Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation.

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10-9) and rs3824417 in PTPRD (P = 3.348 × 10-9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10-4) and triglycerides (P = 2.06 × 10-3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.

Therapeutic outcomes wide association scan of different antipsychotics in patients with schizophrenia: Randomized clinical trials and multi-ancestry validation.

AIM: This study identified discrepant therapeutic outcomes of antipsychotics. METHODS: A total of 5191 patients with schizophrenia were enrolled, 3030 as discovery cohort, 1395 as validation cohort, and 766 as multi-ancestry validation cohort. Therapeutic Outcomes Wide Association Scan was conducted. Types of antipsychotics (one antipsychotic vs other antipsychotics) were dependent variables, therapeutic outcomes including efficacy and safety were independent variables. RESULTS: In discovery cohort, olanzapine related to higher risk of weight gain (AIWG, OR: 2.21-2.86), liver dysfunction (OR: 1.75-2.33), sedation (OR: 1.76-2.86), increased lipid level (OR: 2.04-2.12), and lower risk of extrapyramidal syndrome (EPS, OR: 0.14-0.46); risperidone related to higher risk of hyperprolactinemia (OR: 12.45-20.53); quetiapine related to higher risk of sedation (OR = 1.73), palpitation (OR = 2.87), increased lipid level (OR = 1.69), lower risk of hyperprolactinemia (OR: 0.09-0.11), and EPS (OR: 0.15-0.44); aripiprazole related to lower risk of hyperprolactinemia (OR: 0.09-0.14), AIWG (OR = 0.44), sedation (OR: 0.33-0.47), and QTc prolongation (ß = -2.17); ziprasidone related to higher risk of increased QT interval (ß range: 3.11-3.22), nausea (OR: 3.22-3.91), lower risk of AIWG (OR: 0.27-0.46), liver dysfunction (OR: 0.41-0.38), and increased lipid level (OR: 0.41-0.55); haloperidol related to higher risk of EPS (OR: 2.64-6.29), hyperprolactinemia (OR: 5.45-9.44), and increased salivation (OR: 3.50-3.68). Perphenazine related to higher risk of EPS (OR: 1.89-2.54). Higher risk of liver dysfunction in olanzapine and lower risk of hyperprolactinemia in aripiprazole were confirmed in validation cohort, and higher risk of AIWG in olanzapine and hyperprolactinemia in risperidone were confirmed in multi-ancestry validation cohort. CONCLUSION: Future precision medicine should focus on personalized side-effects.

Association of intestinal anti-inflammatory drug target genes with psychiatric Disorders: A Mendelian randomization study.

INTRODUCTION: Psychiatric disorders present a substantial global public health burden with limited drug options. The gut-brain axis connects inflammatory bowel diseases and psychiatric disorders, which often have comorbidities. While some evidence hints at anti-inflammatory drugs aiding in treating psychiatric conditions, the specific effects of intestinal anti-inflammatory drugs remain unclear. OBJECTIVES: This study investigates the causal effect of intestinal anti-inflammatory drug targets on psychiatric disorders. We hypothesize that these drug targets may offer new insights into the treatment and prevention of such disorders. Additionally, we explore gut microbiota's mediating role between drug target genes and psychiatric disorders. METHODS: We performed two-sample Mendelian randomization (MR) using summary data from existing expression quantitative trait loci (eQTL) and protein QTL in the brain, along with public genome-wide association studies of disease. We also explored gut microbiota's mediating effect. The statistics encompassed six psychiatric disorders involving 9,725-500,199 individuals. Colocalization analysis enhanced the MR evidence. RESULTS: We uncovered a causal link between TPMT (a target of olsalazine) expression in the amygdala and bipolar disorder (BD) risk (odds ratio [OR] = 1.08; P = 4.29 × 10-4). This association was observed even when the sigmoid colon and whole blood eQTL were considered as exposures. Colocalization analysis revealed a shared genetic variant (rs11751561) between TPMT expression and BD, with a posterior probability of 61.6 %. Interestingly, this causal effect was influenced by a decrease in the gut microbiota abundance of the genus Roseburia (effect proportion = 10.05 %). Moreover, elevated ACAT1 expression was associated with higher obsessive-compulsive disorder risk (OR = 1.62; P = 3.64 × 10-4; posterior probability = 3.1 %). CONCLUSION: These findings provide novel targets for the treatment of psychiatric disorders, underscore the potential of repurposing olsalazine, and emphasize the importance of TPMT and ACAT1 in future drug development.

The Association of Redox Regulatory Drug Target Genes with Psychiatric Disorders: A Mendelian Randomization Study.

Redox regulatory drug (RRD) targets may be considered potential novel drug targets of psychosis due to the fact that the brain is highly susceptible to oxidative stress imbalance. The aim of the present study is to identify potential associations between RRD targets' perturbation and the risk of psychoses; to achieve this, Mendelian randomization analyses were conducted. The expression quantitative trait loci (eQTL) and protein QTL data were used to derive the genetic instrumental variables. We obtained the latest summary data of genome-wide association studies on seven psychoses as outcomes, including schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD), attention-deficit/hyperactivity disorder, autism, obsessive-compulsive disorder and anorexia nervosa. In total, 95 unique targets were included in the eQTL panel, and 48 targets in the pQTL one. Genetic variations in the vitamin C target (OGFOD2, OR = 0.784, p = 2.14 × 10-7) and melatonin target (RORB, OR = 1.263, p = 8.80 × 10-9) were significantly related to the risk of SCZ. Genetic variation in the vitamin E (PRKCB, OR = 0.248, p = 1.24 × 10-5) target was related to an increased risk of BD. Genetic variation in the vitamin C target (P4HTM: cerebellum, OR = 1.071, p = 4.64 × 10-7; cerebellar hemisphere, OR = 1.092, p = 1.98 × 10-6) was related to an increased risk of MDD. Cognitive function mediated the effects on causal associations. In conclusion, this study provides supportive evidence for a causal association between RRD targets and risk of SCZ, BD or MDD, which were partially mediated by cognition.

Contribution of copy number variants on antipsychotic treatment response in Han Chinese patients with schizophrenia.

BACKGROUND: Response to antipsychotic drugs (APD) varies greatly among individuals and is affected by genetic factors. This study aims to demonstrate genome-wide associations between copy number variants (CNVs) and response to APD in patients with schizophrenia. METHODS: A total of 3030 patients of Han Chinese ethnicity randomly received APD (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, haloperidol and perphenazine) treatment for six weeks. This study is a secondary data analysis. Percentage change on the Positive and Negative Syndrome Scale (PANSS) reduction was used to assess APD efficacy, and more than 50% change was considered as APD response. Associations between CNV burden, gene set, CNV loci and CNV break-point and APD efficacy were analysed. FINDINGS: Higher CNV losses burden decreased the odds of 6-week APD response (OR = 0.66 [0.44, 0.98]). CNV losses in synaptic pathway involved in neurotransmitters were associated with 2-week PANSS reduction rate. CNV involved in sialylation (1p31.1 losses) and cellular metabolism (19q13.32 gains) associated with 6-week PANSS reduction rate at genome-wide significant level. Additional 36 CNVs associated with PANSS factors improvement. The OR of protective CNVs for 6-week APD response was 3.10 (95% CI: 1.33-7.19) and risk CNVs was 8.47 (95% CI: 1.92-37.43). CNV interacted with genetic risk score on APD efficacy (Beta = -1.53, SE = 0.66, P = 0.021). The area under curve to differ 6-week APD response attained 80.45% (95% CI: 78.07%-82.82%). INTERPRETATION: Copy number variants contributed to poor APD efficacy and synaptic pathway involved in neurotransmitter was highlighted. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, China Postdoctoral Science Foundation.

Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis.

BACKGROUND: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. METHODS: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. FINDINGS: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. INTERPRETATION: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. FUNDING: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

Identifying causal associations between early sexual intercourse or number of sexual partners and major depressive disorders: A bidirectional two-sample Mendelian randomization analysis.

BACKGROUND: Early sexual intercourse and a greater number of sexual partners have been proved associated with depression. However, the causality of these associations is not clear. METHODS: To unveil the causal associations between sexual factors and major depression disorder (MDD). The bidirectional, two-sample Mendelian randomization (MR) study was conducted, which used genetic variants associated with two sexual factors (age first had sexual intercourse, n = 406,457; lifetime number of sexual partners, n = 378,882) and MDD (n = 500,199) from the largest genome-wide association studies (GWASs) conducted by the UK biobank and the Psychiatric Genomics Consortium. The two-step MR analysis was applied to assess mediation. The Genetic predictors for five risky behaviors were also obtained from the most up-to-date GWAS conducted by the UK Biobank (ever self-harmed: 117,733; ever attempted suicide: 4933; psychoactive substance abuse, alcohol use, and tobacco use: 463,010). RESULTS: MR analysis indicated a risky causal effect of age first had sexual intercourse (OR = 0.720, 95 % CI: 0.661-0.784, P = 2.45 × 10-14) and lifetime number of sexual partners (OR = 1.656, 95 % CI: 1.356-2.022, P = 7.46 × 10-7) on MDD. Mediation analysis showed the effects were mediated by tobacco use, with a proportion of 34.20 % on age first had sexual intercourse and 22.94 % on lifetime number of sexual partners separately. LIMITATIONS: The overlap of participants in different traits and unclear gender. CONCLUSIONS: Robust genetic evidence indicated that premature sexual intercourse and more sexual partners were risks for MDD. Risky behaviors, especially the tobacco use, mediated this effect.

Dissecting the causal association between social or physical inactivity and depression: a bidirectional two-sample Mendelian Randomization study.

A growing body of research suggests that social or physical activity can affect the risk of Major depressive disorder (MDD). However, the bidirectional relationship between them remains to be clarified further, especially between inactivity and MDD. Here, we performed a two-sample Mendelian Randomization analysis using genetic variants associated with social/physical activities and MDD, and assessed the mediating effect of obesity-related measures and brain imaging phenotypes. The dataset on MDD, social activities, and physical activities included 500,199; 461,369; 460,376 individuals, respectively. Information regarding body mass index (BMI), body fat percentage (BFP), IDPs for 454,633; 461,460; 8,428 participants, respectively. We identified bidirectional causal relationships between sport clubs or gyms, strenuous sports, heavy do-it-youself, other exercises and MDD. We also observed that leisure/social inactivity (odds ratio [OR] = 1.64; P = 5.14 × 10-5) or physical inactivity (OR = 3.67; P = 1.99 × 10-5) caused an increased risk of MDD, which were partially mediated by BMI or BFP and masked by the weighted-mean orientation dispersion index of left acoustic radiation or volume of right caudate. Furthermore, we discovered that MDD increased the risk of leisure/social inactivity (OR = 1.03; P = 9.89 × 10-4) or physical inactivity (OR = 1.01; P = 7.96 × 10-4). In conclusions, we found that social/physical activities reduced the risk of MDD, while MDD in turn hindered social/physical activities. Inactivity may increase the risk of MDD, which was mediated or masked by brain imaging phenotypes. These results help to understand the manifestations of MDD and provide evidence and direction for the advancement of intervention and prevention.

Multigenetic Pharmacogenomics-Guided Treatment vs Treatment As Usual Among Hospitalized Men With Schizophrenia: A Randomized Clinical Trial.

Importance: Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia. Objective: To evaluate the clinical effectiveness of MPGT in schizophrenia in a randomized clinical trial (RCT). Design, Setting, and Participants: This RCT was conducted from March 2020 to March 2022. Male Chinese Han inpatients aged 18 to 60 years diagnosed with schizophrenia with a Positive and Negative Symptom Scale (PANSS) score of 60 or more from 2 selected study hospitals were included. Patients and raters were masked to MPGT or treatment as usual (TAU) randomization. Interventions: Participants were randomly assigned in a 1:1 ratio to receive either MPGT or TAU for 12 weeks. Main Outcomes and Measures: The primary efficacy outcome was the percentage change in PANSS total scores (range, 30 to 210) from baseline to week 6 analyzed by a modified intention-to-treat mixed model for repeated measures. The secondary outcome included response and symptomatic remission rates. Results: A total of 210 participants (mean [SD] age, 29.2 [8.8] years) were enrolled and analyzed, with 113 assigned to MPGT and 97 to TAU. Compared with those randomized to TAU, participants randomized to MPGT demonstrated a significantly higher percentage change in PANSS score (74.2% vs 64.9%; adjusted mean difference, 9.2 percentage points; 95% CI, 4.4-14.1 percentage points; P < .001) and a higher response rate (93 of 113 [82.3%] vs 63 of 97 [64.9%]; adjusted odds ratio, 2.48; 95% CI, 1.28-4.80; P = .01) at the end of week 6. Conclusions and Relevance: In this RCT of MPGT, MPGT was more effective than TAU in treating patients with schizophrenia. These findings suggest that multigenetic pharmacogenomic testing could serve as an effective tool to guide the treatment of schizophrenia. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000029671.

Predictive role of pulvinar in social functional outcome of schizophrenia.

Identifying objective biological subtypes that predict long-term functional outcomes is crucial for understanding neurobiological mechanisms and identifying potential targets. Using resting-state functional magnetic resonance imaging data from 178 patients and 70 controls, we explored social function patterns using latent profile analysis. Long-term outcomes were compared among the biological subtypes using K-means clustering. Partial least squares regression (PLSR) was used to identify gene expression profiles associated with alterations in activity by leveraging transcriptional data from the Allen Human Brain Atlas. In patients with more functional impairment, left medial pulvinar (PM) exhibited significantly lower regional homogeneity of brain activity (ReHo, [95% CI (0.06-0.27), P = 0.002), a finding validated in the independent cohort. Functional connectivity between PM and secondary visual cortex displayed a suggestive decrease. Patients belonging to "higher pulvinar ReHo - better information processing" demonstrated better long-term outcomes and acute treatment response [95% CI (11.2-34.4), P < 0.001]. The PLSR component of imaging-transcriptomic associations partly explained the ReHo differences among patients with varying levels of functional impairment. It revealed enrichment of genes in the synaptic signaling pathway. Pathological changes in the pulvinar may affect social functioning. Higher pulvinar ReHo and better information processing, two objective biomarkers, have a predictive value for better long-term functional outcomes.

High-risk group and functional subtypes of non-suicidal self-injury in young adults with mental disorders.

Background: Identifying high-risk groups of non-suicidal self-injury (NSSI) with multiple risk factors and different functional subtypes contribute to implementing person-centered interventions. Methods: We investigated NSSI profiles among a sample of 258 psychiatric inpatients aged 18-25 years. All participants completed well-validated measures of internal personal and external environmental characteristics. One-hundred and ninety patients reported a lifetime history of NSSI and completed an additional NSSI assessment. A k-means cluster analysis was conducted to extract characteristics of risk factors and functional subtypes. Independent sample t-test, analysis of variance and χ 2 test were used to test the difference of demographic statistical factors, risk factors and functional scores among groups with different frequency of NSSI. Results: The clustering of risk factors analyses supported 4-clusters. The proportion of repeat NSSI patients was the highest (67.1%) in the group with unfavorable personal and unfavorable environmental characteristics. Functional subtype clustering analyses supported 5-clusters. Among patients with repeated NSSI, those with depression were mainly accompanied by the "Sensation Seeking" subtype (39.7%), bipolar disorder mainly supported the "Anti-suicide" subtype (37.9%), and eating disorders were mostly "Social Influence" subtype (33.3%). There was an interaction between functional subtypes and mental disorders. Limitations: All participants were in treatment in a psychiatric service and the results may not be generalizable to a community sample. The data included retrospective self-report which may be inaccurate due to recall bias. Conclusion: It is necessary to identify high-risk groups of NSSI who with unfavorable personal and environmental characteristics and clinical interventions need to consider the heterogeneity of patients' functional subtypes of NSSI.

The positive association between antipsychotic-induced weight gain and therapeutic response: New biotypes of schizophrenia.

Co-occurrence of antipsychotic-induced weight gain (AIWG) and therapeutic response (TR) did exist in clinic but was rarely studied. This study aims to identify potential TR/ AIWG biotypes and explore the clinical, genetic and neuroimaging features. This study enrolled 3030 patients to identify potential TR/AIWG biotypes and explore the clinical, genetic and neuroimaging features. We found three biotypes: TR+nonAIWG (46.91%), TR+AIWG (18.82%), and nonTR+nonAIWG (34.27%). TR+AIWG showed lower weight and lipid level at baseline, but higher changing rate, and higher genetic risk of obesity than TR+nonAIWG and nonTR+nonAIWG. GWAS identified ADIPOQ gene related to TR+AIWG biotypes and top-ranked loci enriched in one-carbon metabolic process, which related to both schizophrenia and metabolic dysfunction. Genetically predicted TR+AIWG was associated with higher odds of diabetes (OR=1.05). The left supplementary motor area was significantly negatively correlated with PRS of obesity. The distinguishing ability with multi-omics data to identify TR+AIWG reached 0.787. In a word, the "thin" patients with a higher risk of obesity are the target population of early intervention.

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis.

BACKGROUND: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment. METHODS: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R2 for regression, and decision curve analysis. RESULTS: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R2 = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R2 = 0.507]. CONCLUSIONS: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).

Oxidative Stress and Psychiatric Disorders: Evidence from the Bidirectional Mendelian Randomization Study.

Observational studies have shown that oxidative stress is highly related to psychiatric disorders, while its cause−effect remains unclear. To this end, a Mendelian randomization study was performed to investigate the causal relationship between oxidative stress and psychiatric disorders. On the one hand, all causal effects of oxidative stress injury biomarkers (OSIB) on psychiatric disorders were not significant (p > 0.0006), while the findings suggested that part of OSIB was nominally associated with the risk of psychiatric disorders (causal OR of uric acid (UA), 0.999 for bipolar disorder (BD), and 1.002 for attention-deficit/hyperactivity disorder (ADHD); OR of catalase was 0.903 for anorexia nervosa (AN); OR of albumin was 1.162 for autism; p < 0.05). On the other hand, major depressive disorder (MDD) was significantly associated with decreased bilirubin (p = 2.67 × 10−4); ADHD was significantly associated with decreased ascorbate (p = 4.37 × 10−5). Furthermore, there were also some suggestively causal effects of psychiatric disorders on OSIB (BD on decreased UA and increased retinol; MDD on increased UA and decreased ascorbate; schizophrenia on decreased UA, increased retinol and albumin; ADHD on increased UA, and decreased catalase, albumin, and bilirubin; AN on decreased UA). This work presented evidence of potential causal relationships between oxidative stress and psychiatric disorders.

Chronic social defeat stress caused region-specific oligodendrogenesis impairment in adolescent mice.

Introduction: Social stress in adolescents precipitates stress-related emotional disorders. In this study we aimed to investigate oligodendrogenesis in three stress-associated brain regions, medial prefrontal cortex (mPFC), habenula, and amygdala in adolescent mice exposed to social defeat stress. Methods: Four-week-old adolescent mice were subjected to social defeat for 10 days, followed by behavioral tests and evaluations of oligodendroglial proliferation and differentiation. Results: Stressed mice showed reduced social interaction, more stretched approach posture, lower sucrose preference, but no changes in the forced swimming test. EdU labeled proliferative cells, newly formed NG2+EdU + oligodendrocyte precursor cells (OPCs), and Olig2+EdU+ oligodendrocyte lineage cells (OLLs) were significantly decreased in the mPFC and the lateral habenula, but not in the amygdala and the medial habenula in socially defeated mice. APC+Edu+ newly-generated mature oligodendrocytes (OLs) were decreased in the mPFC in stressed mice. However, the total number of NG2+ OPCs, APC+ mature OLs, and Olig2+ OLLs were comparable in all the brain regions examined between stressed and control mice except for a decrease of APC+ mature OLs in the prelimbic cortex of stressed mice. Conclusion: Our findings indicate that adolescent social stress causes emotion-related behavioral changes and region-specific impairment of oligodendrogenesis.

Pharmacological treatment strategies for antipsychotic-induced hyperprolactinemia: a systematic review and network meta-analysis.

Antipsychotic-induced hyperprolactinemia (AP-induced HPRL) occurs overall in up to 70% of patients with schizophrenia, which is associated with hypogonadism and sexual dysfunction. We summarized the latest evidence for the benefits of prolactin-lowering drugs. We performed network meta-analyses to summarize the evidence and applied Grading of Recommendations Assessment, Development, and Evaluation frameworks (GRADE) to rate the certainty of evidence, categorize interventions, and present the findings. The search identified 3,022 citations, 31 studies of which with 1999 participants were included in network meta-analysis. All options were not significantly better than placebo among patients with prolactin (PRL) less than 50 ng/ml. However, adjunctive aripiprazole (ARI) (5 mg: MD = -64.26, 95% CI = -87.00 to -41.37; 10 mg: MD = -59.81, 95% CI = -90.10 to -29.76; more than 10 mg: MD = -68.01, 95% CI = -97.12 to -39.72), switching to ARI in titration (MD = -74.80, 95% CI = -134.22 to -15.99) and adjunctive vitamin B6 (MD = -91.84, 95% CI = -165.31 to -17.74) were associated with significant decrease in AP-induced PRL among patients with PRL more than 50 ng/ml with moderated (adjunctive vitamin B6) to high (adjunctive ARI) certainty of evidence. Pharmacological treatment strategies for AP-induced HPRL depends on initial PRL level. No effective strategy was found for patients with AP-induced HPRL less than 50 ng/ml, while adjunctive ARI, switching to ARI in titration and adjunctive high-dose vitamin B6 showed better PRL decrease effect on AP-induced HPRL more than 50 ng/ml.

Association of NKAPL rs1635 With Cognitive Function in Early-Onset Schizophrenia.

BACKGROUND: Schizophrenia is a severe mental disorder with high heritability, and cognitive dysfunction is one of the core features. Growing evidence suggests the genetic risk of schizophrenia may contribute to cognitive impairments. The variant rs1635 (nucleotide sequence: c.455C>A; amino acid sequence: T152N) located on the (NFKB activating protein like) NKAPL gene confers risk for schizophrenia and might play a role in the neurodevelopmental process, which is particularly relevant to cognitive function. However, the relationship between rs1635 and cognitive function remains unclear. METHODS: A total of 130 patients with early-onset schizophrenia (EOS) and 300 patients with adult-onset schizophrenia (AOS) of Han Chinese were recruited and underwent neurocognitive tests by using the MATRICS Consensus Cognitive Battery (MCCB). The NKAPL rs1635 was genotyped by using DNA sequencing. The peripheral blood NKAPL mRNA expression level was examined in 152T or 152N carriers (n = 20) in EOS patients, by using the qRT-PCR. The phosphorylation level of NAKPL T152N polymorphism was detected by cell experiments. In utero electroporation of mouse embryos was examined to explore the effect of Nkapl on neuronal migration. RESULTS: Compared with rs1635 AA and AC carriers, CC (the CC genotype encodes the protein NKAPL-152T) carriers of EOS patients performed better in cognitive domain of speed of processing (t = 2.644, p = 0.009), trail making test (t = 2.221, p = 0.028) and category fluency (t = 2.578, p = 0.011). However, patients with AOS exhibited no significant differences in seven domains among the three genotype groups. There were no significant differences in cognitive performance between EOS and AOS. In EOS patients, NKAPL mRNA level in NKAPL-152N carriers is significantly lower than that of NKAPL-152T carriers. The phosphorylation level of NKAPL-152N is significantly decreased compared to NKAPL-152T. In utero electroporation showed that Nkapl deletion impairs the embryonic radial migration process. CONCLUSION: The present study found that NKAPL rs1635 was associated with cognitive impairments and peripheral blood mRNA expression level in EOS patients. The NKAPL full-length protein is required for embryonic cortical neuronal migration. The phosphorylation level of NKAPL-152N is significantly decreased. The NKAPL T152N may affect the NAKPL mRNA expression level and embryonic cortical neuronal migration by regulating the NAKPL protein phosphorylation. These data suggest that NKAPL rs1635 affects cognitive function by regulating early brain development in early-onset schizophrenia.

Peripheral non-enzymatic antioxidants as biomarkers for mood disorders: Evidence from a machine learning prediction model.

Background: Oxidative stress is related to the pathogenesis of mood disorders, and the level of oxidative stress may differ between bipolar disorder (BD) and major depressive disorder (MDD). This study aimed to detect the differences in non-enzymatic antioxidant levels between BD and MDD and assess the predictive values of non-enzymatic antioxidants in mood disorders by applying a machine learning model. Methods: Peripheral uric acid (UA), albumin (ALB), and total bilirubin (TBIL) were measured in 1,188 participants (discover cohort: 157 with BD and 544 with MDD; validation cohort: 119 with BD and 95 with MDD; 273 healthy controls). An extreme gradient boosting (XGBoost) model and a logistic regression model were used to assess the predictive effect. Results: All three indices differed between patients with mood disorders and healthy controls; in addition, the levels of UA in patients with BD were higher than those of patients with MDD. After treatment, UA levels increased in the MDD group, while they decreased in the BD group. Finally, we entered age, sex, UA, ALB, and TBIL into the XGBoost model. The area under the curve (AUC) of the XGBoost model for distinguishing between BD and MDD reached 0.849 (accuracy = 0.808, 95% CI = 0.719-0.878) and for distinguishing between BD with depression episode (BD-D) and MDD was 0.899 (accuracy = 0.891, 95% CI = 0.856-0.919). The models were validated in the validation cohort. The most important feature distinguishing between BD and MDD was UA. Conclusion: Peripheral non-enzymatic antioxidants, especially the UA, might be a potential biomarker capable of distinguishing between BD and MDD.

COVID-19 infection outbreak increases anxiety level of general public in China: involved mechanisms and influencing factors.

BACKGROUND: COVID-19 outbreak happened last December in China and is still continuing. Here, we reported effects of COVID-19 outbreak on the mood of general public and ascertained impacts of psychosocial factors on the plague-related emotional measures. METHODS: During Feb. 4-6, 2020, a self-reported questionnaire Beck Anxiety Inventory (BAI) was disseminated to general public via Wechat, along with a sociodemographic information sheet. BAI score and incidences of moderate and severe anxiety in subgroups of respondents were compared. Multiple linear and logistic regressions were done for correlation analysis and to identify factors predictive of anxiety. RESULTS: Averaged BAI score of all respondents is higher than those of general public in two previous studies. The people quarantined for probable COVID-19 infection presented higher BAI score and incidences of moderate and severe anxiety relative to non-quarantined respondents. People in high epidemic area showed higher BAI score and incidences of moderate and severe anxiety compared to those in low epidemic area. Significant associations existed between anxiety level of the respondents and each of the investigated factors, except for gender. Quarantine was the predictor with a highest OR, followed by divorced/widow. The other factors showed smaller but significant effects on the anxiety level of respondents. LIMITATIONS: This cross-sectional study was unable to track the emotional changes in the respondents over time. It had a relatively small sample and involved some of emotional measures only. CONCLUSION: These data are of help in planning psychological interventions for the different subpopulations in general public during and after COVID-19 outbreak.