Sheng-Yu Lee

Neuropsychological functions in patients with bipolar I and bipolar II disorder

UNLABELLED The literature reports persistent cognitive impairments in patients with bipolar disorder even after prolonged remission. However, a majority of studies have focused only on bipolar I disorder (BP-I), primarily because bipolar II disorder (BP-II) is often underdiagnosed or misdiagnosed. More attention should be paid to the differences between BP-I and BP-II, especially the aspects of neuropsychological functioning. We examined the different neuropsychological functions in BP-I and BP-II patients and compared them with those of healthy controls. METHODS The study included 67 patients with interepisode bipolar disorder (BP-I: n = 30; BP-II: n = 37) and 22 healthy controls compared using a battery of neuropsychological tests that assessed memory, psychomotor speed, and certain aspects of frontal executive function. RESULTS The BP-I group performed poorly on verbal memory, psychomotor speed, and executive function compared to the BP-II and control groups. Both bipolar groups performed significantly less well than the control group on measures of working memory and psychomotor speed, while the BP-II group showed an intermediate level of performance in psychomotor speed compared to the BP-I and control groups. There was no difference between the groups on visual memory. CONCLUSIONS BP-I was characterized by reduced performance in verbal memory, working memory, psychomotor speed, and executive function, while BP-II patients showed a reduction only in working memory and psychomotor speed. Cognitive impairment existed in both subtypes of bipolar disorder, and was greater in BP-I patients. Rehabilitation interventions should take into account potential cognitive differences between these bipolar subtypes.

Availability of dopamine and serotonin transporters in opioid-dependent users—a two-isotope SPECT study

Rationale and objectiveThe aims of this study were to examine the differences between 32 opioid-dependent users treated with a very low dose of methadone or undergoing methadone-free abstinence and 32 controls.MethodsSPECT analysis using [99mTc] TRODAT-1 to assess striatal dopamine transporter (DAT) availability and [123I] ADAM to assess midbrain serotonin transporter (SERT) availability were performed.ResultsLower striatal DAT and midbrain SERT availabilities were noted in low-dose methadone users. History of metamphatamine use was associated with the lower striatal DAT. The striatal DAT of methadone-free abstainers was also lower than controls. The midbrain SERT availability tended to be higher in the methadone-free abstainers than the low-dose methadone users. The severity of depressive symptoms was negatively correlated with midbrain SERT availability in the opioid users.ConclusionThe availability of striatal DAT tended to be, and the availability of midbrain SERT was, lower in the opioid users. History of metamphatamine use may confound the difference in straital DAT between controls and opioid users, as midbrain SERT and depressive symptoms are also associated with opioid use and abstinence.

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.

The ALDH2 and DRD2/ANKK1 genes interacted in bipolar II but not bipolar I disorder

Aim Clarifying the association between bipolar I and bipolar II, the two most common subtypes of bipolar disorder, at the genetic level is essential for improving our understanding of these disorders. The dopaminergic system has been implicated in the pathogenesis of bipolar disorder. It may be important to investigate 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. We examined the association of the ALDH2 and DRD2/ANKK1 Taq IA polymorphisms with bipolar I and II disorders and possible interactions between these genes. Methods Seven hundred and fifty participants were recruited: 207 with bipolar I disorder, 277 with bipolar II disorder, and 266 healthy controls. The genotypes of the ALDH2 and DRD2/ANKK1 TaqIA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Results Logistic regression analysis showed a statistically significant interaction for the A1/A1 genotype of the DRD2/ANKK1 TaqIA, and the ALDH2*1*1 genotypes (P=0.009) could predict bipolar II patients compared with individuals without bipolar disorder. However, there was no association between the ALDH2 or DRD2/ANKK1 gene with neither bipolar I nor bipolar II disorder. Conclusion Our findings may provide initial evidence that the ALDH2 and DRD2/ANKK1 genes interact in specific subtypes of bipolar disorders. Our findings also suggest a unique genetic distinction between bipolar I and bipolar II disorders.

Neuropsychological functions in Han Chinese patients in Taiwan with bipolar II disorder comorbid and not comorbid with alcohol abuse/alcohol dependence disorder

OBJECTIVE Studies exploring neuropsychological functions of bipolar disorder (BP) specifically include patients comorbid with alcohol abuse (AB), alcohol dependence (AD), or both (AB/AD). Contradictory assessments of neuropsychological impairment may be caused by not excluding the confounding effects of comorbid AB/AD. Most of the literature discusses BP without subtyping, which overlooks that BP-II may be a valid diagnosis different from BP-I. Because neuropsychological functions are involved in overall BP-II outcomes, we hypothesized that the neuropsychological functions of patients with BP-II comorbid with AD (BP(+AD)) are significantly different from and more impaired than those of patients with BP-II not comorbid with AD (BP(-AD)). METHODS Using DSM-IV criteria, the study included 69 patients with BP-II (19 with BP(+AD); 28 with BP(-AD)) and 22 healthy controls compared using a battery of neuropsychological tests that assessed memory, psychomotor speed, and certain aspects of frontal executive function. All BP-II patients were in an inter-episode period (a period of remission between states of mania, hypomania, and depression). RESULTS BP(+AD) patients had lower scores than did BP(-AD) patients and controls in verbal memory, visual memory, attention, psychomotor speed, and executive function. Working memory was poorer for BP(+AD) than BP(-AD) patients and for both BP groups than for controls. CONCLUSIONS BP(+AD) patients manifested wide neuropsychological dysfunctions, and BP(-AD) patients showed a reduction in working memory, which suggested that working memory might be related to a history of BP-II. Neuropsychological dysfunctions seemed more strongly associated with AB/AD than with BP-II in inter-episode periods.

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.

The COMT and DRD3 genes interacted in bipolar I but not bipolar II disorder

Abstract Objectives. Clarifying the association between bipolar I and bipolar II disorders at the genetic level is essential for improving our understanding of them. In this study, we evaluated the hypothesis that the dopaminergic polymorphisms are risk factors for bipolar disorders. We examined the association between the catechol-O-methyltransferase (COMT) Val158Met and dopamine D3 receptor (DRD3) Ser9Gly polymorphisms and bipolar I and II disorders, as well as possible interactions between these genes. Methods. Seven hundred and eleven participants were recruited: 205 with bipolar I, 270 with bipolar II, and 236 healthy controls. The genotypes of the COMT Val158Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Results. Logistic regression analyses showed a statistically significant main effect for the Met/Met genotype of the COMT Val158Met polymorphism (P=0.032) and a significant interaction effect for the Met/Met genotype of the COMT Val158Met and Ser/Ser genotypes of the DRD3 Ser9Gly polymorphism (P=0.001) predicted bipolar I patients. However, there was no association between the COMT Val158Met or DRD3 Ser9Gly and bipolar II. Conclusions. We provide initial evidence that the COMT Val158Met and DRD3 Ser9Gly genotypes interact in bipolar I and bipolar II disorders and that bipolar I and bipolar II are genetically distinct.

The effects of add-on low-dose memantine on cytokine levels in bipolar II depression: a 12-week double-blind, randomized controlled trial.

Abstract 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 &agr; (TNF-&agr;), 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 &agr; 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-&agr; (P = 0.005) level changes. Treating bipolar II depression with VPA + memantine may improve the plasma TNF-&agr; level. However, adding-on memantine may not improve clinical symptoms or cytokine levels other than TNF-&agr;. Clinical symptoms may be correlated with certain cytokines.

MAOA interacts with the ALDH2 gene in anxiety-depression alcohol dependence.

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.