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.

Neuronal signatures of anger and fear in patients with psychosis.

The present study investigated the functional neuroanatomy in response to sentence stimuli related to anger-provoking situations and fear of negative evaluation in patients with psychosis. The tasks consisted of four active conditions, Self-Anger (SA), Self-Fear, Other-Anger (OA), and Other-Fear (OF), and two neutral conditions, Neutral-Anger (NA) and Neutral-Fear (NF). Several relevant clinical measures were obtained. Under all contrasts, significantly higher activation in the left inferior parietal gyrus or superior parietal gyrus and the left middle occipital gyrus or superior occipital gyrus was observed in patients compared to healthy controls (HCs). However, we observed significantly lower activation in the left angular gyrus (AG) and left middle temporal gyrus (MTG) under the OA vs. NA contrast, as well as in the left precuneus and left posterior cingulate gyrus (PCG) under the OF vs. NF contrast in patients. The mean beta values for the significant regions under the SA vs. NA and OF vs. NF contrasts were significantly associated with the total PI and PANSS scores, respectively. These findings indicate that patients with psychosis exhibit hypoactivation in the AG, MTG, precuneus, and PCG compared to HCs. The findings suggest that patients with psychosis are less efficient at recruiting neural responses in those regions for semantic processing and social evaluation.

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.

Altered Neuroanatomical Signatures of Patients With Treatment-Resistant Schizophrenia Compared to Patients With Early-Stage Schizophrenia and Healthy Controls.

Background: The relationship between brain structural changes and cognitive dysfunction in schizophrenia is strong. However, few studies have investigated both neuroanatomical abnormalities and cognitive dysfunction in treatment-resistant schizophrenia (TRS). We examined neuroanatomical markers and cognitive function between patients with TRS or early-stage schizophrenia (ES-S) and healthy controls (HCs). Relationships between neuroanatomical markers and cognitive function in the patient groups were also investigated. Methods: A total of 46 and 45 patients with TRS and ES-S and 61 HCs underwent structural magnetic resonance imaging (MRI) brain scanning and comprehensive cognitive tests. MRI scans were analyzed using the FreeSurfer to investigate differences in cortical surface area (CSA), cortical thickness (CT), cortical volume (CV), and subcortical volume (SCV) among the groups. Four cognitive domains (attention, verbal memory, executive function, and language) were assessed. Comparisons of neuroanatomical and cognitive function results among the three groups were performed. Results: A widespread reduction in CT was observed in patients with TRS compared to HCs, but differences in cortical thinning between TRS and ES-S patients were mainly limited to the inferior frontal gyrus and insula. Several subcortical structures (accumbens, amygdala, hippocampus, putamen, thalamus and ventricles) were significantly altered in TRS patients compared to both ES-S patients and HCs. Performance in the verbal memory domain was significantly worse in TRS patients compared to ES-S patients. A positive relationship between the thickness of the left middle temporal gyrus and the composite score for language was identified in patients with ES-S. Conclusions: Our findings suggest significant cognitive impairment and reductions in CT and SCV in individuals with TRS compared to those with ES-S and HCs. These abnormalities could act as biomarkers for earlier identification of TRS.

Diagnosis of schizophrenia with functional connectome data: a graph-based convolutional neural network approach.

Previous deep learning methods have not captured graph or network representations of brain structural or functional connectome data. To address this, we developed the BrainNet-Global Covariance Pooling-Attention Convolutional Neural Network (BrainNet-GA CNN) by incorporating BrainNetCNN and global covariance pooling into the self-attention mechanism. Resting-state functional magnetic resonance imaging data were obtained from 171 patients with schizophrenia spectrum disorders (SSDs) and 161 healthy controls (HCs). We conducted an ablation analysis of the proposed BrainNet-GA CNN and quantitative performance comparisons with competing methods using the nested tenfold cross validation strategy. The performance of our model was compared with competing methods. Discriminative connections were visualized using the gradient-based explanation method and compared with the results obtained using functional connectivity analysis. The BrainNet-GA CNN showed an accuracy of 83.13%, outperforming other competing methods. Among the top 10 discriminative connections, some were associated with the default mode network and auditory network. Interestingly, these regions were also significant in the functional connectivity analysis. Our findings suggest that the proposed BrainNet-GA CNN can classify patients with SSDs and HCs with higher accuracy than other models. Visualization of salient regions provides important clinical information. These results highlight the potential use of the BrainNet-GA CNN in the diagnosis of schizophrenia.

Longitudinal symptom network structure in first-episode psychosis: a possible marker for remission.

BACKGROUND: Network approach has been applied to a wide variety of psychiatric disorders. The aim of the present study was to identify network structures of remitters and non-remitters in patients with first-episode psychosis (FEP) at baseline and the 6-month follow-up. METHODS: Participants (n = 252) from the Korean Early Psychosis Study (KEPS) were enrolled. They were classified as remitters or non-remitters using Andreasen's criteria. We estimated network structure with 10 symptoms (three symptoms from the Positive and Negative Syndrome Scale, one depressive symptom, and six symptoms related to schema and rumination) as nodes using a Gaussian graphical model. Global and local network metrics were compared within and between the networks over time. RESULTS: Global network metrics did not differ between the remitters and non-remitters at baseline or 6 months. However, the network structure and nodal strengths associated with positive-self and positive-others scores changed significantly in the remitters over time. Unique central symptoms for remitters and non-remitters were cognitive brooding and negative-self, respectively. The correlation stability coefficients for nodal strength were within the acceptable range. CONCLUSION: Our findings indicate that network structure and some nodal strengths were more flexible in remitters. Negative-self could be an important target for therapeutic intervention.

Altered amygdala-based functional connectivity in individuals with attenuated psychosis syndrome and first-episode schizophrenia.

Altered resting-state functional connectivity (FC) of the amygdala (AMY) has been demonstrated to be implicated in schizophrenia (SZ) and attenuated psychosis syndrome (APS). Specifically, no prior work has investigated FC in individuals with APS using subregions of the AMY as seed regions of interest. The present study examined AMY subregion-based FC in individuals with APS and first-episode schizophrenia (FES) and healthy controls (HCs). The resting state FC maps of the three AMY subregions were computed and compared across the three groups. Correlation analysis was also performed to examine the relationship between the Z-values of regions showing significant group differences and symptom rating scores. Individuals with APS showed hyperconnectivity between the right centromedial AMY (CMA) and left frontal pole cortex (FPC) and between the laterobasal AMY and brain stem and right inferior lateral occipital cortex compared to HCs. Patients with FES showed hyperconnectivity between the right superficial AMY and left occipital pole cortex and between the left CMA and left thalamus compared to the APS and HCs respectively. A negative relationship was observed between the connectivity strength of the CMA with the FPC and negative-others score of the Brief Core Schema Scales in the APS group. We observed different altered FC with subregions of the AMY in individuals with APS and FES compared to HCs. These results shed light on the pathogenetic mechanisms underpinning the development of APS and SZ.

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.

Negative Schema and Rumination as Mediators of the Relationship Between Childhood Trauma and Recent Suicidal Ideation in Patients With Early Psychosis.

OBJECTIVE: High rates of childhood trauma and adult suicidality have been reported in patients who have schizophrenia. This study sought to explore mediators between childhood trauma and suicidality in adulthood to help determine therapeutic approaches. METHODS: This study included 314 adult patients with early psychosis who were participants in the Korean Early Psychosis Cohort Study, which was a prospective naturalistic observational cohort study started in December 2014. DSM-5 criteria were used to assign the diagnosis of schizophrenia spectrum and other psychotic disorders. Cross-sectional data obtained at baseline were used for analysis. The Early Trauma Inventory Self Report-Short Form and the Columbia Suicide Severity Rating Scale were employed to collect data on childhood trauma and suicidal ideation and attempts. Other measures were used to evaluate depression, empathy, psychopathology, and rumination. RESULTS: A total of 90.1% of the participants experienced at least 1 childhood traumatic event. The rates of significant` physical punishment, emotional abuse, and sexual events were 37.3%, 35.6%, and 6.4%, respectively. The rates of recent suicidal ideation and attempts were 32.0% and 10.0%, respectively. Independent predictors of recent suicidal ideation included depression, negative schema, and rumination. Furthermore, negative schema and rumination played partial or full mediating roles in the relationship between childhood trauma and recent suicidal ideation. CONCLUSIONS: These findings highlight the importance of performing careful evaluations of childhood trauma and suicidality and of developing effective strategies to reduce mediating factors that may be amenable to psychosocial approaches.

Psychiatrists' opinion towards medication discontinuation in remitted first-episode psychosis: A multi-site study of the Asian Network for Early Psychosis.

AIM: The study investigated psychiatrists' views towards the issue of medication discontinuation for patients in remission from first-episode psychosis in four countries (Hong Kong, Korea, Singapore and Japan) that are part of the Asian Network for Early Psychosis, focusing on whether the views of these countries differ with one another. METHODS: A questionnaire was distributed to psychiatrists for completion. The questionnaire contained three sections: direct questions probing at views on medication discontinuation, case vignettes to assess applied decision-making and a checklist of criteria psychiatrists may view as necessary for the patient to satisfy before discontinuation. Total of 484 psychiatrists (97 from Hong Kong, 88 from Korea, 64 from Singapore and 233 from Japan) completed the questionnaire. RESULTS: We found that (a) Asian psychiatrists believed that 1% to 19% of remitted patients can discontinue medication, an estimation that was lower than Western psychiatrists; (b) in agreement with clinical guidelines, Asian psychiatrists believed that patients should remain on medication for at least 1 to 2 years following the absence of psychotic symptoms; (c) "Absence of any relapsing episode following first episode" was considered the most important criterion when making a decision; and (d) there were significant differences in clinicians' perceptions across the four countries: for instance, Korean psychiatrists were more conservative with the duration of antipsychotics maintenance, while Singaporean psychiatrists were more open-minded towards clinical trials. CONCLUSIONS: Culture and social norms appear to determine the relative importance of factors that psychiatrists might consider during the decision-making process, thereby producing variations in the views held in different countries.

Neural Signature for Auditory Hallucinations in Schizophrenia: A High-Resolution Positron Emission Tomography Study with Fludeoxyglucose (18F).

OBJECTIVE: Auditory hallucinations (AHs) are a core symptom of schizophrenia. We investigated the neural signature of AHs by comparing hallucinating patients with schizophrenia with non-hallucinating patients with schizophrenia. METHODS: We recruited hallucinating patients with schizophrenia meeting the criteria for persistent, prominent, and predominant AHs (n=10) and non-hallucinating patients with schizophrenia (n=12). Various clinical assessments were performed incluing Psychotic Symptom Rating Scale for Auditory Hallucinations. Using fludeoxyglucose (18F) positron emission tomography, regional differences in neural activity between the groups were analyzed. RESULTS: The regions of interest analysis showed significantly lower standardized uptake value ratio (SUVR) in the superior, middle, and inferior frontal gyri, and higher SUVR in the putamen in patients with AHs versus patients without AHs. These findings were confirmed in the voxel-wise analysis. CONCLUSION: Our findings indicate that hypoactivity in the frontal and cingulate gyri, coupled with hyperactivity in the temporal gyrus and putamen, may contribute to the pathophysiology of AHs.

Acceptance rate of long-acting injection after short information: a survey in patients with first- and multiple-episode psychoses and their caregivers.

AIM: The aim of this study was to investigate the acceptance rates of long-acting injection (LAI) in patients with first- and multiple-episode psychoses before and after providing concise information about LAI to the patients and their caregivers. Additionally, predictors of choosing LAI and the reasons for reluctance to accept LAI were also evaluated. METHODS: The survey included the questionnaire about participants' demographic characteristics, prior knowledge about LAI, attitude towards the importance of medication or psychotherapy and acceptance for LAI - treatment. The acceptance rate for LAI was re-evaluated after providing short information about current LAI or to the hypothetical questions like if there are a 3-ms lasting injection or the cost of injection is cheap. RESULT: This study included 161 patients and 113 caregivers who completed a cross-sectional survey. Following exposure to LAI information, acceptance rates for this method of treatment did not change in all groups. However, acceptance rates increased significantly when asked if the cost of LAI was cheaper than the current oral medication and the effect of LAI lasted for 3 months. Significant predictors of acceptance of LAI in patients with first-episode psychosis were prior knowledge about LAI, attitudes towards the importance of medication and discomfort due to medication side-effects. CONCLUSION: The present study demonstrated that a substantial portion of patients with first- and multiple-episode psychoses and their caregivers prefer LAI over their current oral medication. The acceptance of LAI was not increased by providing succinct information concerning this method of treatment.

Decreased Plasma BDNF Levels of Patients with Somatization Disorder.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF), one of the most abundant and important neurotrophins, is known to be involved in the development, survival, maintenance, and plasticity of neurons in the nervous system. Some studies have suggested that BDNF may play a role in the pathophysiology of several psychiatric illnesses such as depression and schizophrenia. Similarly, it is likely that the alteration of BDNF may be associated with the neuro-modulation that contributes to the development of somatization disorder. METHODS: The purpose of this study was to determine whether there is an abnormality of plasma BDNF levels in patients with somatization disorder, and to analyze the nature of the alteration after pharmacotherapy using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The plasma BDNF levels of the patients with a somatization disorder were significantly lower compared with those of the control volunteers (83.61±89.97 pg/mL vs. 771.36±562.14 pg/mL); moreover, the plasma BDNF levels of those patients who received an antidepressant were significantly increased after the treatment (118.13±91.45 pg/mL vs. 72.92±88.21 pg/mL). CONCLUSION: These results suggest that BDNF may play a role in the pathophysiology of somatization disorder.

Efficacy and Tolerability of Paliperidone Extended-release in the Treatment of First-episode Psychosis: An Eight-week, Open-label, Multicenter Trial.

OBJECTIVE: We investigated the efficacy and tolerability of paliperidone extended-release (ER) tablets in patients with first-episode psychosis (n=75). METHODS: This was an 8-week, open-label, multicenter trial. The primary outcome variable was scores on the Positive and Negative Syndrome Scale (PANSS); secondary measures included the Scale for the Assessment of Negative Symptoms (SANS), the Cognitive Assessment Interview (CAI), and the Global Assessment of Functioning (GAF). To assess safety, we measured drug-related adverse events, weight, lipid-related variables, and prolactin and administered the Simpson-Angus Rating Scale (SARS), the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale (BAS), the Arizona Sexual Experiences Scale (ASEX), and the Udvalg for Kliniske Undersogelser side effect rating scale (UKU). RESULTS: The administration of paliperidone ER resulted in significant improvement in the PANSS, SANS, CAI, and GAF scores (p＜0.001) over time. This improvement was evident as early as 1 week. The most frequent adverse events were akathisia, somnolence, anxiety, and sedation, which were well tolerated. Modest increases in weight and lipid profiles were also noted. Prolactin levels were substantially increased at the endpoint in both male and female patients. CONCLUSION: These results indicate that paliperidone ER is effective and is characterized by good tolerability in the treatment of positive and negative symptoms and cognitive functioning in first-episode psychosis.

Effects of Community Mental Health Service in Subjects with Early Psychosis: One-Year Prospective Follow Up.

The use of a multidisciplinary team approach is essential for increasing the likelihood of recovery among individuals with early psychosis. The aim of the present study was to investigate the effects of community-based mental health services on the symptoms and socio-occupational functioning of subjects with early psychosis. The study included participants who were referred to our Mental Health Promotion Center and who agreed to participate in diverse individual and group programs. During the 1-year follow-up, the medication adherence rate remained high, the recovery rate substantially increased, and the scores on the Positive and Negative Syndrome Scale, Psychotic Symptom Rating Scale-Delusion and Auditory Hallucinations subscales, Global Assessment of Functioning, Interpersonal Sensitivity Measure, and Social Functioning Questionnaire significantly improved over time. The findings suggest that the 1-year outcome of subjects with early psychosis can be improved by diverse community-based psychosocial interventions.

5-Oxo-ETE receptor antagonists.

5-Oxo-ETE is the most powerful eosinophil chemoattractant among lipid mediators. Eosinophil infiltration into the lungs of asthmatics may be responsible for the late phase of inflammatory asthma. We have designed and synthesized a 5-oxo-ETE receptor antagonist, the purpose of which is to prevent eosinophil migration to the lung during an asthma attack and thereby reduce asthma symptoms.

Validation of the Korean version of the Eppendorf Schizophrenia Inventory as a screening measure to detect adolescents at ultra-high risk for psychosis.

AIM: No validated self-report scale is available for use as a screening tool to detect non-help-seeking adolescents at ultra-high risk (UHR) for psychosis in a community setting. The study aims to examine the reliability and validity of the Korean version of the Eppendorf Schizophrenia Inventory (K-ESI) for assessing adolescents at UHR for psychosis in a community setting. METHODS: In the first study, to confirm the reliability and discriminant validity of the K-ESI, community sample (782 adolescents, 281 young adults, 122 early and middle-aged adults) and outpatients with schizophrenia (109) were recruited. A single cross-sectional survey was performed using the K-ESI for the community sample and the K-ESI and Positive and Negative Syndrome Scale for patients. In the second study, the Korean version of Youth Self Report (K-YSR) was administered initially to 1002 students. Of the 217 students whose scores were equal to or higher than the cut-off point of the K-YSR, 120 who agreed to an in-depth evaluation were interviewed using the Comprehensive Assessment of At-Risk Mental States to confirm the predictive validity of the K-ESI. RESULTS: The K-ESI showed good internal consistency and excellent test-retest reliability and discriminant validity. However, the factor structure in adolescents was substantially different from that of the original ESI. The best cut-off point for the K-ESI to identify UHR adolescents was 29, with a sensitivity of 77% and a specificity of 70%. CONCLUSION: The results revealed that the K-ESI can be used as a valid and reliable instrument to identify adolescents at UHR for psychosis in a community setting.