Molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania based on network pharmacology and molecular docking: Evidence from computational biology.

BACKGROUND: Quetiapine monotherapy is recommended as the first-line option for acute mania and acute bipolar depression. However, the mechanism of action of quetiapine is unclear. Network pharmacology and molecular docking were employed to determine the molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania. METHODS: Putative target genes for quetiapine were collected from the GeneCard, SwissTargetPrediction, and DrugBank databases. Targets for bipolar depression and bipolar mania were identified from the DisGeNET and GeneCards databases. A protein-protein interaction (PPI) network was generated using the String database and imported into Cytoscape. DAVID and the Bioinformatics platform were employed to perform the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the top 15 core targets. The drug-pathway-target-disease network was constructed using Cytoscape. Finally, molecular docking was performed to evaluate the interactions between quetiapine and potential targets. RESULTS: Targets for quetiapine actions against bipolar depression (126 targets) and bipolar mania (81 targets) were identified. Based on PPI and KEGG pathway analyses, quetiapine may affect bipolar depression by targeting the MAPK and PI3K/AKT insulin signaling pathways via BDNF, INS, EGFR, IGF1, and NGF, and it may affect bipolar mania by targeting the neuroactive ligand-receptor interaction signaling pathway via HTR1A, HTR1B, HTR2A, DRD2, and GRIN2B. Molecular docking revealed good binding affinity between quetiapine and potential targets. LIMITATIONS: Pharmacological experiments should be conducted to verify and further explore these results. CONCLUSIONS: Our findings suggest that quetiapine affects bipolar depression and bipolar mania through distinct biological core targets, and thus through different mechanisms. Furthermore, our results provide a theoretical basis for the clinical use of quetiapine and possible directions for new drug development.

Insulin Resistance/Diabetes and Schizophrenia: Potential Shared Genetic Factors and Implications for Better Management of Patients with Schizophrenia.

Schizophrenia is a complex psychotic disorder with co-occurring conditions, including insulin resistance and type 2 diabetes (T2D). It is well established that T2D and its precursors (i.e., insulin resistance) are more prevalent in patients with schizophrenia who are treated with antipsychotics, as well as in antipsychotic-naïve patients experiencing their first episode of psychosis, compared with the general population. However, the mechanism(s) underlying the increased susceptibility, shared genetics, and possible cause-effect relationship between schizophrenia and T2D remain largely unknown. The objective of this narrative review was to synthesize important studies, including Mendelian randomization (MR) analyses that have integrated genome-wide association studies (GWAS), as well as results from in vitro models, in vivo models, and observational studies of patients with schizophrenia. Both GWAS and MR studies have found that schizophrenia and T2D/insulin resistance share genetic risk factors, and this may mediate a connection between peripheral or brain insulin resistance and T2D with cognition impairment and an increased risk of developing prediabetes and T2D in schizophrenia. Moreover, accumulating evidence supports a causal role for insulin resistance in schizophrenia and emphasizes the importance of a genetic basis for susceptibility to T2D in patients with schizophrenia before they receive psychotic treatment. The present findings and observations may have clinical implications for the development of better strategies to treat patients with schizophrenia, with both pharmacological (i.e., samidorphan, empagliflozin) and/or nonpharmacological (i.e., lifestyle changes) approaches. Additionally, this review may benefit the design of future studies by physicians and clinical investigators.

Low-dose lithium adjunct to atypical antipsychotic treatment nearly improved cognitive impairment, deteriorated the gray-matter volume, and decreased the interleukin-6 level in drug-naive patients with first schizophrenia symptoms: a follow-up pilot study.

This study was conducted to investigate the effects of long-term low-dose lithium adjunct to antipsychotic agent use on the cognitive performance, whole-brain gray-matter volume (GMV), and interleukin-6 (IL-6) level in drug-naive patients with first-episode schizophrenia, and to examine relationships among these factors. In this double-blind randomized controlled study, 50 drug-naive patients with first-episode schizophrenia each took low-dose (250 mg/day) lithium and placebo (of the same shape and taste) adjunct to antipsychotic agents (mean, 644.70 ± 105.58 and 677.00 ± 143.33 mg/day chlorpromazine equivalent, respectively) for 24 weeks. At baseline and after treatment completion, the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognitive performance, 3-T magnetic resonance imaging was performed to assess structural brain alterations, and serum IL-6 levels were quantified by immunoassay. Treatment effects were assessed within and between patient groups. Relationships among cognitive performance, whole-brain GMVs, and the IL-6 level were investigated by partial correlation analysis. Relative to baseline, patients in the lithium group showed improved working memory, verbal learning, processing speed, and reasoning/problem solving after 24 weeks of treatment; those in the placebo group showed only improved working memory and verbal learning. The composite MCCB score did not differ significantly between groups. The whole-brain GMV reduction was significantly lesser in the lithium group than in the placebo group (0.46% vs. 1.03%; P < 0.001). The GMV and IL-6 reduction ratios correlated with each other in both groups (r = -0.17, P = 0.025). In the lithium group, the whole-brain GMV reduction ratio correlated with the working memory improvement ratio (r = -0.15, P = 0.030) and processing speed (r = -0.14, P = 0.036); the IL-6 reduction ratio correlated with the working memory (r = -0.21, P = 0.043) and verbal learning (r = -0.30, P = 0.031) improvement ratios. In the placebo group, the whole-brain GMV reduction ratio correlated only with the working memory improvement ratio (r = -0.24, P = 0.019); the IL-6 reduction ratio correlated with the working memory (r = -0.17, P = 0.022) and verbal learning (r = -0.15, P = 0.011) improvement ratios. Both treatments implemented in this study nearly improved the cognitive performance of patients with schizophrenia; relative to placebo, low-dose lithium had slightly greater effects on several aspects of cognition. The patterns of correlation among GMV reduction, IL-6 reduction, and cognitive performance improvement differed between groups.

Validation of a modified Chinese-language version of the Davos Assessment of Cognitive Biases Scale (MCL-DACOBS) in a sample of Chinese patients with schizophrenia.

INTRODUCTION: The Davos Assessment of Cognitive Biases Scale (DACOBS) is widely used to assess cognitive biases in patients who have schizophrenia. However, the lack of a modified Chinese-language version of the DACOBS (MCL-DACOBS) precludes Chinese schizophrenic patients from treatment aimed at normalizing cognitive biases, impacting their prognosis. Here, we aimed to produce a DACOBS for China and test the validity and reliability of the resultant MCL-DACOBS. METHODS: Eighteen researchers collaborated to develop the MCL-DACOBS: A total of 15 researchers modified and translated the English version of the DACOBS, 1 native-English-speaking researcher back-translated the scale, and 2 Chinese sinologists localized and optimized the language of the MCL-DACOBS. Forty-two volunteers checked the scale items' comprehensibility, and the two sinologists performed further localization and optimization based on their feedback. The final version of the MCL-DACOBS used in this study was thus derived from the harmonized English-language version of the scale. Confirmatory factor analyses (CFAs) were used to examine the best latent structure of the MCL-DACOBS. Cronbach's α and intraclass correlation coefficients (ICCs) were used to check the reliability. The discriminative ability of the MCL-DACOBS was assessed according to the area under the receiver operating characteristic curve. RESULTS: The CFA showed that all items loaded onto factors with loadings >0.400. A two-factor structure showed a good model fit (root mean square error of approximation = .018, Tucker-Lewis index = .978, comparative fit index = .984). Promax rotation demonstrated that each item had a high factor load (0.432-0.774). Cronbach's α coefficient and ICC for the MCL-DOCABS were .965 and .957, respectively, indicating that the scale has ideal reliability. CONCLUSION: The MCL-DACOBS has good validity and good reliability, and its psychometric properties indicate that it is a valid tool for measuring cognitive biases in Chinese patients with schizophrenia.

Validation and reliability test of Chinese language patient-reported impact of symptoms in schizophrenia scale.

Background: Patient-reported outcomes, or subjective evaluations directly reflecting the patient's views, feelings, and judgments, are now being used to evaluate the outcomes of care and treatment of people with schizophrenia. In this study, we used an updated tool, the patient-reported impact of symptoms in schizophrenia scale (PRISS), translated into Chinese languages to assess the subjective experiences of schizophrenia patients. Objective: This study aimed to test the psychometrics of the Chinese languages PRISS (CL-PRISS). Method: This study used the Chinese version of PRISS (CL-PRISS), acquired from the harmonized English-language version. A total of 280 patients enrolled in this study were asked to complete the CL-PRISS, the positive and negative syndrome scale (PANSS), and the World Health Organization Disability Assessment Schedule (WHO-DAS). Construct and concurrent validity was tested using the confirmatory factor analysis (CFA) and Spearman correlation coefficient, respectively. The reliability of CL-PRISS was tested using Cronbach's α coefficient and the internal correlation coefficient. Results: Confirmatory factor analysis (CFA) analysis demonstrated three major factors in CL_PRISS: the first factor is productive experiences, the second factor is affective-negative, and the third factor experiences. The factor loadings between items and factors ranged from 0.436 to 0.899 (RMSEA = 0.029, TLI = 0.940, CFI = 0.921). The correlation coefficient between the CL_PRISS and PANSS was 0.845, and between the CL-PRISS and WHO-DAS was 0.886. The ICC of the total CL_PRISS was 0.913, and Cronbach's α was 0.903. Conclusion: The Chinese version of the PRISS (CL_PRISS) can be effectively used for assessing the subjective experience of Chinese patients with schizophrenia.

Validity and reliability of a Chinese version of the Bergen Work Addiction Scale.

Background: Work addiction (WA), which can impair personal relationships, engagement in recreational activities, and/or health, is a behavioral addiction. A tool for the early detection of WA in China is needed. Objective: The aim of this study was to develop and determine the validity and reliability of a Chinese version of the Bergen Work Addiction Scale (C-BWAS). Methods: Two hundred social workers who provided post-discharge services for adolescents with non-suicidal self-injury (NSSI) were enrolled in this study. The construct validity of the C-BWAS was assessed by confirmatory factor analysis (CFA). Criterion validity was assessed by conducting Pearson correlation analyses of C-CWAS scores with Hamilton Depression Scale (HAM-D) and Hamilton Anxiety Scale (HAM-A) scores. Cronbach's α and the intra-class correlation coefficient (ICC) were used to evaluate the reliability of the C-BWAS. Results: CFA confirmed a one-dimensional structure of the C-BWAS with good construct validity indices [comparative fit index (CFI) = 0.964, Tucker-Lewis index (TLI) = 0.951, root-mean-square error of approximation (RMSEA) = 0.079, and minimum discrepancy C/degrees of freedom (Cmin/DF) = 0.362]. The standardized regression weights ranged from 0.523 to 0.753. All C-BWAS items loaded on one major factor (loading weights, 0.646-0.943). Coefficients of correlation between C-BWAS scores and HAM-D and HAM-A scores were 0.889 and 0.933, respectively. The Cronbach's α coefficient and ICC for the instrument was 0.837 and 0.905, respectively. Conclusion: The presently developed C-BWAS showed very good reliability and acceptably validity. It can be employed as a useful tool for assessing WA severity in social workers who provide post-discharge services for adolescents with NSSI.

Validity and reliability of a Chinese language suicide screening questionnaire-observer rating (CL-SSQ-OR) assessment for children/adolescents.

Background: A Suicide Screening Questionnaire-Observer Rating (SSQ-OR) has been used to assess risk of suicide among individuals and to help clinicians identify and rescue individuals attempting suicide. To prevent the risk of suicide in China, a Chinese language SSQ-OR (CL-SSQ-OR) needs to be introduced. Objective: To test the validity and reliability of a CL-SSQ-OR. Method: A total of 250 individuals were enrolled in this study. Each completed a CL-SSQ-OR assessment, Patient Health Questionnaire-9, and the Beck Scale for Suicide Ideation. Confirmatory factor analysis (CFA) was adopted to determine structural validity. Spearman correlation coefficients were adopted to determine criterion validity. An internal correlation coefficient (ICC) was used to test inter-consistency and Cronbach's α coefficient was used to test split-half reliability. Results: CFA was conducted with use of the maximum variance method to evaluate the item results. All of the items received scores >0.40. In addition, good model fit indices were observed for the two-factor structure RMSEA = 0.046, TLI = 0.965, CFI = 0.977. The items' factor loading of the CL-SSQ-OR in the first factor ranged from 0.443 to 0.878. The items' factor loading of the CL-SSQ-OR in the second factor ranged from 0.400 to 0.810. The ICC of the total CL-SSQ-OR was 0.855. Cronbach's α was 0.873. Conclusion: The CL-SSQ-OR described here demonstrates ideal psychometric properties and is found to be a suitable tool for screening Chinese children/adolescents who are at risk of suicide.

Low-dose lithium mono- and adjunctive therapies improve MK-801-induced cognitive impairment and schizophrenia-like behavior in mice - Evidence from altered prefrontal lobe Ca2+ activity.

BACKGROUND: Few studies have evaluated lithium either as monotherapy or in combination with anti-psychotic agents to improve cognition in murine models of schizophrenia. METHODS: Visualization of Ca2+ activity in the prefrontal cortex was used to characterize brain neural activity. Novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FCT) tests were used to characterize cognitive performance; while pre-pulse inhibition (PPI), elevated plus maze (EPM) and the open field test (OFT) were used to characterize schizophrenia-like behavior. RESULTS: A 28-day course of low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) improved Ca2+ ratio by 70.10 %, PPI by 69.28 %, NOR by 70.09 %, MWM by 71.28 %, FCT by 68.56 %, EPM by 70.95 % and OFT by 75.23 % compared to the results of positive controls. Unexpectedly, moderate-dose lithium (human equivalent dose of 500 mg/day) used either as monotherapy or as an adjunct with quetiapine worsened Ca2+ activity, PPI, MWM, FCT, EPM, and OPT. LIMITATIONS: Our study cannot explain the contrasting positive and negative effects of low-dose and moderate-dose lithium, respectively, when used either as monotherapies or as adjuncts. Further studies, especially Western blotting, may reveal molecular mechanisms of action. CONCLUSIONS: Low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) provided the best improvements. Furthermore, benefits persisted for 14 days post-treatment. Our data provide directions for further research of therapeutic alternatives to mitigate schizophrenia-related cognopathy.

Lithium bidirectionally regulates depression- and mania-related brain functional alterations without worsening cognitive function in patients with bipolar disorder.

Lithium monotherapy has been proposed to have antidepressant and antimanic effects in patients with bipolar disorder (BP). However, so far, it is lack of evidence to support this proposition. The main aim of this study was to test the hypothesis that lithium bidirectionally regulates depression- and mania-related brain functional abnormalities in patients with BP. We also assessed the effects of lithium, alone and in combination with other pharmacological treatments, on patients' cognitive performance. We enrolled 149 drug-naïve patients with BP; 99 patients experiencing first depressive episodes were allocated randomly to four treatment groups [lithium (DP/Li), lithium with lamotrigine (LTG; DP/Li+LTG), LTG (DP/LTG), and valproate (VPA) with LTG (DP/VPA+LTG)], and 50 experiencing first hypo-manic episodes were allocated to two treatment groups (MA/Li and MA/VPA). For comparative analysis, 60 age-matched healthy individuals were also recruited. Whole-brain global and regional resting-state cerebral blood flow (rs-CBF) and cognitive alterations were examined before and after 12-week treatment. We have the following findings: DP/Li+LTG, and to a lesser extent DP/Li, alleviated the depression-related reduction in rs-CBF. MA/VPA and MA/Li reversed the mania-related elevation of rs-CBF completely and partially, respectively. Lithium alone improved cognitive performance during depressive and manic episodes; other tested treatments have no such effect or worsened cognitive ability. Our results showed that lithium bidirectionally regulates depression- and mania-associated brain functional abnormalities in patients with BP. Lithium monotherapy has a better antimanic effect than VPA, is superior to other tested treatments in improving cognition during the course of BP, and has satisfactory antidepressant effects in patients with BP.

Transcranial direct current stimulation of the occipital lobes with adjunct lithium attenuates the progression of cognitive impairment in patients with first episode schizophrenia.

Background: There is no standard effective treatment for schizophrenia-associated cognitive impairment. Efforts to use non-invasive brain stimulation for this purpose have been focused mostly on the frontal cortex, with little attention being given to the occipital lobe. Materials and methods: We compared the effects of nine intervention strategies on cognitive performance in psychometric measures and brain connectivity measured obtained from functional magnetic resonance imaging analyses. The strategies consisted of transcranial direct current stimulation (t-DCS) or repetitive transcranial magnetic stimulation (r-TMS) of the frontal lobe or of the occipital alone or with adjunct lithium, or lithium monotherapy. We measured global functional connectivity density (gFCD) voxel-wise. Results: Although all nine patient groups showed significant improvements in global disability scores (GDSs) following the intervention period (vs. before), the greatest improvement in GDS was observed for the group that received occipital lobe-targeted t-DCS with adjunct lithium therapy. tDCS of the occipital lobe improved gFCD throughout the brain, including in the frontal lobes, whereas stimulation of the frontal lobes had less far-reaching benefits on gFCD in the brain. Adverse secondary effects (ASEs) such as heading, dizziness, and nausea, were commonly experienced by patients treated with t-DCS and r-TMS, with or without lithium, whereas ASEs were rare with lithium alone. Conclusion: The most effective treatment strategy for impacting cognitive impairment and brain communication was t-DCS stimulation of the occipital lobe with adjunct lithium therapy, though patients often experienced headache with dizziness and nausea after treatment sessions.

Higher benefit-risk ratio of COVID-19 vaccination in patients with schizophrenia and major depressive disorder versus patients with bipolar disorder when compared to controls.

Patients with major psychiatric disorders (MPD) that include schizophrenia (SCH), bipolar disorder (BP), and major depressive disorder (MDD) are at increased risk for coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccines in MPD patients have not been fully evaluated. This study aimed to investigate adverse events (AEs)/side effects and efficacy of COVID-19 vaccines in MPD patients. This retrospective study included 2034 patients with SCH, BP, or MDD who voluntarily received either BBIBP-CorV or Sinovac COVID-19 vaccines, and 2034 matched healthy controls. The incidence of AEs/side effects and the efficacy of COIVD-19 vaccinations among the two groups were compared. The risk ratio (RR) of side effects in patients with MPD was 0.60 (95% confidence interval [CI]: 0.53-0.68) after the first dose and 0.80 (95% CI: 0.65-0.99) following the second dose, suggesting a significantly lower risk in the MPD group versus healthy controls. The RRs of AEs did not differ between patients and controls. Notably, fully vaccinated patients exhibited a decreased risk of influenza with or without fever compared with controls (RR=0.38, 95% CI: 0.31-0.46; RR=0.23, 95% CI: 0.17-0.30; respectively). Further subgroup comparisons revealed a significantly lower risk of influenza with fever in MDD (RR=0.13, 95% CI: 0.08-0.21) and SCH (RR=0.24, 95% CI: 0.17-0.34) than BP (RR=0.85, 95% CI: 0.69-1.06) compared to controls. We conclude that the benefit-risk ratio of COVID-19 vaccination was more favorable in SCH or MDD versus BP when compared with controls. These data indicate that COVID-19 vaccines are safe and protective in patients with MPD from COVID-19.

Lithium produces bi-directionally regulation of mood disturbance, acts synergistically with anti-depressive/-manic agents, and did not deteriorate the cognitive impairment in murine model of bipolar disorder.

Lithium (Li) is a well-established mood disorder treatment and may be neuroprotective. Bi-directional regulation (i.e. affecting manic symptoms and depressive symptoms) by Li has not been demonstrated. This study explored: (1) bidirectional regulation by Li in murine models of depression, mania, and bipolar disorder (BP); and (2) potential Li synergism with antidepressant/anti-mania agents. The chronic unpredictable mild stress (CUMS) and ketamine-induced mania (KM) models were used. These methods were used in series to produce a BP model. In vivo two-photon imaging was used to visualize Ca2+ activity in the dorsolateral prefrontal cortex. Depressiveness, mania, and cognitive function were assessed with the forced swim task (FST), open field activity (OFA) task, and novel object recognition task, respectively. In CUMS mice, Ca2+ activity was increased strongly by Li and weakly by lamotrigine (LTG) or valproate (VPA), and LTG co-administration reduced Li and VPA monotherapy effects; depressive immobility in the FST was attenuated by Li or LTG, and attenuated more strongly by LTG-VPA or LTG-Li; novel object exploration was increased strongly by Li and weakly by LTG-Li, and reduced by LTG, VPA, or LTG-VPA. In KM mice, Li or VPA attenuated OFA mania symptoms and normalized Ca2+ activity partially; Li improved cognitive function while VPA exacerbated the KM alteration. These patterns were replicated in the respective BP model phases. Lithium had bi-directional, albeit weak, mood regulation effects and a cognitive supporting effect. Li co-administration with antidepressant/-manic agents enhanced mood-regulatory efficacy while attenuating their cognitive-impairing effects.

Prevalence of Heavy Menstrual Bleeding and Its Associated Cognitive Risks and Predictive Factors in Women With Severe Mental Disorders.

There has been limited studies examining treatment-induced heavy menstrual bleeding (HMB) in women with severe mental illnesses. The aim of this study was to examine HMB prevalence and HMB-associated factors in young women (18-34 years old) diagnosed with bipolar disorder (BP), major depressive disorder (MDD), or schizophrenia (SCZ) who have full insight and normal intelligence. Eighteen-month menstruation histories were recorded with pictorial blood loss assessment chart assessments of HMB. Multivariate analyses were conducted to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Drug effects on cognition were assessed with the MATRICS Consensus Cognitive Battery (MCCB). HMB prevalence were: BP, 25.85%; MDD, 18.78%; and SCH, 13.7%. High glycosylated hemoglobin (HbA1c) level was a strong risk factor for HMB [BP OR, 19.39 (16.60-23.01); MDD OR, 2.69 (4.59-13.78); and SCZ OR, 9.59 (6.14-12.43)]. Additional risk factors included fasting blood sugar, 2-h postprandial blood glucose, and use of the medication valproate [BP: OR, 16.00 (95%CI 12.74-20.22); MDD: OR, 13.88 (95%CI 11.24-17.03); and SCZ OR, 11.35 (95%CI 8.84-19.20)]. Antipsychotic, antidepressant, and electroconvulsive therapy use were minor risk factors. Pharmacotherapy-induced visual learning impairment was associated with HMB [BP: OR, 9.01 (95%CI 3.15-13.44); MDD: OR, 5.99 (95%CI 3.11-9.00); and SCZ: OR, 7.09 (95%CI 2.99-9.20)]. Lithium emerged as a protective factor against HMB [BP: OR, 0.22 (95%CI 0.14-0.40); MDD: OR, 0.30 (95%CI 0.20-0.62); and SCZ: OR, 0.65 (95%CI 0.33-0.90)]. In SCZ patients, hyperlipidemia and high total cholesterol were HMB-associated factors (ORs, 1.87-2.22). Psychiatrist awareness of HMB risk is concerningly low (12/257, 2.28%). In conclusion, prescription of VPA should be cautioned for women with mental illness, especially BP, and lithium may be protective against HMB.

Metabolic risk factors of cognitive impairment in young women with major psychiatric disorder.

Background: Cognitive performance improves clinical outcomes of patients with major psychiatric disorder (MPD), but is impaired by hyperglycemia. Psychotropic agents often induce metabolism syndrome (MetS). The identification of modifiable metabolic risk factors of cognitive impairment may enable targeted improvements of patient care. Objective: To investigate the relationship between MetS and cognitive impairment in young women with MPD, and to explore risk factors. Methods: We retrospectively studied women of 18-34 years of age receiving psychotropic medications for first-onset schizophrenia (SCH), bipolar disorder (BP), or major depressive disorder (MDD). Data were obtained at four time points: presentation but before psychotropic medication; 4-8 and 8-12 weeks of psychotropic therapy; and enrollment. MATRICS Consensus Cognitive Battery, (MCCB)-based Global Deficit Scores were used to assess cognitive impairment. Multiple logistic analysis was used to calculate risk factors. Multivariate models were used to investigate factors associated with cognitive impairment. Results: We evaluated 2,864 participants. Cognitive impairment was observed in 61.94% of study participants, and was most prevalent among patients with BP (69.38%). HbA1c within the 8-12 week-treatment interval was the most significant risk factor and highest in BP. Factors in SCH included pre-treatment waist circumference and elevated triglycerides during the 8-12 weeks treatment interval. Cumulative dosages of antipsychotics, antidepressants, and valproate were associated with cognitive impairment in all MPD subgroups, although lithium demonstrated a protect effect (all P < 0.001). Conclusions: Cognitive impairment was associated with elevated HbA1c and cumulative medication dosages. Pre-treatment waist circumference and triglyceride level at 8-12 weeks were risk factors in SCH. Monitoring these indices may inform treatment revisions to improve clinical outcomes.

Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target.

Schizophrenia is a severe mental illness, as the efficacies of current antipsychotic medications are far from satisfactory. An improved understanding of the signaling molecules involved in schizophrenia may provide novel therapeutic targets. Acid sphingomyelinase (ASM) catalyzes cellular membrane sphingomyelin into ceramide, which is further metabolized into sphingosine-1-phophate (S1P). ASM, ceramide, and S1P at the cell surface exert critical roles in the regulation of biophysical processes that include proliferation, apoptosis, and inflammation, and are thereby considered important signaling molecules. Although research on the ASM/ceramide system is still in its infancy, structural and metabolic abnormalities have been demonstrated in schizophrenia. ASM/ceramide system dysfunction is linked to the two important models of schizophrenia, the dopamine (DA) hypothesis through affecting presynaptic DA signaling, and the vulnerability-stress-inflammation model that includes the contribution of stress on the basis of genetic predisposition. In this review, we highlight the current knowledge of ASM/ceramide system dysfunction in schizophrenia gained from human and animal studies, and formulate future directions from the biological landscape for the development of new treatments. Collectively, these discoveries suggest that aberrations in the ASM/ceramide system, especially in ASM activity and levels of ceramide and S1P, may alter cerebral microdomain structure and neuronal metabolism, leading to neurotransmitter (e.g., DA) dysfunction and neuroinflammation. As such, the ASM/ceramide system may offer therapeutic targets for novel medical interventions. Normalization of the aberrant ASM/ceramide system or ceramide reduction by using approved functional inhibitors of ASM, such as fluvoxamine and rosuvastatin, may improve clinical outcomes of patients with schizophrenia. These transformative findings of the ASM/ceramide system in schizophrenia, although intriguing and exciting, may pose scientific questions and challenges that will require further studies for their resolution.

Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy.

Antipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

Differential effects of alcohol-drinking patterns on the structure and function of the brain and cognitive performance in young adult drinkers: A pilot study.

INTRODUCTION: This study was aimed to determine how different patterns of alcohol consumption drive changes to brain structure and function and their correlation with cognitive impairments in young adult alcohol drinkers. METHODS: In this study, we enrolled five groups participants and defined as: long-term abstinence from alcohol (LA), binge drinking (BD), long-term low dosage alcohol consumption but exceeding the safety drinking dosage (LD), long-term alcohol consumption of damaging dosage (LDD), and long-term heavy drinking (HD). All participants underwent magnetic resonance imaging (MRI) and functional MRI (fMRI) to acquire data on brain structure and function, including gray matter volume (GMV), fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), functional connectivity (FC), and brain network properties. The cognitive ability was evaluated with the California Verbal Learning Test (CVLT), intelligence quotient (IQ), and short delay free recall (SDFR). RESULTS: Compared to LA, GMV significantly decreased in the brain regions in VN, SMN, and VAN in the alcohol-drinking groups (BD, LD, LDD, and HD). ReHo was significantly enhanced in the brain regions in VN, SMN, and VAN, while fALFF significantly increased in the brain regions in VN and SMN. The number of intra- and inter-modular connections within networks (VN, SMN, sensory control network [SCN], and VAN) and their connections to other modules were abnormally changed. These changes adversely affected cognition (e.g., IQ, CVLT, SDFR). CONCLUSION: Despite the small sample size, this study provides new evidence supporting the need for young people to abstain from alcohol to protect their brains. These findings present strong reasoning for updating anti-alcohol slogans and guidelines for young people in the future.

Case Report: Effect of Electroconvulsive Therapy on Obsessive-Compulsive Disorder Comorbid With Body Dysmorphic Disorder.

Obsessive-compulsive disorder (OCD) is a chronic psychiatric condition that is associated with considerable morbidity, and ~90% of individuals with OCD have another psychiatric comorbidity. Patients with comorbid OCD and body dysmorphic disorder (BDD) have limited insight and poor psychosocial function, respond poorly to drug treatment, and have an increased risk of suicide. Modified electroconvulsive therapy (ECT) has been attempted to improve symptoms of OCD when drug treatment does not have a satisfactory effect. This report describes a patient who had OCD comorbid with BDD that was successfully treated with modified ECT. Although the mechanism of its effect is unclear, modified ECT may be an alternative treatment for patients with comorbid OCD and BDD. Its efficacy and mechanism of action require further investigation in a large sample of patients with these comorbid disorders.

Exploration of the cortical pathophysiology underlying visual disturbances in schizophrenia comorbid with depressive disorder-An evidence from mouse model.

INTRODUCTION: Patients with schizophrenia frequently present with visual disturbances including hallucination, and this symptom is particularly prevalent in individuals with comorbid depressive disorders. Currently, little is known about the neurobiological mechanisms of such psychiatric symptoms, and few explanations for the co-occurrence of schizophrenia, depression, and visual disturbances are available. METHODS: In this study, we generated a mouse schizophrenia model in which depressive symptoms were also induced. We adopted in vivo two-photon calcium imaging and ex vivo electrophysiological recording of the primary visual cortex to reveal the synaptic transmission and neural activity in the mouse schizophrenia model. RESULTS: In vivo two-photon calcium imaging and ex vivo electrophysiological recording of the primary visual cortex revealed impaired synaptic transmission and abnormal neural activity in the schizophrenia model, but not in the depression model. These functional deficits were most prominent in the combined schizophrenia and depression model. CONCLUSION: Overall, our data support a mechanism by which the visual cortex plays a role in visual disturbances in schizophrenia.

Abberant inverted U-shaped brain pattern and trait-related retinal impairment in schizophrenia patients with combined auditory and visual hallucinations: a pilot study.

Schizophrenic patients often experience auditory hallucinations (AHs) and visual hallucinations (VHs). However, brain and retinal alterations associated with combined AHs and VHs in schizophrenic patients are unknown. This study aimed o investigate brain and retinal alterations in first episode un-treated schizophrenic patients with combined AHs and VHs (FUSCHAV). FUSCHAV patients (n = 120), divided into four groups according to severity of AH and VH symptoms, were compared to healthy controls (n = 30). Gray matter volume (GMV) and global functional connectivity density (gFCD) were recorded to reflect brain structure and functional alterations. Total retinal thickness was acquired by optical coherence tomography to assess retinal impairment. The majority of FUSCHAV patients (85.8%) demonstrated both GMV reduction and gFCD increases along with retinal thinning compared to healthy controls. The severity of GMV reduction and gFCD increase differed between patient groups, ranked from highest to lowest severity as follows: severe AHs combined with severe VHs (FUSCHSASV, 20 patients), moderate AHs combined with severe VHs (FUSCHMASV, 23 patients), severe AHs combined with moderate VHs (FUSCHSAMV, 28 patients), and moderate AHs combined with moderate VHs (FUSCHMAMV, 26). Retinal impairment was similar among the four FUSCHAV groups. GMV reduction and gFCD increases in the frontal-parietal lobule show an inverted U-shaped pattern among FUSCHAV patients according to AH and VH severity, while retinal impairment remains stable among FUSCHAV groups. These findings indicate a reciprocal deterioration in auditory and visual disturbances among FUSCHAV patients.