and HC. Correlations between the thalamic nuclei or altered FC, and clinical symptoms and cognitive functioning were explored. RESULTS: Modest cognitive impairments and reduced thalamic nuclei volumes were evident in the recovered patients. Moreover, we found altered thalamo-cortical connectivity and its associations with negative symptoms and cognitive functioning in the recovered patients compared with HC. CONCLUSION: These findings suggest that there are still cognitive impairments, and aberrant neuronal changes in the recovered patients. The implication of differential FC patterns between the maintained and the relapsed patients remain to be further explored.

Deep Learning-based Brain Age Prediction in Patients With Schizophrenia Spectrum Disorders.

BACKGROUND AND HYPOTHESIS: The brain-predicted age difference (brain-PAD) may serve as a biomarker for neurodegeneration. We investigated the brain-PAD in patients with schizophrenia (SCZ), first-episode schizophrenia spectrum disorders (FE-SSDs), and treatment-resistant schizophrenia (TRS) using structural magnetic resonance imaging (sMRI). STUDY DESIGN: We employed a convolutional network-based regression (SFCNR), and compared its performance with models based on three machine learning (ML) algorithms. We pretrained the SFCNR with sMRI data of 7590 healthy controls (HCs) selected from the UK Biobank. The parameters of the pretrained model were transferred to the next training phase with a new set of HCs (n = 541). The brain-PAD was analyzed in independent HCs (n = 209) and patients (n = 233). Correlations between the brain-PAD and clinical measures were investigated. STUDY RESULTS: The SFCNR model outperformed three commonly used ML models. Advanced brain aging was observed in patients with SCZ, FE-SSDs, and TRS compared to HCs. A significant difference in brain-PAD was observed between FE-SSDs and TRS with ridge regression but not with the SFCNR model. Chlorpromazine equivalent dose and cognitive function were correlated with the brain-PAD in SCZ and FE-SSDs. CONCLUSIONS: Our findings indicate that there is advanced brain aging in patients with SCZ and higher brain-PAD in SCZ can be used as a surrogate marker for cognitive dysfunction. These findings warrant further investigations on the causes of advanced brain age in SCZ. In addition, possible psychosocial and pharmacological interventions targeting brain health should be considered in early-stage SCZ patients with advanced brain age.

Effects and safety of virtual reality-based mindfulness in patients with psychosis: a randomized controlled pilot study.

Virtual reality (VR) technology can be a supporting tool to enhance mindfulness. Recently, many research using VR-based mindfulness (VBM) has been carried out in various psychiatric disorders but not in psychosis. We investigated safety and effects of virtual reality-based mindfulness (VBM) in patients with psychosis as a pilot study. Sixty-four patients were randomly assigned to VBM or to VR control. For VBM, education and meditation videos were provided. For VR control, 3-dimensional natural scenes were shown. Both programs consisted of 8 weekly sessions, each lasting about 30 min. Pre- and post-assessments were performed using the experiences questionnaire (EQ), psychotic symptom rating scales-delusion (PSYRATS-D), PSYRATS-auditory hallucinations (AH), motivation and pleasure scale-self rating (MAP-SR) and etc. The safety questionnaire was also surveyed after 1st and 8th session. Physiological measures such as skin conductance level (SCL), heart rate (HR) and RR interval, were collected during the VR interventions. Limited individuals participated in the safety questionnaire and physiological measures. All the results were presented in mean and standard deviation. We did not observe significant results in group x time interaction and main effects of group and time in the decentering and clinical scales. However, within group comparison showed that patients randomized to VBM showed increased decentering (p = 0.029) and decreased amount (p = 0.032) and duration of preoccupation (p = 0.016) in the PSYRATS-D. For the feelings and motivations about close caring relationships of the MAP-SR, we observed a significant group x time interaction (p = 0.027). The frequency of VR sickness was high but its severity was mild. There were significant differences only in HR over time in the VBM group (p = 0.01). These results suggest that VBM was not more effective in reducing decentering and psychiatric symptoms than VR control but its adversity was modest.

Network biomarkers in recovered psychosis patients who discontinued antipsychotics.

There are no studies investigating topological properties of resting-state fMRI (rs-fMRI) in patients who have recovered from psychosis and discontinued medication (hereafter, recovered patients [RP]). This study aimed to explore topological organization of the functional brain connectome in the RP using graph theory approach. We recruited 30 RP and 50 age and sex-matched healthy controls (HC). The RP were further divided into the subjects who were relapsed after discontinuation of antipsychotics (RP-R) and who maintained recovered state without relapse (RP-M). Using graph-based network analysis of rs-fMRI signals, global and local metrics and hub information were obtained. The robustness of the network was tested with random failure and targeted attack. As an ancillary analysis, Network-Based Statistic (NBS) was performed. Association of significant findings with psychopathology and cognitive functioning was also explored. The RP showed intact network properties in terms of global and local metrics. However, higher global functional connectivity strength and hyperconnectivity in the interconnected component were observed in the RP compared to HC. In the subgroup analysis, the RP-R were found to have lower global efficiency, longer characteristic path length and lower robustness whereas no such abnormalities were identified in the RP-M. Associations of the degree centrality of some hubs with cognitive functioning were identified in the RP-M. Even though network properties of the RP were intact, subgroup analysis revealed more altered topological organizations in the RP-R. The findings in the RP-R and RP-M may serve as network biomarkers for predicting relapse or maintained recovery after the discontinuation of antipsychotics.

Stage-Specific Brain Aging in First-Episode Schizophrenia and Treatment-Resistant Schizophrenia.

BACKGROUND: Brain age is a popular brain-based biomarker that offers a powerful strategy for using neuroscience in clinical practice. We investigated the brain-predicted age difference (PAD) in patients with schizophrenia (SCZ), first-episode schizophrenia spectrum disorders (FE-SSDs), and treatment-resistant schizophrenia (TRS) using structural magnetic resonance imaging data. The association between brain-PAD and clinical parameters was also assessed. METHODS: We developed brain age prediction models for the association between 77 average structural brain measures and age in a training sample of controls (HCs) using ridge regression, support vector regression, and relevance vector regression. The trained models in the controls were applied to the test samples of the controls and 3 patient groups to obtain brain-based age estimates. The correlations were tested between the brain PAD and clinical measures in the patient groups. RESULTS: Model performance indicated that, regardless of the type of regression metric, the best model was support vector regression and the worst model was relevance vector regression for the training HCs. Accelerated brain aging was identified in patients with SCZ, FE-SSDs, and TRS compared with the HCs. A significant difference in brain PAD was observed between FE-SSDs and TRS using the ridge regression algorithm. Symptom severity, the Social and Occupational Functioning Assessment Scale, chlorpromazine equivalents, and cognitive function were correlated with the brain PAD in the patient groups. CONCLUSIONS: These findings suggest additional progressive neuronal changes in the brain after SCZ onset. Therefore, pharmacological or psychosocial interventions targeting brain health should be developed and provided during the early course of SCZ.

Predictors of full recovery in patients with early stage schizophrenia spectrum disorders.

To promote recovery in psychosis, targeting modifiable factors related to recovery is critical. Using more strict definition of full recovery, we examined predictors for recovery in patients with early stage schizophrenia spectrum disorders (SSD) followed up to 6.5 years. The target subjects were 375 patients with early stage SSD who had been over at least 1-year after registration and evaluated. The criteria for full recovery were having the score of the Positive and Negative Syndrome Scale (PANSS) 8-item ≤ 2 and adequate functional recovery for at least 1-year. We performed univariate Cox and stepwise Cox regression in both total and acute patients. In stepwise Cox regression, several independent predictors for recovery, i.e., negative symptoms of the PANSS, duration of untreated psychosis (DUP) and non-professional job were identified in patients with early stage SSD. In acute patients, other factors such as professional job and subjective well-being under neuroleptics were more important. The present study identified independent predictors for recovery modifiable by various psychosocial intervention and early intervention services. Moreover, it highlights the need of providing different treatment strategies depending on clinical status.

Three-year outcomes and predictors for full recovery in patients with early-stage psychosis.

In the present study, various outcomes over 3-year period in patients with early stage psychosis including remission, recovery, relapse and medication adherence were investigated. Predictor for full recovery at year 3 was also examined. Three-year follow-up data in 534 patients with schizophrenia spectrum disorders (SSD) and psychotic disorder not otherwise specified (PNOS) were examined for overall outcome trajectories. The data of completers at year 3 (n = 157) were used to identify predictors for recovery using logistic regression. The rates of symptomatic remission and full recovery at 6-, 12-, 24-, and 36-month follow-up were 76.10, 69.20, 79.50, and 79.10%, and 22.80, 26.40, 28.60, and 39.60%, respectively. The rates of drop-out and relapse at 6-, 12-, 24-, and 36-month follow-up were 25.4, 29.5, 38.6, and 51.1%, and 3.7, 8.9, 19.0, and 38.9%, respectively. The rates of good adherence and prescription of Long-Acting Injectable Antipsychotics (LAIA) at 6-, 12-, 24- and 36-month follow-up were 87.8, 88.0, 91.9, and 93.9%, and 18.3, 21.7, 22.0, and 25.5%, respectively. Significant predictors for full recovery were duration of untreated psychosis (DUP), family intimacy and physical activity. We observed similar or better results on remission, recovery, and relapse rates compared to other previous studies. Effective psychosocial intervention should be provided to shorten the gap between remission and recovery rates and to address DUP, family issues, and exercise to enhance recovery.

DNA Methylation Profiles of the DRD2 and NR3C1 Genes in Patients with Recent-Onset Psychosis.

Objectives: Dopamine receptor D2 gene (DRD2) and glucocorticoid receptor gene (NR3C1) are implicated in the development of psychosis. We investigated methylation levels of DRD2 and NR3C1 in peripheral blood of patients with recent-onset (RO) psychosis using bisulfite pyrosequencing as well as its association with childhood trauma and rumination. Methods: In all, 51 individuals with RO psychosis and 47 healthy controls were recruited. DNA methylation levels in the targeted regions of two genes were analyzed and compared. Childhood trauma and rumination were evaluated using the Early Trauma Inventory Self-Report Short Form (ETI-SF) and Brooding Scale (BS), respectively. Correlations between the scores of the ETI-SF and BS and methylation levels were explored. Results: For DRD2, we found no significant differences between groups in terms of methylation level or association with childhood trauma or rumination. For NR3C1, we found a trend level significance for average value of all CpG sites and significant hypermethylation or hypomethylation at specific sites. There was also a significant positive correlation between the methylation level at the CpG8 site of NR3C1 exon 1F and negative symptom subscale score of the PANSS (PANSS-N). Conclusion: Epigenetic alterations of NR3C1 are associated with the pathophysiology of psychosis. Further epigenetic studies will elucidate the molecular mechanisms underpinning the pathophysiology of psychosis.

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.

Risperidone Induced DNA Methylation Changes in Dopamine Receptor and Stathmin Genes in Mice Exposed to Social Defeat Stress.

Objective: Understanding complex epigenetic mechanisms is necessary to fully elucidate the effects of antipsychotic drug. This study investigated DNA methylation and mRNA expression levels of dopamine D2 and D1 receptor (Drd2 and Drd1, respectively), nuclear receptor subfamily 3, group C, member 1 (Nr3c1) and stathmin 1 (Stmn1) in brain regions of mice exposed to social defeat stress (SDS) and effects of risperidone on altered methylation and mRNA expression levels induced by SDS. Methods: Following SDS for 10 days, risperidone (0.2 mg/kg) or vehicle was administered to adult mice for 7 days. Brain tissues from the prefrontal cortex (PFC), hippocampus (HIP) and amygdala (AMY) were processed to measure methylation and mRNA levels of Drd2, Drd1, Nr3c1 and Stmn1 using pyrosequencing and real time-polymerase chain reaction. Results: We found altered methylation status of Nr3c1 and Stmn1 in the HIP and AMY of mice exposed to SDS. These changes were reversed by risperidone treatment. In addition, different methylation patterns of Drd2 and Drd1 in the PFC and AMY between defeated and control mice were identified with risperidone treatment. Conclusion: These findings suggest that risperidone can cause epigenetic changes in Drd2, Drd1, Nr3c1 and Stmn1 in defeated mice. These changes could be epigenetic mechanisms underlying antipsychotic efficacy.

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.

Comparison of clinical features and 1-year outcomes between patients with psychotic disorder not otherwise specified and those with schizophrenia.

AIM: Research on psychotic disorder not otherwise specified (PNOS) that clearly mentions its subgroups is very rare. This study was conducted to identify the demographic and clinical features, cognitive function, and 1-year outcomes of patients with early stage PNOS compared with those with early stage schizophrenia (SZ). METHODS: The study subjects were 54 and 321 patients with PNOS and SZ, respectively, who were registered at least more than 1 year ago. Due to drop out, only 37 and 210 patients with PNOS and SZ were evaluated at the 1-year follow-up. We compared clinical variables (duration of untreated psychosis, symptom severity, self-rating scales, and so on), cognitive function, and short-term outcomes (treatment response, remission, compliance, drop out, relapse) between the two groups. RESULTS: The patients with PNOS were associated with higher diagnostic stability (53.7%) compared with those in previous studies. They had lower symptom severity, better treatment response at 2 months and higher remission rates at 12 months, but poorer compliance at 6 months compared with patients with SZ. Level of cognitive impairment in PNOS was intermediate between those of SZ patients and healthy controls. CONCLUSIONS: These findings indicate that PNOS has unique clinical features, suggesting that it should be treated as a distinct clinical syndrome. At the same time, however, prevention of its possible progression to other psychotic disorders in some patients with PNOS is also important.

Impact of Social Defeat Stress on DNA Methylation in Drd2, Nr3c1, and Stmn1 in Wild-type and Stmn1 Knock-out Mice.

OBJECTIVE: Epigenetic profiles can be modified by stress. Dopamine receptor D2 (Drd2), glucocorticoid receptor gene (Nr3c1) and Stathmin 1 (Stmn1) genes are all implicated in adaptation to stress. The aim of study is to investigate impact of social defeat on DNA methylation in Drd2, Nr3c1, and Stmn1 in wild-type (WT) and Stmn1 knock-out (KO) mice. METHODS: The WT and Stmn1 KO mice were subjected to chronic social defeat. Brain tissues of the prefrontal cortex (PFC), amygdala (AMY) and hippocampus (HIP) were obtained. We measured DNA methylation levels of the Drd2, Nr3c1, and Stmn1 genes in the PFC, AMY, and HIP using pyrosequencing. RESULTS: In WT mice, social defeat stress did not induce any changes in Drd2 methylation, whereas significant hypermethylation occurred in Nr3c1 and Stmn1 in the susceptible and unsusceptible groups, respectively, compared to the control group. The methylation responses in the Stmn1 KO mice differed from those seen in the WT mice, such that hypermethylation was evident in all three genes in the susceptible and unsusceptible groups compared to control group. Comparison of the Stmn1 KO and WT mice revealed the same pattern of hypermethylation for all three genes. CONCLUSION: Social defeat stress induced different epigenetic modifications in three genes among control, unsusceptible, and susceptible groups of WT and Stmn1 KO mice. In particular, hypermethylation of Nr3c1 in the HIP of the susceptible group, and of Stmn1 in the AMY of the unsusceptible group in WT mice, could serve as epigenetic biomarkers of stress susceptibility and stress resilience, respectively.

Symptomatic and full remission rates in first-episode psychosis: A 12-month follow-up study in Korea.

AIM: In the present study, the prevalence and predictors of symptomatic and full remission were investigated in patients with first-episode psychosis (FEP) at the 12-month follow-up. METHODS: A total of 308 participants aged 18-45 years fulfilled the study inclusion criteria and 214 completed the 12-month follow-up. RESULTS: At the 12-month follow-up, 67.3% (142) and 25.9% (55) of the FEP patients met the criteria for symptomatic and full remission, respectively. Stepwise logistic regression analysis showed a shorter duration of untreated psychosis (DUP), no family history, lower Positive and Negative Syndrome Scale (PANSS) negative symptom scores at baseline and higher familial support predicted symptomatic remission at the 12-month follow-up. A higher educational level, shorter DUP, lower PANSS general symptoms scores at baseline and higher subjective well-being under neuroleptics emotional regulation scores predicted full remission. CONCLUSIONS: Our findings regarding the rates of symptomatic and full remission are consistent with previous studies. The results indicate a large discrepancy between symptomatic versus full remission rates at a 12-month follow-up in patients with FEP. Effective psychosocial interventions are necessary to improve the outcomes of FEP patients.

Network analysis of trauma in patients with early-stage psychosis.

Childhood trauma (ChT) is a risk factor for psychosis. Negative lifestyle factors such as rumination, negative schemas, and poor diet and exercise are common in psychosis. The present study aimed to perform a network analysis of interactions between ChT and negative lifestyle in patients and controls. We used data of patients with early-stage psychosis (n = 500) and healthy controls (n = 202). Networks were constructed using 12 nodes from five scales: the Brief Core Schema Scale (BCSS), Brooding Scale (BS), Dietary Habits Questionnaire, Physical Activity Rating, and Early Trauma Inventory Self Report-Short Form (ETI). Graph metrics were calculated. The nodes with the highest predictability and expected influence in both patients and controls were cognitive and emotional components of the BS and emotional abuse of the ETI. The emotional abuse was a mediator in the shortest pathway connecting the ETI and negative lifestyle for both groups. The negative others and negative self of the BCSS mediated emotional abuse to other BCSS or BS for patients and controls, respectively. Our findings suggest that rumination and emotional abuse were central symptoms in both groups and that negative others and negative self played important mediating roles for patients and controls, respectively.Trial Registration: ClinicalTrials.gov identifier: CUH201411002.