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Abstract Background Air pollution, a reversible environmental factor, was significantly associated with the cognitive domains that are impaired in major depressive disorder (MDD), notably processing speed. Limited evidence explores the interactive effect of air pollution and the genetic risk of depression on cognition. This cross-sectional study aims to extend the research by specifically examining how this interaction influences depression-related cognitive impairment and resting-state brain function. Methods Eligible participants were 497 healthy adult volunteers (48.7% males, mean age 24.5) living in Beijing for at least 1 year and exposed to relatively high air pollution from the local community controlling for socioeconomic and genomic. Six months’ ambient air pollution exposures were assessed based on residential addresses using monthly averages of fine particulate matter with a diameter of less than or equal to 2.5 μm (PM2.5). A cross-sectional analysis was conducted using functional magnetic resonance imaging (fMRI) and cognitive performance assessments. The polygenic risk score (PRS) of MDD was used to estimate genetic susceptibility. Results Using a general linear model and partial least square regression, we observed a negative association between resting-state local connectivity in precuneus and PRS-by-PM2.5 interactive effect (P FWE = 0.028), indicating that PM2.5 exposure reduced the spontaneous activity in precuneus in individuals at high genetic risk for MDD. DNA methylation and gene expression of the SLC30A3 gene, responsible for maintaining zinc-glutamate homeostasis, was suggestively associated with this local connectivity. For the global functional connectivity, the polygenic risk for MDD augmented the neural impact of PM2.5 exposure, especially in the frontal-parietal and frontal-limbic regions of the default mode network (P FDR

Summary: 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.

Summary: 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.

Abstract 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.

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.

Abstract 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.

BackgroundIdentifying high-risk groups of non-suicidal self-injury (NSSI) with multiple risk factors and different functional subtypes contribute to implementing person-centered interventions.MethodsWe 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 χ2 test were used to test the difference of demographic statistical factors, risk factors and functional scores among groups with different frequency of NSSI.ResultsThe 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.LimitationsAll 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.ConclusionIt 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.

IntroductionSocial 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.MethodsFour-week-old adolescent mice were subjected to social defeat for 10 days, followed by behavioral tests and evaluations of oligodendroglial proliferation and differentiation.ResultsStressed 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.ConclusionOur findings indicate that adolescent social stress causes emotion-related behavioral changes and region-specific impairment of oligodendrogenesis.

BackgroundOxidative 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.MethodsPeripheral 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.ResultsAll 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.ConclusionPeripheral non-enzymatic antioxidants, especially the UA, might be a potential biomarker capable of distinguishing between BD and MDD.

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.

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.