Shiou Lan Chen

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

Background: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Methods: Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Results: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. Conclusions: We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT.

Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage.

BACKGROUND AND PURPOSE Prevention or disease‐modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimers disease, Parkinsons disease and Huntingtons disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinsons disease models.

Low-Dose Memantine Attenuated Morphine Addictive Behavior Through its Anti-Inflammation and Neurotrophic Effects in Rats

Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer’s disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2–1xa0mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6xa0days of morphine treatment, cytokine (IL-1β, IL-6) levels had significantly increased in serum; IL-1β and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects.

Microglial regulation of immunological and neuroprotective functions of astroglia

Microglia and astroglia play critical roles in the development, function, and survival of neurons in the CNS. However, under inflammatory conditions the role of astrogliosis in the inflammatory process and its effects on neurons remains unclear. Here, we used several types of cell cultures treated with the bacterial inflammogen LPS to address these questions. We found that the presence of astroglia reduced inflammation‐driven neurotoxicity, suggesting that astrogliosis is principally neuroprotective. Neutralization of supernatant glial cell line‐derived neurotrophic factor (GDNF) released from astroglia significantly reduced this neuroprotective effect during inflammation. To determine the immunological role of astroglia, we optimized a highly‐enriched astroglial culture protocol and demonstrated that LPS failed to induce the synthesis and release of TNF‐α and iNOS/NO. Instead we found significant enhancement of TNF‐α and iNOS expression in highly‐enriched astroglial cultures required the presence of 0.5–1% microglia, respectively. Thus suggesting that microglial‐astroglial interactions are required for LPS to induce the expression of pro‐inflammatory factors and GDNF from astroglia. Specifically, we found that microglia‐derived TNF‐α plays a pivotal role as a paracrine signal to regulate the neuroprotective functions of astrogliosis. Taken together, these findings suggest that astroglia may not possess the ability to directly recognize the innate immune stimuli LPS, but rather depend on crosstalk with microglia to elicit release of neurotrophic factors as a counterbalance to support neuronal survival from the collateral damage generated by activated microglia during neuroinflammation. GLIA 2015;63:118–131

The differential levels of inflammatory cytokines and bdnf among bipolar spectrum disorders

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<.001). Three of the 5 measured biomarkers (tumor necrosis factor-α, transforming growth factor-β1, and interleukin-8) were significantly (P=.006, .01, and <.001) higher in all bipolar disorder patients than in controls. Moreover, covarying for multiple associated confounders showed that bipolar I disorder patients had significantly higher IL-8 levels than did bipolar II disorder and other specified bipolar disorder with short duration hypomania patients in multivariate analysis of covariance (P=.03) and linear regression (P=.02) analyses. Biomarkers differences between bipolar II disorder and other specified bipolar disorder with short duration hypomania patients were nonsignificant. Conclusion: The immunological disturbance along the bipolar spectrum was most severe in bipolar I disorder patients. Other specified bipolar disorder with short duration hypomania patients and bipolar II disorder patients did not differ in these biological markers.

The DRD2/ANKK1 gene is associated with response to add-on dextromethorphan treatment in bipolar disorder

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.

Interaction between ALDH2*1*1 and DRD2/ANKK1 TaqI A1A1 genes may be associated with antisocial personality disorder not co-morbid with alcoholism

Previous studies on acetaldehyde dehydrogenase 2 (ALDH2) focused on drinking behavior or alcoholism because the ALDH2*2 allele protects against the risk of developing alcoholism. The mechanism provides that the ALDH2 genes protective effect is also involved in dopamine metabolism. The interaction of the ALDH2 gene with neurotransmitters, such as dopamine, is suggested to be related to alcoholism. Because alcoholism is often co‐morbid with antisocial personality disorder (ASPD), previous association studies on antisocial alcoholism cannot differentiate whether those genes relate to ASPD with alcoholism or ASPD only. This study examined the influence of the interaction effect of the ALDH2*1*1, *1*2 or *2*2 polymorphisms with the dopamine 2 receptor (DRD2) Taq I polymorphism on ASPD. Our 541 Han Chinese male participants were classified into three groups: antisocial alcoholism (ASPD co‐morbid with alcohol dependence, antisocial ALC; nu2003=u2003133), ASPD without alcoholism (ASPD not co‐morbid with alcohol dependence, antisocial non‐ALC; nu2003=u2003164) and community controls (healthy volunteers from the community; nu2003=u2003244). Compared with healthy controls, individuals with the DRD2 A1/A1 and the ALDH2*1/*1 genotypes were at a 5.39 times greater risk for antisocial non‐ALC than were those with other genotypes. Our results suggest that the DRD2/ANKK1 and ALDH2 genes interacted in the antisocial non‐ALC group; a connection neglected in previous studies caused by not separating antisocial ALC from ASPD. Our study made this distinction and showed that these two genes may be associated ASPD without co‐morbid alcoholism.

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.

The interaction between BDNF and DRD2 in Bipolar II disorder but not in bipolar i disorder

Bipolar I (BP‐I) and bipolar II (BP‐II) disorders are the two most common subtypes of bipolar disorder. However, most studies have not differentiated bipolar disorder into BP‐I and BP‐II groups, for which the underlying etiology differentiating these two subtypes remains unclear. The genetic association between both subtypes is essential for improving our understanding. The dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1), one of the dopaminergic pathways, as well as the brain‐derived neurotrophic factor (BDNF) gene, were reported as candidate genes in the etiology of bipolar disorder. Therefore, we examined the contribution of the BDNF and DRD2/ANKK1 genes and their interaction to the differentiation of BP‐I and BP‐II. Seven hundred ninety‐two participants were recruited: 208 with BP‐I, 329 with BP‐II, and 255 healthy controls. The genotypes of the BDNF and DRD2/ANKK1 Taq1A polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. A significant main effect for the Val/Val genotype of the BDNF Val66Met polymorphism predicted BP‐II patients. The significant interaction effect for the Val/Val genotype of the BDNF Val66Met polymorphism and A1/A2 genotype of DRD2/ANKK1 Taq1A polymorphism was found only in BP‐II patients. We provide initial evidence that the BDNF Val66Me and DRD2/ANKK1 Taq1A polymorphisms interact only in BP‐II disorder and that BP‐I and BP‐II are genetically distinct.

The effect of comorbid anxiety disorder on neuropsychological function in bipolar II disorder

OBJECTIVESnBipolar disorder (BP) is often comorbid with anxiety disorder (ANX), especially in bipolar II disorder (BP-II). BP patients with comorbid ANX often manifest intensified symptoms and harmful dysfunctions. However, most studies have focused on bipolar I disorder (BP-I); few have investigated the effect of comorbid ANX on the neuropsychological function of BP-II patients. We examined neuropsychological functions in BP-II patients with and without comorbid ANX.nnnMETHODSnFifty-nine participants were recruited: 20 patients with interepisode (symptom-free) BP-II without comorbid ANX, 20 with interepisode BP-II with comorbid ANX, and 19 healthy controls. All participants were screened using the Chinese version of the Modified Schedule of Affective Disorder and Schizophrenia-Lifetime (SADS-L). Individuals comorbid with major or minor mental illness other than BP-II were excluded. Comparisons were made between the three groups using neuropsychological tests to assess memory, attention, psychomotor speed, and frontal executive function.nnnRESULTSnBP-II patients with comorbid ANX showed poorer neuropsychological functions than those in the BP-II-only and control groups. Additionally, BP-II-only patients and controls showed equal cognitive performance.nnnCONCLUSIONSnBecause BP-II patients with comorbid ANX had the lowest scores in the majority of neuropsychological functional tests, we conclude that they have greater cognitive impairments than do BP-II patients without comorbid ANX. Neuropsychological dysfunctions seemed more strongly associated with ANX than with BP-II in interepisode periods. Identifying and managing ANX comorbidity is critical when treating BP-II patients.