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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

Previous studies on acetaldehyde dehydrogenase 2 (ALDH2) focused on drinking behavior or alcoholism because the ALDH2*2 allele protects against the risk of developing alcoholism. The mechanism provides that the ALDH2 gene's protective effect is also involved in dopamine metabolism. The interaction of the ALDH2 gene with neurotransmitters, such as dopamine, is suggested to be related to alcoholism. Because alcoholism is often co-morbid with antisocial personality disorder (ASPD), previous association studies on antisocial alcoholism cannot differentiate whether those genes relate to ASPD with alcoholism or ASPD only. This study examined the influence of the interaction effect of the ALDH2*1*1, *1*2 or *2*2 polymorphisms with the dopamine 2 receptor (DRD2) Taq I polymorphism on ASPD. Our 541 Han Chinese male participants were classified into three groups: antisocial alcoholism (ASPD co-morbid with alcohol dependence, antisocial ALC; n = 133), ASPD without alcoholism (ASPD not co-morbid with alcohol dependence, antisocial non-ALC; n = 164) and community controls (healthy volunteers from the community; n = 244). Compared with healthy controls, individuals with the DRD2 A1/A1 and the ALDH2*1/*1 genotypes were at a 5.39 times greater risk for antisocial non-ALC than were those with other genotypes. Our results suggest that the DRD2/ANKK1 and ALDH2 genes interacted in the antisocial non-ALC group; a connection neglected in previous studies caused by not separating antisocial ALC from ASPD. Our study made this distinction and showed that these two genes may be associated ASPD without co-morbid alcoholism. [ABSTRACT FROM AUTHOR]

No evidence-based consensus has been reached regarding effective interventions in the immediate and midterm post mass trauma phases. Through a community survey, the mental health of 14,013 evacuees was assessed to assist in the delivery of mental health programmes 2 months after a major earthquake. Three months later, 241 high-risk patients recruited in the second survey were actively served at mobile clinics, having been either identified through the first community survey or referred by mental health aides. The estimated psychiatric morbidity rate at the second month was 13.8 per cent. The sensitivity of the screening survey and the aide-referral method were 76.6 and 61.0 per cent, respectively. Post-traumatic stress disorder (PTSD), major depressive episode and dysthymia were the three most prevalent psychiatric diagnoses at the fifth month. Among those with diagnosis of PTSD, 57 per cent had psychiatric comorbidity, and approximately 50 per cent had other anxiety or depressive disorders before the earthquake. The psychiatrically morbid subjects rarely use health services. The rate of help seeking improved because of this programme. A high risk of mental disorder was found among middle-aged and nervous trait. According to our experience, in addition to development of a sensitive community screening tool, the implementation of programmes to mobilize local resources is critical. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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]

BACKGROUND: suggested that the genetic variation at ADH1B and ALDH2 influences the risk of alcoholism. The ADH1B*2 and ALDH2*2 alleles had been thought to be protective against alcoholism. Recent studies have suggested that either physiological tolerance of blood acetaldehyde, or innate insensitivity to it, or both may play a crucial role in keeping alcoholism from developing by protecting against adverse reactions. ALDH inactive form resulting from ALDH2*2, which slows the elimination of acetaldehyde and the more active isozymes produced by ADH1B*2, could generate higher acetaldehyde levels and thus deter heavy drinking (). The genotype frequency of ADH1B*2/*2 and ALDH2*(1/*2 or 2/*2), which are regarded protective against drinking behavior, is about 70% and 50%, respectively, among the Han Chinese population in Taiwan (Chen et al., 1999a). Most previous studies, however, have failed to separate the effects of antisocial personality disorder from those of alcoholism because of their high comorbidity. To understand the relationship among alcoholism, antisocial personality disorder, and the protective effects of ADH and ALDH, it is necessary to recruit individuals with antisocial personality disorder but without alcoholism. This study was designed to stratify subjects by various ADH1B and ALDH2 genotypes for a more effective association study. The strata were: antisocial alcoholics, antisocial non-alcoholics, community alcoholics, and normal controls. METHODS: We recruited 579 Han Chinese individuals in Taiwan, intending to examine the alcoholism-protection effects of different ADH1B and ALDH2 genotypes with or without antisocial personality disorder. RESULTS: We found no difference of ADH1B*2 allele frequency between the subjects of antisocial alcoholism and subjects of antisocial non-alcoholism, but we found significant difference of ALDH2*2 allele between these two groups. CONCLUSIONS: We concluded that there is no alcoholism-protection effect of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan. [ABSTRACT FROM AUTHOR]

Chronic use of morphine causes rewarding and behavioral sensitization, which may lead to the development of psychological craving. In our previous study, we found that a widely used antitussive dextromethorphan (known as a low affinity NMDA receptor antagonist), at doses of 10-20mg/kg (i.p.), effectively decreased morphine rewarding in rats. In this study, we further investigated the effects and mechanisms of low doses of DM ([mu]g/kg range) on morphine rewarding and behavioral sensitization. A conditioned place preference test was used to determine the rewarding and a locomotor activity test was used to determine the behavioral sensitization induced by the drug(s) in rats. When a low dose of DM (3 or 10[mu]g/kg, i.p.) was co-administered with morphine (5mg/kg, s.c.), the rewarding effect, but not behavioral sensitization, induced by morphine was inhibited. The inhibiting effect of DM could be blocked by systemically administering a sigma-1 receptor antagonist, BD1047 (3mg/kg, i.p.). When BD1047 (5nmole/site) was locally given at the VTA, it also blocked the effects of a low dose of DM in inhibiting morphine rewarding. Our findings suggest that the activation of the sigma-1 receptor at the VTA may be involved in the mechanism of low doses of DM in inhibiting the morphine rewarding effect and the possibility of using extremely low doses of DM in treatment of opioid addiction in clinics. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) is hypothesized to be associated with accelerated biological aging. Telomere length (TL) is a biomarker of aging, and although TL decreases with each cell division, the rate of telomere shortening may be affected by inflammation. We aimed to investigate whether TL is decreased in BD patients and to determine the association between TL and inflammatory markers in such patients., Methods: 137 BD patients and 118 healthy controls (HCs) were recruited. Leukocyte TL and plasma levels of cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-6, IL-10, transforming growth factor (TGF)-β1], C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were assessed., Results: TL did not differ significantly between the BD patients and HCs after adjustment for potential confounding factors (P = 0.79). TL was significantly negatively associated with age (β = -0.007, P < 0.001). In addition, log TNF-α levels were significantly negatively associated with TL (P = 0.009), in both the BD patients (P = 0.02) and HCs (P = 0.05)., Conclusion: We found a significant association between TNF-α levels and TL shortening in both BD patients and HCs. However, BD patients did not display increased TL shortening relative to HCs. Studies that involve larger sample sizes and control for the heterogeneity of BD participants will be needed., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: We previously identified certain peripheral biomarkers of bipolar II disorder (BD-II) including circulating miRNAs (miR-7-5p, miR-142-3p, miR-221-5p, and miR-370-3p) and 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)). We try to explore the connection between these biomarkers., Methods: We explored correlations between the peripheral levels of above circulating miRNAs and proteins in our previously collected BD-II (N = 96) patients and control (N = 115) groups. We further searched TargetScan and BioGrid websites to identify direct and indirect interactions between these protein-coding genes and circulating miRNAs., Results: In the BD-II group, we identified significant correlations between the miR-221-5p and CA-1 (rho = -0.323, P = 0.001), FARSB (rho = 0.251, P = 0.014), MMP-9 (rho = 0.313, P = 0.002) and PCSK9 (rho = 0.252, P = 0.014). The miR-370-3p also significantly correlated with FARSB expression (rho = 0.330, P = 0.001) and PCSK9 expression (rho = 0.221, P = 0.031) in the BD-II group. Our findings were in line with the modulating axis identified from TargetScan and BioGrid, miR-221-5p/CA-1/MMP9 and miR-370-3p/FARSB/PCSK9, suggesting their association with BD-II., Conclusion: Our result supported that peripheral candidate miRNA and protein biomarkers may interact in BD-II. We concluded that miR-221-5p/CA-1/MMP9 and miR-370-3p/FARSB/PCSK9 axes might act a critical role in the pathomechanism of BD-II., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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: Alcohol use disorder (AUD) is a highly prevalent comorbid disorder in patients with bipolar disorder (BD). Both BD and AUD were found to be associated with inflammation and cognitive deficits, but few study has been done on BD comorbid with AUD (BD+AUD). We aimed to investigate the impacts of comorbid AUD and BD on cognitive function, inflammatory and neurotrophic markers., Method: We recruited 641 BD patients, 150 patients with BD+AUD, and 185 healthy controls (HC). Neuropsychological tests [Wisconsin card sorting test (WCST), continuous performance test (CPT), and Wechsler memory scale - third edition (WMS-III)] and cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-β1 (TGF-β1), and brain-derived neurotrophic factor (BDNF)] were assessed., Results: BD+AUD patients had worse cognitive performance than those without AUD. There was a significant difference in the plasma levels of TNF-α, IL-8, and BDNF (P < 0.001, <0.001, and 0.01, respectively) between the patients and the HC groups. Post hoc analysis showed that BD+AUD patients had higher levels of TNF-α and IL-8 than BD-only patients (P < 0.001). Additionally, plasma IL-8 levels were negatively associated with number of completed categories in WCST (P = 0.02), and TNF-α levels were negatively associated with visual immediate index in WMS-III (P = 0.05)., Conclusion: Our results suggest that comorbid AUD and BD might worsen cognitive impairments and inflammatory processes. Further longitudinal studies on BD+AUD may be needed., Competing Interests: Conflict of interest All authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Ltd. 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.

A novel enamovirus was identified in common bean plants with disease symptoms. Its genome of 5,781 nucleotides (nt) contains five open reading frames. This virus and other members of the genus Enamovirus share 50.4-68.4% nucleotide sequence identity in the complete genome and 19.9-51.9% amino acid sequence identity in the P0 protein, 24.9-52.5% in P1, 33.4-62.9% in P1-P2, 30.6-81.1% in P3, and 32.3-74.2% in P3-P5. Phylogenetic analysis showed that the virus is most closely related to alfalfa enamovirus 1 and pea enation mosaic virus 1 in the genus Enamovirus of the family Solemoviridae. These results suggest that this virus, tentatively named "bean enamovirus 1", should be classified as a member of a new species in the genus Enamovirus., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

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.

Bipolar disorder I (BD-I) and bipolar disorder II (BD-II) have specific characteristics and clear diagnostic criteria, but quite different treatment guidelines. In clinical practice, BD-II is commonly mistaken as a mild form of BD-I. This study uses data science technique to identify the important Single Nucleotide Polymorphisms (SNPs) significantly affecting the classifications of BD-I and BD-II, and develops a set of complementary diagnostic classifiers to enhance the diagnostic process. Screening assessments and SNP genotypes of 316 Han Chinese were performed with the Affymetrix Axiom Genome-Wide TWB Array Plate. The results show that the classifier constructed by 23 SNPs reached the area under curve of ROC (AUC) level of 0.939, while the classifier constructed by 42 SNPs reached the AUC level of 0.9574, which is a mere addition of 1.84 percent. The accuracy rate of classification increased by 3.46 percent. This study also uses Gene Ontology (GO) and Pathway to conduct a functional analysis and identify significant items, including calcium ion binding, GABA-A receptor activity, Rap1 signaling pathway, ECM proteoglycans, IL12-mediated signaling events, Nicotine addiction), and PI3K-Akt signaling pathway. The study can address time-consuming SNPs identification and also quantify the effect of SNP-SNP interactions.

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 : Repetitive transcranial magnetic stimulation (rTMS) shows potential therapeutic effects for individuals with addiction, but few studies have examined individuals with opioid use disorder (OUD). Objectives : We conducted an add-on double-blinded, sham-controlled rTMS feasibility pilot trial to examine OUD participants undergoing methadone maintenance therapy (MMT). The current report focused on the effects of rTMS on (1) craving and heroin use behavior and (2) depression, impulsivity, and attention. Methods : Active or sham rTMS treatment was applied to the left dorsolateral prefrontal cortex (DLPFC) over a total of 11 sessions in 4 weeks (15-Hz frequency, 4 seconds per train, intertrain interval of 26 seconds, 40 trains per session) in OUD participants (ClinicalTrials.gov registration number: NCT03229642). Craving, heroin use severity, urine morphine tests, the Hamilton Depression Rating Scale (HDRS), the Barratt Impulsiveness Scale-11 (BIS-11), and the Continuous Performance Tests (CPTs) were measured. Results : Twenty-two OUD participants were enrolled, of which eleven (8 males) were undergoing active rTMS and nine (8 males) were in the sham rTMS group. After 12 weeks of follow-up, the active rTMS group did not show significantly greater improvements than the sham group with respect to craving, heroin use, or urine morphine test results. However, HDRS scores, BIS-11 attentional subscales, and CPTs commission T-scores (C-TS) were significantly lower in the active rTMS group ( P = .003, 0.04, and 0.02, respectively) than in the sham group. Conclusion : Add-on rTMS did not appear to improve heroin use behavior but may have benefitted depressive symptoms, impulse control and attention in OUD participants undergoing MMT.

Objectives: We have identified the association between peripheral levels of candidate miRNAs (miR-7-5p, miR-142-3p, miR-221-5p, and miR-370-3p) for BD-II in previous study. Most of these miRNAs are associated with regulation of expression of peripheral brain derived neurotrophic factor (BDNF) levels. In order to clarify the underlying mechanism of BDNF and miRNAs in the pathogenesis of BD-II, it is of interest to investigate the relation between the peripheral levels of miR-7-5p, miR-142-3p, miR-221-5p, miR-370-3p with BDNF levels. Because the BDNF Val66Met polymorphism influence the secretion of BDNF, we further stratified the above correlations by this polymorphism., Methods: We have recruited 98 BD-II patients. Beside analyzing peripheral levels of miR-7-5p, miR-142-3p, miR-221-5p, miR-370-3p, and BDNF, the genetic distribution of the BDNF Val66Met polymorphism was also analyzed., Results: We found that the miR7-5p, miR221-5p, and miR370-3p significantly correlated with the BDNF levels for all patients. If stratified by the BDNF Val66Met polymorphism, the significant correlation between miR221-5p and miR370-3p with BDNF only remained in the Val/Met genotype. However, the correlation between miR7-5p and BDNF level is significant in all 3 genotypes., Conclusion: Our result supported that these miRNAs may be involved in the pathomechanism of BD-II through relation with BDNF., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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: Chronic inflammation and neuroprogression underlie bipolar disorder (BP) and associated cognitive deficits. Memantine (MM) exerts neuroprotective effects by reducing neuroinflammation. Therefore, we investigated whether add-on low-dose MM (5 mg/day) in BP-II patients may improve cognition and inflammation., Methods: We combined two 12-week randomized, double-blind, placebo-controlled studies (NCT01188148 and NCT03039842) for analysis. Each participant was allocated to the MM or placebo group. Symptom severity, neuropsychological tests, and the cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-β1 (TGF-β1), and brain-derived neurotrophic factor (BDNF)] were evaluated at baseline and endpoint. A subgroup analysis of middle- to old-aged BP-II patients was also performed., Results: We recruited 155 BP-II patients (23 of which were middle- to old-aged) for the MM group and 170 patients (20 of which were middle- to old-aged) for the placebo group. Add-on MM did not result in significant improvements in cognitive functions in all BP-II patients, but a group difference in TNF-α levels was found in the MM group (P=0.04). Specifically, in middle- to old-aged BP-II patients, there was a significant time and group interaction effect on omission T-scores, hit reaction time T-scores, and hit reaction time standard error T-scores on continuous performance tests (CPTs) in the MM group (P=0.007, 0.02, and 0.01, respectively), and a decrease in plasma TNF-α levels (P=0.04)., Limitations: The sample size of middle- to old-aged BP-II patients were limited., Conclusion: Add-on MM may attenuate inflammation in BP-II and improve cognition in middle- to old-aged BP-II patients., (Copyright © 2020. Published by Elsevier B.V.)

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 association between illness perceptions and the effectiveness of patients' illness-management strategies has been supported across a range of medical and psychiatric disorders. Few studies have examined these variables or their association in bipolar disorder (BD). This study examined the main and interactive associations between illness perceptions and one important illness management strategy - social rhythms stability on mood symptom severity in adults with BD., Methods: A cross-sectional study with 131 patients with BD in Taiwan was conducted using clinician- and patient-rated mood symptoms, self-reported illness perceptions, and a measure of daily and nightly social rhythms., Results: Illness perceptions were associated with mood symptom severity, but social rhythms were not. Unfavorable illness perceptions (e.g., beliefs of experiencing more BD symptoms, having stronger emotional responses to the illness) were associated with more severe mood symptoms. Favorable illness perceptions (e.g., beliefs of being able to understand and control the illness) were associated with less severe mood symptoms, with personal control as the strongest correlate of mood symptom severity. Finally, social rhythm stability moderated the relationship between unfavorable illness perceptions and clinician-rated manic symptoms., Limitations: The cross-sectional design limits our ability to make causal conclusions. Also, the effects pertain to patients in remission and may not generalize to more severely ill or hospitalized bipolar patients., Conclusions: This study indicates that in patients with BD, illness perceptions are associated with symptom severity. Interventions to enhance favorable IPs and reduce unfavorable IPs may improve mood outcomes, particularly when patients have adopted regular social rhythms., (Copyright © 2020. Published by Elsevier B.V.)

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.

Background: The outcome of methadone maintenance therapy (MMT) varies in each patient with opioid use disorder (OUD). Opioid abuse activates proinflammatory processes by increasing cytokine production and impairing neurotrophic factor expression, and possibly leads to a vicious cycle that hinders recovery. Therefore, we investigated whether markers of inflammation and neurotrophic expression correlate with the MMT outcomes in OUD patients., Method: We investigated OUD patients undergoing MMT and followed them up for 12 weeks. We measured plasma tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-6, IL-1β, transforming growth factor (TGF)-β1, brain-derived neurotrophic factor (BDNF), urinary morphine tests, and plasma morphine levels at baseline and on weeks 1, 4, 8, and 12 during MMT. Multiple linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between the cytokine and BDNF levels and MMT outcomes., Results: We initially enrolled 104 patients, but only 78 patients completed end-of-study assessments. Plasma levels of CRP, TGF-β1, and BDNF fell during MMT. Plasma IL-6 levels were significantly associated with plasma morphine levels (P = 0.005) and urinary morphine-positive ( + ) results (P = 0.04), and significantly associated with poor compliance (P = 0.009) and early dropout from MMT (P = 0.001). However, other cytokine and BDNF levels were not consistently associated with MMT outcomes., Conclusion: Higher IL-6 levels were associated with poor MMT outcomes. Additional studies on regulating IL-6 expression to improve treatment outcomes in OUD patients might be warranted., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Dopamine plays an important role in reward system of heroin dependence (HD), and dopaminergic D2 receptor (DRD2) gene is a candidate for the aetiology of HD. Ankyrin repeat and kinase domain containing 1 (ANKK1) gene is proximal to DRD2 and may influence its expression. We explored whether DRD2 and ANKK1 associate with occurrence of HD, and whether the genetic variants influence personality traits in male patients with HD. Methods: DRD2 / ANKK1 polymorphisms were analysed in 950 unrelated Han Chinese male participants (601 HD patients and 349 healthy controls). All participants were screened using the same assessment tools and all patients met the diagnostic criteria of HD. Personality traits were assessed in 274 patients and 142 controls using the Tridimensional Personality Questionnaire. Results: According to the allele, genotype and haplotype frequency analysis, we observed an association between HD and several DRD2 / ANKK1 polymorphisms (rs1800497, rs1800498, rs1079597 and rs4648319); this was most notable in the late-onset HD subgroup. However, these DRD2 / ANKK1 polymorphisms did not associate with specific personality traits in HD patients and controls. Conclusions: DRD2 / ANKK1 may play an important role in occurrence of late-onset HD, but does not mediate the relationship between personality traits and HD in Han Chinese male population.

This study aims to investigate the association between pulmonary embolism (PE) and the risk of psychiatric disorders. A total of 21,916 patients aged ≥20 years with PE between January 1, 2000, and December 31, 2015, were selected from the National Health Insurance Research Database of Taiwan, along with 65,748 (1:3) controls matched for sex and age. Cox regression model revealed the crude HR was 1.539 (95% CI 1.481 to 1.599; p<0.001), and after adjusting all the covariates, the adjusted HR was 1.704 (95% CI 1.435 to 1.991, p<0.001), for the risk of psychiatric disorders in the PE cohort. PE was associated with the overall psychiatric disorders, dementia, anxiety, depression, and sleep disorders, after the exclusion of the psychiatric diagnoses in the first year. PE was associated with the overall psychiatric disorders, dementia, anxiety, and depression, after the exclusion of the psychiatric diagnoses in the first 5 years. The patients with PE were associated with psychiatric disorders. This finding could serve as a reminder to the physicians to be more watchful and aware in the long-term follow-up of patients with PE for their care and potential mental health problems., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study aimed to investigate the association between adults with ADHD and the risk of developing dementia., Method: Utilizing National Health Insurance Research Database of Taiwan, ADHD patients were identified and compared with age- and gender-matched controls (1:3)., Results: Of the study participants, 37 (5.48%) developed dementia compared with 81 (4.0%) in the control group. Cox proportional hazards regression analysis revealed that the study participants were more likely to develop dementia. The crude hazard ratio (HR) is 3.418 (95% confidence interval [CI] = [2.289, 5.106], p < .001), and adjusted HR is 4.008 (95% CI = [2.526, 6.361], p < .001) in risk of developing dementia after adjusted for age, gender, comorbidities, geographical area of residence, urbanization level of residence, and monthly income., Conclusion: Adults with ADHD have a 3.4-fold risk of developing dementia, and other large or national data sets should be explored to support the current findings.

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.)

Population-based cohort study investigating the risk of depression and other psychiatric disorders for patients with overactive bladder (OAB) syndrome is unavailable. This study investigated the subsequent risk of psychiatric disorders among patients with OAB in an Asian population. Using data from the National Health Insurance Research Database of Taiwan, we established a cohort with 811 patients in an exposed group with OAB between January 1, 2000 and December 31, 2000, and a non-exposed group, without OAB, of 2433 patients without OAB matched by age and year of diagnosis. The occurrence of psychiatric disorders and Cox regression model measured adjusted HRs (aHR) were monitored until the end of 2013. The overall incidence of psychiatric disorders was 41.7% higher in the exposed group with OAB than in the non-exposed group without OAB (14.2% vs 10.1%, p<0.001), with an aHR of 1.34 (95% CI 1.12 to 1.80, p<0.001) for the OAB cohort. OAB was associated with the increased risk of dementia, anxiety, depressive, sleep, and psychotic disorders, with aHRs as 1.53 (p=0.040), 1.61 (p<0.001), 2.10 (p<0.001), 1.43 (p<0.001), and 2.49 (p=0.002), respectively. The risk of psychiatric disorders, including depression and anxiety, is significantly higher in patients with OAB than in those without OAB. Evaluation of psychiatric status in patients with OAB is strongly recommended., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Amphetamine exposure impacts on innate and adaptive immunity and DRD3 may modulate the effect of amphetamine on the immune response. We assessed the immune-cytokine markers in 72 female patients with amphetamine dependence (AD) at baseline and after 4-week drug abstinence and in 51 healthy women. Multiplex magnetic bead assay was used to measure the plasma cytokine expression level simultaneously in all participants and DRD3 rs6280 polymorphism was genotyped in patients. We demonstrated an increase of the T helper 1 (Th1) cytokines (IL-2), Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) and other cytokines (IL-1β) in the entire AD cohort. A similar cytokine pattern, along with a significantly decreased IL-8 and IL-10 levels was observed after 4-week abstinence. Among AD patients with DRD3 rs6280 TT genotype, the cytokine expression profile was consistent with total AD cohort at baseline and revealed a significant down-regulated plasma level of the Th1, Th2, and other cytokines except for IL-6 after 4-week abstinence. In AD group with DRD3 rs6280 C allele carrier, we found IL-2 level was significantly higher than healthy controls at baseline and remained higher, accompanied with a borderline increase in IL-4, IL-6 and IL-1β levels after 4-week abstinence. Our results suggest that chronic use of amphetamine increased both pro- and anti-inflammatory cytokines in AD patients, indicating the immune imbalance that may persist for 4 weeks or more. Besides, DRD3 rs6280 TT genotype may be associated with favorable recovery in general inflammatory cytokines during period of abstinence., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Patients with opioid use disorder (OUD) show memory deficiencies and impaired treatment outcomes. Emerging evidence suggests that opioid abuse activates proinflammatory processes by increasing cytokine production and impairing neuroprotection, which damages the memory function in OUD patients. Therefore, we investigated whether plasma-based inflammatory and neurotrophic markers correlate with memory function in OUD patients., Method: OUD patients undergoing methadone maintenance therapy (MMT) were investigated and followed up for 12 weeks. Plasma tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-6, transforming growth factor (TGF)-β1, brain-derived neurotrophic factor (BDNF) levels, and Wechsler Memory Scale-Revised (WMS-R) scores were assessed at baseline and after 12 weeks of MMT. Multiple linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between cytokines and memory performance., Results: We enrolled 89 patients at baseline; 47 patients completed the end-of-study assessments. Although Pearson correlations showed that CRP and TGF-β1 levels were significantly, negatively associated with some memory indices, the results were not significant after correction. The GEE results, controlled for several confounding factors and multiple testing, showed that changes in TNF-α levels were negatively correlated with changes in the visual memory index (P = 0.01), and that changes in IL-6 levels were negatively correlated with changes in the verbal memory index (P = 0.009)., Conclusion: Memory performance, TNF-α, and IL-6 levels in OUD patients were negative correlated. Additional studies on regulating TNF-α and IL-6 expression to improve memory function in OUD patients might be warranted., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study investigated the physiological regulation of brain immune homeostasis in rat primary neuron-glial cultures by sub-nanomolar concentrations of prostaglandin E2 (PGE 2 ). We demonstrated that 0.01 to 10 nM PGE 2 protected dopaminergic neurons against LPS-induced neurotoxicity through a reduction of microglial release of pro-inflammatory factors in a dose-dependent manner. Mechanistically, neuroprotective effects elicited by PGE 2 were mediated by the inhibition of microglial NOX2, a major superoxide-producing enzyme. This conclusion was supported by (1) the close relationship between inhibition of superoxide and PGE 2 -induced neuroprotective effects; (2) the mediation of PGE 2 -induced reduction of superoxide and neuroprotection via direct inhibition of the catalytic subunit of NOX2, gp91 phox , rather than through the inhibition of conventional prostaglandin E2 receptors; and (3) abolishment of the neuroprotective effect of PGE 2 in NOX2-deficient cultures. In summary, this study revealed a potential physiological role of PGE 2 in maintaining brain immune homeostasis and protecting neurons via an EP receptor-independent mechanism.

Background and Objectives: Heroin dependence (HD) is a chronic relapsing brain illness with substantial heritability. Nerve growth factor (NGF) is a crucial modulator in the neurodevelopment, and may be a key mediator of reward processes in HD. The purpose of this genetic study was to investigate whether NGF gene polymorphisms associate with the occurrence of HD and the specific personality traits of patients with HD., Methods: We selected a homogeneous Han Chinese male population to overcome possible confounding effects of population and gender. For the study, 272 HD patients and 141 controls completed the Tridimensional Personality Questionnaire to evaluate their personality traits. In addition, a further sample 303 HD patients and 204 controls was added (with totally 920 participants) for the gene association and genotype-phenotype interaction studies., Results: Patients with HD had higher novelty seeking (NS) and harm avoidance (HA) scores than healthy subjects. Nonetheless, NGF gene polymorphisms did not associate with specific personality traits in HD patients and controls. There is no significant difference in NGF gene polymorphisms between patients with HD and controls., Discussion and Conclusions: The NGF gene may neither contribute to the risk of development of HD, nor mediate the relationship between specific personality traits and HD in Han Chinese male population., Scientific Significance: Patients with HD had higher novelty seeking (NS) and harm avoidance (HA) scores than healthy subjects. However, none of the polymorphisms in the NGF gene affected the NS and HA scores in both patients and healthy subjects. (Am J Addict 2018;27:516-523)., (© 2018 American Academy of Addiction Psychiatry.)

Objectives: We investigated the association of the aldehyde dehydrogenase 2 ( ALDH2) polymorphism (rs671), which is involved with the dopaminergic function, and with changes in cytokine levels and cognitive function, in a 12-week follow-up study in patients with bipolar disorder., Methods: Patients with a first diagnosis of bipolar disorder were recruited. Symptom severity and levels of plasma cytokines (tumor necrosis factor α, C-reactive protein, interleukin 6 and transforming growth factor β1) were examined during weeks 0, 1, 2, 4, 8 and 12. Neurocognitive function was evaluated at baseline and endpoint. The ALDH2 polymorphism genotype was determined., Results: A total of 541 patients with bipolar disorder were recruited, and 355 (65.6%) completed the 12-week follow-up. A multiple linear regression analysis showed a significant ( p = 0.000226) association between the ALDH2 polymorphism and changes in C-reactive protein levels. Different aspects of cognitive function improved in patients with different ALDH2 genotypes. Only patients with the ALDH2*1*1 genotype showed significant correlations between improvement of cognitive function and increased transforming growth factor -β1., Conclusion: The ALDH2 gene might influence changes in cytokine levels and cognitive performance in patients with bipolar disorder. Additionally, changes in cytokine levels and cognitive function were correlated only in patients with specific ALDH2 genotypes.

Background: Bipolar disorder (BD), especially BD-II, is frequently comorbid with alcohol dependence. Because BD-II and alcohol dependence are neurodegenerative disorders, agents with anti-inflammatory and neurotrophic effects might provide effective therapy. We investigated whether add-on memantine to regular valproic acid treatment ameliorated clinical symptoms, reduced alcohol use, and cytokine levels, and increased plasma brain-derived neurotrophic factor (BDNF) in BD-II patients with comorbid alcohol dependence., Methods: In a single-arm 12-week clinical trial, BD-II patients with comorbid alcohol dependence (n = 45) undergoing regular valproic acid treatments were given add-on memantine (5 mg/d). Symptom severity, alcohol use, cytokine (plasma tumor necrosis factor-α and C-reactive protein [CRP], transforming growth factor-β1 [TGF-β1], interleukin-8 [IL-8], IL-10), and plasma BDNF levels were regularly assessed., Results: Mean within-group decreases in Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) scores, alcohol use, CRP, BDNF, and IL-8 levels were significantly different from baseline after 12 weeks of treatment. We found no significant correlation between alcohol use levels and changes in HDRS or YMRS scores. The correlation between reduced alcohol use and reduced TGF-β1 level was significant (B = 0.003, p = 0.019)., Conclusions: BD-II comorbid with alcohol dependence might benefit from add-on memantine treatment, which significantly reduced clinical severity, alcohol use, and plasma cytokine levels, and increased BDNF levels., (Copyright © 2018 by the Research Society on Alcoholism.)

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.

The dopamine receptor D3 (DRD3) gene, one of the candidate genes for amphetamine dependence (AD), is involved in the mesolimbic dopaminergic system, implicated as the underlying mechanism of addiction. Our case-control study aimed to investigate whether the DRD3 gene is associated with the susceptibility to AD and specific personality traits in AD patients. A total of 1060 unrelated Han Chinese subjects (559 AD patients and 501 controls) were screened using the same assessment tool and genotyped for eight DRD3 polymorphisms. All patients met the DSM-IV-TR criteria for AD, and personality traits of 539 were assessed using a Tridimensional Personality Questionnaire. Furthermore, AD individuals were divided into four clinical subgroups based on gender and psychosis status, to reduce the clinical heterogeneity. We found that the ATA haplotype combination for SNPs rs324029, rs6280, and rs9825563, respectively, was significantly associated with total AD patients (p = 0.0003 after 10,000 permutations). Similar results were observed in the both male and non-psychosis subgroup but not in other subgroups. In addition, DRD3 rs9825563 may influence onset age of drug use, partially mediated by novelty seeking in the non-psychosis AD group. In conclusion, DRD3 is a potential genetic factor in the susceptibility to AD and is associated with onset age of drug use through interaction with novelty seeking in a specific patient group in the Han Chinese population.

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.