Changes of neurofilament light chain in patients with alcohol dependence following withdrawal and the genetic effect from ALDH2 Polymorphism.

Neurofilament light chain (NFL), as a measure of neuroaxonal injury, has recently gained attention in alcohol dependence (AD). Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme which metabolizes the alcohol breakdown product acetaldehyde. An ALDH2 single nucleotide polymorphism (rs671) is associated with less ALDH2 enzyme activity and increased neurotoxicity. We examined the blood NFL levels in 147 patients with AD and 114 healthy controls using enzyme-linked immunosorbent assay and genotyped rs671. We also followed NFL level, alcohol craving and psychological symptoms in patients with AD after 1 and 2 weeks of detoxification. We found the baseline NFL level was significantly higher in patients with AD than in controls (mean ± SD: 264.2 ± 261.8 vs. 72.1 ± 35.6 pg/mL, p < 0.001). The receiver operating characteristic curve revealed that NFL concentration could discriminate patients with AD from controls (area under the curve: 0.85; p < 0.001). The NFL levels were significantly reduced following 1 and 2 weeks of detoxification, with the extent of reduction correlated with the improvement of craving, depression, and anxiety (p < 0.001). Carriers with the rs671 GA genotype, which is associated with less ALDH2 activity, had higher NLF levels either at baseline or after detoxification compared with GG carriers. In conclusion, plasma NFL level was increased in patients with AD and reduced after early abstinence. Reduction in NFL level corroborated well with the improvement of clinical symptoms. The ALDH2 rs671 polymorphism may play a role in modulating the extent of neuroaxonal injury and its recovery.

Cluster analysis dissecting cognitive deficits in older adults with major depressive disorder and the association with neurofilament light chain.

BACKGROUND: Cognitive impairment is a growing problem with increasing burden in global aging. Older adults with major depressive disorder (MDD) have higher risk of dementia. Neurofilament light chain (NfL) has been proven as a potential biomarker in neurodegenerative disease, including dementia. We aimed to investigate the association between cognitive deficits and NfL levels in older adults with MDD. METHODS: In this cross-sectional study, we enrolled 39 MDD patients and 15 individuals with mild neurocognitive disorder or major neurocognitive disorder, Alzheimer's type, as controls, from a tertiary psychiatric hospital. Both groups were over age 65 and with matched Mini-Mental State Examination (MMSE) score. Demographic data, clinical variables, and plasma NfL levels were obtained. We used cluster analysis according to their cognitive profile and estimated the correlation between plasma NfL levels and each cognitive domain. RESULTS: In the MDD group, participants had higher rate of family psychiatry history and current alcohol use habit compared with controls. Control group of neurocognitive disorders showed significantly lower score in total MMSE and higher plasma NfL levels. Part of the MDD patients presented cognitive deficits clustered with that of neurocognitive disorders (cluster A). In cluster A, the total MMSE score (r=-0.58277, p=0.0287) and the comprehension domain (r=-0.71717, p=0.0039) were negatively correlated to NfL levels after adjusting for age, while the associations had not been observed in the other cluster. CONCLUSIONS: We noted the negative correlation between NfL levels and cognition in MDD patients clustered with neurodegenerative disorder, Alzheimer's type. NfL could be a promising candidate as a biomarker to predict subtype of patients in MDD to develop cognitive decline. Further longitudinal studies and within MDD cluster analysis are required to validate our findings for clinical implications.

GxE interaction effects of HCRTR2 single nucleotide polymorphism and adverse childhood experiences on methamphetamine use disorder.

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

Effects of Vitamin D Supplementation on Cognitive Outcomes: A Systematic Review and Meta-Analysis.

Clinical studies examining the effects of vitamin D on cognition have reported inconsistent results. To date, no comprehensive study has examined this effect on the basis of sample characteristics or intervention model-related factors. This systematic review and meta-analysis of randomized controlled trials investigated the effects of vitamin D supplementation on global cognitive function and specific cognitive domains. This review was preregistered in the PROSPERO database (CRD42021249908) and comprised 24 trials enrolling 7557 participants (mean age: 65.21 years; 78.54% women). The meta-analysis revealed that vitamin D significantly influenced global cognition (Hedges' g = 0.128, p = .008) but not specific cognitive domains. A subgroup analysis indicated that the effect size of vitamin D was stronger for vulnerable populations (Hedges' g = 0.414) and those with baseline vitamin D deficiency (Hedges' g = 0.480). On the basis of subgroup analyses in studies without biological flaws (Hedges' g = 0.549), we suggest that an intervention model should correct baseline vitamin D deficiency. Our results indicate that vitamin D supplementation has a small but significant positive effect on cognition in adults.

Characterization of clinical features and comorbidities between bipolar affective disorder with and without depressive episodes.

BACKGROUNDS: A proportion of patients with bipolar disorder (BD) manifests with only unipolar mania (UM). This study examined relevant clinical features and psychosocial characteristics in UM compared with depressive-manic (D-M) subgroups. Moreover, comorbidity patterns of physical conditions and psychiatric disorders were evaluated between the UM and D-M groups. METHODS: This clinical retrospective study (N = 1015) analyzed cases with an average of 10 years of illness duration and a nationwide population-based cohort (N = 8343) followed up for 10 years in the Taiwanese population. UM was defined as patients who did not experience depressive episodes and were not prescribed adequate antidepressant treatment during the disease course of BD. Logistic regression models adjusted for relevant covariates were used to evaluate the characteristics and lifetime comorbidities in the two groups. RESULTS: The proportion of UM ranged from 12.91% to 14.87% in the two datasets. Compared with the D-M group, the UM group had more psychotic symptoms, fewer suicidal behaviors, a higher proportion of morningness chronotype, better sleep quality, higher extraversion, lower neuroticism, and less harm avoidance personality traits. Substantially different lifetime comorbidity patterns were observed between the two groups. CONCLUSIONS: Patients with UM exhibited distinct clinical and psychosocial features compared with patients with the D-M subtype. In particular, a higher risk of comorbid cardiovascular diseases and anxiety disorders is apparent in patients with D-M. Further studies are warranted to investigate the underlying mechanisms for diverse presentations in subgroups of BDs.

FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus.

BACKGROUND: Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inflammatory stress-associated mental disturbance remained unclear. METHODS: Fkbp5-deficient (Fkbp5-KO) mice were used to study inflammatory stress by a single intraperitoneal injection of lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging, immunofluorescence staining, immunohistochemistry, protein and mRNA expression analysis of inflammation- and neurotransmission-related mediators were evaluated. A dexamethasone drinking model was also applied to examine the effect of Fkbp5-KO in glucocorticoid-induced stress. RESULTS: LPS administration induced FKBP51 elevation in the liver and hippocampus accompanied with transient sickness. Notably, Fkbp5-KO but not wild-type (WT) mice showed anxiety-like behaviors 7 days after LPS injection (LPS-D7). LPS challenge rapidly increased peripheral and central immune responses and hippocampal microglial activation followed by a delayed GR upregulation on LPS-D7, and these effects were attenuated in Fkbp5-KO mice. Whole-brain [18F]-FEPPA neuroimaging, which target translocator protein (TSPO) to indicate neuroinflammation, showed that Fkbp5-KO reduced LPS-induced neuroinflammation in various brain regions including hippocampus. Interestingly, LPS elevated glutamic acid decarboxylase 65 (GAD65), the membrane-associated GABA-synthesizing enzyme, in the hippocampus of WT but not Fkbp5-KO mice on LPS-D7. This FKBP51-dependent GAD65 upregulation was observed in the ventral hippocampal CA1 accompanied by the reduction of c-Fos-indicated neuronal activity, whereas both GAD65 and neuronal activity were reduced in dorsal CA1 in a FKBP51-independent manner. GC-induced anxiety was also examined, which was attenuated in Fkbp5-KO and hippocampal GAD65 expression was unaffected. CONCLUSIONS: These results suggest that FKBP51/FKBP5 is involved in the systemic inflammation-induced neuroinflammation and hippocampal GR activation, which may contribute to the enhancement of GAD65 expression for GABA synthesis in the ventral hippocampus, thereby facilitating resilience to inflammation-induced anxiety.

Increase in plasma CCL11 (Eotaxin-1) in patients with alcohol dependence and changes during detoxification.

BACKGROUND: Alcohol is known to modulate the immune system. Neuroinflammatory cytokine dysregulation plays an essential role in the pathophysiology of alcohol dependence (AD). Preclinical studies have indicated that alcohol consumption upregulates the pro-inflammatory cytokine CC motif ligand 11 (CCL11, also known as eotaxin-1). We examined CCL11 levels in patients with AD and in mice administered alcohol. METHODS: The plasma CCL11 levels of 151 patients with AD and 116 healthy controls were measured. In addition, we followed the CCL11 levels, alcohol cravings and psychological symptoms in patients with AD after 1 and 2 weeks of detoxification. Furthermore, we examined CCL11 changes in mice administered alcohol for 5 days. RESULTS: CCL11 levels were higher in patients with AD than in controls and declined during detoxification. CCL11 levels were positively correlated with AD severity (p < 0.001). Furthermore, mice exposed to alcohol exhibited a higher CCL11 level. The receiver operating characteristic curve revealed that a CCL11 level of 72.5 pg/mL could significantly differentiate patients with AD from controls (area under the curve: 0.77; p < 0.001). Reductions in CCL11 levels during detoxification were correlated with reductions in alcohol craving, depression, and anxiety. CONCLUSIONS: Our data from humans and mice suggest that chronic alcohol consumption is associated with an increase in CCL11 levels. CCL11 levels are correlated with AD severity and may be a potential indicator of AD. The CCL11 reduction after alcohol discontinuation is associated with alleviation of clinical symptoms. Collectively, our findings suggest that CCL11 is involved in the neurobiological mechanisms underlying AD.

Increased medical utilization and psychiatric comorbidity following a new diagnosis of methamphetamine use disorder.

Background: Evidence of patterns of medical utilization and distribution of comorbidities among individuals using methamphetamine remains limitedObjective: This study aims to investigate changes in medical utilization and comorbidities before and after a diagnosis of methamphetamine use disorder.Methods: A total of 3321 cases (79% were male) of methamphetamine use disorder between January 1, 1996, and December 31, 2012, were identified from Psychiatric Inpatient Medical Claims database in Taiwan. Information was collected on demographics, diagnoses, and medical utilizations. The date of newly diagnosed with methamphetamine use disorder was defined as the baseline. Mirror-image study design was used to compare changes in medical utilization and comorbidities between the pre-baseline period (within 1 year before diagnosis) and the post-baseline period (within 1 year after diagnosis). Conditional logistic regression was used to estimate changes in medical utilization and comorbidities.Results: Most cases (77%) were first identified in a psychiatric department. There is a significant increase (P < .001) in psychiatric admission (odds ratio[OR] = 2.19), psychiatric emergency visits (OR = 1.31), and psychiatric outpatient visits (OR = 1.15) after diagnosis. Multivariable analysis revealed significantly increased risks (P < .001) of non-methamphetamine drug induced mental disorders (adjusted OR[aOR] = 29.47), schizophrenia (aOR = 2.62), bipolar disorder (aOR = 2.14), organic mental disorder (aOR = 1.82), and upper respiratory tract infection (aOR = 2.03) after diagnosis.Conclusions: We found significant increases of medical utilization and psychiatric comorbidities after diagnosed with methamphetamine use disorder. These findings may reflect the problem of delayed diagnosis and treatment. Enhancement of early identification of methamphetamine use disorder in general practice is required for early intervention and decreased subsequent morbidities.

Orexin-a elevation in antipsychotic-treated compared to drug-free patients with schizophrenia: A medication effect independent of metabolic syndrome.

BACKGROUND/PURPOSE: Orexin-A levels are reportedly increased in antipsychotic (APD)-treated patients with schizophrenia compared to healthy controls and have been associated with metabolic abnormalities. It is not clear whether the orexin-A elevation is related specifically to the drug (APDs) effect, which should be clarified by including a drug-free group for comparison, or related to drug-induced metabolic abnormalities. METHODS: Blood orexin-A levels and metabolic profiles were compared between 37 drug-free, 45 aripiprazole-treated, and 156 clozapine-treated patients with schizophrenia. The association between orexin-A and metabolic outcomes were examined. We explored the effects of APDs treatment and metabolic status on orexin-A levels by linear regression. RESULTS: Patients under APDs treatment had increased orexin-A levels compared to drug-free patients, with aripiprazole-treated group having higher orexin-A levels than clozapine-treated group. Higher orexin-A levels reduced the risks of metabolic syndrome (MS) and type 2 diabetes mellitus, indicating a relationship between orexin-A levels and metabolic problems. After adjusting the effect from metabolic problems, we found APD treatment is still associated with orexin-A regulation, with aripiprazole more significantly than clozapine. CONCLUSION: With the inclusion of drug-free patients rather than healthy controls for comparison, we demonstrated that orexin-A is upregulated following APD treatment even after we controlled the potential effect from MS, suggesting an independent effect of APDs on orexin-A levels. Furthermore, the effect differed between APDs with dissimilar obesogenicity, i.e. less obesogenicity likely associated with higher orexin-A levels. Future prospective studies exploring the causal relationship between APDs treatment and orexin-A elevation as well as the underlying mechanisms are warranted.

Intraindividual association between shift work and risk of drinking problems: data from the Finnish Public Sector Cohort.

OBJECTIVES: Studies concerning the association between shift work and drinking problems showed inconsistent results. We used data from a large occupational cohort to examine the association between shift work and different types of drinking behaviour. METHODS: A total of 93 121 non-abstinent workers from the Finnish Public Sector Study were enrolled in the study. Six waves of survey data were collected between 2000 and 2017. Work schedules were categorised as regular day, non-night shift and night shift work, and shift intensities were calculated from registered working hour data. Two indicators of adverse drinking behaviour were measured: at-risk drinking (>7 and >14 drinks per week in women and men, respectively) and high-intensity drinking (measured as pass-out experience). Intraindividual analysis was conducted using fixed-effects regression to examine the association between shift work and drinking behaviours. RESULTS: Compared with regular day work, night shift work was associated with an increased risk of high-intensity drinking (OR 1.28, 95% CI 1.07 to 1.52) but a lower risk of at-risk drinking (OR 0.85, 95% CI 0.74 to 0.99). Shift workers who worked long shifts had a lower risk of at-risk drinking compared with those who rarely worked long shifts (OR 0.58, 95% CI 0.37 to 0.93). CONCLUSIONS: Associations between shift work and alcohol use vary according to drinking patterns. Workers engaged in high-intensity drinking more often during night shift schedules compared with day work, but did not drink averagely higher volume.

Psychiatric and Other Medical Manifestations of Nitrous Oxide Abuse: Implications From Case Series.

BACKGROUND: Nitrous oxide (N2O), a commonly used anesthetic agent in dentistry, has emerged as a global public health threat in young population. Although N2O-related neurological sequelae such as spinal cord degeneration and sensorimotor peripheral neuropathy are well known, psychiatric manifestations of heavy N2O use remain unclear. Here, we presented 7 treatment-seeking patients with severe N2O use disorder to delineate the psychiatric profiles of N2O users in Asia. METHODS: Seven patients with severe N2O use disorder who sought treatment in Taipei City Psychiatric Center between 2017 and 2018 were enrolled. We used chart review method to retrospectively collect their clinical information including sociodemographics, psychiatric and substance history, urine toxicology findings, and treatment course. RESULTS: These N2O users all had diagnoses of severe N2O use disorder. They usually initiated N2O use in late adolescence and early adulthood. Six of them had histories of mood disorders; all of them reported other illicit substance use before using N2O. The main reasons for treatment seeking were irritability, psychotic symptoms, self-harm, or violent behaviors as four of them were given a diagnosis of substance-induced psychotic disorder. Urine drug screen showed negative for other illicit drug use except for 1 positive case for cannabis and 1 for amphetamine. Three of 7 cases were hospitalized because of the severity of their psychiatric symptoms and suicidal risk. CONCLUSIONS: These cases with severe N2O use disorder showed high prevalence of psychotic symptoms and dangerous behaviors such as suicide or violence. This study highlights the addiction potential of N2O and its related adverse consequences in the psychiatric aspect.

Association of Craving and Depressive Symptoms in Ketamine-Dependent Patients Undergoing Withdrawal Treatment.

BACKGROUND AND OBJECTIVES: Ketamine has emerged as one of the major illicit substances worldwide. Craving, a primary symptom for addiction, is a key challenge for ketamine abusers attempting abstinence. A link between craving and negative affect has been suggested previously for other substances. We examined the relationship between craving and negative effect (depression and anxiety) in patients with ketamine dependence (KD) undergoing withdrawal treatment. METHODS: We included 104 patients with KD (76 males and 28 females) who received inpatient treatment for ketamine withdrawal and assessed them by using Beck Depression Inventory (BDI), Beck Anxiety Inventory, and a visual analog scale (VAS; 0-100 mm) for ketamine craving on day 2 to 3 of admission. RESULTS: Fifty-nine (59%) and 38 (38.7%) of our patients reported moderate-to-severe depression and anxiety symptoms, respectively. Patients with greater cravings (ie, greater than the median VAS) reported spending more days on ketamine in the preceding month and displayed severer depressive symptoms than did those with lower cravings. VAS was significantly correlated with BDI scores after adjustment. Patients who stayed in the treatment longer (more than 2 weeks) experienced more cravings and depressive symptoms than those who did not. DISCUSSION AND CONCLUSIONS: We observed a high prevalence of depression in patients with KD, particularly those with higher cravings. Patients with greater cravings and severer depression might require a longer duration of withdrawal treatment. SCIENTIFIC SIGNIFICANCE: This research provides intimal evidence for an association between depression and craving in patients with KD. Screening and management of depression are recommended for this population. (Am J Addict 2019;00:00-00).

Orexin-A Levels in Relation to the Risk of Metabolic Syndrome in Patients with Schizophrenia Taking Antipsychotics.

Background: The role of orexin-A in regulating metabolic homeostasis has been recognized, but its association with antipsychotic-induced metabolic abnormalities remains unclear. We investigated the association between orexin-A levels and metabolic syndrome in patients with schizophrenia treated with clozapine or less obesogenic antipsychotics compared with nonpsychiatric controls. Methods: Plasma orexin-A levels and metabolic parameters were determined in 159 patients with schizophrenia: 109 taking clozapine; 50 taking aripiprazole, amisulpride, ziprasidone, or haloperidol; and 60 nonpsychiatric controls. Results: Orexin-A levels were significantly higher in the group taking less obesogenic antipsychotics, followed by the clozapine group and the controls (F=104.6, P<.01). Higher orexin-A levels were correlated with better metabolic profiles in the patient groups but not in the controls. Regression analyses revealed that the patients with higher orexin-A levels had significantly lower risk of metabolic syndrome (adjusted odds ratio [OR]=0.04, 95% CI: 0.01-0.38 for the 2nd tertile; OR=0.04, 95% CI: 0.01-0.36 for the 3rd tertile, compared with the first tertile), after adjustment for age, sex, smoking history, types of antipsychotics (clozapine vs less obesogenic antipsychotics), duration of antipsychotic treatment, and disease severity. Conclusions: Our results revealed that the orexin-A level was upregulated in patients with schizophrenia treated with antipsychotics, especially for the group taking less obesogenic antipsychotics. Furthermore, higher orexin-A levels were independently associated with better metabolic profiles. These observations suggest that an upregulation of orexin-A has a protective effect against the development of metabolic abnormalities in patients with schizophrenia receiving antipsychotic treatment.

Delirium Phenotype by Age and Sex in a Pooled Data Set of Adult Patients.

The authors aimed to evaluate whether the clinical phenotype of delirium differs if dichotomized either by sex or age (cutoff age, 65 years old) in a pooled sample of 406 nondemented adult patients with delirium as defined by DSM-IV criteria. Delirium characteristics were measured with the Delirium Rating Scale-Revised-98 (DRS-R-98). DRS-R-98 items were subgrouped to represent subscores representing the three core domains of delirium (cognitive, higher-order thinking, and circadian), noncore accessory symptoms (psychotic and affective), and diagnostic characteristics (temporal onset, fluctuation, and physical disorder). The authors compared means of the DRS-R-98 subscores and medians of individual items. Exploratory factor analyses evaluated delirium characteristics for each subgroup for each of the four groups-male, female, nongeriatric, and geriatric-while taking into account active medical diagnoses. Males had higher scores on motor agitation and affective lability (behavioral), whereas females had a higher frequency of hypoactive delirium. Delirium had a two-factor structure that emerged in all four study groups, and all its core domains loaded (i.e., correlated together) onto some of these two factors and with circadian domain correlating with accessory symptoms. Although the influence of a variety of active diagnoses on delirium was small and complex, traumatic brain injury had a clear influence on cognitive domain and abrupt onset. Age had a mild influence over delirium characteristics for both males and females. In conclusion, the authors confirmed a two-factor structure for delirium phenomenology, regardless of age and sex, with few significant differences between etiological groups.

Increased blood 8-hydroxy-2-deoxyguanosine levels in methamphetamine users during early abstinence.

BACKGROUND: Reactive oxygen species (ROS) are thought to play a role in the adverse physical and mental consequences of methamphetamine usage. The oxidative DNA adduct 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a well-known biomarker of ROS-induced DNA damage. Currently, there is insufficient clinical information about methamphetamine-induced oxidative DNA damage. OBJECTIVES: This study examined differences in blood levels of 8-OHdG between methamphetamine users and non-users as well as alterations in 8-OHdG levels after 2 weeks of methamphetamine abstinence. METHODS: We recruited 182 methamphetamine users (78.6% of male) and 71 healthy controls (95.8% of male). Baseline serum 8-OHdG levels were measured in both groups using a competitive enzyme-linked immunosorbent assay. In methamphetamine users, 8-OHdG levels were measured again 2 weeks after baseline measurement. RESULTS: The results showed that methamphetamine users had significantly higher 8-OHdG levels (0.34 ± 0.13 ng/mL) than healthy controls (0.30 ± 0.08 ng/mL) (p < 0.001). The 8-OHdG levels did not alter after 2 weeks of methamphetamine abstinence (0.32 ± 0.12 ng/mL, p = 0.051 compared to baseline measurement; p = 0.12 compared to healthy controls). No significant correlations were observed between baseline 8-OHdG levels in methamphetamine users and post-abstinence interval, age of the first methamphetamine use, duration of methamphetamine use, or history of frequent methamphetamine use. CONCLUSION: Our findings suggest that methamphetamine users had an enhanced level of oxidative damage, which did not normalize during early abstinence. Future studies are required to determine the effects of long-term methamphetamine abstinence and potential confounders on 8-OHdG levels in methamphetamine users.

No association of CYP2E1 genetic polymorphisms with alcohol dependence in Han Taiwanese population.

Cytochrome P450 2E1 (CYP2E1) gene is one of the candidate genes for alcohol dependence (AD). Four single nucleotide polymorphisms (SNPs) of CYP2E1 gene (CYP2E1*1D, *5B, *6 and *1B) have been associated with AD previously in other ethnic populations. To date, only CYP2E1*5B and *6 SNPs have been investigated in relation to AD in our population. The objective of the study was to examine the genetic associations of CYP2E1 covering the four above-noted SNPs conjointly with AD in Han Taiwanese population based on single SNP analysis and haplotype-based approach. We enrolled a total of 340 patients fulfilling DSM-IV-TR diagnostic criteria of AD and 319 healthy controls and genotyped them for the above four SNPs of CYP2E1 gene. By comparing the differences of genotype, allele, and pertinent haplotype frequencies, we did not support a genetic association between CYP2E1 and AD in Han Taiwanese either by single allele tests or haplotype-based analyses.

Valproic Acid and Lithium Meditate Anti-Inflammatory Effects by Differentially Modulating Dendritic Cell Differentiation and Function.

Valproic acid (VPA), with inhibition activity mainly toward histone deacetylase (HDAC) and Glycogen Synthase Kinase (GSK)-3, and lithium, with inhibition activity mainly toward GSK-3, are both prescribed in clinical as mood-stabilizers and anticonvulsants for the control of bipolar disorder. This study aims to compare the immuno-modulation activities of VPA and lithium, especially on the differentiation and functions of dendritic cells (DC). Our data show that treatment with VPA or lithium effectively alleviated the severity of collagen-induced arthritis triggered by LPS in mice. Both agents reduced the serum level of IL-6 and IL-10 after LPS challenge in mice. VPA and lithium both induce significant down-regulation of group I CD1 expression and secretion of IL-6 during differentiation of human monocyte-derived immature DC, while they differ in the induction of CD83 and CD86 expression, secretion of IL-8, IL-10, and TNF-α. Upon stimulation of immature DC with LPS, VPA, and lithium both reduced the secretion of IL-6 and TNF-α. However, only lithium significantly increased the production of IL-10, while VPA increased the production of IL-8 but substantially reduce the secretion of IL-10 and IL-23. Treatment with VPA resulted in a reduced capacity of LPS-stimulated DC to promote the differentiation of T helper 17 cells that are critical in the promotion of inflammatory responses. Taken together, our results suggest that VPA and lithium may differentially modulate inflammation through regulating the capacity of DC to mediate distinct T cell responses, and they may provide a complementary immunomodulatory effects for the treatment of inflammation-related diseases. J. Cell. Physiol. 232: 1176-1186, 2017. © 2016 Wiley Periodicals, Inc.

Effects of caffeinated alcoholic beverages with low alcohol and high caffeine content on cognitive and motor functions.

OBJECTIVE: In Taiwan, caffeinated alcoholic beverages (CABs), with high caffeine but low alcohol concentrations compared to those sold in Western countries, are commonly consumed at work and have been associated with work-related injuries. However, the effects on cognitive and motor functions and self-perception have not been examined. METHODS: Twenty-eight healthy male volunteers (mean age: 32.6 ± 2.7) participated in the study. Each participant visited our laboratory 4 times at intervals of at least 1 week and was assigned to one of 4 trials in a counterbalanced order at each visit: placebo, alcohol, caffeinated energy drink, and CAB. They completed the subjective perception ratings, go/no-go tasks, Stroop color-word tests, Purdue pegboard tests, and the standardized field sobriety test. We used analysis of variance to examine the intraindividual differences in the performance. RESULTS: Consuming alcohol of 0.23 g/kg typically consumed by Taiwanese CAB drinkers caused significant impairments in fine and crude motor functions; caffeine (1.5 mg/kg) did not antagonize these effects but led to an improvement in response speed in the go/no-go task. The subjective perceptions produced by alcohol were not masked by caffeine. CONCLUSIONS: CABs that contains a higher ratio of caffeine to alcohol did not counteract the motor function impairments induced by alcohol.

Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies.

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.