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Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of cognitive dysfunction. We previously showed that patients with metabolic syndrome (MetS) had significantly higher plasma levels of electronegative very-low-density lipoprotein (VLDL) than did healthy controls. However, the effects of electronegative-VLDL on the brain and cognitive function remain unclear. In this study, VLDL isolated from healthy volunteers (nVLDL) or patients with MetS (metVLDL) was administered to mice by means of tail vein injection. Cognitive function was assessed by using the Y maze test, and plasma and brain tissues were analyzed. We found that mice injected with metVLDL but not nVLDL exhibited significant hippocampus CA3 neuronal cell loss and cognitive dysfunction. In mice injected with nVLDL, we observed mild glial cell activation in the medial prefrontal cortex (mPFC) and hippocampus CA3. However, in mice injected with metVLDL, plasma and brain TNF-α and Aβ-42 levels and glial cell activation in the mPFC and whole hippocampus were higher than those in control mice. In conclusion, long-term exposure to metVLDL induced levels of TNF-α, Aβ-42, and glial cells in the brain, contributing to the progression of cognitive dysfunction. Our findings suggest that electronegative-VLDL levels may represent a new therapeutic target for cognitive dysfunction.

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 (NCT 01188148 and NCT 03039842) 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.

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 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.

Epidemiological studies have reported that elderly patients with metabolic syndrome (MetS) are significantly more likely to develop neuronal degenerative diseases than those without MetS. Our previous study showed that patients with MetS had significantly higher levels of negatively charged very low density lipoproteins (VLDLs) in the plasma than healthy controls. Highly electronegative VLDL is a key risk factor for endothelial dysfunction and atrial fibrillation. However, the impact of negatively charged VLDL in brain immunity remains unclear. In this study, VLDLs were isolated from normal healthy (nVLDL) individuals or patients with MetS (metVLDL). Primary astroglia and microglia mixed cell cultures as well as microglial-enriched cultures were used to test the effects of VLDLs. Microglia/astroglia activation as evidenced by their morphological changes and production of pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2), were assessed by immunofluorescence staining and ELISA, respectively. Our results showed that metVLDLs mainly act on the microglia, and not the astroglia, with low concentration (0.05–0.5 μg/mL) inducing cell morphological changes and decreased cellular processes in the microglia. However, nVLDL treatment at these concentrations had no effects on microglia and astroglia. Most importantly, TNF-α and PGE2 levels significantly increased in the microglia treated with metVLDL via a dose-dependent manner. Together, our data indicate that metVLDLs can contribute to MetS-associated brain disorders through microglia activation and neuroinflammation.

Sleep apnea disrupts physiologic homeostasis and causes neuronal dysfunction. In addition to signs of mental disorders and cognitive dysfunction, patients with sleep apnea have a higher anxiety rate. Here, we examined the mechanisms underlying this critical health issue. We used a mouse model with sleep-associated chronic intermittent hypoxia (IH) to verify the effects of sleep apnea on neuronal dysfunction. To evaluate how IH alters neuronal function to yield anxiety-like behavior and cognitive dysfunction, we examined synaptic plasticity and neuronal inflammation in related brain areas, including the medial prefrontal cortex (mPFC), striatum, and hippocampus. Mice subjected to chronic IH for 10 days exhibited significant anxiety-like behaviors in the elevated plus maze test. IH mice spent less travel time in open arms and more travel time in enclosed arms compared to control mice. However, cognitive impairment was minimal in IH mice. Increased glutamate N-methyl-D-aspartate (NMDA) receptor subunits 2B (GluN2B) and phosphorylated-ERK1/2 were seen in the mPFC, striatum, and hippocampus of IH mice, but no significant microglial and astrocyte activation was found in these brain areas. Chronic IH in mice induced compensatory increases in GluN2B to disturb neuronal synaptic plasticity, without neuronal inflammation. The altered synaptic plasticity subsequently led to anxiety-like behavior in mice. Treatment with the NMDA receptor antagonist dextromethorphan attenuated chronic IH-induced anxiety-like behavior and GluN2B expression. Our findings provide mechanistic evidence of how IH may provoke anxiety and support for the importance of early intervention to alleviate anxiety-associated complications in patients with chronic sleep apnea.

Epidemiologic studies have indicated that chronic hypertension may facilitate the progression of abnormal behavior, such as emotional irritability, hyperactivity, and attention impairment. However, the mechanism of how chronic hypertension affects the brain and neuronal function remains unclear. In this study, 58-week-old male spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) control rats were used. Their locomotor activity and neuronal function were assessed by the open field test, novel object, and Y maze recognition test. Moreover brain tissues were analyzed. We found that the aged SHR exhibited significant locomotor hyperactivity when compared to the WKY rats. However, there was no significant difference in novel object and novel arm recognition between aged SHR and the WKY rats. In the analysis of synaptic membrane protein, the expression of glutamatergic receptors, such as the N-methyl-D-aspartate (NMDA) receptor receptors subunits 2B (GluN2B) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 1 (GluA1) in the hippocampus of SHR were significantly higher than those of WKY rats. In addition, in the synaptic membrane of SHR's hippocampus and medial prefrontal cortex (mPFC), a down-regulation of astrocytes was found, though the excitatory amino acid transporter 2 (EAAT2) remained constant. Moreover, a down-regulation of microglia in the hippocampus and mPFC was seen in the SHR brain. Long-term exposure to high blood pressure causes upregulation of glutamate receptors. The upregulation of glutamatergic receptors in hippocampus may contribute to the hyper-locomotor activity of aged rodents and may as a therapeutic target in hypertension-induced irritability and hyperactivity.

Introduction:\ud \ud Delirium, a serious condition observed in critically ill patients, clinically presents with impaired cognition and consciousness. The relationship between delirium and peripheral levels of insulin growth factor-1 (IGF-1) is unclear. Thus we conducted a meta-analysis to address this issue.\ud \ud Methods:\ud \ud Seven major electronic databases were searched from inception until October 2, 2017 to obtain relevant clinical variables to compare the difference in IGF-1 levels between delirious and non-delirious elderly in-patients. A random effects meta-analysis was conducted.\ud \ud Results:\ud \ud We studies 10 articles involving 294 delirious patients (mean age 73.0 years) and 604 non-delirious patients (mean age 76.9 years). We found that peripheral levels of IGF-1 in patients with delirium were significantly lower than in those without delirium (Hedges‘ g = −0.209, 95% confidence interval [CI] = −0.393 to −0.026, p = 0.025). Meta-regression analyses found that no variables such as percentage of cognitive impairment, mean age, and female proportion contribute to heterogeneity in terms of the entire population.\ud \ud Conclusions:\ud \ud Our data suggests that lower peripheral levels of IGF-1 could be associated with a higher incidence of delirium among elderly patients. Further prospective studies with larger sample sizes are needed to investigate the association between peripheral levels of IGF-1 and delirium.

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 valproate (VPA) 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. METHOD: As a single-arm 12-week clinical trial, BD-II patients with comorbid alcohol dependence undergoing regular VPA treatments were given add-on memantine (5 mg/day). Symptom severity, alcohol use, cytokine (plasma tumor necrosis factor [TNF]-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 AND RELEVANCE: 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.

Antisocial personality disorder (ASPD) is highly comorbid with substance use disorders (SUDs). We hypothesize that chronic neuroinflammation and the loss of neurotrophic factors prompts the pathogenesis of both disorders. We used ELISA to measure plasma levels of proinflammatory (tumor necrosis factor-α [TNF-α], C-reactive protein [CRP]) and anti-inflammatory factors (transforming growth factor-β1 [TGF-β1] and interleukin-10 [IL-10]), and brain-derived neurotrophic factor (BDNF) in male patients with ASPD (n=74), SUDs (n=168), ASPD comorbid with SUDs (ASPD+SUDs) (n=438), and Healthy Controls (HCs) (n=81). A multivariate analysis of covariance (MANCOVA) controlled for possible confounders was used to compare cytokines and BDNF levels between groups. The results of MANCOVA adjusted for age showed a significant (p

BACKGROUND: Balance in the immune system plays roles in bipolar disorder (BD) and its metabolic co-morbidities. Memantine is an NMDA receptor antagonist with anti-inflammatory effects. However, the effects of memantine adjunct treatment on metabolic status of BD are unclear. METHODS: During the 12 weeks period, a total of 191 BD patients were enrolled and split into valproate (VPA) + placebo and VPA + memantine (5 mg/day) arms. The fasting plasma levels of high-sensitivity C-reactive protein (CRP) and metabolic indices were assessed. BD patients were stratified according to their initial CRP level. RESULTS: A cut-off value of initial CRP level of 2322 ng/mL discriminated the waist circumference in these BD patients after 12-week VPA treatment. In the high CRP (> 2322 ng/mL) group, patients in the VPA + memantine arm had a significantly decreased in their CRP (p= 0.009), total cholesterol (p= 0.002), LDL (p= 0.002) levels, BMI (p= 0.001), and waist circumference (p< 0.001), compared to those in the VPA + placebo arm. However, analysis of the low CRP group did not showed the effect. LIMITATIONS: We recruited BD patients in depressed states and the sample size was relative small. The effects of the fixed dose of memantine on metabolic indices were 12-week follow up in BD patients treated with VPA. CONCLUSIONS: BD patients with high initial CRP levels receiving memantine adjunct treatment have a reduced risk of inflammation and metabolic imbalance. Prospective studies are needed to confirm the long-term outcome for memantine adjunct therapy in BD patients.

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 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.

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.

Objective Increasing the evidence of inflammation's contribution to schizophrenia; using anti-inflammatory or neurotrophic therapeutic agents to see whether they improve schizophrenia treatment. Dextromethorphan (DM), a non-competitive N-methyl- d -aspartate (NMDA) receptor antagonist, might protect monoamine neurons. Whether treating schizophrenia with risperidone plus add-on DM is more effective than risperidone (RISP) alone, and the association between the ALDH2 polymorphism and treatment response were investigated. Methods A double-blind study in which patients with schizophrenia were randomly assigned to the RISP + DM (60 mg/day; n = 74) or the RISP + Placebo (n = 75) group. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) scores were used to evaluate clinical response during weeks 0, 1, 2, 4, 6, 8, and 11. The genotypes of the ALDH2 polymorphism were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. A generalized estimating equation was used to analyze the effects of ALDH2 polymorphism on the clinical performance of DM. Results PANSS and SANS scores were significantly lower in both groups after 11 weeks of treatment. SANS total scores were significantly lower in the RISP + DM group in patients with the ALDH2*2*2 genotype. Conclusions RISP plus add-on DM treatment reduced negative schizophrenia symptoms in patients with the ALDH2 polymorphism.

Objectives A high prevalence rate of bipolar disorder (BP) comorbid with alcohol dependence (AD) (BP+AD) in Western patients with BP has been reported, but whether this is true for Han Chinese with BP is uncertain. We explored the prevalence of BP+AD in a Han Chinese population with BP, and investigated the effect of alcohol-metabolizing genotypes on bipolar I disorder (BP-I) + AD and bipolar II disorder (BP-II) + AD. Methods Healthy controls (HCs) (n = 672) and 18- to 65-year-old patients with BP (BP-I: n = 530; BP-II: n = 788) were recruited. Patients with any other major or minor mental illnesses, neurological disorders, or organic mental disorders were excluded. A polymerase chain reaction and restriction fragment length polymorphism analysis was used to determine genotypes for alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), two alcohol-metabolizing enzymes. Results AD comorbidity rates were 11.7% with BP-I and 17.1% with BP-II. Significantly fewer patients with BP not comorbid with AD (BP–AD) carried the AHD1B*1 allele than did the HCs. Logistic regression analysis showed a main effect of ALDH2*1/*1 only in the BP-I–AD group. In BP+AD patients, logistic regression analysis showed main effects of ALDH2*1/*1 and ADH1B*1/*1 only in the BP-II+AD group. Conclusions Having BP-II+AD may be related to ALDH2 and ADH1B, but having BP-I+AD may be related only to ALDH2. We conclude that ALDH2 and ADH1B have different effects in Han Chinese patients with BP-I+AD and BP-II+AD.

Changes in inflammatory cytokines and dysfunction of the neurotrophic system are thought to be involved in the pathology of bipolar disorder (BP). We investigated whether inflammatory and neurotrophic factors were changed in BP. We also investigated whether treating BP with valproic acid (VPA) plus low-dose (30 or 60 mg/day) dextromethorphan (DM) is more effective than treating it with VPA only, and whether DM affects plasma cytokines and brain derived neurotrophic factor (BDNF) levels. In a 12-week, randomized, double-blind study, patients were randomly assigned to the VPA+DM30, VPA+DM60, or VPA+Placebo groups. The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) were used to evaluate symptom severity, and ELISA to analyze plasma cytokine and BDNF levels. We recruited 309 patients with BP and 123 healthy controls. Before treatment, patients with BP had significantly higher plasma cytokine and lower plasma BDNF levels than did healthy controls. After treatment, HDRS and YMRS scores in each group showed significant improvement. Plasma cytokine levels tended to decline in all groups. Changes in plasma BDNF levels were significantly greater in the VPA+DM60 group than in the VPA+Placebo group. Conclusion: patients with BP have a certain degree of systemic inflammation and BDNF dysfunction. Treatment with VPA plus DM (60 mg/day) provided patients with BP significantly more neurotrophic benefit than did VPA treatment alone.

OBJECTIVE: Brain-derived neurotropic factor (BDNF) is widely distributed in the peripheral and central nervous systems. BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of several mental illnesses. To elucidate the role of BDNF, we compared the plasma BDNF levels and the BDNF Val66Met gene variants effect in several mental disorders. METHOD: We enrolled 644 participants: 177 patients with bipolar I disorder (BP-I), 190 with bipolar II disorder (BP-II), 151 with schizophrenia, and 126 healthy controls. Their plasma BDNF levels and BDNF Val66Met single nucleotide polymorphisms (SNP) were checked before pharmacological treatment. RESULTS: Plasma levels of BDNF were significantly lower in patients with schizophrenia than in healthy controls and patients with bipolar disorder (F = 37.667, p < 0.001); the distribution of the BDNF Val66Met SNP was not different between groups (χ(2) = 5.289, p = 0.507). Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not influence plasma BDNF levels in our participants. Plasma BDNF levels were, however, significantly negatively correlated with depression scores in patients with bipolar disorder and with negative symptoms in patients with schizophrenia. CONCLUSION: We conclude that plasma BDNF profiles in different mental disorders are not affected by BDNF Val66Met gene variants, but by the process and progression of the illness itself.

Memantine is a non-competitive N -methyl-d-asparate (NMDA) receptor antagonist with a mood-stabilizing effect. We investigated whether using valproic acid (VPA) plus add-on memantine to treat bipolar II disorder (BP-II) is more effective than using VPA alone (VPA + Pbo). We also evaluated, in BP-II patients, the association between the brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism with treatment response to VPA + add-on memantine and to VPA + Pbo. In this randomized, double-blind, controlled 12 wk study, BP-II patients undergoing regular VPA treatments were randomly assigned to a group: VPA + Memantine (5 mg/day) ( n = 115) or VPA + Pbo ( n = 117). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical response during week 0, 1, 2, 4, 8 and 12. The genotypes of the BDNF Val66Met polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. To adjust within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was used to analyze the effects of the BDNF Val66Met polymorphism on the clinical performance of memantine. Both groups showed significantly decreased YMRS and HDRS scores after 12 wk of treatment; the differences between groups were non-significant. When stratified by the BDNF Val66Met genotypes, significantly greater decreases in HDRS scores were found in the VPA + memantine group in patients with the Val Met genotype ( p = 0.004). We conclude that the BDNF Val66Met polymorphism influenced responses to add-on memantine by decreasing depressive symptoms in patients with BP-II.

Purpose/background We previously conducted a randomized, double-blind, controlled, 12-week study evaluating the effect of add-on dextromethorphan (DM), a noncompetitive N-methyl-D-aspartate receptor antagonist, on patients with bipolar disorder (BD) treated using valproate (VPA), which showed negative clinical differences. The genetic variation between each individual may be responsible for interindividual differences. The catechol-O-methyltransferase (COMT) gene has been a candidate gene for BD. In the current study, we investigated whether the COMT Val158Met polymorphism predicts treatment response to VPA + add-on DM and to VPA + placebo. Methods/procedures Patients with BD (n = 309) undergoing regular VPA treatments were randomly assigned to groups given either add-on DM (30 mg/d) (n = 102), DM (60 mg/d) (n = 101), or placebo (n = 106) for 12 weeks. The Hamilton Depression Rating Scale and Young Mania Rating Scale were used to evaluate clinical response during weeks 0, 1, 2, 4, 8, and 12. The genotypes of the COMT Val158Met polymorphism were determined using polymerase chain reaction plus restriction fragment length polymorphism analysis. To adjust for within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was used. Findings/results When stratified by the COMT Val158Met genotypes, significantly greater decreases in Hamilton Depression Rating Scale scores were found in the VPA + DM (30 mg/d) group in patients with the Val/Met genotype (P = 0.008). Conclusions We conclude that the COMT Val158Met polymorphism may influence responses to DM (30 mg/d) by decreasing depressive symptoms in BD patients.

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

Patients with bipolar II disorder (BDII) have a higher prevalence rate of metabolic disturbance. Whether BDII itself, in addition to its current standard treatment, is a risk factor for metabolic syndrome warrants additional study. The dopamine receptor D3 (DRD3) gene, one of the candidate genes for BDII, is also involved in the dopaminergic system. We investigated whether it is related to changes in the metabolic indices of patients with BDII given 12 weeks of standard treatment. Patients with a first diagnosis of BDII (n = 117) were recruited. Metabolic profiles (cholesterol, triglycerides, fasting serum glucose, body mass index) were measured at baseline and at 2, 8, and 12 weeks. The genotype of the DRD3 Ser9Gly polymorphism (rs6280) was determined. Multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0%) patients completed the 12-week intervention. Significant differences in triglyceride change were associated with the DRD3 Ser9Gly genotype (P = 0.03). Patients with the Ser/Ser genotype had significantly smaller triglyceride increases and a lower risk of developing metabolic syndrome than did those with the Ser/Gly+Gly/Gly genotype. However, the associations between the DRD3 Ser9Gly polymorphism with changes in triglyceride level become nonsignificant after correcting for multiple comparisons. We conclude that the DRD3 Ser9Gly polymorphism is nominally associated with changes in triglycerides and metabolic syndrome after 12 weeks of standard BDII treatment.

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

Objective: Emerging evidence suggests that inflammation and neurodegeneration underlies bipolar disorder. To investigate biological markers of cytokines and brain-derived neurotrophic factor between bipolar I, bipolar II, and other specified bipolar disorder with short duration hypomania may support the association with inflammatory dysregulation and bipolar disorder and, more specifically, provide evidence for other specified bipolar disorder with short duration hypomania patients were similar to bipolar II disorder patients from a biological marker perspective. Methods: We enrolled patients with bipolar I disorder (n=234), bipolar II disorder (n=260), other specified bipolar disorder with short duration hypomania (n=243), and healthy controls (n=140). Their clinical symptoms were rated using the Hamilton Depression Rating Scale and Young Mania Rating Scale. Inflammatory cytokine (tumor necrosis factor-α, C-reactive protein, transforming growth factor-β1, and interleukin-8) and brain-derived neurotrophic factor levels were measured in each group. Multivariate analysis of covariance and linear regression controlled for possible confounders were used to compare cytokine and brain-derived neurotrophic factor levels among the groups. Results: Multivariate analysis of covariance adjusted for age and sex and a main effect of diagnosis was significant ( P

Background Determining the influences of genes involved in metabolizing dopamine and encoding dopamine receptors, such as the aldehyde dehydrogenase 2 ( ALDH2 ) and dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 ( DRD2/ANKK1 ) genes, is critical for understanding addictive behavior. Therefore, we investigated the association between the ALDH2 and DRD2/ANKK1 Taq IA polymorphisms and heroin dependence. Methods Heroin-dependent Han Chinese patients (250) and healthy controls (312) were recruited. ALDH2 and DRD2/ANKK1 Taq IA polymorphisms were genotyped. Results The frequency of ALDH2*1/*2 and *2/*2 genotypes was significantly higher in heroin-dependent patients than in controls, but the frequency of DRD2 Taq IA genotypes was not significantly different. Logistic regression analysis showed no significant interaction between ALDH2 and DRD2 Taq IA genotypes in patients. Conclusions The ALDH2 polymorphism, but not the DRD2 , was associated with heroin dependence.

Background: Several studies have suggested that the serotonin receptor 1B gene (5HT1B) may be important in the pathogenesis of alcohol dependence (alcoholism; ALC; AD). We examined whether 5HT1B gene A-161T polymorphisms (rs130058) are a susceptibility factor for total AD and subgroups of AD. We further explored correlation of this 5HT1B gene variant between anxiety–depression alcoholism (ANX/DEP ALC) and antisocial alcoholism (antisocial ALC) subgroups because of the high comorbidity of anxiety–depression, antisocial personality disorder, and AD. Methods: We recruited 522 Han Chinese in Taiwan for this study: 322 AD patients and 200 controls. The patient group was recruited primarily from medical teaching hospitals; patients with antisocial alcoholism were recruited from Taiwanese prisons. Individuals with AD were classified into 3 homogeneous clinical subgroups—pure alcoholism (pure ALC), ANX/DEP ALC, and antisocial ALC—using DSM-IV diagnosis. The 5HT1B gene A-161T polymorphism was determined using PCR–RFLP. Results: No significant differences in genotypic and allelic frequencies were found between controls and the total AD group or between controls and the 3 AD subgroups. However, there were significant differences in the 5HT1B gene A-161T polymorphism at both the genotype and allelic levels between the ANX/DEP ALC and antisocial ALC subgroups. Conclusions: This study suggests that the 5HT1B gene A-161T polymorphism alone is not a risk factor for increasing susceptibility to either AD or its subtypes. However, 5HT1B gene A-161T polymorphisms might be one of the common genetic factors between the ANX/DEP ALC and antisocial ALC subgroups.

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

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

Major depressive disorder (MDD), one of the most common psychiatric disorders in the world, is a serious, recurrent and chronic mental disorder, which is associated with significant psychosocial disability and economic burden. Until recently, short-term effectiveness of antidepressants has been measured in terms of patients' response to the medications in significantly reduced depressive symptoms. Remission, a long-term elimination of symptoms and the restoration of normal functioning, has become the primary outcome of therapy. In the current study, the efficacy of three frequently prescribed antidepressants, venlafaxine (75-225 mg/day), paroxetine (20 mg/day) and milnacipran (100 mg/day), used in treating 249 MDD patients with Hamilton Rating Scale of Depression (HRSD₁₇) scores higher than 16 was compared. Each patient was evaluated at week 0, 1, 2, 4, 8, 12, 16, 20 and 24 in a 24-week open-label study. Eighty-two patients took venlafaxine, 97 took paroxetine and 70 patients took milnacipran. No significant differences were found between the three groups in the response condition (HRSD₁₇ scores decreased more than 50%) after 24 weeks of follow-up. For remission, the paroxetine was the least efficacious medication than either the milnacipran (HRSD₁₇ ≤ 7) or the venlafaxine (HRSD₁₇ ≤ 5) by the last observation carried forward (LOCF) analysis. Our results suggest that the absence of depressive symptoms alone may not be an indicator for MDD remission, but the duration of absent depressive symptoms may be a better indicator.

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

It is hypothesized that dopaminergic genes-dopamine type-2 receptor (DRD2), aldehyde dehydrogenase 2 (ALDH2), and catechol-O-methyltransferase (COMT)-are associated with bipolar disorder (BP) and anxiety disorder (AD). Bipolar II (BP-II) is reported to be highly comorbid with AD. We examined whether interactions among these three genes are susceptibility factors in BP-II with AD (BP-II(+AD)) and without AD (BP-II(-AD)). In this study, we hypothesize that the interaction of the dopaminergic genes between BP-II(+AD) and BP-II(-AD) is significant different. We recruited 1260 participants: 495 with BP-II(-AD), 170 with BP-II(+AD), and 595 healthy controls without BP-II or AD. Genotyping was done using polymerase chain reactions plus restriction fragment length polymorphism analysis. Genotypic frequencies of the DRD2TaqIA, COMT, and ALDH2 polymorphisms between the two BP-II groups were nonsignificant. In logistic regression, the ALDH2 and DRD2TaqIA genes showed a main effect that was protective against BP-II(-AD) (odds ratio [OR] = 0.497, p = 0.010, and OR = 0.415, p = 0.017, respectively). The interaction of DRD2TaqIA A1/A1 and ALDH2*1/*1 had a significant risk effect on the BP-II(-AD) group (OR = 7.177, p

Regulatory mechanisms of the expression of interleukin-10 (IL-10) in brain inflammatory conditions remain elusive. To address this issue, we used multiple primary brain cell cultures to study the expression of IL-10 in lipopolysaccharide (LPS)-elicited inflammatory conditions. In neuron-glia cultures, LPS triggered well-orchestrated expression of various immune factors in the following order: tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and lastly IL-10, and these inflammatory mediators were mainly produced from microglia. While exogenous application of individual earlier-released pro-inflammatory factors (e.g., TNF-α, IL-1β, or PGE2) failed to induce IL-10 expression, removal of LPS from the cultures showed the requirement of continuing presence of LPS for IL-10 expression. Interestingly, genetic disruption of tnf-α, its receptors tnf-r1/r2, and cox-2 and pharmacological inhibition of COX-2 activity enhanced LPS-induced IL-10 production in microglia, which suggests negative regulation of IL-10 induction by the earlier-released TNF-α and PGE2. Further studies showed that negative regulation of IL-10 production by TNF-α is mediated by PGE2. Mechanistic studies indicated that PGE2-elicited suppression of IL-10 induction was eliminated by genetic disruption of the PGE2 receptor EP2 and was mimicked by the specific agonist for the EP2, butaprost, but not agonists for the other three EP receptors. Inhibition of cAMP-dependent signal transduction failed to affect PGE2-mediated inhibition of IL-10 production, suggesting that a G protein-independent pathway was involved. Indeed, deficiency in β-arrestin-1 or β-arrestin-2 abolished PGE2-elicited suppression of IL-10 production. In conclusion, we have demonstrated that COX-2-derived PGE2 inhibits IL-10 expression in brain microglia through a novel EP2- and β-arrestin-dependent signaling pathway.

Memantine, a noncompetitive N-methyl-d-aspartate receptor antagonist with a mood-stabilizing effect, and an association between bipolar disorder and proinflammatory cytokine levels have been reported. Whether adding-on memantine would reduce cytokine levels and is more effective than valproic acid (VPA) alone in bipolar II disorder was investigated. A randomized, double-blind, controlled, 12-week study was conducted. Patients undergoing regular VPA treatments were randomly assigned to a group: VPA + memantine (5 mg/d) (n = 106) or VPA + placebo (n = 108). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical response. Symptom severity, plasma tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-8, and IL-1 levels were examined during weeks 0, 1, 2, 4, 8, and 12. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Tumor necrosis factor α levels were significantly lower in the VPA + memantine group than in the VPA + placebo group (P = 0.013). Posttreatment HDRS and YMRS scores decreased significantly in both groups, but not significant, nor was the other between-group cytokine level difference pretreatment and posttreatment. The HDRS score changes were significantly associated with IL-6 (P = 0.012) and IL-1 (P = 0.005) level changes and changes in YMRS score changes with TNF-α (P = 0.005) level changes. Treating bipolar II depression with VPA + memantine may improve the plasma TNF-α level. However, adding-on memantine may not improve clinical symptoms or cytokine levels other than TNF-α. Clinical symptoms may be correlated with certain cytokines.

Background The high comorbidity rate between bipolar disorder (BP) and anxiety disorder (AD) has been studied in depth. This comorbidity is not as high in Han Chinese in Taiwan. Therefore, we explored the genetic effects BP comorbid with AD. Methods We recruited 1316 participants: 286 with BP-I, 681 with BP-II, and 349 healthy Controls. Genotypes of the BDNF Val66Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Results The DRD3 Ser9Gly polymorphism was associated with BP-II comorbid with AD (BPII+AD), and the BDNF Val66Met polymorphism was associated with BP-I comorbid with AD (BPI+AD). An interaction between the Val/Val genotype of the BDNF Val66Met and Gly/Gly polymorphism of the DRD3 Ser9Gly was found in BPII+AD, but not in BP-II not comorbid with AD (BPI−AD) compared with healthy Controls. Limitation The low comorbidity rate of AD in both BP subtypes, especially BP-I, limit generalizing our findings. Conclusion The involvement of the dopaminergic pathway in AD was confirmed, particularly with BP-II rather than BP-I. Because the Val/Val genotype of the BDNF Val66Met polymorphism, rather than the other two polymorphisms, has been associated with anxiety, it seems to affect BP-I comorbid with AD without the involvement of the DRD3 Seg9Gly polymorphism, but may modify the involvement of DRD3 Gly/Gly in BP-II comorbid with AD.

UNLABELLED:Inflammation is thought to be involved in the pathophysiology of bipolar disorder (BP) and metabolic syndrome. Prior studies evaluated the association between metabolic profiles and cytokines only during certain mood states instead of their changes during treatment. We enrolled drug-naïve patients with BP-II and investigated the correlation between changes in mood symptoms and metabolic indices with changes in plasma cytokine levels after 12 weeks of pharmacological treatment. Drug-naïve patients (n = 117) diagnosed with BP-II according to DSM-IV criteria were recruited. Metabolic profiles (cholesterol, triglyceride, HbA1C, fasting serum glucose, body mass index (BMI) and plasma cytokines (TNF-α, CRP, IL-6, and TGF-β) were measured at baseline and 2, 8, and 12 weeks post-treatment. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0%) patients completed the intervention. Changes in plasma CRP were significantly associated with changes in BMI (P = 1.7E-7) and triglyceride (P = 0.005) levels. Changes in plasma TGF-β1 were significantly associated with changes in BMI (P = 8.2E-6), cholesterol (P = 0.004), and triglyceride (P = 0.006) levels. However, changes in plasma TNF-α and IL-6 were not associated with changes in any of the metabolic indices. Changes in Hamilton Depression Rating Scale scores were significantly associated with changes in IL-6 (P = 0.003) levels; changes in Young Mania Rating Scale scores were significantly associated with changes in CRP (P = 0.006) and TNF-α (P = 0.039) levels. Plasma CRP and TGF-β1 levels were positively correlated with several metabolic indices in BP-II after 12 weeks of pharmacological intervention. We also hypothesize that clinical symptoms are correlated with certain cytokines. These new findings might be important evidence that inflammation is the pathophysiology of clinical symptoms and metabolic disturbance in BP-II. TRIAL REGISTRATION:ClinicalTrials.gov NCT01188148.

Memantine is a noncompetitive NMDA receptor antagonist. As an augmenting agent, it has an antidepressant-like and mood-stabilizing effect. Memantine also reduces binge eating episodes and weight. We investigated whether memantine added on to valproate (VPA) is more effective than VPA alone for treating BP-II depression and improving the patient's metabolic profile. This was a randomized, double-blind, controlled study. BP-II patients undergoing regular VPA treatments were randomly assigned to one of two groups: VPA plus either add-on [1] memantine (5 mg/day) ( n = 62) or [2] placebo ( n = 73) for 12 weeks. The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) were used to evaluate clinical response. Height, weight, fasting serum glucose, fasting total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides were followed regularly. Multiple linear regressions with generalized estimating equation methods were used to analyze the effects of memantine on clinical performance. There were no significant differences in pre- and post-treatment YMRS and HDRS scores between the VPA + memantine and VPA + placebo groups. Although there were no significant differences in the pre- and post-treatment values of most metabolic indices between the two groups, there was a significant increase of HDL-C ( p = 0.009) in the VPA + memantine group compared with the VPA + placebo group. This increase remained significant even after controlling for body mass index (BMI) ( p = 0.020). We conclude that add-on memantine plus VPA treatment of BP-II depression increases the blood level of HDL-C even in the absence of change in affective symptoms. Trial registration : NCT01188148 ( https://register.clinicaltrials.gov/ ), Trial date was from 1st August, 2008 to 31st July, 2012 in National Cheng Kung University and Tri-Service General Hospital.

Bipolar disorder (BP), especially bipolar II disorder (BP-II), is highly comorbid with anxiety disorder (AD). Monoaminergic dysfunction has been implicated in the pathogenesis of BP, it may be important to investigate genes such as the catechol-O-methyltransferase (COMT), involved in monoamine metabolism and brain-derived neurotrophic factor (BDNF) genes, modulating the monoamine system. We therefore examined the association of the COMT Val158Met and BDNF Val66Met polymorphisms with BP-II with and without comorbidity of AD, and possible interactions between these genes. Seven hundred and seventy-one participants were recruited: 314 with bipolar-II without AD, 117 with bipolar-II with AD, and 340 healthy controls. The genotypes of the COMT and BDNF polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant effect of the COMT and the BDNF polymorphisms, and a significant interaction effect for the Val/Val genotypes of the BDNF Val66Met polymorphism and the COMsT Val158Met Val/Met and Met/Met genotypes (P = 0.007, 0.048) discriminated between BP-II without AD patients and controls. Our findings provide initial evidence that the COMT and BDNF genes interact in bipolar-II without AD. Our findings suggest the involvement of dopaminergic pathway in the pathogenesis of bipolar-II.

Dextromethorphan (DM) is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that may be neuroprotective for monoamine neurons. We hypothesized that adding DM to valproate (VPA) treatment would attenuate bipolar disorder (BP) symptoms. We evaluated in BP patients the association between the DRD2/ANKK1 TaqIA polymorphism with treatment response to VPA+add-on DM and to VPA+placebo. This double-blind, stratified, randomized study ran from January 2007 through December 2010. BP patients undergoing regular VPA treatments were randomly assigned to groups given either add-on DM (60 mg/day) (n=167) or placebo (n=83) for 12 weeks. The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) were used to evaluate clinical response. The genotypes of the DRD2/ANKK1 TaqIA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. To adjust within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was used to analyze the effects of the DRD2/ANKK1 TaqIA polymorphism on clinical performance. Both groups showed significantly decreased YMRS and HDRS scores after 12 weeks of treatment; the differences between groups were non-significant. Decreases in YMRS scores were greater in patients with the A1A1 (P=0.004) genotypes than with the A2A2 genotype. We conclude that the DRD2/ANKK1 TaqIA polymorphism influenced responses to DM by decreasing manic symptoms in BP patients.

Bipolar disorder (BP) patients with comorbid anxiety disorders (ADs) showed more severe clinical characteristics and psychosocial function impairment, worse response to treatment, and more substance use than those without AD. However, few studies focus on differences in neuropsychological function between BP-I and BP-II and patients with and without AD. Seventy-nine BP patients in their interepisode state classified into four groups-BP-I without AD (BP-I(-AD)) (n=22), BP-I with AD (BP-I(+AD)) (n=20), BP-II without AD (BP-II(-AD)) (n=18), BP-II with AD (BP-II(+AD)) (n=19), and healthy controls (HC) (n=30)-were given neuropsychological tests. BP-I(+AD) patients did less well than BP-I(-AD) patients, but only in working memory. BP-II(+AD) patients did less well than the BP-II(-AD) patients in visual immediate memory, visual delayed memory, working memory, and psychomotor speed. BP-I(+AD) has limited effects on neuropsychological performance. However, significant effects were found only in BP-II(+AD) patients compared with BPII(-AD) patients. We hypothesized that comorbid AD worsens neuropsychological performance more in BP-II than in BP-I patients.

Objective Bipolar disorder (BP) is a mental disorder most likely to co-occur with substance dependence and abuse, especially alcohol dependence (ALD). Whether the effect of comorbid alcoholism is different between the BP-I and BP-II subtypes remains unclear. We aimed to identify the neuropsychological performance of BP patients with and without comorbid ALD in partial remission from depression or mania, and compare it with that of healthy controls (HCs). Methods We recruited 29 HCs and 94 BP patients, whom we categorized into four groups: (1) BP-I without a history of alcohol abuse or dependence (BP-I − ALD ; n = 22), (2) BP-II without a history of alcohol abuse and dependence (BP-II − ALD ; n = 38), (3) BP-I with comorbid ALD (BP-I + ALD ; n = 16), and (4) BP-II with comorbid ALD (BP-II + ALD ; n = 18). Only males were recruited in this study. Results When patients comorbid with ALD were not excluded, there were no significant differences on neuropsychological tests between the BP-I and BP-II groups. However, when patients with comorbid ALD were excluded, there were significant differences between the two BP − ALD groups. The BP-I − ALD group had lower scores on memory subtests (p ≤ 0.01) than the HC and BP-II − ALD groups, but the BP-II − ALD and HC groups had similar scores. Conclusion We found it important to exclude ALD comorbidity when evaluating neuropsychological functions due to our finding that ALD affected the cognitive performance in BP-I more severely than in the BP-II group. ALD not only impairs neuropsychological function, but also worsen the clinical course and leads to a more pernicious status and negative cycle.

Background: Alcohol dependence is usually comorbid with anxiety disorder, depressive disorder, or both; this comorbidity may increase drinking behavior. We previously hypothesized that anxiety–depressive alcohol dependence (ANX/DEP ALC) was a genetically specific subtype of alcohol dependence. ANX/DEP ALC may be related to dopamine and serotonin, which are catalyzed by monoamine oxidase A (MAOA) and acetaldehyde dehydrogenase 2 (ALDH2). The aim of this study was to determine whether the interaction between the MAOA and the ALDH2 genes is associated with ANX/DEP ALC. Methods: We recruited 383 Han Chinese men in Taiwan: 143 ANX/DEP ALC and 240 healthy controls. The diagnosis of ANX/DEP ALC (alcohol dependence with a past or current history of anxiety, depressive disorder, or both) was made using DSM-IV criteria. Genotypes of ALDH2 and MAOA-uVNTR (variable number of tandem repeat located upstream) were determined using PCR-RFLP. Results: The ALDH2, but not the MAOA-uVNTR, polymorphism was associated with ANX/DEP ALC. After stratifying the MAOA-uVNTR polymorphism, we found a stronger association between the ALDH2*1/*2 and *2/*2 genotypes and the controls in the MAOA-uVNTR 4-repeat subgroup. Logistic regression significantly associated the interaction between ALDH2 and MAOA variants with ANX/DEP ALC. Conclusion: We conclude that the MAOA and ALDH2 genes interact in ANX/DEP ALC. Although the MAOA gene alone is not associated with ANX/DEP ALC, we hypothesize that different variants of MAOA-uVNTR polymorphisms modify the protective effects of the ALDH2*2 allele on ANX/DEP ALC in Han Chinese in Taiwan.