Combination of dextromethorphan and memantine in treating bipolar spectrum disorder: a 12-week double-blind randomized clinical trial.

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.

Add-On Memantine Treatment for Bipolar II Disorder Comorbid with Alcohol Dependence: A 12-Week Follow-Up Study.

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 valproic acid 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. METHODS: In a single-arm 12-week clinical trial, BD-II patients with comorbid alcohol dependence (n = 45) undergoing regular valproic acid treatments were given add-on memantine (5 mg/d). Symptom severity, alcohol use, cytokine (plasma tumor necrosis factor-α and C-reactive protein [CRP], transforming growth factor-ß1 [TGF-ß1], 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-ß1 level was significant (B = 0.003, p = 0.019). CONCLUSIONS: 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.

The COMT Val158Met Polymorphism Is Associated With Response to Add-on Dextromethorphan Treatment in Bipolar Disorder.

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.

The DRD3 Ser9Gly Polymorphism Predicted Metabolic Change in Drug-Naive Patients With Bipolar II Disorder.

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.

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.

Association of novelty seeking scores and striatal dopamine D2/D3 receptor availability of healthy volunteers: single photon emission computed tomography with ¹²³i-iodobenzamide.

It has been speculated that novelty seeking (NS) behavior is related to the dopaminergic system. Fifty-two subjects completed the Tridimensional Personality Questionnaire and underwent single photon emission computed tomography with (123)I-iodobenzamide. A marginally positive correlation was noted between NS and striatal dopamine D(2)/D(3) receptor availability (r = 0.25, p =0.07). A positive association was noted between the NS scores and left striatal D(2)/D(3) receptor availability (r= 0.29, p =0.04). The results suggest that a relationship might exist between NS score and dopaminergic activity.

A 64-week, multicenter, open-label study of aripiprazole effectiveness in the management of patients with schizophrenia or schizoaffective disorder in a general psychiatric outpatient setting.

OBJECTIVE: To evaluate the overall long-term effectiveness of aripiprazole in patients with schizophrenia in a general psychiatric practice setting in Taiwan. METHODS: This was a prospective, open-label, multicenter, post-market surveillance study in Taiwanese patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia or schizoaffective disorder requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled. Eligible patients were titrated to aripiprazole (5-30 mg/day) over a 12-week switching phase, during which their previous medication was discontinued. Patients could then enter a 52-week, long-term treatment phase. Aripiprazole was flexibly dosed (5-30 mg/day) at the discretion of the treating physicians. Efficacy was assessed using the Clinical Global Impression scale Improvement (CGI-I) score, the Clinical Global Impression scale Severity (CGI-S) score, The Brief Psychiatry Rating Scale (BPRS), and the Quality of Life (QOL) scale, as well as Preference of Medicine (POM) ratings by patients and caregivers. Safety and tolerability were also assessed. RESULTS: A total of 245 patients were enrolled and switched from their prior antipsychotic medications, and 153 patients entered the 52-week extension phase. In all, 79 patients (32.2%) completed the study. At week 64, the mean CGI-I score was 3.10 and 64.6% of patients who showed response. Compared to baseline, scores of CGI-S, QOL, and BPRS after 64 weeks of treatment also showed significant improvements. At week 12, 65.4% of subjects and 58.9% of caregivers rated aripiprazole as better than the prestudy medication on the POM. The most frequently reported adverse events (AEs) were headache, auditory hallucinations and insomnia. A total of 13 patients (5.3%) discontinued treatment due to AEs. No statistically significant changes were noted with respect to fasting plasma glucose, lipid profile, body weight, and body mass index after long-term treatment with aripiprazole. CONCLUSIONS: Although the discontinuation rate was high, aripiprazole was found to be effective, safe and well tolerated in the long-term treatment of Taiwanese patients with schizophrenia who continued to receive treatment for 64 weeks.

The association between the harm avoidance subscale of the Tridimensional Personality Questionnaire and serotonin transporter availability in the brainstem of male volunteers.

The relationship between harm avoidance scores of the Tridimensional Personality Questionnaire and serotonin transporter availability, as approximated using single photon emission computed tomography with [(123)I] ADAM, was examined. Our results showed a significant negative correlation between the harm avoidance total score, as well as the asthenia subscore, and serotonin transporter availability, particularly in males.

Age, gender, depression, and sexual dysfunction in Taiwan.

INTRODUCTION: The effects of age and gender on sexual function have attracted much attention in recent years, though few studies have focused on this issue in Asian populations. AIMS: The Changes in Sexual Functioning Questionnaire (CSFQ) was used to: (i) assess the differences in sexual functioning between unmedicated outpatients with depressive disorders and healthy volunteers; and (ii) investigate the influences of gender and age on sexual functioning in both groups. MAIN OUTCOME MEASURES: The CSFQ was used to assess sexual dysfunction. METHODS: Two groups of subjects, 73 unmedicated patients with depressive disorders and 116 healthy volunteers, were recruited to the study, and changes in their sexual function were assessed using the CSFQ. Subjects' global depressive level and psychiatric morbidity were assessed using the Taiwanese Depression Questionnaire (TDQ) and the Chinese Health Questionnaire (CHQ). RESULTS: The depressed subjects had significantly lower total CSFQ scores than did the controls. A negative correlation between age and total CSFQ score was found in both genders of depressed patients. Age generally predicted the sum of the CSFQ scores for both genders in the depressed group after controlling for TDQ score; however, a positive correlation between age and total CSFQ score was identified in the female controls. We also found that the S-curve was the best-fit curve for both the male and female controls, the cut-off point for which was the age of 40. CONCLUSIONS: Our study confirmed that, as a screening tool for clinically significant sexual dysfunction, the CSFQ offered good sensitivity for both the healthy and depressed subjects. In addition, our findings suggested that age and gender differences should be taken into account when measuring sexual satisfaction. It is possible that the age of 40 could be an anchor point in sexual functioning for the female population of Taiwan.

Association between serotonin transporter availability and overall rating scores of quality of life in healthy volunteers.

Depression and impaired quality of life (QOL) are frequently observed in patients suffering from a variety of diseases. In addition, it has been reported that an enhanced degradation of the serotonin precursor tryptophan may contribute to QOL deterioration in some diseases. However, it is unclear whether the correlation between the QOL scores and the central serotonergic tone is only mediated by the severity of either the depression symptoms or the physical illness itself. The present study examined the relationship between serotonin transporter (SERT) availability and life quality as measured by the World Health Organization Quality of Life brief version questionnaire (WHO-QOL) in healthy participants in order to exclude the influence of depressive mood and disease. The SERT availability in the midbrain was approximated using SPECT with [(123)I] ADAM ligand in fifty-eight healthy volunteers. The overall rating sub scores of the WHO-QOL correlated positively with serotonin transporter availability in the males. Central serotoninergic activity may play a role in the overall rating scores of the WHO-QOL.

The risk factors of Internet addiction--a survey of university freshmen.

This study was designed to explore the risk factors of Internet addiction in 1360 freshmen of the National Cheng Kung University in Taiwan in 2003. The test battery included a self-administrated structured questionnaire, the Chinese Internet Addiction Scale-Revision (CIAS-R), the 12-item Chinese Health Questionnaire (CHQ-12), the Measurement of Support Functions (MSF), and the neuroticism subscale of the Maudsley Personality Inventory (MPI). Of the total study population, there were 680 college freshmen (17.9%) in the Internet addiction group, as defined by high CIAS-R scores. Using logistic regression analyses, we found positive relationships between Internet addiction and male gender, neuroticism scores and the CHQ score. In addition, the freshmen who skipped breakfast and those who had poorer social support also had a higher probability of Internet addiction. Internet addiction is prevalent among university freshmen in Taiwan. Risk factors included male gender, habit of skipping breakfast, mental health morbidity, deficient social support; and neurotic personality characteristics.

The relationships between daily life events and the availabilities of serotonin transporters and dopamine transporters in healthy volunteers--a dual-isotope SPECT study.

The aim of this study was to examine the relationships between the daily life events and the availabilities of serotonin transporters (SERT) and dopamine transporters (DAT) in healthy volunteers. Thirty-seven volunteers, 19 males and 18 females, were recruited. The SERT availability was approximated using SPECT and [123I] ADAM while the DAT availability was approximated using SPECT and [99mTc] TRODAT-1. All participants completed the Recent Life Change Questionnaire. The results showed that SERT and DAT may be sensitive to the presence of stressful events.

Screening for bipolar disorder in medicated patients treated for unipolar depression in a psychiatric outpatient clinic using the Mood Disorder Questionnaire.

Objective. The aim of this study was to examine the rate of the misdiagnosis of bipolar disorder in outpatients who had been treated for unipolar depression with antidepressants in Taiwan and to verify the validity of the Mood Disorder Questionnaire (MDQ) in this population. Method. Fifty-three outpatients who had been treated for unipolar depression were recruited. All patients completed the MDQ and were administered the Structured Clinical Interview. The sensitivity and specificity were calculated for each possible MDQ symptom cut-off score relative to a Structured Clinical Interview diagnosis of bipolar spectrum disorder. Results. A total of 11.3% were diagnosed with bipolar spectrum disorder. The optimal model we found contained only the first portion of the MDQ with a cut-off score of 2. This model provided both good sensitivity (0.83) and specificity (0.53). Conclusion. The misdiagnosis of bipolar disorder as unipolar depression disorder is prevalent. Based on the results of the current study, the probability of bipolar disorder in depression outpatients who are in a mildly depressed state and score higher than 2 points in the first portion of the MDQ deserves to be investigated.

The reliability and validity of the Chinese version of the Modified Overt Aggression Scale.

Objective. Instruments to assess aggressive behaviors in the psychiatric ward are crucial for monitoring risky behaviors. The purpose of this study was to assess the validity and reliability of the Chinese version of the Modified Overt Aggression Scale (MOAS). Methods. We translated the English version of MOAS into Chinese. We interviewed and trained two volunteers to act as agitated patients in the seclusion room. One senior psychiatrist, experienced in using the MOAS, directed scenarios of different aggressive intensity and established the standard scores. The validity was assessed by comparing the other raters' scores with those of the director's. Inter-rater reliability was also assessed. Results. Inter-rater reliability, based on Intra-class correlation coefficient (ICC=0.94, P<0.001) and Kendall's W coefficient of concordance (W=0.83, P= 0.001), was high. The validity was assessed by the Mann-Whitney test. The results showed that the raters adequately differentiated (z=- 2.89, P= 0.002) between the above-average and below-average scores of the MOAS. Conclusion. The Chinese version of the MOAS has modest psychometric properties. The model, which used trained volunteers acting as patients and compared their scores with those of the director, may be used in further studies for developing psychometric instruments to assess abrupt behaviors.

Sexual dysfunction and physicians' perception in medicated patients with major depression in Taiwan.

Although prevalent during antidepressant treatment, sexual dysfunction (SD) is frequently ignored by both physicians and patients in Asia. In spite of impact of SD on medicated patients with major depression, sexual issues and illness remain a forbidden topic for most Asian people. The aims of this study were to: (1) estimate the prevalence of SD among stable outpatients taking different antidepressants in Taiwan; (2) investigate the factors related to SD; (3) compare physician-perceived with patient-reported prevalence rates of antidepressant-associated SD; and (4) study the differences of SD among antidepressant subgroups. In this cross-sectional observational study, 125 medicated patients with major depression were recruited. Patients were assessed using the Changes in Sexual Functioning Questionnaire (CSFQ), Taiwanese Depression Questionnaire (TDQ), Quality of Life Index (QOL), and neuroticism scores in the Maudsley Personality Inventory (MPI). Sixty-two physicians completed the Physician Antidepressant Experience Questionnaire. The estimated prevalence rate of SD was 53.6% (95% CI = 44.9-62.3%) in medicated patients with major depression. There were no significant differences in prevalence rate of SD among different antidepressants. The SD subgroup had poorer quality of life and lower moods than the non-dysfunction subgroup. An underestimation of the prevalence of SD by physicians was noted. Because antidepressant-associated SD is highly prevalent and seriously underestimated by physicians, greater physicians' recognition and better patients' education are imperative when prescribing antidepressants.

Association between serotonin transporter availability and hostility scores in healthy volunteers - a single photon emission computed tomography study with [(123)I] ADAM.

The present study examined the relationship between serotonin transporter (SERT) availability and hostility scores in healthy volunteers. SERT availability was measured by using SPECT with [(123)I] ADAM in 10 healthy participants. Hostility was measured with the Cook-Medley Hostility Scale. Hostile attribution, but not the other subscales of hostility, was negatively correlated with SERT availability. Central serotoninergic activities may play a role in hostility.

The relationship among insight, cognitive function of patients with schizophrenia and their relatives' perception.

Medically, insight is a multidimensional concept. Results of previous studies are inconclusive regarding the relationship between insight and global and cognitive functions. The aim of this study was to evaluate the relationship among insight, patients' global function, cognitive function of patients with schizophrenia and their key caregivers' perception about this disorder. Thirty-one patients with schizophrenia were recruited. Cognitive function such as memory index proved to be a significant predictor for patients' insight; environmental factors such as caregivers' perception was not. In addition to cognitive deficit, whether the other factors such as genetic variability, medication use, environmental factors, and illness severity, etc., could influence insight of patients will still be a controversial issue. Further multidimensional survey of the relationship with insight in a larger and comprehensive design is necessary.

Two case studies of hypothermia induced by an increased dosage of zotepine in a combination therapy.

The purpose of the present paper was to remind physicians that hypothermia is a possible side-effect of combining zotepine, valproate,and benzodiazepine. Two cases of hypothermia occurred after combining the use of zotepine, valproate, and benzodiazepine. The valproate was under therapeutic blood level when zotepine dosage was raised to 200 mg/day, and hypothermia occurred. The dosage of zotepine might constitute a positive correlation with hypothermia. The combination of zotepine, valproate or benzodiazepine may cause hypothermia as a side-effect.