Search

The search for susceptibility genes underlying the heterogeneous bipolar disorder has been inconclusive, often with irreproducible results. There is a hope that narrowing the phenotypes will increase the power of genetic analysis. Early-onset bipolar disorder is thought to be a genetically homogeneous subtype with greater symptom severity. We conducted a genome-wide association study (GWAS) for this subtype in bipolar I (BPI) disorder. Study participants included 1779 patients of Han Chinese descent with BPI disorder recruited by the Taiwan Bipolar Consortium. We conducted phenotype assessment using the Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry and prepared a life chart with graphic depiction of lifetime clinical course for each of the BPI patient recruited. The assessment of onset age was based on this life chart with early onset defined as ≤20 years of age. We performed GWAS in a discovery group of 516 early-onset and 790 non-early-onset BPI patients, followed by a replication study in an independent group of 153 early-onset and 320 non-early-onset BPI patients and a meta-analysis with these two groups. The SNP rs11127876, located in the intron of CADM2, showed association with early-onset BPI in the discovery cohort (P = 7.04 × 10-8) and in the test of replication (P = 0.0354). After meta-analysis, this SNP was demonstrated to be a new genetic locus in CADM2 gene associated with early-onset BPI disorder (P = 5.19 × 10-8).

Background: Ketamine has emerged as a prominent substance of misuse. Leptin, an adipocyte-derived polypeptide hormone, has been implicated in the development of addiction. Sex-specific changes in leptin levels have been demonstrated following acute ketamine administration; the persistence of long-term ketamine use on leptin levels is uncertain.Objectives: To assess the sex-difference of leptin levels, and their persistence, in individuals with ketamine use disorder (KUD) compared to healthy controls.Methods: Plasma leptin levels were measured in 62 healthy controls (37 males, 25 females) and 68 participants with KUD (50 males, 18 females) on the first day (baseline) and after 1 and 2 weeks of abstinence. As leptin levels are affected by body mass index (BMI), BMI-adjusted leptin (leptin/BMI ratio) was also examined. Mixed model for repeated measures was used to examine changes after ketamine abstinence.Results: Compared to same-sex controls, female, but not male, participants with KUD demonstrated lower leptin levels and leptin/BMI ratio at baseline, week 1, and week 2 (leptin levels: p = .001, 0.006 and 0.032, respectively; leptin/BMI ratio: p = .004, 0.022, and 0.09, respectively). Repeated measures showed that leptin levels and the leptin/BMI ratio increased after 2 weeks of abstinence in male participants with KUD (p = .002 and 0.011, respectively), but females did not show such an increase (p > .05).Conclusions: Sex-specific differences were observed in leptin levels and the leptin/BMI ratio in individuals with KUD compared to controls. Lower leptin levels in females with KUD persisted after 2 weeks of abstinence. [ABSTRACT FROM AUTHOR]

Background: Clozapine is the primary antipsychotic (APD) for treatment-resistant schizophrenia (TRS). However, only 40% of patients with TRS respond to clozapine, constituting a subgroup of clozapine-resistant patients. Recently, the neuropeptide orexin-A was shown to be involved in the pathophysiology of schizophrenia. This study evaluated the association of orexin-A levels with the clozapine response in patients with TRS. Methods: We recruited 199 patients with schizophrenia, including 37 APD-free and 162 clozapine-treated patients. Clozapine-treated patients were divided into clozapine-responsive (n = 100) and clozapine-resistant (n = 62) groups based on whether they had achieved psychotic remission defined by the 18-item Brief Psychiatric Rating Scale (BPRS-18). We compared blood orexin-A levels among the three groups and performed regression analysis to determine the association of orexin-A level with treatment response in clozapine-treated patients. We also explored the correlation between orexin-A levels and cognitive function, assessed using the CogState Schizophrenia Battery. Results: Clozapine-responsive patients had higher orexin-A levels than clozapine-resistant and APD-free patients. Orexin-A level was the only factor significantly associated with treatment response after adjustment. Orexin-A levels were negatively correlated with BPRS-18 full scale and positive, negative, and general symptoms subscale scores. We also observed a positive correlation between orexin-A levels and verbal memory, visual learning and memory, and working memory function. Conclusions: This cross-sectional study showed that higher levels of orexin-A are associated with treatment response to clozapine in patients with TRS. Future prospective studies examining changes in orexin-A level following clozapine treatment and the potential benefit of augmenting orexin-A signaling are warranted. [ABSTRACT FROM AUTHOR]

Background: Methamphetamine use disorder (MUD) is a worldwide health concern. The hypothalamic orexin system regulates stress response and addictive behaviors. The genetic variation in the hypocretin receptor 2 (HCRTR2), rs2653349, is associated with substance use disorder. Objectives: We explored the gene-environment (GxE) interaction of rs2653349 and adverse childhood experiences (ACEs) associated with MUD susceptibility. Methods: Four hundred and one individuals (336 males, 65 females) with MUD and 348 healthy controls (288 males, 60 females) completed a self-report questionnaire evaluating ACEs, encompassing childhood abuse and household dysfunction categories, and were genotyped for SNP rs2653349. Methamphetamine use variables were collected using the Diagnostic Interview for Genetic Studies. We used regression analyses to assess the GxE effect on MUD risk. Results: The MUD group had a comparable genotypic distribution for rs2653349 to the control group, albeit with a higher prevalence and number of types of ACEs, correlating with an increased MUD risk (p <.05). No significant genetic impact of rs2653349 on MUD risk was found. However, we observed a GxE interaction effect between the minor allele of rs2653349 and the number of childhood abuse or household dysfunction types, correlating with a reduced MUD risk (OR = -0.71, p =.04, Benjamini-Hochberg adjusted p =.08 and OR = -0.59, p =.045, Benjamini-Hochberg adjusted p =.09, respectively). Conclusion: HCRTR2 SNP rs2653349 has no significant impact on MUD risk, but ACEs may increase this risk. GxE results suggest that rs2653349 could offer protection against developing MUD in individuals experiencing multiple types of ACEs. [ABSTRACT FROM AUTHOR]