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Hsuan-Han Lee,1 Cheng-Ho Chang,1 Liang-Jen Wang,2 Chih-Ching Wu,3,4 Hsing-Ling Chen,5 Ti Lu,1 Ru-Band Lu6,7 Sheng-Yu Lee1,6,8,9 1Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 2Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 4Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan; 5Department of Nuclear Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 6Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan; 7Institute of Behavioral Medicine Sciences, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan; 8Department of Psychiatry, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 9Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan Introduction: In this study, we aim to determine 1) the differences in cortisol in patients with bipolar II disorder (BD-II) and control subjects and 2) the correlation between cortisol levels and cognitive function in patients with BD-II during a 24-week follow-up period.Methods: We recruited a total of 32 BD-II patients and 30 healthy control subjects. The BD-II patients were assessed for clinical severity and serum cortisol level at baseline and at weeks 8, 16, and 24. The Brief Assessment of Cognition in Affective Disorders (BACA) was adopted to evaluate cognitive function at baseline and endpoint (week 24). Meanwhile, we assessed the controls for serum cortisol level and BACA at baseline.Results: We observed that the BD-II group had a higher serum cortisol level and lower BACA composite scores compared with the healthy controls at baseline. A significant correlation was found between changes in Verbal Fluency, a subset of BACA, and changes in serum cortisol level after the 24-week follow-up, controlling for age, gender, years of education, and clinical severity (P

OBJECTIVE: Low monoamine oxidase (MAO) activity and the neurotransmitter dopamine are 2 important factors in the development of alcohol dependence. MAO is an important enzyme associated with the metabolism of biogenic amines. Therefore, the present study investigates whether the association between the dopamine D2 receptor (DRD2) gene and alcoholism is affected by different polymorphisms of the MAO type A (MAOA) gene. METHODS: A total of 427 Han Chinese men in Taiwan (201 control subjects and 226 with alcoholism) were recruited for the study. Of the subjects with alcoholism, 108 had pure alcohol dependence (ALC) and 118 had both alcohol dependence and anxiety, depression or both (ANX/DEP ALC). All subjects were assessed with the Chinese Version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime. Alcohol dependence, anxiety and major depressive disorders were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. CONCLUSION: The genetic variant of the DRD2 gene was only associated with the ANX/DEP ALC phenotype, and the genetic variant of the MAOA gene was associated with pure ALC. Subjects carrying the MAOA 3-repeat allele and genotype A1/A1 of the DRD2 were 3.48 times (95% confidence interval = 1.47-8.25) more likely to be ANX/DEP ALC than the subjects carrying the MAOA 3-repeat allele and DRD2 A2/A2 genotype. The MAOA gene may modify the association between the DRD2 gene and ANX/DEP ALC phenotype. [ABSTRACT FROM AUTHOR]

Weight regain after weight loss is a major challenge in the treatment of obesity. Immune cells adapt to fluctuating nutritional stress, but their roles in regulating weight regain remain unclear. Here, we identify a stem cell-like CD7 + monocyte subpopulation accumulating in the bone marrow (BM) of mice and humans that experienced dieting-induced weight loss. Adoptive transfer of CD7 + monocytes suppresses weight regain, whereas inducible depletion of CD7 + monocytes accelerates it. These cells, accumulating metabolic memories via epigenetic adaptations, preferentially migrate to the subcutaneous white adipose tissue (WAT), where they secrete fibrinogen-like protein 2 (FGL2) to activate the protein kinase A (PKA) signaling pathway and facilitate beige fat thermogenesis. Nevertheless, CD7 + monocytes gradually enter a quiescent state after weight loss, accompanied by increased susceptibility to weight regain. Notably, administration of FMS-like tyrosine kinase 3 ligand (FLT3L) remarkably rejuvenates CD7 + monocytes, thus ameliorating rapid weight regain. Together, our findings identify a unique bone marrow-derived metabolic-memory immune cell population that could be targeted to combat obesity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: We performed Mendelian randomization (MR) to assess the causal effect of tea intake on rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)., Methods: Genetic instruments for tea intake were obtained from a large genome-wide association study (GWAS) dataset of the UK Biobank. Genetic association estimates for RA (6236 cases and 147,221 controls) and SLE (538 cases and 213,145 controls) were obtained from the FinnGen study through the IEU GWAS database., Results: MR analyses using the inverse-variance weighted method showed that tea intake was not associated with risk of RA [odds ratio (OR) per standard deviation increment in genetically predicted tea intake = 0.997, 95% confidence interval (CI) 0.658-1.511] and SLE (OR per standard deviation increment in genetically predicted tea intake = 0.961, 95% CI 0.299-3.092). Weighted median, weighted mode, MR-Egger, leave-one-out and multivariable MR controlling for several confounding factors including current tobacco smoking, coffee intake, and alcoholic drinks per week yielded completely consistent results. No evidence of heterogeneity and pleiotropy was found., Conclusion: Our MR study did not suggest a causal effect of genetically predicted tea intake on RA and SLE., (© 2023. The Author(s).)

Background: Long-term opioid and amphetamine-type stimulants (ATS) abuse may affect immunological function and impair executive function. We aimed to determine whether biomarkers of inflammation and executive function were associated with substance use in individuals with opioid use disorder (OUD) and ATS use disorder (ATSUD). The interactions between these biomarkers were also explored., Methods: We assessed plasma cytokines [tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-8, IL-6, transforming growth factor (TGF)-β1, brain-derived neurotrophic factor (BDNF), and executive function in terms of the Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) in OUD and ATSUD patients and healthy controls (HC). OUD and ATSUD patients were followed for 12 weeks, and their urine morphine and amphetamine tests, cytokine levels, and executive function were repeatedly measured., Results: We enrolled 483 patients and 145 HC. Plasma TNF-α, CRP, IL-8, IL-6, and BDNF levels and most subscale scores on the WCST and CPT significantly differed between OUD and ATSUD patients and HC. Increased TNF-α levels and more perseveration error on the WCST were significantly associated with more urine drug-positive results and less abstinence. Plasma IL-6 and CRP levels were significantly negatively correlated with WCST and CPT performance., Conclusion: OUD and ATSUD patients had more inflammation and worse executive function than HC. Inflammatory markers and WCST performance were associated with their urinary drug results, and higher inflammation was associated with poor executive function. Studies on regulating the inflammatory process and enhancing executive function in OUD and ATSUD are warranted., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Recent studies suggest that improper resolution of acute neuroinflammation may lead to long-lasting low-grade chronic neuroinflammation and drive progressive neurodegeneration. However, the molecular mechanism underlying the transition from acute to chronic neuroinflammation remains unclear. The main purpose of this study was to search for potential pathways mediating LPS-elicited chronic neuroinflammation and resultant neurodegeneration. Using microglia cultures prepared from C57BL/6J, MAC1-deficient, and MyD88-deficient mice, the initial study showed that activation of TLR-4 is not sufficient for maintaining chronic neuroinflammation despite its essential role in LPS-initiated acute neuroinflammation. Opposite to TLR-4, our studies showed significantly reduced intensity of chronic neuroinflammation, oxidative stress, and progressive loss of nigral dopaminergic neurons in MAC1-deficient neuron/glial cultures or mice stimulated with LPS. Mechanistic studies revealed the essential role ERK1/2 activation in chronic neuroinflammation-elicited neurodegeneration, which was demonstrated by using an ERK1/2 inhibitor in neuron-glial cultures. Taken together, we propose a key role of the MAC1-NOX2-ERK1/2 signaling pathway in the initiation and maintenance of low-grade chronic neuroinflammation. Continuing ERK1/2 phosphorylation and NOX2 activation form a vicious feedforward cycle in microglia to maintain the low-grade neuroinflammation and drive neurodegeneration.

We have previously identified five candidate proteins (matrix metallopeptidase 9 (MMP9), phenylalanyl-TRNA synthetase subunit beta (FARSB), peroxiredoxin 2 (PRDX2), carbonic anhydrase 1 (CA-1), and proprotein convertase subtilisin/kexin Type 9 (PCSK9)) as potential biomarkers for bipolar II disorder (BD-II). These candidate proteins have been associated with neuroprotective factors (BDNF) and inflammatory factors (cytokines, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α)). However, the correlations between these proteins with plasma BDNF and inflammatory factors remain unknown. We recruited a total of 185 patients with BD-II and 186 healthy controls. Plasma levels of candidate proteins, BDNF, cytokines (TNF-α, CRP, and interleukin-8 (IL-8)) were assessed from each participant. The correlations between levels of candidate proteins, BDNF, and cytokines were analyzed. In the BD-II group, we found that the level of FARSB was positively correlated with the BDNF level (r = 0.397, p < 0.001) and IL-8 (r = 0.320, p < 0.001). The CA-1 level positively correlated with IL-8 (r = 0.318, p < 0.001). In the control group, we found that the FARSB level positively correlated with the BDNF level (r = 0.648, p < 0.001). The CA-1 level positively correlated with TNF-α (r = 0.231, p = 0.002), while the MMP-9 level positively correlated with the CRP level (r = 0.227, p = 0.002). Our results may help in clarifying the underlying mechanism of these candidate proteins for BD-II.

The diagnostic peripheral biomarkers are still lacking for the bipolar II disorder (BD-II). We used isobaric tags for relative and absolute quantification technology to identify five upregulated candidate proteins [matrix metallopeptidase 9 (MMP9), phenylalanyl-tRNA synthetase subunit beta (FARSB), peroxiredoxin 2 (PRDX2), carbonic anhydrase 1 (CA-1), and proprotein convertase subtilisin/kexin type 9 (PCSK9)] for the diagnosis of BD-II. We analysed the differences in the plasma levels of these candidate proteins between BD-II patients and controls (BD-II, n = 185; Controls, n = 186) using ELISA. To establish a diagnostic model for the prediction of BD-II, the participants were divided randomly into a training group (BD-II, n = 149; Controls, n = 150) and a testing group (BD-II, n = 36; Controls, n = 36). Significant increases were found in all five protein levels between BD-II and controls in the training group. Logistic regression was analysed to form the composite probability score of the five proteins in the training group. Receiver-operating characteristic curve analysis revealed the diagnostic validity of the probability score [area under curve (AUC) = 0.89, P < 0.001]. The composite probability score of the testing group also showed good diagnostic validity (AUC = 0.86, P < 0.001). We propose that plasma levels of PRDX2, CA-1, FARSB, MMP9, and PCSK9 may be associated with BD-II as potential biomarkers.

Background: An emotional intelligence (EI) deficit has been noticed in euthymic bipolar spectrum disorder (BD) patients. However, whether this deficit is affected by mood or subtype is unclear. Objectives: The aim of this study was to investigate whether an EI deficit is mood-dependent, and which mood symptoms have more impact on EI in BD. Methods: Two hundred and thirty participants aged between 18 and 65 years old were recruited [130 BD patients (51 bipolar I disorder (BDI) and 79 bipolar II disorder (BDII): 39.2% males; 91 healthy controls (HCs): 48.4% males)]. The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT), which contains experiential and strategic EI ratings, was used to assess social cognition. The Hamilton Depression Rating Scale (HDRS) and the Young's Mania Rating Scale (YMRS) were used for evaluating the severity [HAMD and YMRS scores ≦7 were euthymic (BD eut ) and HAMD YMRS sores ≧8 were episodic (BD epi )]. Analyses of covariance (ANCOVA) were performed, with adjustment for background information between the BD patients and HCs. Results: The results showed that, compared to the HCs, the BD eut patients showed no difference in any MSCEIT measures, while the BD epi patients showed lower scores in all MSCEIT measures, except for perceiving emotions. In addition, a main effect of mood state instead of BD subtype was found for the managing emotions branch ( p < 0.0007). Regression analyses showed that the duration of illness and HDRS scores were correlated with the scores in the strategic area of the MSCEIT, while age and YMRS scores were more relevant to the scores in the experiential area of the MSCEIT. Conclusion: The results confirm that an EI deficit is mood-dependent in BD patients. In addition, a depressive mood is more related to the strategic EI area, while a manic mood is correlated with the experiential EI area. Understanding the different domains of EI deficits in BD patients may be helpful for developing interventions for BD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kuo, Chang, Wang, Tseng, Huang, Chen, Lane, Yang and Lu.)

Objectives: Cases of patients with bipolar disorder (BD) having neuropsychological impairment have been reported, although inconsistently. The possibility of comorbidity with anxiety disorder (AD) has been suggested. The association between mood episodes and AD comorbidity on neuropsychological performance is unclear and thus was investigated in the current study., Methods: All participants were informed about and agreed to participate in this study. Patients with BD were recruited from outpatient and inpatient settings, and healthy controls (HCs) were recruited as a comparison group. Six hundred and twenty-eight participants (175 HCs and 453 BD-56 BDI and 397 BDII) were studied based on their current mood episode, namely, depressive (BD d ), manic/hypomanic (BDm), mixed (BDmix), and euthymic (BDeu), compared with/without AD comorbidity (164 with AD)., Results: Compared to HCs, all BD groups had significantly more impaired neuropsychological profiles, but the BDeu group was found to have less impairment in memory and executive function than the episodic BD groups. The percentage of AD comorbidity in BDd, BDm, BDmix, and BDeu was 33.9%, 40.3%, 33.0%, and 35.6%, respectively (χ 2  = 1.61, p > .05). The results show that AD plays a different role in neuropsychological impairment across various mood episodes in BD., Conclusion: Memory impairment and executive dysfunction may be state-like cognitive phenotypes and are affected by AD comorbidity during mixed and depressive episodes in BD, while sustained attention deficiencies are more like trait markers, regardless of mood episodes, and persist beyond the course of the illness. The AD comorbidity effect on attentional deficit is greater when suffering from a manic episode., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: The aim of this study is to determine whether adding combination of agents with anti-inflammatory and neurotrophic effects is more efficacious than mood stabilizer alone in improving clinical symptoms, plasma brain-derived neurotrophic factor (BDNF), cytokine levels, and metabolic profiles in patients with bipolar spectrum disorder., Methods: In a randomized, double-blind, controlled 12-week clinical trial, patients with moderate mood symptoms (HDRS ≥ 18 or YMRS ≥ 14) were recruited. The patients were randomly assigned to a group while still undergoing regular valproate (VPA) treatments: VPA + dextromethorphan (DM) (30 mg/day) + memantine (MM) (5 mg/day) (DM30 + MM5) (n = 66), VPA + DM (30 mg/day) (DM30) (n = 69), VPA + MM (5 mg/day) (MM5) (n = 66), or VPA + Placebo (Placebo) (n = 69). Symptom severity, immunological parameters [plasma tumor necrosis factor (TNF)-α and C-reactive protein (CRP)] and plasma brain-derived neurotrophic factor (BDNF) were regularly examined. Metabolic profiles [cholesterol, triglycerides, glycosylated hemoglobin (HbA1C), fasting serum glucose, body mass index (BMI)] were measured at baseline and at 2, 8, and 12 weeks., Results: Depression scores were significantly (P = 0.03) decreases and BDNF levels significantly (P = 0.04) increased in the DM30 + MM5 group than in the Placebo group. However, neither depressive scores nor BDNF levels were significantly different between the DM30, MM5, and Placebo groups. Changes in certain plasma cytokine and BDNF levels were significantly correlated with metabolic parameters., Conclusion: We concluded that add-on DM30 + MM5 was significantly more effective than placebo for clinical symptoms and plasma BDNF levels. Additional studies with larger samples and mechanistic studies are necessary to confirm our findings. Trial registration NCT03039842 (https://register.clinicaltrials.gov/). Trial date was from 1 Jan 2013 to 31 December 2016 in National Cheng Kung University Hospital. Registered 28 February 1 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03039842?term=NCT03039842&rank=1.

Objective: Valproic acid (VPA) is an anticonvulsant and commonly long term used as a mood stabilizer for patients with mood disorders. However its chronic effects on the hematological changes were noticed and need to be further evaluated. In this study, we evaluated, in Taiwanese Han Chinese patients with bipolar disorders (BD), the chronic effects of VPA or VPA plus dextromethorphan (DM) on the hematological molecules (white blood cell [WBCs], red blood cells [RBCs], hemoglobin, hematocrit, and platelets)., Methods: In a 12-week, randomized, double-blind study, we randomly assigned BD patients to one of three groups: VPA plus either placebo (VPA＋P, n = 57) or DM (30 mg/day, VPA＋DM30, n = 56) or 60 mg/day (VPA＋DM60, n = 53). The Young Mania Rating Scale and Hamilton Depression Rating Scale were used to evaluate symptom severity, and the hematological molecules were checked., Results: Paired t test showed that the WBC, neutrophils, platelets and RBCs were significantly lowered after 12 weeks of VPA＋P or VPA＋DM30 treatment. VPA＋DM60 represented the protective effects in the WBCs, neutrophils, and RBCs but not in the platelets. We further calculated the changes of each hematological molecules after 12 weeks treatment. We found that combination use of DM60 significantly improved the decline in neutrophils induced by the long-term VPA treatment., Conclusion: Hematological molecule levels were lower after long-term treatment with VPA. VPA＋DM60, which yielded the protective effect in hematological change, especially in the neutrophil counts. Thus, DM might be adjunct therapy for maintaining hematological molecules in VPA treatment.

Objective: Patients with opioid use disorder (OUD) have impaired attention, inhibition control, and memory function. The aldehyde dehydrogenase 2 ( ALDH2 ) gene has been associated with OUD and ALDH2 gene polymorphisms may affect aldehyde metabolism and cognitive function in other substance use disorder. Therefore, we aimed to investigate whether ALDH2 genotypes have significant effects on neuropsychological functions in OUD patients undergoing methadone maintenance therapy (MMT)., Methods: OUD patients undergoing MMT were investigated and followed-up for 12 weeks. ALDH2 gene polymorphisms were genotyped. Connors' Continuous Performance Test (CPT) and the Wechsler Memory Scale-Revised (WMS-R) were administered at baseline and after 12 weeks of MMT. Multivariate linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between the ALDH2 genotypes and performance on the CPTs and WMS-R., Results: We enrolled 86 patients at baseline; 61 patients completed the end-of-study assessments. The GEE analysis showed that, after the 12 weeks of MMT, OUD patients with the ALDH2 *1/*2 ＋ *2/*2 ( ALDH2 inactive) genotypes had significantly higher commission error T-scores ( p = 0.03), significantly lower hit reaction time T-scores ( p = 0.04), and significantly lower WMS-R visual memory index scores ( p = 0.03) than did patients with the ALDH2 1*/*1 ( ALDH2 active) genotype., Conclusion: OUD patients with the ALDH2 inactive genotypes performed worse in cognitive domains of attention, impulse control, and memory than did those with the ALDH2 active genotype. We conclude that the ALDH2 gene is important in OUD and is associated with neuropsychological performance after MMT.

The diagnosis of Bipolar II disorder (BD-II) is currently based on the patients' description of symptoms and clinical behavioral observations. This study explored the possibility of miRNA in peripheral blood (serum) as a specific biomarker for BD-II. We identified 6 candidate miRNAs to differentiate BD-II patients from controls using next-generation sequencing. We then examined these candidate miRNAs using real-time PCR in the first cohort (as training group) of 79 BD-II and 95 controls. A diagnostic model was built based on these candidate miRNAs and then tested on an individual testing group (BD-II: n = 20, controls: n = 20). We found that serum expression levels of miR-7-5p, miR-23b-3p, miR-142-3p, miR-221-5p, and miR-370-3p significantly increased in BD-II compared with controls in the first cohort, whereas that of miR-145-5p showed no significant difference. The diagnostic power of the identified miRNAs was further analyzed using receiver-operating characteristic (ROC). Support vector machine (SVM) measurements revealed that a combination of the significant miRNAs reached good diagnostic accuracy (AUC: 0.907). We further examined an independent testing group and the diagnostic power reached fair for BD-II (specificity = 90%, sensitivity = 85%). We constructed miRNA panels using SVM model, which may aid in the diagnosis for BD-II.

Objectives: Methylphenidate (MPH) is highly effective in controlling the symptoms of attention-deficit/hyperactivity disorder (ADHD), but some children with ADHD either do not respond to, or do not tolerate, treatment. Dextromethorphan (DM) is a neuroprotective agent which has been used in the treatment of neuropsychiatric disorders. This clinical trial had examined the effect of DM on the use of MPH in the children with ADHD. Methods: This randomized double-blind clinical trial had evaluated 44 male outpatients, aged between 6 and 12 years, with a diagnosis of ADHD. The study subjects were randomly assigned into one of the two groups: receiving MPH alone (15-60 mg per day) or MPH plus DM (30-60 mg per day) for 8 weeks. Assessments, comprising the Chinese version of the Child Behavior Checklist (CBCL-C) scale and the Swanson, Nolan and Pelham Questionnaire (SNAP)-IV rating tests conducted by parents and the serum cytokines measured by microarray and enzyme-linked immunosorband assay (ELISA), were compared between groups at baseline and at 8 weeks after the medication was started. Results: There were a significant decrease at the mean scores of both CBCL-C and SNAP-IV scales after 8 weeks of treatment, but no significant differences between MPH and MPH+DM groups. Compared with the MPH-only group, the mean scores of some psychometric parameters reported on the CBCL-C and SNAP-IV scales regarding time effects as well as the attention problems on the CBCL-C scale regarding group effect were significantly higher in the DM+MPH group. Although there were no significant differences in the levels of various serum cytokines between groups, the subjects in the DM-MPH group had relatively fewer and lower levels of adverse effects. Significant interactions were found between the withdrawn/depression item reported on the CBCL-C scale and tumor necrosis factor α (ခTNF-α) ( p = 0.027), as well as between thought problems item on the CBCL-C and TNF-α ( p = 0.028) in subjects who had received DM+MPH treatment. Conclusion: Following the trial, DM+MPH was not superior to MPH alone for the treatment of children with ADHD, yet DM may potentially have negative effects on ADHD symptoms when combined with MPH. Clinical Trial Registration: Clinicaltrials.gov, trial number: NCT01787136.

Study Objectives: This study has investigated the risk of major adverse cardiovascular events (MACEs), including acute myocardial infarction, coronary artery disease, peripheral artery disease, and acute stroke, among children and adolescents (age younger than 20 years) with obstructive sleep apnea (OSA)., Methods: In this study, the population-based National Health Insurance Research Database of Taiwan was used to identify patients in whom OSA had been first diagnosed between 2000 and 2015. Children and adolescents with OSA (n = 6,535) were included with 1:3 ratio by age, sex, and index year of control participants without OSA (n = 19,605). The Cox proportional regression model was used to evaluate the risk of MACEs in this cohort study., Results: After a 15-year follow-up, the incidence rate of MACEs was higher in the OSA cohort when compared with the non-OSA control cohort (15.97 and 8.20 per 100,000 person-years, respectively). After adjusting for covariates, the risk of MACEs among children and adolescents with OSA was still significantly higher (hazard ratio = 2.050; 95% confidence interval = 1.312-3.107; P = .010). No MACEs were found in the children and adolescents with OSA who received continuous airway positive pressure treatment or pharyngeal surgery., Conclusions: This study found a significantly higher risk of MACEs in children and adolescents with OSA. These findings strongly suggest that clinicians should provide careful follow-up and medical treatment for children and adolescents with OSA., (© 2019 American Academy of Sleep Medicine.)

Objective: Hospitalization of patients with delirium after visiting the emergency department (ED) is often required. However, the readmission risk after discharge from the ED should also be considered. This study aimed to explore whether (i) immediate hospitalization influences the readmission risk of patients with delirium; (ii) the readmission risk is affected by various risk factors; and (iii) the healthcare cost differs between groups within 28 days of the first ED visit., Methods: Using the National Health Insurance Research Database, the data of 2,780 subjects presenting with delirium at an ED visit from 2000 to 2008 were examined. The readmission risks of the groups of patients (i.e., patients who were and were not admitted within 24 hours of an ED visit) within 28 days were compared, and the effects of the severities of different comorbidities (using Charlson's comorbidity index, CCI), age, gender, diagnosis and differences in medical healthcare cost were analyzed., Results: Patients without immediate hospitalization had a higher risk of readmission within 3, 7, 14, or 28 days of discharge from the ED, especially subjects with more severe comorbidities (CCI≥3) or older patients (≥65 years). Subjects with more severe comorbidities or older subjects who were not admitted immediately also incurred a greater healthcare cost for re-hospitalization within the 28-day follow-up period., Conclusion: Patients with delirium with a higher CCI or of a greater age should be carefully considered for immediate hospitalization from ED for further examination in order to reduce the risk of re-hospitalization and cost of healthcare.

Studies suggest that a functional polymorphism of brain-derived neurotrophic factor (BDNF), polymorphism BDNF Val 66 Met affects cognitive functions, however, the effect is unclear in bipolar II (BD-II) disorder. We used the Wechsler Memory Scale-third edition (WMS-III), the presence of the BDNF Val 66 Met polymorphism, and plasma concentrations of BDNF to investigate the association between memory impairment and BDNF in BD-II disorder. We assessed the memory functions of 228 BD-II patients and 135 healthy controls (HCs). BD-II patients had significantly lower scores on five of the eight WMS-III subscales. In addition to education, the BDNF polymorphism were associated with the following subscales of WMS-III, auditory delayed memory, auditory delayed recognition memory and general memory scores in BD-II patients, but not in HC. Moreover, BD-II patients with the Val -homozygote scored significantly higher on the visual immediate memory subscale than did those with the Met/Met and Val/Met polymorphisms. The significantly positive effect of the Val -homozygote did not have a significantly positive effect on memory in the HC group, however. We found no significant association between BDNF polymorphisms and plasma concentrations of BDNF. The plasma BDNF was more likely to be associated with clinical characteristics than it was with memory indices in the BD-II group. The impaired memory function in BD-II patients might be dependent upon the association between the BDNF Val 66 Met polymorphism and peripheral BDNF levels.

Background: Patients with bipolar disorder are at high risk of metabolic disturbance after mood stabilizer treatment. However, the mediators linking the two conditions remain unknown. In this study, we investigated whether fibroblast growth factor-21 (FGF21) was associated with metabolic effects and treatment response in depressed bipolar disorder patients., Methods: We recruited 78 community-dwelling controls and 137 bipolar disorder patients; the latter were interviewed using the Chinese Version of the Modified Schedule of Affective Disorder and Schizophrenia-Life Time. Upon study entry, the bipolar disorder patients were all in a major depressive status, with 17-item Hamilton Depression Rating Scale (HDRS) scores >15. They received valproate (500-1000 mg daily) for 12 weeks, and fluoxetine 20 mg daily was permitted to treat depressive symptoms. Fasting plasma level of FGF21, lipid profiles, and body weight were collected at baseline and after 12 weeks of treatment., Results: At baseline, the demographic characteristics, FGF21 level, and metabolic indices did not differ significantly between the controls and bipolar disorder patients. After 12 weeks of treatment, the FGF21 level (167.7±122.0 to 207.1±162.3 pg/mL, P=.001), body weight and waist circumference had increased significantly (P<.001 and P=.028, respectively). Moreover, the change in FGF21 level was significantly correlated with the changes in HDRS score (r=0.393, P=.002), total cholesterol (r=-0.344, P=.008), and low-density lipoprotein (r=-0.347, P=.007)., Conclusions: The central and peripheral mediating effects of FGF21 on bipolar disorder depression treatment might be opposite. High peripheral FGF21 levels might link regulation of metabolic effect and resistance to treatment in bipolar disorder.

This retrospective cohort study is to investigate the association between herpes simplex virus (HSV) infections and dementia, and the effects of anti-herpetic medications on the risk involved, using Taiwan's National Health Insurance Research Database (NHIRD). We enrolled a total of 33,448 subjects, and identified 8362 with newly diagnosed HSV infections and 25,086 randomly selected sex- and age-matched controls without HSV infections in a ratio of 1:3, selected from January 1, to December 31, 2000. A multivariable Cox proportional hazards regression model was used to evaluate the risk of developing dementia in the HSV cohort. This analysis revealed an adjusted hazard ratio of 2.564 (95% CI: 2.351-2.795, P < 0.001) for the development of dementia in the HSV-infected cohort relative to the non-HSV cohort. Thus, patients with HSV infections may have a 2.56-fold increased risk of developing dementia. A risk reduction of dementia development in patients affected by HSV infections was found upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95% CI 0.079-0.108], P < 0.001). The usage of anti-herpetic medications in the treatment of HSV infections was associated with a decreased risk of dementia. These findings could be a signal to clinicians caring for patients with HSV infections. Further research is, therefore, necessary to explore the underlying mechanism(s) of these associations.

Anxiety disorders (ADs), the most common comorbid illnesses with bipolar disorder (BP) has been reported to associate with dopamine system. Dopamine, metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase 2 (ALDH2), and the distribution of the ALDH2*1/*1, and ALDH2*1/*2+ALDH*2/*2 alleles in the Han Chinese general population is relatively equal. The association between dopamine metabolic enzymes and cognitive performance in patients with bipolar II disorder (BP-II) comorbid with AD is unclear. This study proposed to explore the role of ALDH2 polymorphisms on neuropsychological performance between BP-II comorbid with or without AD. One hundred ninety-seven BP-II patients with and without a comorbid AD were recruited and compared with 130 healthy controls (HCs). A polymerase chain reaction and a restriction fragment length polymorphism analysis were used to determine genotypes for ALDH2, and study participants underwent neuropsychological tests. An interaction between AD comorbidity and the ALDH2 polymorphisms was found in different domain of cognitive dysfunction in the BP-II patients. The ALDH2 polymorphisms might have different effects on the neuropsychological performance of BP-II patients with and without comorbid AD.

This corrects the article DOI: 10.1038/srep09708.

Aim: Clozapine-associated fever is common but the specific cytokine changes and treatment durations that may cause fever remain unknown. We investigated the association between inflammatory cytokine changes and clozapine-induced fever in patients who were treated with clozapine., Methods: Forty-three patients with schizophrenia or schizoaffective disorder, diagnosed by using the Chinese Version of the Mini International Neuropsychiatric Interview, were treated with clozapine for the first time (first-time use group, n = 22) or for more than 6 months (long-term use group, n = 21). The Positive and Negative Syndrome Scale, tympanic temperature, and levels of tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), interleukin-2 (IL-2), and interleukin-6 (IL-6) were determined at baseline and weeks 1, 2, 3, 4, and 6. A multiple linear regression with generalized estimating equation methods was used to analyze the association between the changes in the cytokine levels and clozapine-induced fever in the different groups., Results: The IL-6 level changes were significantly different between the two groups (P = 0.04). In the first-time use group, the fever rate was increased (47.1%) compared with the long-term use group (5.6%, P = 0.005). Moreover, in these patients, the TNF-α, INF-γ, IL-2, and IL-6 levels were significantly (P < 0.001) different from patients who did not develop a fever. An interaction effect with the different treatment duration groups and fever development was only significant for IL-6 (P < 0.001)., Conclusion: Patients who were treated with clozapine for the first time have an increased rate of developing a fever, and IL-6 might have a specific role in the interaction effect between treatment duration and fever development., (© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.)

This longitudinal study aimed to investigate the associations between the polymorphisms of guanine nucleotide-binding protein subunit β-3 (GNB3) C825T and metabolic disturbance in bipolar II disorder (BP-II) patients being treated with valproate (VPA). A 100 BP-II patients received a 12-week course of VPA treatment, and their body weight and metabolic indices were measured. At baseline, the GNB3 C825T polymorphisms were associated with the triglyceride level (P=0.032) in BP-II patients. During the VPA treatment course, the polymorphisms were not only associated with body mass index (BMI) and waist circumference (P-values=0.009 and 0.001, respectively), but also with total cholesterol, triglyceride, low-density lipoprotein and leptin levels (P-values=0.004, 0.002, 0.031 and 0.015, respectively). Patients with the TT genotype had a lower BMI, smaller waist circumference, and lower levels of lipids and leptin than those with the CT or CC genotypes undergoing the VPA treatment course.

Dopaminergic dysfunction has an important role in the pathoetiology of alcohol dependence (AD). The purpose of this study was to determine whether the solute carrier family 6 member 3 (SLC6A3) gene (also known as the dopamine transporter DAT gene) was associated with AD, and whether variants in the SLC6A3 locus were associated with specific personality traits in patients with AD. Sixteen polymorphisms in SLC6A3 were analyzed using 637 patients with AD and 523 healthy controls. To reduce clinical heterogeneity, patients were classified into two subgroups: early-onset AD (EOAD) and late-onset AD (LOAD). The Tridimensional Personality Questionnaire was used to assess the personality traits novelty seeking (NS) and harm avoidance (HA) in the patients with AD. Using allele frequency and genotype distribution comparisons and logistic regression analysis, we found evidence of association between rs6350 and AD (P < 0.05). Following subgroup analysis, we confirmed evidence of an association in patients with LOAD (P = 0.003), but not in patients with EOAD. Heterozygous carriers of the A allele have a nearly 3 times greater risk to develop LOAD compared to individuals who do not have an A allele. Although we found that patients with AD had higher NS and HA scores compared to controls (P < 0.001), we did not find evidence of association between SLC6A3 polymorphisms and either NS or HA in patients with AD using linear regression analysis. The findings from our study indicate that the SLC6A3 gene may have a role in susceptibility to late-onset AD in the Han Chinese population., Competing Interests: The authors have declared that no competing interests exist.

Background: This study aimed to identify susceptible loci and enriched pathways for bipolar disorder subtype II., Methods: We conducted a genome-wide association scan in discovery samples with 189 bipolar disorder subtype II patients and 1773 controls, and replication samples with 283 bipolar disorder subtype II patients and 500 controls in a Taiwanese Han population using Affymetrix Axiom Genome-Wide CHB1 Array. We performed single-marker and gene-based association analyses, as well as calculated polygeneic risk scores for bipolar disorder subtype II. Pathway enrichment analyses were employed to reveal significant biological pathways., Results: Seven markers were found to be associated with bipolar disorder subtype II in meta-analysis combining both discovery and replication samples (P<5.0×10 -6 ), including markers in or close to MYO16, HSP90AB3P, noncoding gene LOC100507632, and markers in chromosomes 4 and 10. A novel locus, ETF1, was associated with bipolar disorder subtype II (P<6.0×10 -3 ) in gene-based association tests. Results of risk evaluation demonstrated that higher genetic risk scores were able to distinguish bipolar disorder subtype II patients from healthy controls in both discovery (P=3.9×10 -4 ~1.0×10 -3 ) and replication samples (2.8×10 -4 ~1.7×10 -3 ). Genetic variance explained by chip markers for bipolar disorder subtype II was substantial in the discovery (55.1%) and replication (60.5%) samples. Moreover, pathways related to neurodevelopmental function, signal transduction, neuronal system, and cell adhesion molecules were significantly associated with bipolar disorder subtype II., Conclusion: We reported novel susceptible loci for pure bipolar subtype II disorder that is less addressed in the literature. Future studies are needed to confirm the roles of these loci for bipolar disorder subtype II., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

We explored the effect of the Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) on correlation between changes in plasma BDNF levels with cognitive function and quality of life (QoL) after 12 weeks of treatment in bipolar disorder (BD). Symptom severity and plasma BDNF levels were assessed upon recruitment and during weeks 1, 2, 4, 8 and 12. QoL, the Wisconsin Card Sorting Test (WCST), and the Conners' Continuous Performance Test (CPT) were assessed at baseline and endpoint. The BDNF Val66Met polymorphism was genotyped. Changes in cognitive function and QoL over 12 weeks were reduced using factor analysis for the evaluation of their correlations with changes in plasma BDNF. Five hundred forty-one BD patients were recruited and 65.6% of them completed the 12-week follow-up. Changes in plasma BDNF levels with factor 1 (WCST) were significantly negatively correlated (r = -0.25, p = 0.00037). After stratification of BD subtypes and BDNF genotypes, this correlation was significant only in BP-I and the Val/Met genotype (r = -0.54, p = 0.008). We concluded that changes in plasma BDNF levels significantly correlated with changes in WCST scores in BD and is moderated by the BDNF Val66Met polymorphism and the subtype of BD.

Objective: Emerging evidence suggests that inflammation and neurodegeneration underlies bipolar disorder. To investigate biological markers of cytokines and brain-derived neurotrophic factor between bipolar I, bipolar II, and other specified bipolar disorder with short duration hypomania may support the association with inflammatory dysregulation and bipolar disorder and, more specifically, provide evidence for other specified bipolar disorder with short duration hypomania patients were similar to bipolar II disorder patients from a biological marker perspective., Methods: We enrolled patients with bipolar I disorder (n=234), bipolar II disorder (n=260), other specified bipolar disorder with short duration hypomania (n=243), and healthy controls (n=140). Their clinical symptoms were rated using the Hamilton Depression Rating Scale and Young Mania Rating Scale. Inflammatory cytokine (tumor necrosis factor-α, C-reactive protein, transforming growth factor-β1, and interleukin-8) and brain-derived neurotrophic factor levels were measured in each group. Multivariate analysis of covariance and linear regression controlled for possible confounders were used to compare cytokine and brain-derived neurotrophic factor levels among the groups., Results: Multivariate analysis of covariance adjusted for age and sex and a main effect of diagnosis was significant (P<.001). Three of the 5 measured biomarkers (tumor necrosis factor-α, transforming growth factor-β1, and interleukin-8) were significantly (P=.006, .01, and <.001) higher in all bipolar disorder patients than in controls. Moreover, covarying for multiple associated confounders showed that bipolar I disorder patients had significantly higher IL-8 levels than did bipolar II disorder and other specified bipolar disorder with short duration hypomania patients in multivariate analysis of covariance (P=.03) and linear regression (P=.02) analyses. Biomarkers differences between bipolar II disorder and other specified bipolar disorder with short duration hypomania patients were nonsignificant., Conclusion: The immunological disturbance along the bipolar spectrum was most severe in bipolar I disorder patients. Other specified bipolar disorder with short duration hypomania patients and bipolar II disorder patients did not differ in these biological markers., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

The dopamine transporter (DAT) plays a crucial role in the pathogenesis of alcohol dependence (AD) and major depression (MD), and males have more risk factors for the development of AD. However, imaging studies on brain DAT availability in males with AD comorbid with MD (AD/MD) are limited, and the association of DAT availability with cognitive function and depressive scores in patients with AD/MD has not been analyzed. Hence, this study examined the relationship between brain DAT availability, cognitive function, and depressive symptoms in different subgroups of males with AD.Single-photon emission computed tomography imaging with Tc-TRODAT-1 as a ligand was used to measure striatal DAT availability in 49 patients with AD (28 pure AD and 21 AD/MD) and 24 age- and sex-matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and 17-item Hamilton Depression Rating Scale were used to assess neurocognitive function and depressive scores, respectively. Patients with AD showed a significant reduction of DAT availability in 3 brain regions (P < 0.001), and this reduction was more pronounced in the patients with pure AD compared to healthy controls. The patients with AD showed significantly poorer performance on the WCST, but only in the control group was DAT availability significantly negatively correlated with total errors and perseverative errors (P < 0.001).These preliminary findings suggest that DAT availability is associated with neurocognitive function, and incongruent reduction of DAT may play a pathophysiological role in different subgroups of AD. In addition, decreased DAT availability may be associated with the severity of depressive symptoms in patients with AD/MD.

Patients with subthreshold hypomania (SBP; subthreshold bipolar disorder) were indistinguishable from those with bipolar disorder (BP)-II on clinical bipolar validators, but their analyses lacked biological and pharmacological treatment data. Because inflammation and neuroprogression underlies BP, we hypothesized that cytokines and brain-derived neurotrophic factor (BDNF) are biomarkers for BP. We enrolled 41 drug-naïve patients with SBP and 48 with BP-II undergoing 12 weeks of pharmacological treatment (valproic acid, fluoxetine, risperidone, lorazepam). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical responses at baseline and at weeks 0, 1, 2, 4, 8, and 12. Inflammatory cytokines (tumour necrosis factor [TNF]-α, transforming growth factor [TGF]-β1, interleukin [IL]-6, IL-8 and IL-1β) and BDNF levels were also measured. Mixed models repeated measurement was used to examine the therapeutic effect and changes in BDNF and cytokine levels between the groups. HDRS and YMRS scores significantly (P < 0.001) declined in both groups, the SBP group had significantly lower levels of BDNF (P = 0.005) and TGF-β1 (P = 0.02). Patients with SBP and BP-II respond similarly to treatment, but SBP patients may have different neuroinflammation marker expression.

Patients with bipolar II disorder (BDII) have a higher prevalence rate of metabolic disturbance. Whether BDII itself, in addition to its current standard treatment, is a risk factor for metabolic syndrome warrants additional study. The dopamine receptor D3 (DRD3) gene, one of the candidate genes for BDII, is also involved in the dopaminergic system. We investigated whether it is related to changes in the metabolic indices of patients with BDII given 12 weeks of standard treatment.Patients with a first diagnosis of BDII (n = 117) were recruited. Metabolic profiles (cholesterol, triglycerides, fasting serum glucose, body mass index) were measured at baseline and at 2, 8, and 12 weeks. The genotype of the DRD3 Ser9Gly polymorphism (rs6280) was determined. Multiple linear regressions with generalized estimating equation methods were used.Seventy-six (65.0%) patients completed the 12-week intervention. Significant differences in triglyceride change were associated with the DRD3 Ser9Gly genotype (P = 0.03). Patients with the Ser/Ser genotype had significantly smaller triglyceride increases and a lower risk of developing metabolic syndrome than did those with the Ser/Gly+Gly/Gly genotype. However, the associations between the DRD3 Ser9Gly polymorphism with changes in triglyceride level become nonsignificant after correcting for multiple comparisons.We conclude that the DRD3 Ser9Gly polymorphism is nominally associated with changes in triglycerides and metabolic syndrome after 12 weeks of standard BDII treatment., Competing Interests: All authors declare that they have no conflicts of interest.

Background: Clozapine, an atypical antipsychotic medication, has been effectively used to treat refractory schizophrenia. However, the clinical usage of clozapine is limited due to a high incidence of neutropenia or agranulocytosis. We previously reported that clozapine protected dopaminergic neurons through inhibition of microglial activation. The purpose of this study was to explore the neuroprotective effects of clozapine metabolites clozapine N-oxide (CNO) and N-desmethylclozapine (NDC), as well as their propensity to cause neutropenia., Methods: The primary midbrain neuron-glia culture was applied to detect the neuroprotective and anti-inflammatory effect of clozapine and its metabolites in lipopolysaccharide (LPS) and MPP(+)-induced toxicity. And the subsequent mechanism was demonstrated by gp91 (phox) mutant cell cultures as well as microgliosis cell lines. In vivo, to confirm the neuroprotective effect of clozapine and CNO, we measured the dopaminergic neuronal loss and rotarod motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-generated mouse Parkinson's disease (PD) model. The neutropenia or agranulocytosis of clozapine and its metabolites was illustrated by white blood cell count of the treated mice., Results: We found that, in midbrain neuron-glia cultures, CNO and NDC were more potent than clozapine in protecting dopaminergic neurons against LPS and MPP(+)-induced toxicity. CNO and NDC-afforded neuroprotection was linked to inhibition of microglia-mediated neuroinflammation, as demonstrated by abolished neuroprotection in microglia-depleted cultures and their capacity of inhibiting LPS-induced release of proinflammatory factors from activated microglia. NADPH oxidase (NOX2) was subsequently recognized as the main target of CNO and NDC since genetic ablation of gp91 (phox) , the catalytic subunit of NOX2, abolished their neuroprotective effects. CNO and NDC inhibited NOX2 activation through interfering with the membrane translocation of the NOX2 cytosolic subunit, p47 (phox) . The neuroprotective effects of CNO were further verified in vivo as shown by attenuation of dopaminergic neurodegeneration, motor deficits, and reactive microgliosis in MPTP-generated mouse PD model. More importantly, unlike clozapine, CNO did not lower the white blood cell count., Conclusions: Altogether, our results show that clozapine metabolites elicited neuroprotection through inactivation of microglia by inhibiting NOX2. The robust neuroprotective effects and lack of neutropenia suggest that clozapine metabolites may be promising candidates for potential therapy for neurodegenerative diseases.

Long noncoding RNAs (lncRNAs) play important roles in the formation and progression of many types of human malignancies. The aim of our study was to investigate the expression and biological functions of the lncRNA BRAF-activated noncoding RNA (BANCR) in human osteosarcoma. BANCR expression was quantified by real-time PCR in human osteosarcoma cell lines and tissues. We analyzed the association between BANCR levels and clinicopathological factors and patient prognosis. MTT, flow cytometric, and transwell invasion assays were performed to observe the effects of BANCR on MG-63 cell biological behaviors. BANCR overexpression was observed in osteosarcoma cell lines and clinical specimens. Increased BANCR expression was significantly associated with large tumor size, positive distant metastasis, and advanced clinical stage. High BANCR expression in osteosarcoma was an independent predictor of poor survival. Downregulation of BANCR inhibited MG-63 cell proliferation and invasion and promoted cell apoptosis in vitro. These findings suggested that BANCR may act as a tumor promoter in osteosarcoma and could serve as a potential therapeutic target for this disease.

Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine transporter activity is critically involved in alcohol dependence, studies observing this relationship are limited. Thus the current study examined whether dopamine transporter availability is associated with developing of alcohol dependence and cognitive dysfunction. Brain imaging with 99mTc-TRODAT-1 as a ligand was used to measure dopamine transporter availability among 26 male patients with pure alcohol dependence and 22 age- and sex- matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and Tridimensional Personality Questionnaire (TPQ) were administered to assess neurocognitive functioning and personality traits, respectively. Compared to healthy controls, patients with alcohol dependence showed a significant reduction in dopamine transporter availability (p < 0.001), as well as diminished performance on the WCST (p < 0.001). Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls, but only patients with alcohol dependence showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Thus, reductions in dopamine transporter availability may play a pathophysiological role in the development of pure alcohol dependence, given its association with neurocognitive deficits. Moreover, personality may influence the development of pure alcohol dependence; however, additional clinical subgroups should be examined to confirm this possibility.

Low-dose memantine might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. We investigated whether add-on memantine reduced cytokine levels and benefitted patients with opioid dependence undergoing methadone maintenance therapy (MMT) in a randomized, double-blind, controlled 12-week study. Patients were randomly assigned to a group: Memantine (5 mg/day) (n = 53) or Placebo (n = 75). The methadone dose required and retention in treatment were monitored. Plasma tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-6, IL-8, transforming growth factor (TGF)-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. General linear mixed models were used to examine therapeutic effect. After 12 weeks, Memantine-group required a somewhat lower methadone dose than did Placebo-group (P = 0.039). They also had significantly lower plasma TNF-α and significantly higher TGF-β1 levels. We provide evidence of the benefit of add-on memantine in opioid dependent patients undergoing MMT.

An important interaction between opioid and dopamine systems has been indicated, and using opioids may negatively affect cognitive functioning. Memantine, a medication for Alzheimer's disease, increasingly is being used for several disorders and maybe important for cognitive improvement. Opioid-dependent patients undergoing methadone-maintenance-therapy (MMT) and healthy controls (HCs) were recruited. Patients randomly assigned to the experimental (5 mg/day memantine (MMT+M) or placebo (MMT+P) group: 57 in MMT+M, 77 in MMT+P. Those completed the cognitive tasks at the baseline and after the 12-week treatment were analyzed. Thirty-seven age- and gender-matched HCs, and 42 MMT+P and 39 MMT+M patients were compared. The dropout rates were 49.4% in the MMT+P and 26.3% in the MMT+M. Both patient groups' cognitive performances were significantly worse than that of the HCs. After the treatment, both patient groups showed improved cognitive performance. We also found an interaction between the patient groups and time which indicated that the MMT+M group's post-treatment improvement was better than that of the MMT+P group. Memantine, previously reported as neuroprotective may attenuate chronic opioid-dependence-induced cognitive decline. Using such low dose of memantine as adjuvant treatment for improving cognitive performance in opioid dependents; the dose of memantine might be a worthy topic in future studies.

Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and gene-based association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test gene-gene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6×10-6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0.027), respectively. Gene-based association was significant for RORA gene (P = 0.0007). Our results support for the involvement of RORs genes in the risk of developing BD. Investigation of the functional properties of genes in the circadian pathway may further enhance our understanding about the pathogenesis of bipolar illness.

Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and chronic psychiatric illness. However, BP-II is commonly under-recognized, even in psychiatric settings. Because dopaminergic disturbance is thought to be involved in the development of bipolar disorder (BPD), it seems essential to investigate dopamine-related genes like the catechol-O-methyltransferase (COMT) gene, which are involved in dopamine metabolism, and the methylenetetrahydrofolate reductase (MTHFR) gene, which may affect COMT methylation and COMT function. The current study examined the association and interaction of the COMT Val158Met and MTHFR C677T variants with BP-II. Nine hundred seventy-eight participants were recruited: 531 with BP-II and 447 healthy controls. The genotypes of the COMT and MTHFR polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant interaction effect of the COMT Val158Met Val/Val genotype and the MTHFR C677T C/T + T/T genotype (P = 0.039) for the protective effect on the odds of developing BP-II. Our findings support preliminary evidence that the COMT and MTHFR genes interact in BP-II, and they imply the connection of both dopaminergic pathways and methylation pathways in the pathogenesis of BP-II.

Background: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT)., Methods: Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect., Results: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different., Conclusions: We provide evidence-decreased concomitant heroin use-of low-dose add-on DM's efficacy for treating opioid-dependent patients undergoing MMT., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.

Background: Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants., Methods: We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more., Results: Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders., Conclusions: The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Background: Much evidence supports the role of the serotonin transporter (SERT) in the pathophysiology and pharmacotherapy of major depressive disorder (MDD) and suicidal behaviors., Methods: In this study, we recruited 17 antidepressant-naïve patients with MDD and 17 age- and gender-matched healthy controls. SERT availability was measured in vivo with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) positron emission tomography (PET) imaging. The 21-item Hamilton Depression Rating Scale (HDRS) and Beck Scale for Suicide Ideation were used to assess the severity of depression and the intent of suicide ideation prior to PET imaging. All subjects with MDD were in a current state of depression with HDRS scores ≧18. Subjects who attempted suicide within two weeks of the study onset were recruited in the depressed suicidal group (n = 8). Subjects with MDD who denied any prior suicide attempt were recruited into the depressed non-suicidal group (n = 9)., Results: A significant reduction of SERT availability in the midbrain, thalamus, and striatum was noted in the MDD group relative to the control group (Bonferroni-adjusted p-value < 0.05). Moreover, this effect was more pronounced in the depressed suicidal group compared to the control group (Bonferroni-adjusted p-value < 0.01). Relative to both the depressed non-suicidal and control groups, the depressed suicidal group showed an increased prefrontal cortex (PFC)/midbrain SERT binding ratio (Bonferroni-adjusted p-value < 0.01)., Conclusions: This study suggests an incongruent reduction of PFC SERT binding relative to the midbrain might discriminate between depressed suicide attempters and non-attempters in patients with MDD and may be involved in the pathophysiology of suicide behaviors., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Nelson and Narens have proposed a metacognition model that dissociates the objective processing of information (object-level) and the subjective evaluation of the performance (i.e., the metalevel). Neurophysiological evidence also indicates that the prefrontal cortices (PFC) are the brain areas which perform the metalevel function [1]-[3]. A corresponding neural mechanism of Nelson and Narens's model, called dynamic filtering theory [4], [5], indicates that object-level processing is distributed in the posterior cortices and regulated by the prefrontal cortices with a filtering or gating mechanism to select appropriate signals and suppress inappropriate signals and noise. Based on this model, a hypothesis can be developed that, in the case of uncertainty or overloading of object-level processing, the prefrontal cortices will become more active in order to modulate signals and noise. This hypothesis is supported by a recent fMRI study [6] showing that the PFC (Brodmann area 9, BA9) was activated when subjects were overloaded in a bimodal attentional task, compared to a unimodal task. Here, we report a study showing that applying repetitive transmagnetic stimulation (rTMS) over the BA9 in order to interfere with its functional activity resulted in significant increas in guessed responses, compared to three other control conditions (i.e., no-TMS, sham TMS on BA9, and rTMS on Cz). The results are compatible with the dynamic filtering theory and suggest that a malfunction of the PFC would weaken the quality of meta-cognitive percepts and increase the number of guessed responses.

Aims: Decreased heart rate variability (HRV) has been proposed in bipolar disorder. To date, there has been no adequate study that has investigated resting HRV in unmedicated patients with bipolar disorder in the manic state., Methods: To examine whether bipolar mania is associated with decreased HRV, 61 unmedicated patients with bipolar mania and 183 healthy volunteers aged 20-65 years were recruited for this case-control analysis. The Young Mania Rating Scale (YMRS), Clinical Global Impression-Severity, Hamilton Depression Rating Scale (HAM-D), and Hamilton Anxiety Rating Scale (HAM-A) were used for the clinical ratings. Cardiac autonomic function was evaluated by measuring HRV parameters and the frequency-domain indices of HRV were obtained., Results: Patients with bipolar mania exhibited significantly lower mean RR interval, variance, low-frequency (LF)-HRV, and high-frequency (HF)-HRV but higher LF/HF compared to controls. Decreased HRV (variance) was associated with the YMRS total scores. Both the YMRS total scores and the Clinical Global Impression-Severity scores were positively correlated with the LH/HF ratio and inversely correlated with the HF-HRV. There was no significant correlation between the HAM-D/HAM-A scores and any HRV parameter., Conclusions: Bipolar mania is associated with cardiac autonomic dysregulation, highlighting the importance of assessing HRV in manic patients. Further studies examining the influence of anti-manic psychotropic drugs on cardiac autonomic regulation in bipolar mania are needed., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

The aim of this study was to explore memory deficits and psychopathology and their relationships with P300 in drug-naïve patients with schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Wechsler Memory Scale-Revised were administered. Auditory event-related potentials elicited by an oddball paradigm were obtained. After controlling for age, sex, the results showed a statistically significant negative correlation between the total PANSS score and P300 amplitude at the parietal position (r = -0.66, p < 0.05). Moreover, visual memory was significantly positively correlated with P300 amplitude at the parietal position (r = 0.67, p < 0.05). After controlling for the duration of illness, the above correlations remained statistically significant. The correlation between P300 and the severity of psychopathology was reconfirmed in drug-naïve patients with schizophrenia. A possible contribution of memory decompensation in P300 among drug-naïve patients with schizophrenia may be considered, and the compensatory or Default Model Network might be a possible explanation of this association., (Copyright © 2013. Published by Elsevier B.V.)

Bipolar disorder is a complex psychiatric disorder with high heritability, but its genetic determinants are still largely unknown. Copy number variation (CNV) is one of the sources to explain part of the heritability. However, it is a challenge to estimate discrete values of the copy numbers using continuous signals calling from a set of markers, and to simultaneously perform association testing between CNVs and phenotypic outcomes. The goal of the present study is to perform a series of data filtering and analysis procedures using a DNA pooling strategy to identify potential CNV regions that are related to bipolar disorder. A total of 200 normal controls and 200 clinically diagnosed bipolar patients were recruited in this study, and were randomly divided into eight control and eight case pools. Genome-wide genotyping was employed using Illumina Human Omni1-Quad array with approximately one million markers for CNV calling. We aimed at setting a series of criteria to filter out the signal noise of marker data and to reduce the chance of false-positive findings for CNV regions. We first defined CNV regions for each pool. Potential CNV regions were reported based on the different patterns of CNV status between cases and controls. Genes that were mapped into the potential CNV regions were examined with association testing, Gene Ontology enrichment analysis, and checked with existing literature for their associations with bipolar disorder. We reported several CNV regions that are related to bipolar disorder. Two CNV regions on chromosome 11 and 22 showed significant signal differences between cases and controls (p < 0.05). Another five CNV regions on chromosome 6, 9, and 19 were overlapped with results in previous CNV studies. Experimental validation of two CNV regions lent some support to our reported findings. Further experimental and replication studies could be designed for these selected regions.