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.

Efficacy and feasibility of aerobic exercise interventions as an adjunctive treatment for patients with schizophrenia: a meta-Analysis.

Schizophrenia is a chronic mental disorder primarily treated with antipsychotics, which have limited efficacy for negative symptoms. This study aims to evaluate the effectiveness and feasibility of exercise interventions as adjuncts to pharmacotherapy through a meta-analysis, providing valuable insights for rational intervention design. Four databases were searched, and randomized controlled trials with no language restrictions published up to March 27, 2023, were included. The primary outcome indicator was the Positive and Negative Symptom Scale (PANSS) total score along with its three sub-scales. Secondary outcomes included the Scale for Assessment of Negative Symptoms (SANS) and Body Mass Index (BMI), which were used to assess the efficacy of aerobic exercise interventions in patients with schizophrenia. Subgroup analyses were conducted to explore the impact of intervention duration and total weekly exercise time, while treatment feasibility was assessed through adherence rates. A total of 17 publications involving 973 patients with schizophrenia were deemed eligible and included in the analysis. Compared to other forms of adjunctive interventions, the network meta-analysis of 12 PANSS-based studies revealed that adjunctive aerobic exercise interventions were the most effective in reducing overall PANSS scores in patients with schizophrenia, with statistically significant pooled results (MD = -4.84, 95% CI: -5.72, -3.96). Both the PANSS negative symptom subscale (MD = -2.11, 95% CI: -3.26, -0.95) and SANS (MD = -9.11, 95% CI: -11.94, -6.27) indicated that adjunctive aerobic exercise interventions effectively alleviate negative symptoms. Subgroup meta-analysis indicated that 2-3 month interventions involving 100-220 min of exercise per week were the most effective. Additionally, adherence to the adjunctive aerobic exercise regimen was found to be comparable to that of conventional treatment alone. Aerobic exercise interventions, as adjunctive therapy, are an effective measure for reducing PANSS scores in patients with schizophrenia, contributing to the alleviation of both the positive and negative symptoms, and patients demonstrated strong adherence to aerobic exercise.

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.

Longitudinal Network Analysis Reveals Interactive Change of Schizophrenia Symptoms During Acute Antipsychotic Treatment.

BACKGROUND AND HYPOTHESIS: Complex schizophrenia symptoms were recently conceptualized as interactive symptoms within a network system. However, it remains unknown how a schizophrenia network changed during acute antipsychotic treatment. The present study aimed to evaluate the interactive change of schizophrenia symptoms under seven antipsychotics from individual time series. STUDY DESIGN: Data on 3030 schizophrenia patients were taken from a multicenter randomized clinical trial and used to estimate the partial correlation cross-sectional networks and longitudinal random slope networks based on multivariate multilevel model. Thirty symptoms assessed by The Positive and Negative Syndrome Scale clustered the networks. STUDY RESULTS: Five stable communities were detected in cross-sectional networks and random slope networks that describe symptoms change over time. Delusions, emotional withdrawal, and lack of spontaneity and flow of conversation featured as central symptoms, and conceptual disorganization, hostility, uncooperativeness, and difficulty in abstract thinking featured as bridge symptoms, all showing high centrality in the random slope network. Acute antipsychotic treatment changed the network structure (M-test = 0.116, P < .001) compared to baseline, and responsive subjects showed lower global strength after treatment (11.68 vs 14.18, S-test = 2.503, P < .001) compared to resistant subjects. Central symptoms and bridge symptoms kept higher centrality across random slope networks of different antipsychotics. Quetiapine treatment network showed improvement in excitement symptoms, the one featured as both central and bridge symptom. CONCLUSION: Our findings revealed the central symptoms, bridge symptoms, cochanging features, and individualized features under different antipsychotics of schizophrenia. This brings implications for future targeted drug development and search for pathophysiological mechanisms.

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.

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.

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.

A deep learning-based model for detecting depression in senior population.

Objectives: With the attention paid to the early diagnosis of depression, this study tries to use the biological information of speech, combined with deep learning to build a rapid binary-classification model of depression in the elderly who use Mandarin and test its effectiveness. Methods: Demographic information and acoustic data of 56 Mandarin-speaking older adults with major depressive disorder (MDD), diagnosed with the Mini-International Neuropsychiatric Interview (MINI) and the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and 47 controls was collected. Acoustic data were recorded using different smart phones and analyzed by deep learning model which is developed and tested on independent validation set. The accuracy of the model is shown by the ROC curve. Results: The quality of the collected speech affected the accuracy of the model. The initial sensitivity and specificity of the model were respectively 82.14% [95%CI, (70.16-90.00)] and 80.85% [95%CI, (67.64-89.58)]. Conclusion: This study provides a new method for rapid identification and diagnosis of depression utilizing deep learning technology. Vocal biomarkers extracted from raw speech signals have high potential for the early diagnosis of depression in older adults.

ATAD3B and SKIL polymorphisms associated with antipsychotic-induced QTc interval change in patients with schizophrenia: a genome-wide association study.

QTc interval prolongation is one of the most common antipsychotic-induced side effects which could lead to ventricular tachycardia or Torsade de Pointes, even cardiac arrest. There is very limited understanding on the genetic factors that associated with antipsychotic-induced QTc interval change. We conducted a genome-wide association study (GWAS) of antipsychotic-induced QTc interval change among patients with schizophrenia. A total of 2040 patients with schizophrenia were randomly assigned to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and first-generation antipsychotics; first-generation antipsychotics including haloperidol or perphenazine were also assigned randomly) and received 6-week antipsychotic treatment. We identified two novel loci (rs200050752 in ATAD3B and rs186507741 in SKIL) that were associated with antipsychotic-induced QTc interval change at a genome-wide significance level. The combination of polygenic risk score (PRS), based the GWAS of myocardial infarction from BioBank Japan project, and clinical data (sex, heart rate and QTc interval at baseline) could be applied to predict whether patients with schizophrenia have QTc interval prolongation (10 ms was applied as threshold, P < 0.001, area under the curve [AUC] was 0.797), especially for the first episode patients (P < 0.001, AUC was 0.872). We identified two loci located within genes related to mitochondrial function and cell growth and differentiation, which were both associated with schizophrenia and heart function. The combination of PRS and clinical data could predict whether patients with schizophrenia have the side effect of QTc interval prolongation, which could fundamentally guide the choice of antipsychotic in patients with schizophrenia, especially for the first-episode patients.

Generalized eigenvalue minimization for uncertain first-order plus time-delay processes.

This paper shows how to apply generalized eigenvalue minimization to processes that can be described by a first-order plus time-delay model with uncertain gain, time constant and delay. An algorithm to transform the uncertain first-order plus time delay model into a state-space model with uncertainty polyhedron is firstly described. The accuracy of the transformation is studied using numerical examples. Then, the uncertainty polyhedron is rewritten as a linear-matrix-inequality constraint and generalized eigenvalue minimization is adopted to calculate a feedback control law. Case studies show that even if uncertainties associated with the first-order plus time delay model are significant, a stable feedback control law can be found. The proposed control is tested by comparing with a robust internal model control. It is also tested by applying it to the temperature control of air-handing units.