Machine learning for prediction of schizophrenia based on identifying the primary and interaction effects of minor physical anomalies.

In the neurodevelopmental model of schizophrenia, minor physical anomalies (MPAs) are considered neurodevelopmental markers of schizophrenia. To date, there has been no research to evaluate the interaction between MPAs. Our study built and used a machine learning model to predict the risk of schizophrenia based on measurements of MPA items and to investigate the potential primary and interaction effects of MPAs. The study included 470 patients with schizophrenia and 354 healthy controls. The models used are classical statistical model, Logistic Regression (LR), and machine leaning models, Decision Tree (DT) and Random Forest (RF). We also plotted two-dimensional scatter diagrams and three-dimensional linear/quadratic discriminant analysis (LDA/QDA) graphs for comparison with the DT dendritic structure. We found that RF had the highest predictive power for schizophrenia (Full-training AUC = 0.97 and 5-fold cross-validation AUC = 0.75). We identified several primary MPAs, such as the mouth region, high palate, furrowed tongue, skull height and mouth width. Quantitative MPA analysis indicated that the higher skull height and the narrower mouth width, the higher the risk of schizophrenia. In the interaction, we further identified that skull height and mouth width, furrowed tongue and skull height, high palate and skull height, and high palate and furrowed tongue, showed significant two-item interactions with schizophrenia. A weak three-item interaction was found between high palate, skull height, and mouth width. In conclusion, we found that the two machine learning methods showed good predictive ability in assessing the risk of schizophrenia using the primary and interaction effects of MPAs.

MoodSensing: A smartphone app for digital phenotyping and assessment of bipolar disorder.

BACKGROUND: Daily life tracking has proven to be of great help in the assessment of patients with bipolar disorder. Although there are many smartphone apps for tracking bipolar disorder, most of them lack academic verification, privacy policy and long-term maintenance. METHODS: Our developed app, MoodSensing, aims to collect users' digital phenotyping for assessment of bipolar disorder. The data collection was approved by the Institutional Review Board. This study collaborated with professional clinicians to ensure that the app meets both clinical needs and user experience requirements. Based on the collected digital phenotyping, deep learning techniques were applied to forecast participants' weekly HAM-D and YMRS scale scores. RESULTS: In experiments, the data collected by our app can effectively predict the scale scores, reaching the mean absolute error of 0.84 and 0.22 on the scales. The statistical data also demonstrate the increase in user engagement. CONCLUSIONS: Our analysis reveals that the developed MoodSensing app can not only provide a good user experience, but also the recorded data have certain discriminability for clinical assessment. Our app also provides relevant policies to protect user privacy, and has been launched in the Apple Store and Google Play Store.

Glibenclamide promotes FGF21 secretion in interscapular BAT and attenuates depression-like behaviors in male mice with HFD-induced obesity.

AIMS: Epidemiological evidence suggests that comorbidity of obesity and depression is extremely common and continues to grow in prevalence. However, the mechanisms connecting these two conditions are unknown. In this study, we explored how treatment with KATP channel blocker glibenclamide (GB) or the well-known metabolic regulator FGF21 impact male mice with high-fat diet (HFD)-induced obesity and depressive-like behaviors. MATERIALS AND METHODS: Mice were fed with HFD for 12 weeks and then treated with recombinant FGF21 protein by infusion for 2 weeks, followed by intraperitoneal injection of 3 mg/kg recombinant FGF21 once per day for 4 days. Measurements were made of catecholamine levels, energy expenditure, biochemical endpoints and behavior tests, including sucrose preference and forced swim tests were. Alternatively, animals were infused with GB into brown adipose tissue (BAT). The WT-1 brown adipocyte cell line was used for molecular studies. KEY FINDINGS: Compared to HFD controls, HFD + FGF21 mice exhibited less severe metabolic disorder symptoms, improved depressive-like behaviors, and more extensive mesolimbic dopamine projections. FGF21 treatment also rescued HFD-induced dysregulation of FGF21 receptors (FGFR1 and co-receptor ß-klotho) in the ventral tegmental area (VTA), and it altered dopaminergic neuron activity and morphology in HFD-fed mice. Importantly, we also found that FGF21 mRNA level and FGF21 release were increased in BAT after administration of GB, and GB treatment to BAT reversed HFD-induced dysregulation of FGF21 receptors in the VTA. SIGNIFICANCE: GB administration to BAT stimulates FGF21 production in BAT, corrects HFD-induced dysregulation of FGF21 receptor dimers in VTA dopaminergic neurons, and attenuates depression-like symptoms.

Taiwan consensus on biological treatment of bipolar disorder during the acute, maintenance, and mixed phases: The 2022 update.

BACKGROUND: Bipolar disorder is a mood dysregulation characterized by recurrent symptoms and episodes of mania, hypomania, depression, and mixed mood. The complexity of treating patients with bipolar disorder prompted the Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN) to publish the first Taiwan consensus on pharmacological treatment of bipolar disorders in 2012. This paper presents the updated consensus, with changes in diagnostic criteria (i.e., mixed features) and emerging pharmacological evidence published up to April 2022. METHODS: Our working group systemically reviewed the clinical research evidence and international guidelines and determined the levels of evidence for each pharmacological treatment on the basis of the most recent World Federation of Societies of Biological Psychiatry grading system. Four clinical-specific issues were proposed. The current TSBPN Bipolar Taskforce then discussed research evidence and clinical experience related to each treatment option in terms of efficacy and acceptability and then appraised final recommendation grades through anonymous voting. RESULTS: In the updated consensus, we include the pharmacological recommendations for bipolar disorder with mixed features considering its high prevalence, the severe clinical prognosis, and the absence of approved medications. Cariprazine, lurasidone, repetitive transcranial magnetic stimulation, and ketamine are incorporated as treatment options. In the maintenance phase, the application of long-acting injectable antipsychotics is emphasized, and the hazards of using antidepressants and conventional antipsychotics are proposed. CONCLUSIONS: This updated Taiwan consensus on pharmacological treatment for bipolar disorder provides concise evidence-based and empirical recommendations for clinical psychiatric practice. It may facilitate treatment outcome improvement in patients with bipolar disorder.

DNA methylation signature aberration as potential biomarkers in treatment-resistant schizophrenia: Constructing a methylation risk score using a machine learning method.

Treatment-resistant schizophrenia (TRS) is defined as a non-response to at least two trials of antipsychotic medication with an adequate dose and duration. We aimed to evaluate the discriminant abilities of DNA methylation probes and methylation risk score between treatment-resistant schizophrenia and non-treatment-resistant schizophrenia. This study recruited 96 schizophrenia patients (TRS and non-TRS) and 56 healthy controls (HC). Participants were divided into a discovery set and a validation set. In the discovery set, we conducted genome-wide methylation analysis (human MethylationEPIC 850K BeadChip) on the subject's blood DNA and discriminated significant methylation signatures, then verified these methylation signatures in the validation set. Based on genome-wide scans of TRS versus non-TRS, thirteen differentially methylated probes were identified at FDR <0.05 and >20% differences in DNA methylation ß-values. Next, we selected six probes within gene coding regions (LOC404266, LOXL2, CERK, CHMP7, and SLC17A9) to conduct verification in the validation set using quantitative methylation-specific PCR (qMSP). These six methylation probes showed satisfactory discrimination between TRS patients and non-TRS patients, with an AUC ranging from 0.83 to 0.92, accuracy ranging from 77.8% to 87.3%, sensitivity ranging from 80% to 90%, and specificity ranging from 65.6% to 85%. This methylation risk score model showed satisfactory discrimination between TRS patients and non-TRS patients, with an accuracy of 88.3%. These findings support that methylation signatures may be used as an indicator of TRS vulnerability and provide a model for the clinical use of methylation to identify TRS.

High-fat diet induces depression-like phenotype via astrocyte-mediated hyperactivation of ventral hippocampal glutamatergic afferents to the nucleus accumbens.

Comorbidity exists between metabolic disorders and depressive syndrome with unclear mechanisms. To characterize the causal relationship, we adopted a 12-week high-fat diet (HFD) to induce metabolic disorder and depressive phenotypes in mice. Initially, we identified an enhanced glutamatergic input in the nucleus accumbens of HFD mice. Retrograde tracing and chemogenetic inhibition showed that the hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behavior in HFD mice. Using lentiviral knockdown and overexpression approaches, we proved that HFD-induced downregulation of glial glutamate transporters, GLAST and GLT-1, contributed to the observed circuit maladaptations and subsequent depression-like behaviors. Finally, we identified a potential therapeutic agent, riluzole, which could mitigate the HFD-induced behavioral deficits by normalizing the expressions of GLAST and GLT-1 and ventral hippocampal glutamatergic afferents to the nucleus accumbens. Overall, astrocyte-mediated disturbance in glutamatergic transmission underlies the metabolic disorder-related depressive syndrome and represents a therapeutic target for this subtype of depressive mood disorders.

Profiling antibody signature of schizophrenia by Escherichia coli proteome microarrays.

Schizophrenia (SZ) is influenced by genetic and environmental factors, and associated with chronic neuroinflammation. If the symptoms express after adolescence, environmental impacts are more substantial, and the disease is defined as adult-onset schizophrenia (AOS). Effects of environmental factors on antibody responses such as Escherichia coli (E. coli) to immunoglobulin G (IgG) and immunoglobulin M (IgM) might increase the severity of symptoms in SZ via the gut-brain axis. The purpose of this study is to reveal antibody profiles of SZ against bacterial protein antigens. We analyzed the IgG and IgM antibodies using E. coli proteome microarrays from 80 SZ patients and 40 healthy controls (HC). Using support vector machine to select panels of proteins differentiating between groups and conducted enrichment analysis for those proteins. We identified that the groL, pldA, yjjU, livG, and ftsE can classify IgGs in AOS vs HC achieved accuracy of 0.7. The protein yjjU, livG and ftsE can form the best combination panel to classify IgG in AOS vs HC with accuracy of 0.8. The enrichment results are highly related to ABC (ATP binding cassette) transporter in the protein domain and cellular component. We further found that the human ATP binding cassette subfamily b member 1 (ABCB1) autoantibody level in AOS is significantly higher than in HC. The findings suggest that AOS had different immunoglobulin production compared to early-onset schizophrenia (EOS) and HC. We also identified potential antibody biomarkers of AOS and found their antigens are enriched in ABC transporter related domains, including human ABCB1 protein.

Loneliness and isolated living status in middle-aged and older adults in Taiwan: exploration on stress-related biomarkers, depressive symptoms, and disability.

PURPOSE: Loneliness is a subjective feeling by which an individual perceives a lack of closeness in interpersonal relationships. An isolated living status is linked with higher odds of risky health behavior. The conflicting impacts of loneliness and isolated living status on stress-related biomarkers, depressive symptoms, and disability remain unexplained. METHODS: Six hundred twenty-nine participants aged 66.0 (SD=7.3) separated into four groups: "Lonely and Isolated," "Not Lonely, but Isolated," "Lonely, but Not Isolated," and "Neither Lonely, nor Isolated," were retrieved from the Social Environment and Biomarkers of Aging Study conducted in 2000. Follow-up health indicators in 2006 included three stress-related biomarkers, depressive symptoms, and two physical disability indicators. A hierarchical regression was performed for the analysis. RESULTS: Firstly, compared to the "Neither Lonely nor Isolated" group, only the "Lonely, but Not Isolated" participants at baseline retained positive associations with the stress-related biomarkers levels 6 years later (urine cortisol level (B=9.25, 95% CI=3.24-15.27), serum Interleukin-6 level (B=2.76, 95% CI=0.72-4.79) and the serum high sensitivity C-reactive protein (hsCRP) level (B=0.40, 95% CI=0.17-0.62)). However, such associations were not observed in the "Lonely and Isolated" participants. Secondly, only "Lonely and Isolated" participants at baseline were positively associated with depressive symptoms 6 years later (B=1.70, 95% CI=0.11-3.30). Finally, the associations between combinations of loneliness and isolated living status and physical disability were eliminated after adjusting the covariables. CONCLUSION: Four combinations of loneliness and isolated living status were associated with different impacts on stress-related biomarkers, depressive symptoms, and physical disability. Further dynamic investigations are warranted.

Development and validation of a web-based prediction tool on minor physical anomalies for schizophrenia.

In support of the neurodevelopmental model of schizophrenia, minor physical anomalies (MPAs) have been suggested as biomarkers and potential pathophysiological significance for schizophrenia. However, an integrated, clinically useful tool that used qualitative and quantitative MPAs to visualize and predict schizophrenia risk while characterizing the degree of importance of MPA items was lacking. We recruited a training set and a validation set, including 463 schizophrenia patients and 281 healthy controls to conduct logistic regression and the least absolute shrinkage and selection operator (Lasso) regression to select the best parameters of MPAs and constructed nomograms. Two nomograms were built to show the weights of these predictors. In the logistic regression model, 11 out of a total of 68 parameters were identified as the best MPA items for distinguishing between patients with schizophrenia and controls, including hair whorls, epicanthus, adherent ear lobes, high palate, furrowed tongue, hyperconvex fingernails, a large gap between first and second toes, skull height, nasal width, mouth width, and palate width. The Lasso regression model included the same variables of the logistic regression model, except for nasal width, and further included two items (interpupillary distance and soft ears) to assess the risk of schizophrenia. The results of the validation dataset verified the efficacy of the nomograms with the area under the curve 0.84 and 0.85 in the logistic regression model and lasso regression model, respectively. This study provides an easy-to-use tool based on validated risk models of schizophrenia and reflects a divergence in development between schizophrenia patients and healthy controls ( https://www.szprediction.net/ ).

Inhibitory Effects of Trifluoperazine on Peripheral Proinflammatory Cytokine Expression and Hypothalamic Microglia Activation in Obese Mice Induced by Chronic Feeding With High-Fat-Diet.

Microglia and astrocytes are the glial cells of the central nervous system (CNS) to support neurodevelopment and neuronal function. Yet, their activation in association with CNS inflammation is involved in the initiation and progression of neurological disorders. Mild inflammation in the periphery and glial activation called as gliosis in the hypothalamic region, arcuate nucleus (ARC), are generally observed in obese individuals and animal models. Thus, reduction in peripheral and central inflammation is considered as a strategy to lessen the abnormality of obesity-associated metabolic indices. In this study, we reported that acute peripheral challenge by inflammagen lipopolysaccharide (LPS) upregulated the expression of hypothalamic dopamine type 2 receptor (D2R) mRNA, and chronic feeding by high-fat-diet (HFD) significantly caused increased levels of D2R in the ARC. The in vitro and in vivo studies indicated that an FDA-approved antipsychotic drug named trifluoperazine (TFP), a D2R inhibitor was able to suppress LPS-stimulated activation of microglia and effectively inhibited LPS-induced peripheral inflammation, as well as hypothalamic inflammation. Further findings showed daily peripheral administration intraperitoneally (i.p.) by TFP for 4 weeks was able to reduce the levels of plasma tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in accompany with lower levels of plasma glucose and insulin in obese mice receiving HFD for 16 weeks when compared those in obese mice without TFP treatment. In parallel, the activation of microglia and astrocytes in the ARC was also inhibited by peripheral administration by TFP. According to our results, TFP has the ability to suppress HFD-induced ARC gliosis and inflammation in the hypothalamus.

Taiwan Expert Consensus Recommendations for Switching to Aripiprazole Long-Acting Once-Monthly in Patients with Schizophrenia.

In the last decade, long-acting injectable antipsychotics has been widely used in schizophrenia. Aripiprazole long-acting once-monthly (AOM) is the only long-acting dopamine partial agonist antipsychotic approved for schizophrenia; however, a literature search revealed no guidance on safely switching from oral and long-acting injectable antipsychotics to AOM. This study aimed to develop recommendations of AOM use based on existing data and expert consensus. A committee of 30 experts in psychopharmacology from major hospitals across Taiwan was invited. A modified Delphi method was conducted, consisting of two rounds of questionnaires, literature review, three rounds of face-to-face discussion meeting, and two rounds of anonymous voting. The consensus recommendations were developed based on existing data, clinical experiences, and consensus opinions, with 80% agreement among panel members required for final adoption. The panel developed nine consensus statements of switching to AOM for both acute and stable schizophrenia patients receiving oral or long-acting injectable atypical antipsychotics. Recommendations regarding dose adjustment of oral medication and pregnancy/breastfeeding were also included. The nine consensus recommendations provide a guidance on safely switching to AOM. Substantial gaps in knowledge, and more research is necessary.

Residential green space structures are associated with a lower risk of bipolar disorder: A nationwide population-based study in Taiwan.

Although many researchers have identified the potential psychological benefits offered by greenness, the association between green space structures and mental disorders is not well understood. The purpose of this study was to identify associations between green space structures and the incidence of bipolar disorder. To this end, we investigated 1,907,776 individuals collected from Taiwan's National Health Insurance Research Database. After a follow-up investigation from 2005 to 2016, among those with no history of bipolar disorder, 20,548 individuals were further found to be diagnosed with bipolar disorder. A geographic information system and landscape index were used to quantify three indices of green space structures: mean patch area (area and edge), mean fractal dimension index (shape), and mean proximity index (proximity). Additionally, greenness indices, the normalized difference vegetation index, and the enhanced vegetation index were used to confirm the association between greenness and incidence of bipolar disorder. These five indices were used to represent the individual's exposure according to the township of the hospital that they most frequently visited with symptoms of the common cold. Spearman's correlation analysis was performed to select variables by considering their collinearity. Subsequently, the frailty model for each index was used to examine the specific associations between those respective indices and the incidence of bipolar disorder by adjusting for related risk factors, such as socioeconomic status, metabolic syndrome, and air pollution. A negative association was identified between the mean patch area and the mean proximity index, and the incidence of bipolar disorder. In contrast, a positive association was found between the mean fractal dimension index and the incidence of bipolar disorder. We observed similar results in sensitivity testing and subgroup analysis. Exposure to green spaces with a larger area, greater proximity, lower complexity, and greener area may reduce the risk of bipolar disorder.

Glibenclamide restores dopaminergic reward circuitry in obese mice through interscauplar brown adipose tissue.

BACKGROUND: Obesity, a critical feature in metabolic disorders, is associated with medical depression. Recent evidence reveals that brown adipose tissue (BAT) activity may contribute to mood disorders, Adenosine triphosphate (ATP)-sensitive K+ (KATP) channels regulate BAT sympathetic nerve activity. However, the mechanism through which BAT activity affects mood control remains unknown. We hypothesized the BAT is involved in depressive-like symptoms regulation by trafficking KATP channels. METHODS: Eight-week-old male B6 mice fed with a high-fat diet (HFD) for 12 weeks exhibited characteristics of metabolic disorders, including hyperglycemia, hyperinsulinemia, and hyperlipidemia, as well as depressive symptoms. In this study, we surgically removed interscapular BAT in mice, and these mice exhibited immobility in the forced swim test and less preference for sugar water compared with other mice. To delineate the role of KATP channels in BAT activity regulation, we implanted a miniosmotic pump containing glibenclamide (GB), a KATP channel blocker, into the interscapular BAT of HFD-fed mice. RESULTS: GB infusion improved glucose homeostasis, insulin sensitivity, and depressive-like symptoms. KATP channel expression was lower in HFD-fed mice than in chow-fed mice. Notably, GB infusion in HFD-fed mice restored KATP channel expression. CONCLUSION: KATP channels are functionally expressed in BAT, and inhibiting BAT-KATP channels improves metabolic syndromes and reduces depressive symptoms through beta-3-adrenergic receptor-mediated protein kinase A signaling.

The associations between illness perceptions and social rhythm stability on mood symptoms among patients with bipolar disorder.

BACKGROUND: The association between illness perceptions and the effectiveness of patients' illness-management strategies has been supported across a range of medical and psychiatric disorders. Few studies have examined these variables or their association in bipolar disorder (BD). This study examined the main and interactive associations between illness perceptions and one important illness management strategy - social rhythms stability on mood symptom severity in adults with BD. METHODS: A cross-sectional study with 131 patients with BD in Taiwan was conducted using clinician- and patient-rated mood symptoms, self-reported illness perceptions, and a measure of daily and nightly social rhythms. RESULTS: Illness perceptions were associated with mood symptom severity, but social rhythms were not. Unfavorable illness perceptions (e.g., beliefs of experiencing more BD symptoms, having stronger emotional responses to the illness) were associated with more severe mood symptoms. Favorable illness perceptions (e.g., beliefs of being able to understand and control the illness) were associated with less severe mood symptoms, with personal control as the strongest correlate of mood symptom severity. Finally, social rhythm stability moderated the relationship between unfavorable illness perceptions and clinician-rated manic symptoms. LIMITATIONS: The cross-sectional design limits our ability to make causal conclusions. Also, the effects pertain to patients in remission and may not generalize to more severely ill or hospitalized bipolar patients. CONCLUSIONS: This study indicates that in patients with BD, illness perceptions are associated with symptom severity. Interventions to enhance favorable IPs and reduce unfavorable IPs may improve mood outcomes, particularly when patients have adopted regular social rhythms.

Intermittent peripheral exposure to lipopolysaccharide induces exploratory behavior in mice and regulates brain glial activity in obese mice.

BACKGROUND: Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. High-fat diet (HFD) intake has been reported to stimulate the activation of astrocytes and microglia in the arcuate nucleus (ARC) of the hypothalamus in obese rodents and humans. However, it is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals. METHODS: In this study, we administered 1 mg/kg LPS (or saline) by intraperitoneal (i.p.) injection to 8-week-old male mice after 1, 2, or 8 weeks of a regular diet (show) or HFD. The level of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) expression in the plasma and hypothalamic tissue was analyzed 24 h after each LPS injection. The behaviors of the animals in the four groups (the chow-saline, chow-LPS, HFD-saline, and HFD-LPS groups) were examined 5 months after exposure to chow or a HFD. Morphological examination of microglia in related brain regions was also conducted. RESULTS: The plasma levels and hypothalamic mRNA levels of IL-1ß and TNF-α were significantly upregulated 24 h after the first injection of LPS but not after the second or third injection of LPS. Chow-LPS mice displayed increased exploratory behavior 5 months after feeding. However, this LPS-induced abnormal exploratory behavior was inhibited in HFD-fed mice. Chronic HFD feeding for 5 months induced apparent increases in the number and cell body size of microglia, mainly in the ARC, and also increased the size of microglia in the nucleus accumbens (NAc) and insula. Moreover, microglial activation in the ARC, anterior cingulate cortex (ACC), insula, and basolateral amygdala (BLA) was observed in chow-LPS mice. However, microglial activation in the analyzed brain regions was suppressed in HFD-LPS mice. CONCLUSIONS: Altogether, the results indicate that intermittent peripheral challenge with LPS might prime microglia in the ARC and NAc to modify their response to chronic HFD feeding. Alternatively, chronic HFD feeding might mediate microglia in LPS-affected brain regions and subsequently suppress LPS-induced atypical exploratory behavior. Our findings suggest that the interaction of intermittent acute peripheral immune challenges with chronic HFD intake can drive microglia to amend the microenvironment and further modify animal behaviors in the later life.

Combination of dextromethorphan and memantine in treating bipolar spectrum disorder: a 12-week double-blind randomized clinical trial.

BACKGROUND: The aim of this study is to determine whether adding combination of agents with anti-inflammatory and neurotrophic effects is more efficacious than mood stabilizer alone in improving clinical symptoms, plasma brain-derived neurotrophic factor (BDNF), cytokine levels, and metabolic profiles in patients with bipolar spectrum disorder. METHODS: In a randomized, double-blind, controlled 12-week clinical trial, patients with moderate mood symptoms (HDRS ≥ 18 or YMRS ≥ 14) were recruited. The patients were randomly assigned to a group while still undergoing regular valproate (VPA) treatments: VPA + dextromethorphan (DM) (30 mg/day) + memantine (MM) (5 mg/day) (DM30 + MM5) (n = 66), VPA + DM (30 mg/day) (DM30) (n = 69), VPA + MM (5 mg/day) (MM5) (n = 66), or VPA + Placebo (Placebo) (n = 69). Symptom severity, immunological parameters [plasma tumor necrosis factor (TNF)-α and C-reactive protein (CRP)] and plasma brain-derived neurotrophic factor (BDNF) were regularly examined. Metabolic profiles [cholesterol, triglycerides, glycosylated hemoglobin (HbA1C), fasting serum glucose, body mass index (BMI)] were measured at baseline and at 2, 8, and 12 weeks. RESULTS: Depression scores were significantly (P = 0.03) decreases and BDNF levels significantly (P = 0.04) increased in the DM30 + MM5 group than in the Placebo group. However, neither depressive scores nor BDNF levels were significantly different between the DM30, MM5, and Placebo groups. Changes in certain plasma cytokine and BDNF levels were significantly correlated with metabolic parameters. CONCLUSION: We concluded that add-on DM30 + MM5 was significantly more effective than placebo for clinical symptoms and plasma BDNF levels. Additional studies with larger samples and mechanistic studies are necessary to confirm our findings. Trial registration NCT03039842 (https://register.clinicaltrials.gov/). Trial date was from 1 Jan 2013 to 31 December 2016 in National Cheng Kung University Hospital. Registered 28 February 1 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03039842?term=NCT03039842&rank=1.

Factors associated with internalized stigma for Indonesian individuals diagnosed with schizophrenia in a community setting.

WHAT IS KNOWN ON THE SUBJECT?: Internalized stigma in people diagnosed with mental illness has several negative outcomes; however, it remains unclear in an Indonesian context. The human rights of people diagnosed with mental illness in Indonesia have been routinely violated because of the existing stigma against mental illness and deficiencies in the country's mental healthcare services. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: To the best of our knowledge, this is the first study to examine the level of internalized stigma and related factors among Indonesians diagnosed with schizophrenia. Almost one-third of the subjects had moderate-to-severe levels of internalized stigma, among which discrimination was the strongest type. Specifically, younger and unemployed people with more psychotic symptoms had higher levels of internalized stigma. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The provision of adequate pharmacological and psychosocial treatments to help people manage their psychotic symptoms is extremely important to ameliorate stigma. Vocational rehabilitation and employment support for unemployed people may potentially reduce their internalized stigma and promote recovery. ABSTRACT: Introduction The human rights of people diagnosed with mental illness in Indonesia have been routinely violated because of societal stigma associated with mental illness and deficiencies in the country's mental healthcare services. Knowledge about internalized stigma among people diagnosed with schizophrenia in lower middle-income Muslim countries is also scarce. Aim To identify the level of internalized stigma and related factors among people diagnosed with schizophrenia in Indonesia. Method A cross-sectional survey was conducted with a purposive sample of 300 people diagnosed with schizophrenia from an urban Indonesian psychiatric hospital. Results Almost one-third of the subjects had moderate-to-severe levels of internalized stigma, among which discrimination was the strongest type. Younger age, unemployment status and having psychotic symptoms significantly increased the risk of internalized stigma when analysed in a multivariable ordinal logistic regression. Discussion The present study firstly identified the high levels of internalized stigma among Indonesian individuals diagnosed with schizophrenia. Implications for practice Mental health nurses are suggested to provide early anti-stigma illness management and family psychoeducation interventions to people diagnosed with schizophrenia and their family caregivers, helping them to develop an optimistic understanding about the concept of schizophrenia and mitigating the negative consequences of public and internalized stigma.

Dextromethorphan Protect the Valproic Acid Induced Downregulation of Neutrophils in Patients with Bipolar Disorder.

OBJECTIVE: Valproic acid (VPA) is an anticonvulsant and commonly long term used as a mood stabilizer for patients with mood disorders. However its chronic effects on the hematological changes were noticed and need to be further evaluated. In this study, we evaluated, in Taiwanese Han Chinese patients with bipolar disorders (BD), the chronic effects of VPA or VPA plus dextromethorphan (DM) on the hematological molecules (white blood cell [WBCs], red blood cells [RBCs], hemoglobin, hematocrit, and platelets). METHODS: In a 12-week, randomized, double-blind study, we randomly assigned BD patients to one of three groups: VPA plus either placebo (VPA＋P, n = 57) or DM (30 mg/day, VPA＋DM30, n = 56) or 60 mg/day (VPA＋DM60, n = 53). The Young Mania Rating Scale and Hamilton Depression Rating Scale were used to evaluate symptom severity, and the hematological molecules were checked. RESULTS: Paired t test showed that the WBC, neutrophils, platelets and RBCs were significantly lowered after 12 weeks of VPA＋P or VPA＋DM30 treatment. VPA＋DM60 represented the protective effects in the WBCs, neutrophils, and RBCs but not in the platelets. We further calculated the changes of each hematological molecules after 12 weeks treatment. We found that combination use of DM60 significantly improved the decline in neutrophils induced by the long-term VPA treatment. CONCLUSION: Hematological molecule levels were lower after long-term treatment with VPA. VPA＋DM60, which yielded the protective effect in hematological change, especially in the neutrophil counts. Thus, DM might be adjunct therapy for maintaining hematological molecules in VPA treatment.

Chronic exposure to high fat diet triggers myelin disruption and interleukin-33 upregulation in hypothalamus.

BACKGROUND: Hypothalamic inflammation including astrogliosis and microglia activation occurs after intake of high fat diet (HFD) in rodent models or in obese individuals. However, the effect of chronic HFD feeding on oligodendrocytes (OLGs), a myelin-producing glial population in the central nervous system (CNS), remains unclear. In this study, we used 8-week old male C57BL/6 mice fed by HFD for 3-6 months to induce chronic obesity. RESULTS: The transmission electron microscopy imaging analysis showed that the integrity of hypothalamic myelin was disrupted after HFD feeding for 4 and 6 months. Moreover, the accumulation of Iba1+-microglia with an amoeboid hypertrophic form was continually observed in arcuate nucleus of HFD-fed mice during the entire feeding time period. Interleukin-33 (IL-33), a tissue alarmin upon injury to the CNS, was detected with an increased level in hypothalamus after HFD feeding for 3 and 4 months. Furthermore, the in vitro study indicated that exposure of mature OLGs to IL-33 impaired OLG cell structure along with a decline in the expression of myelin basic protein. CONCLUSIONS: Altogether, our findings demonstrate that chronic HFD feeding triggers hypothalamic myelin disruption in accompany with IL-33 upregulation and prolonged microglial activation in hypothalamus. Given that the addition of exogenous IL-33 was harmful for the maturation of OLGs, an increase in IL-33 by chronic HFD feeding might contribute to the induction of hypothalamic myelin disruption.

Stress Aggravates High-Fat-Diet-Induced Insulin Resistance via a Mechanism That Involves the Amygdala and Is Associated with Changes in Neuroplasticity.

BACKGROUND: The notion that exposure to chronic stress predisposes individuals to developing type 2 diabetes (T2D) has gained much attention in recent decades. Long-term stress induces neuroadaptation in the amygdala and increases corticosterone levels. Corticosterone, the major stress hormone in rodents, induces insulin resistance and obesity in mice. However, little is known about whether the stress-induced amygdalar neuroadaptation could promote the risk of T2D. METHODS: We used an 11-week high-fat diet (HFD) feeding paradigm to induce insulin dysfunction in mice, followed by implementation of a 10-day social defeat (SD) stress protocol. RESULTS: Mice receiving SD at the beginning of the HFD feeding aggravated HFD-induced insulin resistance and white adipose tissue expansion. HFD mice had higher levels of plasma corticosterone, which was not affected by the SD. The SD stress upregulated the expression of TrkB and synaptotagmin-4 in the amygdala of HFD mice. Bilateral lesions of the central amygdalae before SD stress inhibited the stress-induced aggravating effect without affecting the HFD-induced elevation of plasma corticosterone. CONCLUSIONS: Stress aggravates HFD-induced insulin resistance and neuroadaptation in the amygdala. The HFD-induced insulin resistance is amygdala-dependent. Understanding the role of stress-induced amygdalar adaptation in the development of T2D could inform therapies aimed at reducing chronic stressors to decrease the risk for T2D.