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BackgroundThe 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.MethodsA 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.ResultsA 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.ConclusionsOur 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.

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.

BackgroundNetwork 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.MethodsParticipants (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.ResultsGlobal 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.ConclusionOur findings indicate that network structure and some nodal strengths were more flexible in remitters. Negative-self could be an important target for therapeutic intervention.

Background: Previous deep learning methods have not captured graph or network representations of brain structural or functional connectome data. To address this, we developed the Brain Graph Covariance Pooling Network (BrainGCPNet) by incorporating global covariance pooling and BrainNetCNN into the self-attention mechanism. Methods: 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 BrainGCPNet 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. Findings: The BrainGCPNet 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. Interpretation: Our findings suggest that the proposed BrainGCPNet 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 BrainGCPNet in the diagnosis of schizophrenia. Funding: Korean Mental Health Technology R&D Project, and Korea Health Technology R&D Project Declaration of Interests: The authors report no biomedical financial interests or potential conflicts of interest. Ethics Approval Statement: The study was approved by the Ethics Committee of Jeonbuk National University.

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.

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.

This study assessed fatty acid and brain-derived neurotrophic factor levels in patients with first-episode schizophrenia and related disorders. The levels of erythrocyte fatty acids and plasma brain-derived neurotrophic factor were measured at baseline and week 8 after treatment with paliperidone extended release. Cognitive function was evaluated using the Cognitive Assessment Interview and the cognition subscale of the Neuroleptic-Induced Deficit Syndrome Scale. There were significant decreases in stearic acid and nervonic acid levels and a significant increase in eicosapentaenoic acid levels after eight weeks. At week 8, cognition was positively associated with dihomo-γ-linolenic acid, linoleic acid, and eicosapentaenoic acid levels, and negatively associated with nervonic acid levels. Psychopathology was positively correlated with polyunsaturated fatty acid levels, and negatively correlated with saturated fatty acid levels at week 8. At both baseline and week 8, brain-derived neurotrophic factor level had a negative association with polyunsaturated fatty acids and a positive association with saturated fatty acids and monounsaturated fatty acids. The present study demonstrated that fatty acids have significant associations with cognition and psychopathology at week 8, and with brain-derived neurotrophic factor levels at both baseline and week 8.

BACKGROUND: Social defeat, which refers to experiences of loss during a confrontation among conspecific animals or during a hostile dispute among humans, can occur in either dyadic or group–individual encounters. Various animal models have been used to study the molecular mechanisms underpinning major depressive disorder. Among these, the social defeat paradigm has emerged as among the best approaches to evaluating depressed behavior. People frequently encounter stimuli generated by interactions with other people, and social challenges appear to be the most prevalent stressor in humans and other social animals. Furthermore, this procedure may also be considered an animal model of schizophrenia given that social defeat results in deficits in prepulse inhibition, an enhanced mesocorticolimbic dopamine response, increased phasic activity in the ventral tegmental area (VTA) dopaminergic neurons, and behavioral and neuronal cross-sensitization to amphetamines. Metabolomics is well suited for elucidating the systemic changes associated with stress because the systems underlying the stress response need to respond rapidly to threatening stimuli, and the initial events associated with the acute stress response are primarily metabolite-based. Moreover, metabolic changes have been reported in animals using a social defeat stress procedure. Specifically, the metabolism of lipids, amino acids, and energy was significantly perturbed by such a procedure. We hypothesized that measurement of the metabolomes in several key brain regions implicated in psychiatric disorders would illuminate the endogenous metabolic perbutations related to stress vulnerability and resilience, leading towards specific biomarker discovery. METHODS: Adult C57BL/6N mice were subjected social defeat stress for 10 days. Defeated mice were classified into unsusceptible (stress resilient) and susceptible (stress susceptible). 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. DISCUSSION: To deepen our understanding of the pathophysiology of stress-related disorders, we measured metabolites in the AMY, dST, dHIP, and PFC of mice exposed to social defeat stress. Significant perturbations were observed in the metabolism of amino acids, lipids, and neurotransmitters. It was of great interest to observe that the Cho, Glu, and Gly levels of the susceptible and unsusceptible groups differed significantly. Using HR-MAS 1H NMR, we observed perturbations of Gln in the AMY, of Glu in the dHIP, of Gly and m-Ins in the dST, and of Asp, Cho, and PE in the PFCs of susceptible and/or unsusceptible groups compared with the control group. Interestingly, three metabolites, Glu, Gly, and Cho, differed significantly between susceptible and unsusceptible groups. These findings suggest that social defeat stress induces disturbances in the metabolism of amino acids, lipids, and neurotransmitters in several brain areas. Furthermore, the resulting understanding of susceptibility-related metabolites may move us a step closer to elucidating the factors underpinning resistance to stress-related mental illnesses and identifying diagnostic biomarkers.

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.

Additional file 1: Figure S1. Additional western blot results showing band of interest (D2L). Figure S2. Additional western blot results showing band of interest (D2S).

Identification of early clinical markers that predict later treatment outcomes in first-episode psychosis is highly valuable. The present study was conducted to determine the best time at which to predict the late treatment response in first-episode psychosis patients treated with paliperidone extended release (ER), the factors predicting early treatment responses (at Week 2 and Week 3) and the relationships between the paliperidone ER plasma concentrations at Week 2 and Week 3, and the treatment responses at Week 2, Week 3 and Week 8. Various criteria for assessing treatment response were employed. We determined the plasma paliperidone concentrations at Week 2 and Week 3, using validated high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS). The treatment response at Week 3 optimally predicted the later (Week 8) response, in terms of negative predictive value (NPV). Independent predictors for good treatment responses at Week 2 and Week 3 were: Female gender, a higher educational level, a higher Positive and Negative Syndrome Scale (PANSS) excited score, and/or a shorter duration of untreated psychosis (DUP). The plasma paliperidone concentration at Week 3, but not Week 2, was a significant predictor of the late treatment response at Week 8. These results may help appropriate clinical decision-making for early non-responders after having their first episode of psychosis.

Aim This article compares the socio-demographic and clinical characteristics of patients with schizophrenia who recovered with those who achieved remission. Methods Participants were classified based on predetermined criteria for recovery and remission. Data on demographic characteristics, information on duration of untreated psychosis, and assessments of current and historical symptom profiles and socio-occupational functioning emerged from careful chart review and direct interviews. Cross-sectional assessments of clinical variables were derived from the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Personal and Social Performance Scale, the Social Functioning Questionnaire, the Schizophrenia Cognition Rating Scale (ScoRS), the Basic Empathy Scale, and the Brief Core Schema Scales (BCSS). Results We found no significant differences between recovered and remitted groups with respect to demographic variables or duration of untreated psychosis. Cognitive and total empathy scores, positive-self schema score on the BCSS, and global score on the ScoRS were significantly higher in the recovered than the remitted group. Furthermore, patients with good levels of empathy and positive-self schema and intact neurocognitive functioning were more likely to achieve recovery. Conclusion These results suggest that empathy, positive-self schema and neurocognitive functioning may serve as important clinical characteristics distinguishing those patients who have recovered from those who have achieved only remission.

The aim of this study was to investigate the efficacy and safety of ziprasidone in first-episode psychosis. This was an 8-week, open-label, multicenter trial. In total, 27 patients (14 male patients, 13 female patients) with a Diagnostic and Statistical Manual of Mental Disorders--Fourth Edition diagnosis of schizophreniform disorder, schizoaffective disorder, schizophrenia, or psychotic disorder not otherwise specified comprised the study population. The initial recommended dose of ziprasidone was 40 mg/day. Within the first 2 weeks, the dose could be increased to 120-160 mg/day depending on the patient's condition. The primary outcome variables were scores on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Severity scale; secondary measures included the Calgary Depression Scale for Schizophrenia and others. To assess safety, we measured drug-related adverse events, weight, lipid variables, prolactin, and corrected QT (QTc) interval. Among the 27 enrolled participants, 16 dropped out [lack of efficacy (n = 7), loss to follow-up (n = 7), withdrawn consent (n = 1), and serious adverse event (n = 1)]. The mean total daily and endpoint doses of ziprasidone were 120.30 ± 40.34 and 131.85 ± 51.22 mg/day, respectively. The administration of ziprasidone resulted in significant improvement in the PANSS (P < 0.0001) and CGI scores (P < 0.0001) over time. Significant improvement in the Calgary Depression Scale for Schizophrenia score (P < 0.0001) was also observed at week 8. The response rate (defined as a 30% or greater decrease in the PANSS total score from baseline to last observation) was 51.85%. No significant differences in extrapyramidal symptoms rating scale scores, and lipid and prolactin levels from baseline to last observation were found. However, modest side effects regarding the incidence of extrapyramidal symptoms and hyperprolactinemia, and weight change from baseline in male patients were observed. These results indicate that ziprasidone is effective in the treatment of the positive, negative, and depressive symptoms of first-episode psychosis and has a modest side-effect burden.

Noncompliance and poor outcome in patients with schizophrenia are closely related to the negative symptoms secondary to antipsychotics. No controlled study has evaluated whether amisulpride and aripiprazole induce negative symptoms. The aim of this study was to assess the effects of single doses of amisulpride, aripiprazole, haloperidol, and risperidone in healthy volunteers. Seventy-eight young volunteers took part in this double-blind, randomized, placebo-controlled, parallel study of four antipsychotics: 400 mg amisulpride, 10 mg aripiprazole, 3 mg haloperidol, and 2 mg risperidone. Assessments of negative symptoms were done 4 h after administration using both subjective rating scales (Neuroleptic Induced Deficit Syndrome Scale and Subjective Deficit Syndrome Scale) and an objective rating scale (Scale for the Assessment of Negative Symptoms). Risperidone only produced significant increases on the avolition score of the Neuroleptic Induced Deficit Syndrome Scale and blunted affect and alogia scores of the Scale for the Assessment of Negative Symptoms compared with placebo. The effect on blunted affect persisted after controlling for mental sedation. Amisulpride, aripiprazole, and haloperidol did not induce negative symptoms. Aripiprazole and risperidone induced mild extrapyramidal symptoms. The most common adverse events were somnolence and cognitive slowing. These data indicate that a single risperidone dose induces negative symptoms in normal volunteers, whereas amisulpride, aripiprazole, and haloperidol do not. These characteristics of antipsychotics should be considered when choosing optimal drugs for patients with psychosis.

The objective of this cross-sectional study was to investigate the relationships of anger, self-esteem, and depression with suicidal ideation. A survey was conducted in a wide range of community areas across Jeollabuk-do Province, Korea. A total of 2964 subjects (mean age=44.4yr) participated in this study. Hierarchical regression was used to investigate predictors of suicidal ideation in terms of their sociodemographic characteristics, depression, self-esteem, and anger. Hierarchical regression analyses revealed that anger and self-esteem were significantly associated with suicidal ideation regardless of age and after controlling for depression. Moderation analysis showed that the impact of anger on suicidal ideation was significantly greater among females than males in adolescents, but not in other age groups. Additionally, there were some differences in sociodemographic predictors of suicidal ideation among age groups. Predictors included gender and family harmony in adolescents, marital status and family harmony in middle-aged individuals, and economic status and family harmony in elderly individuals. Our results revealed that anger and self-esteem play important roles in suicidal ideation beyond the effect of depression. Development and implementation of preventive strategies, including management of anger and self-esteem, could possibly reduce suicidal ideation and subsequent suicide attempts.

This article compares the socio-demographic and clinical characteristics of patients with schizophrenia who recovered with those who achieved remission.Participants were classified based on predetermined criteria for recovery and remission. Data on demographic characteristics, information on duration of untreated psychosis, and assessments of current and historical symptom profiles and socio-occupational functioning emerged from careful chart review and direct interviews. Cross-sectional assessments of clinical variables were derived from the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Personal and Social Performance Scale, the Social Functioning Questionnaire, the Schizophrenia Cognition Rating Scale (ScoRS), the Basic Empathy Scale, and the Brief Core Schema Scales (BCSS).We found no significant differences between recovered and remitted groups with respect to demographic variables or duration of untreated psychosis. Cognitive and total empathy scores, positive-self schema score on the BCSS, and global score on the ScoRS were significantly higher in the recovered than the remitted group. Furthermore, patients with good levels of empathy and positive-self schema and intact neurocognitive functioning were more likely to achieve recovery.These results suggest that empathy, positive-self schema and neurocognitive functioning may serve as important clinical characteristics distinguishing those patients who have recovered from those who have achieved only remission.

As adolescence is a critical period when dopaminergic neuronal maturation peaks, we hypothesized that 6-hydroxydopamine (OHDA) lesions of the medial prefrontal cortex (mPFC) in adolescent rats would have more negative effects than lesions in adult rats. Therefore, we investigated the effects of 6-OHDA lesions of the mPFC in adolescent and adult rats on stress-induced c-fos expression in the brain. Adolescent and adult Sprague-Dawley rats, aged 4 and 7 weeks on arrival, respectively, were studied. 6-OHDA (8.0 microg) for the lesion groups and ascorbic acid for the sham groups were injected bilaterally into the mPFC. All animals were pretreated with desipramine 30 min before being anesthetized. The control group did not undergo any surgery-related procedure except the desipramine injection. After recovery for 1 week, the rats were subjected to restraint stress for 1 h. Immediately after the stress, the rats were killed and c-fos immunohistochemistry was examined. The c-fos expression in the nucleus accumbens core (AcbC), nucleus accumbens shell (AcbSh), CA1, CA3, dentate gyrus (DG), central amygdaloid (Ce), basolateral amygdaloid (BL), and temporal cortex (Tc) was compared. Adolescent rats with 6-OHDA lesions subjected to restraint stress had greater c-fos expression in the AcbC, AcbSh, DG, Ce, BL, and Tc, compared to the sham and control groups, whereas these differences were not observed among the adult groups. These results suggest that a hypodopaminergic state in the mPFC of adolescent rats, but not adult rats, is related to increased sensitivity to stress, suggesting that damage to or maldevelopment of dopaminergic neurons during adolescence has an age-specific effect. Further research is warranted to investigate the mechanism of the age-specific effect of 6-OHDA lesions of the mPFC.

Clozapine causes few extrapyramidal symptoms and is recommended as a treatment drug for severe tardive dyskinesia (TD). However, several case reports have suggested that clozapine could also cause TD. We investigated whether clozapine used as a first-line antipsychotic drug can cause TD.We identified 101 patients at Yanbian Socio-Mental Hospital and Yanbian Brain Hospital in China who had received clozapine as a primary antipsychotic drug since their first episode of illness and evaluated the prevalence rate, type, and severity of TD using the Extrapyramidal Symptoms Rating Scale (ESRS). The criterion for TD was a score ofor = 3 on one item or 2 on two or more items of the ESRS.The mean age and duration of illness of the patients were 38.93+/-8.36 and 12.88+/-6.90 years, respectively. The mean duration of clozapine treatment was 12.10+/-6.26 years. The prevalence of TD was 3.96% (4/101). Compared to patients without TD, patients with TD had a long duration of illness and clozapine treatment; all had the orolingual type of TD. TD was relatively mild, with a mean score of 4.75, and tended to accentuate with an activation procedure of rapid pronation and supination of the hands.These results suggest that clozapine may cause TD; however, the prevalence is low and the severity is relatively mild, with no or mild self-reported discomfort. Therefore, we recommend that regular examination for TD using the activation procedure should be performed in patients who use clozapine on a long-term basis.