Unraveling the molecular relevance of brain phenotypes: A comparative analysis of null models and test statistics.

Correlating transcriptional profiles with imaging-derived phenotypes has the potential to reveal possible molecular architectures associated with cognitive functions, brain development and disorders. Competitive null models built by resampling genes and self-contained null models built by spinning brain regions, along with varying test statistics, have been used to determine the significance of transcriptional associations. However, there has been no systematic evaluation of their performance in imaging transcriptomics analyses. Here, we evaluated the performance of eight different test statistics (mean, mean absolute value, mean squared value, max mean, median, Kolmogorov-Smirnov (KS), Weighted KS and the number of significant correlations) in both competitive null models and self-contained null models. Simulated brain maps (n = 1,000) and gene sets (n = 500) were used to calculate the probability of significance (Psig) for each statistical test. Our results suggested that competitive null models may result in false positive results driven by co-expression within gene sets. Furthermore, we demonstrated that the self-contained null models may fail to account for distribution characteristics (e.g., bimodality) of correlations between all available genes and brain phenotypes, leading to false positives. These two confounding factors interacted differently with test statistics, resulting in varying outcomes. Specifically, the sign-sensitive test statistics (i.e., mean, median, KS, Weighted KS) were influenced by co-expression bias in the competitive null models, while median and sign-insensitive test statistics were sensitive to the bimodality bias in the self-contained null models. Additionally, KS-based statistics produced conservative results in the self-contained null models, which increased the risk of false negatives. Comprehensive supplementary analyses with various configurations, including realistic scenarios, supported the results. These findings suggest utilizing sign-insensitive test statistics such as mean absolute value, max mean in the competitive null models and the mean as the test statistic for the self-contained null models. Additionally, adopting the confounder-matched (e.g., coexpression-matched) null models as an alternative to standard null models can be a viable strategy. Overall, the present study offers insights into the selection of statistical tests for imaging transcriptomics studies, highlighting areas for further investigation and refinement in the evaluation of novel and commonly used tests.

Safety and effectiveness of oral medium to high dose blonanserin in patients with schizophrenia: subgroup analysis from a prospective, multicenter, post-marketing surveillance study in mainland China.

BACKGROUND: Blonanserin (BNS) had been undergoing post-market surveillance (PMS) since September 2018. Using the surveillance data, we did this analysis to assess the safety and effectiveness of different doses of BNS to explore a sufficient dose range of BNS in Chinese patients with schizophrenia (SZ). METHODS: A 12-week, prospective, observational, single-arm, multicenter, open-label PMS was conducted. In this analysis, we divided the patients from PMS into low, medium to high, and high dose groups based on the dose of BNS they received, with medium to high dose group being the focus. The Brief Psychiatric Rating Scale (BPRS) scores at week 2 or 4, 6 or 8, and 12 were calculated to evaluate the effectiveness of BNS in improving psychiatric symptoms. The safety of BNS was reported as the incidence of adverse drug reactions. RESULTS: 364 patients were included in the medium to high dose group, of which 321 completed the surveillance, with a dropout rate of 11.8%. The mean daily dose was 15.1 ± 1.92 mg. The BPRS total score was 50.1 ± 11.95 at baseline and decreased to 26.6 ± 7.43 at 12 weeks (P < 0.001). When compared with other groups, the median to high dose group achieved significantly more reduction in BPRS score at week 12 (P = 0.004 versus low dose and P = 0.033 versus higher dose). Extrapyramidal symptoms [EPS (46.4%)] were the most common adverse reactions in the medium to high group. The average weight gain during the surveillance was 0.5 ± 2.56 kg and prolactin elevation occurred in 2.2% patients. Most adverse reactions were mild. CONCLUSIONS: BNS at medium to high doses (mean 15.1 mg/d) significantly improved symptoms of SZ and was well-tolerated. Most ADRs were mild, and the likelihood of causing metabolic side effects and prolactin elevations was low. Medium to high dose of BNS is a more potent treatment choice for SZ. TRIAL REGISTRATION NUMBER: ChiCTR2100048734. Date of registration: 2021/07/15 (retrospectively registered).

Effectiveness and safety of blonanserin in young and middle-aged female patients with schizophrenia: data from a post-marketing surveillance.

BACKGROUND: A post-marketing surveillance of blonanserin has been ongoing since September 2018. The aim of this study was to assess the effectiveness and safety of oral blonanserin in Chinese young and middle-aged female patients with schizophrenia in real clinical settings, using the data from the post-marketing surveillance. METHODS: A 12-week, prospective, multi-center, open-label, post-marketing surveillance was conducted. Female patients aged 18-40 years were included in this analysis. The Brief Psychiatric Rating Scale (BPRS) was used to evaluate the effectiveness of blonanserin in improving psychiatric symptoms. The incidence of adverse drug reactions (ADRs) such as of extrapyramidal symptoms (EPS), prolactin elevation and the weight gain were used to evaluate the safety profile of blonanserin. RESULTS: A total of 392 patients were included both in the safety and full analysis sets, 311 patients completed the surveillance protocol. The BPRS total score was 48.8 ± 14.11 at the baseline, decreasing to 25.5 ± 7.56 at 12 weeks (P < 0.001, compared with baseline). EPS (20.2%) including akathisia, tremor, dystonia, and parkinsonism were found as the most frequent ADRs. The mean weight gain was 0.27 ± 2.5 kg at 12 weeks from the baseline. Four cases (1%) of prolactin elevation were observed during the period of surveillance. CONCLUSION: Blonanserin significantly improved the symptoms of schizophrenia in female patients aged 18-40 years; the drug was well tolerated and had a low tendency to cause metabolic side effects, including prolactin elevation in these patients. Blonanserin might be a reasonable drug for the treatment of schizophrenia in young and middle-aged female patients.

Safety and Effectiveness of Blonanserin in Chinese Patients with Schizophrenia: An Interim Analysis of a 12-Week Open-Label Prospective Multi-Center Post-marketing Surveillance.

Schizophrenia is an unexplained, complex and serious mental illness. Blonanserin (BNS) is a new antipsychotic drug widely used in the treatment of schizophrenia. However, large-scale clinical studies have not been conducted in China. A multi-center, prospective, open-label, 12-week surveillance was carried out to evaluate the safety and effectiveness of BNS in patients with schizophrenia in China. Safety assessments included adverse drug reactions (ADRs), extrapyramidal symptoms (EPS), akathisia, concomitant medications for EPS by the end of treatment, and the changes in body weight from baseline by the end of treatment. The effectiveness was evaluated by the Brief Psychiatric Rating Scale (BPRS). From September 2018 to May 2020, of the 1,060 patients enrolled, 1,018 were included in the full analysis set (FAS) and safety set (SS), respectively. ADRs were developed in 205 patients among the included, the incidence being 20.1%. ADRs of EPS occurred in 169 patients, the incidence being 16.6%, ADRs of akathisia occurred in 90 patients, the incidence being 8.8%; concomitant therapeutic and prophylactic agents for EPS accounts for 19.2%; 4.0% of patients had a ≥7% increase in body weight from baseline at 12 weeks after initiating treatment. Using the last-observation-carried-forward (LOCF) method, the changes in total BPRS scores were -11.2 ± 10.17 (N = 1,018), -16.8 ± 12.69 (N = 1,018) and -20.6 ± 13.99 (N = 1,018) after 2/4, 6/8, or 12 weeks, respectively. 53.5% (545/1,018) patients showed response to blonanserin treatment in week 12. The post-marketing surveillance results of BNS demonstrates safety profile and effectiveness of the drug.

The GWAS Risk Genes for Depression May Be Actively Involved in Alzheimer's Disease.

Depression is one of the most frequent psychiatric symptoms observed in people during the development of Alzheimer's disease (AD). We hypothesized that genetic factors conferring risk of depression might affect AD development. In this study, we screened 31 genes, which were located in 19 risk loci for major depressive disorder (MDD) identified by two recent large genome-wide association studies (GWAS), in AD patients at the genomic and transcriptomic levels. Association analysis of common variants was performed by using summary statistics of the International Genomics of Alzheimer's Project (IGAP), and association analysis of rare variants was conducted by sequencing the entire coding region of the 31 MDD risk genes in 107 Han Chinese patients with early-onset and/or familial AD. We also quantified the mRNA expression alterations of these MDD risk genes in brain tissues of AD patients and AD mouse models, followed by protein-protein interaction network prediction to show their potential effects in AD pathways. We found that common and rare variants of L3MBTL2 were significantly associated with AD. mRNA expression levels of 18 MDD risk genes, in particular SORCS3 and OAT, were differentially expressed in AD brain tissues. 13 MDD risk genes were predicted to physically interact with core AD genes. The involvement of HACE1, NEGR1, and SLC6A15 in AD was supported by convergent lines of evidence. Taken together, our results showed that MDD risk genes might play an active role in AD pathology and supported the notion that depression might be the "common cold" of psychiatry.

Naltrexone and Bupropion Combination Treatment for Smoking Cessation and Weight Loss in Patients With Schizophrenia.

Objective: The rates of obesity and cigarette smoking are much higher in patients with schizophrenia compared to the general population. This study was to examine whether naltrexone and bupropion combination treatment can help weight loss and smoking cessation in patients with schizophrenia. Methods: Obese male schizophrenia patients with current cigarette smoking were randomized to receive adjunctive naltrexone (25 mg/day) and bupropion (300 mg/day) combination or placebo for 24 weeks. Twenty-two patients were enrolled in the study, and 21 patients completed the study (11 in the treatment group, and 10 in the placebo group). Body weight, body mass index (BMI), fasting lipids, smoking urge, expired carbon monoxide (CO) level and cigarettes smoked per week were measured at baseline and week 24. Results: There was no significant difference between two groups in changes in weight, BMI, fasting lipids, or cigarette smoking measures (p's > 0.05) Conclusion: Naltrexone and bupropion combination treatment didn't show weight loss or smoking cessation effect in patients with schizophrenia in this pilot study.Implications for future studies were discussed. ClinicalTrials.gov identifier: NCT02736474.

Single-blind, randomized controlled trial of effectiveness of Naikan therapy as an adjunctive treatment for schizophrenia over a one-year follow-up period.

BACKGROUND: Current treatments for schizophrenia are often only partially effective. AIMS: Assess the possible benefit of using adjunctive Naikan therapy, a cognitive approach based on self-reflection that originated in Japan for the treatment of schizophrenia. METHODS: After resolution of acute psychotic symptoms, 235 psychiatric inpatients with schizophrenia who had a middle school education or higher were randomly assigned to a control group (n=112) that received routine medication and inpatient rehabilitative treatment or an intervention group (n=123) that also received adjunctive Naikan therapy for 2 hours daily, 5 days a week for 4 weeks. The patients were then discharged and followed up for 12 months. The Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance scale (PSP), and Insight and Attitude Questionnaire (ITAQ) were used to assess patients at enrollment, after the 1-month intervention, and after the 12-month follow-up. Evaluators were blind to the group assignment of patients. RESULTS: Only 13 (10.6%) of the intervention group participants relapsed over the 12-month follow-up, but 23 (20.5%) control group participants relapsed (X(2)=4.50, p=0.034). Using a modified intention-to-treat analysis and a repeated measure analysis of variance, the PANSS, PSP, and ITAQ total scores all showed significantly greater improvement over the 12-month follow-up in the Naikan group than in the control group. The drop in mean chlorpromazine-equivalent dosage from enrollment to the end of follow-up was significantly different in the intervention group but not in the control group, though the change in dosage over time between groups was not statistically significant. CONCLUSIONS: This study provides robust support for the effectiveness of Naikan therapy as an adjunctive treatment during the recovery period of schizophrenia. Compared to treatment as usually, adjunctive Naikan therapy can sustain the improvement in psychotic symptoms achieved during acute treatment, improve insight about the illness, enhance social functioning, and reduce relapse over a one-year follow-up period. Further research of this treatment with larger and more diverse samples of patients with schizophrenia is merited.

Metabolic syndrome and its factors affect cognitive function in chronic schizophrenia complicated by metabolic syndrome.

The aim of this study was to investigate the characteristics of cognitive function damage in chronic schizophrenia patients with metabolic syndrome (MS); 388 patients were divided into two groups: MS group (180 people with schizophrenia and MS) and non-MS group (208 people with schizophrenia but without MS). The Positive and Negative Syndrome Scale (PANSS) and the Treatment Emergent Symptom Scale (TESS) were used to evaluate clinical symptoms and drug adverse reaction. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess cognitive function. There was no significant change in PANSS (p = 0.53) and TESS score (p = 0.26) between the MS group and the non-MS group. However, RBANS total scale score as well as attention, immediate memory, and delayed memory scores in the MS group were significantly lower than those in the non-MS group (p < 0.05). There was no significant change in visuospatial skill (p = 0.07) and language scores (p = 0.08) between the two groups. Besides, course of disease, triglyceride, antipsychotic drug type, systolic pressure, negative symptom factor, and education level showed a notable significance for cognitive function damage in turn. MS might aggravate injury of cognitive function in chronic schizophrenia, especially in immediate memory, delayed memory, and attention.