Tzu-Yun Wang

Inflammation’s Association with Metabolic Profiles before and after a Twelve-Week Clinical Trial in Drug-Naïve Patients with Bipolar II Disorder

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.

The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese patients with bipolar disorder and schizophrenia.

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.

Quality of life and its correlates among heroin users in Taiwan.

The aims of this study were to compare the quality of life (QOL) between subjects with and without heroin use and to examine the association of QOL with sociodemographic characteristics, characteristics of heroin use, family support, and depression among heroin users at entry to a methadone maintenance treatment program. A group of 123 heroin users who visited an outpatient addiction treatment clinic in southern Taiwan for methadone maintenance treatment were recruited into this study. We also recruited 106 subjects who had never used heroin as the control group. Their QOL status was assessed by the short form of the Taiwan Version of the World Health Organization Questionnaire on Quality of Life (the WHOQOL‐BREF Taiwan version). The level of QOL between subjects with and without heroin use was compared, and the correlates of QOL among heroin users were examined. Heroin users had poorer QOL than nonusers in the physical, psychological, and social relationship domains but not the environment domain of the WHOQOL‐BREF after controlling for the influences of other factors. In addition, heroin users with obvious depression had poorer QOL in all four domains than those without obvious depression. Also, heroin users who perceived higher family support had better QOL in the social relationship and environment domains. Heroin users had poorer QOL than nonusers in multiple domains. Relief of depressive symptoms and enhancement of family support should be important strategies to improve QOL in heroin users.

Genetic variants of the BDNF and DRD3 genes in bipolar disorder comorbid with anxiety disorder

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.

Association between DRD2, 5-HTTLPR, and ALDH2 genes and specific personality traits in alcohol- and opiate-dependent patients.

The vulnerability of developing addictions is associated with genetic factors and personality traits. The predisposing genetic variants and personality traits may be common to all addictions or specific to a particular class of addiction. To investigate the relationship between genetic variances, personality traits, and their interactions in addiction are important. We recruited 175 opiate-dependent patients, 102 alcohol-dependent patients, and 111 healthy controls. All participants were diagnosed using DSM-IV criteria and assessed with Tridimensional Personality Questionnaire (TPQ). The dopamine D2 receptor (DRD2), 5-HTT-linked promoter region (5-HTTLPR), and aldehyde dehydrogenase 2 (ALDH2) genes were genotyped using PCR. The genotype frequency of the 5-HTTLPR and ALDH2 was significantly different between the patients and controls (P=0.013, P<0.001, respectively), and borderline significant (P=0.05) for DRD2 polymorphism. Both Novelty Seeking (NS) and Harm Avoidance (HA) scores were higher for patients (P<0.001). After stratification by candidate genes, addicts with ALDH2 *1/*1 interacting with the low-functional group of DRD2 and 5-HTTLPR genes have higher HA traits, whereas addicts with ALDH2 *1/*2 or *2/*2 and low-functional group of DRD2 and 5-HTTLPR genes have higher NS traits. We concluded that addicts, both alcohol- and opiate-dependent patients, have common genetic variants in DRD2 and 5-HTTLPR but specific for ALDH2. Higher NS and HA traits were found in both patient groups with the interaction with DRD2, 5-HTTLPR, and ALDH2 genes. The ALDH2 gene variants had different effect in the NS and HA dimension while the DRD2 and 5-HTTLPR genes did not.

Therapeutic effects of add-on low-dose dextromethorphan plus valproic acid in bipolar disorder

UNLABELLED 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.

Correlation of plasma brain-derived neurotrophic factor and metabolic profiles in drug-naïve patients with bipolar II disorder after a twelve-week pharmacological intervention

Brain‐derived neurotrophic factor (BDNF) is thought to be involved in the pathophysiology of bipolar disorder (BD) and metabolic syndrome. We investigated the correlation between plasma BDNF with mood symptoms and metabolic indices in patients with BD‐II over a 12‐week pharmacological intervention.

Interaction between serotonin transporter and serotonin receptor 1 B genes polymorphisms may be associated with antisocial alcoholism.

BackgroundSeveral studies have hypothesized that genes regulating the components of the serotonin system, including serotonin transporter (5-HTTLPR) and serotonin 1 B receptor (5-HT1B), may be associated with alcoholism, but their results are contradictory because of alcoholism’s heterogeneity. Therefore, we examined whether the 5-HTTLPR gene and 5-HT1B gene G861C polymorphism are susceptibility factors for a specific subtype of alcoholism, antisocial alcoholism in Han Chinese in Taiwan.MethodsWe recruited 273 Han Chinese male inmates with antisocial personality disorder (ASPD) [antisocial alcoholism (AS-ALC) group (n = 120) and antisocial non-alcoholism (AS-N-ALC) group (n = 153)] and 191 healthy male controls from the community. Genotyping was done using PCR-RFLP.ResultsThere were no significant differences in the genotypic frequency of the 5-HT1B G861C polymorphism between the 3 groups. Although AS-ALC group members more frequently carried the 5-HTTLPR S/S, S/LG, and LG/LG genotypes than controls, the difference became non-significant after controlling for the covarying effects of age. However, the 5-HTTLPR S/S, S/LG, and LG/LG genotypes may have interacted with the 5-HT1B G861C C/C polymorphism and increased the risk of becoming antisocial alcoholism.ConclusionOur study suggests that neither the 5-HTTLPR gene nor the 5-HT1B G861C polymorphism alone is a risk factor for antisocial alcoholism in Taiwan’s Han Chinese population, but that the interaction between both genes may increase susceptibility to antisocial alcoholism.

Role of DRD2 and ALDH2 genes in bipolar II disorder with and without comorbid anxiety disorder

The presence of comorbid anxiety disorders (AD) and bipolar II disorders (BP-II) compounds disability complicates treatment, worsens prognosis, and has been understudied. The genes involved in metabolizing dopamine and encoding dopamine receptors, such as aldehyde dehydrogenase 2 (ALDH2) and dopamine D2 receptor (DRD2) genes, may be important to the pathogenesis of BP-II comorbid with AD. We aimed to clarify ALDH2 and DRD2 genes for predisposition to BP-II comorbid with and without AD. The sample consisted of 335 subjects BP-II without AD, 127 subjects BP-II with AD and 348 healthy subjects as normal control. The genotypes of the ALDH2 and DRD2 Taq-IA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a statistically significant association between DRD2 Taq-I A1/A2 genotype and BP-II with AD (OR=2.231, P=0.021). Moreover, a significant interaction of the DRD2 Taq-I A1/A1 and the ALDH2*1*1 genotypes in BP-II without AD was revealed (OR=5.623, P=0.001) compared with normal control. Our findings support the hypothesis that a unique genetic distinction between BP-II with and without AD, and suggest a novel association between DRD2 Taq-I A1/A2 genotype and BP-II with AD. Our study also provides further evidence that the ALDH2 and DRD2 genes interact in BP-II, particularly BP-II without AD.

The ADH1B and DRD2 gene polymorphism may modify the protective effect of the ALDH2 gene against heroin dependence

Understanding the influences of genes involved in dopamine and serotonin metabolism, such as the aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) genes, is critical for understanding addictive behavior. In addition, dopamine D2 receptor (DRD2) gene may also interact with the dopamine metabolizing genes and link to addiction. Therefore, we investigated the association between the ALDH2, ADH1B and DRD2 polymorphisms and heroin dependence. Heroin-dependent Han Chinese patients (n=304) and healthy controls (n=335) were recruited. Genotypes of ALDH2, ADH1B and DRD2 polymorphisms were analyzed using a polymerase chain reaction with restriction fragment length polymorphism. The frequency of the ALDH2*1/*1 genotype was significantly lower in heroin-dependent patients than in controls, but the frequency of ADH1B and DRD2 genotypes was not significantly different. Further stratification of the ALDH2 gene with the ADH1B gene showed that the protective effect of ALDH2*1/*1 existed only in patients who also carried the ADH1B*1/*1 and ADH1B*1/*2 genotype. Logistic regression analysis showed a significant interaction between ALDH2 and ADH1B (P=0.022) and DRD2, ALDH2 and ADH1B in patients (P=0.037). The ALDH2*1/*1, ADH1B*1/*1, and ADH1B*1/*2 genotypes may interact and protect their carriers against heroin dependence and the protective effect may be varied by the DRD2 gene polymorphism. We conclude that the protective effect of the ALDH2 polymorphism against heroin dependence may be modified by the ADH1B and DRD2 polymorphism.