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Objective: Prior early prediction models for antipsychotic treatment response demonstrate good specificity but poor sensitivity (i.e., high false-negative rates). The purpose of this study was to refine the early prediction model in schizophrenia patients taking an atypical antipsychotic agent, zotepine. Method: 135 acutely ill inpatients with DSM-IV-defined schizophrenia received 4 weeks of 150 mg/day zotepine treatment. Psychopathology severity was assessed weekly with the Brief Psychiatric Rating Scale (BPRS) and subscales for positive, negative, and general symptoms. Clinical response was defined as a reduction of 20% or more in the BPRS total score at week 4. A logistic regression model was used to obtain early predictors. The receiver operating characteristic curve was employed to determine the optimal cutoff points of the variables for predicting response. The study was conducted from June 2004 to April 2005. Results: The most significant early predictors for ultimate response at week 4 were BPRS positive subscale score changes at week 1 and, better, at week 2 (p

The DNA-repair gene X-ray repair cross-complementing group 3 (XRCC3) is important in DNA double-strand break repair and plays a critical part in initiation of carcinogenesis. Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype with no existing gene-targeting drugs and little knowledge on its genetic etiology. This study aimed to investigate the contribution of the XRCC3 genotype to individual TNBC susceptibility.A total of 2,464 Taiwan citizens consisting of 1,232 breast cancer cases and 1,232 controls were enrolled in this case-control study, and genotyping of XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539 and rs28903081 were performed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We also conducted risk-stratified sub-group analyses to determine the association between the genotype and age- and hormone-related characteristics of breast cancer sub-groups.There was no significant difference between breast cancer and control groups in the distributions of the genotypic or allelic frequencies as for the XRCC3 rs1799794 (p=0.5195 and 0.9545), rs45603942 (p=0.3478 and 0.1449), rs861530 (p=0.4567 and 0.5081), rs3212057 (p=1.0000 and 1.0000), rs1799796 (p=0.8487 and 0.7315) and rs28903081 (p=1.0000 and 1.0000), respectively. However, the XRCC3 rs861539 TT genotype was more prevalent in patients with breast cancer [odds ratio (OR)=2.99, 95% confidence interval (CI)=1.62-5.55; p=0.0002], and especially among those who were younger than 55 years (OR=2.61, 95% CI=1.82-3.73; p=0.0001), with first menarche earlier than 12.2 years (OR=2.47, 95% CI=1.74-3.52; p=0.0001), with menopause at 49.0 years old or later (OR=2.53, 95% CI=1.76-3.62; p=0.0001), or with TNBC (OR=2.05, 95% CI=1.46-4.28; p=4.63*10(-4)).XRCC3 rs861539 TT is a potential predictive marker for TNBC in Taiwanese women and investigations in other populations are warranted for further universal application in cancer detection and prediction.

// Chia-Min Chung 1, 2 , Tzer-Min Kuo 1 , Shang-Lun Chiang 1, 3 , Zhi-Hong Wang 1 , Chung-Chieh Hung 2, 4 , Hsien-Yuan Lane 2, 4 , Chiu-Shong Liu 5 , Ying-Chin Ko 1, 2 1 Environment-Omics-Disease Research Center, China Medical University Hospital, Taichung, Taiwan 2 Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan 3 Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan 4 Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan 5 Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan Correspondence to: Ying-Chin Ko, e-mail: ycko0406@gmail.com Keywords: oral cancer, antidepressants, cohort Received: September 08, 2015 Accepted: January 20, 2016 Published: January 28, 2016 ABSTRACT Objectives: Several studies suggested that antidepressant use may increase or decrease the risk of cancer occurrence, depending on specific cancer types. The possible carcinogenic effect of antidepressants has received substantial attention; however, evidence remains inconclusive. Here we investigated associations between the use of antidepressants and occurrences of oral cancer (OC). Methods: Two million samples were randomly collected from the National Health Insurance Research Database in Taiwan, which covers 98% of the total population (23 million). All patients from2000 to 2009 were followed up. We identified 5103 patients newly diagnosed with OC after antidepressants use in addition to 20,412 non-OC matched subjects and 95,452 unmatched non-OC subjects. Results: In nested case control analysis, factors associating with OC, including age [OR = 1.02; 95% confidence interval (CI) = 1.01–1.03) and male (OR = 5.30; 95% CI = 4.92–5.70) were independently associated with increased risk of OC. Based on the functions of antidepressants, antidepressants treatment medications were further classified to investigate risk of OC. Selective serotonin reuptake inhibitors (OR = 0.61; 95% CI = 0.53–0.70) and tricyclic antidepressants (OR = 0.57; 95% CI = 0.52–0.63) were associated with reduced risk of OC. The risk of developing OC among subjects taking antidepressants was less than 26% [hazard ratio (HR) =0.74; 95% CI = 0.68–0.81] in prospective cohort study. The effect of a cumulative duration and dose was a significantly reduced risk of OC. Conclusions: The association between antidepressant use and decreasing OC risk were demonstrated by both prospective and nested case–control studies.

Although it is well known that valproic acid (VPA) can induce hyperammonemia [1], few reports have been concerned with its relationship to hypothyroidism. Here we present a bipolar disorder patient with hypothyroidism (in fact, merely subclinical hypothyroidism) who experienced hyperammonemic delirium during VPA treatment.

A large number of patients with neurosyphilis present dementia with a progressive course and psychiatric symptoms such as depression, mania, and psychosis. Despite prompt and proper antibiotic treatment, the recovery is often incomplete, especially when tissue damage has occurred. We reported a patient with persisted cognitive decline associated with neurosyphilis that improved substantially after donepezil therapy. A 43-year-old man manifested significant psychiatric symptoms such as mania, psychosis, and cognitive impairment due to neurosyphilis. Subsequently, the patient was treated with antipsychotics and donepezil concurrent with an adequate antibiotic treatment for neurosyphilis. During the 1-year follow-up, his rapid plasma reagin titer approached from 1:256 to 1:64. His Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale scores improved from 12 to 25 and 42.3 to 6.3, respectively, after a 6-month donepezil treatment. Donepezil was discontinued. Three months later, worsening of cognitive impairment (MMSE score, 23) was noted. After donepezil was started again for 3 months, his MMSE score improved to 26. Persistent cognitive impairment is commonly associated with neurosyphilis despite adequate penicillin treatment. Treatment of the cognitive impairment is important but difficult. Cholinergic pathways are considered as involving in the cognitive deficit induced by neurosyphilis and donepezil, a cholinesterase inhibitor, which may be useful for the improvement of cognition. In this case report, we described for the first time the successful use of donepezil in treating cognitive impairment associated with neurosyphilis. The role of cholinesterase inhibitors in the treatment of cognitive impairments caused by neurosyphilis needs further studies.

Background Few studies have investigated the relationship between the use of different generations of antipsychotics and mortality with contradictory results. The aim of this study is to compare mortality among patients suffering schizophrenia taking different generations of antipsychotics in a nationwide population-based cohort study in Taiwan. Methods A total of 812 patients suffering newly diagnosed schizophrenia under monotherapy of second generation antipsychotics (SGAs) comprised the group of cases. The matched controls were under monotherapy of first generation antipsychotics (FGAs). Each case was matched individually with their initial antipsychotics prescription calendar year and month, gender, and age. Cox regression analyses were applied to estimate survival time, adjusting for gender, age, residence, insurance premium, Charlson comorbidity index, hospital admission days, and hospital admission times. An analysis including the number of antipsychotic prescriptions, a proxy indicator of adherence, into the fully adjusted model to reveal the effect of adherence on survival of patients served as a sensitivity analysis. Results Subjects receiving SGAs had lower admission times and inpatient days, more antipsychotic prescriptions, and longer follow-up time than FGAs. Compared with the FGAs group, the adjusted hazard ratio of mortality was 0.58 (95% confidence interval = 0.34–0.96, p = .034) for SGAs group. After controlling for the number of antipsychotic prescriptions, the difference in mortality between antipsychotic generations was non-significant. Conclusions The results of this study suggest that SGAs were better than FGAs in mortality among patients suffering schizophrenia. The difference in mortality can be explained by the better medication adherence of SGAs.

Background: Screening for the schizotypal personality trait is one strategy to identify people whomay be susceptible to early psychosis or be at high risk for prodromal psychosis. The Schizotypal Personality Questionnaire-Brief (SPQ-B) has been widely used to assess the schizotypal personality and has been translated into Chinese. However, the psychometric properties of the Chinese-version scale have yet to be evaluated. Purpose: This study evaluates the construct validity of the Chinese-version SPQ-B on a sample ofmale and female undergraduate students in Taiwan. Methods: A cross-sectional design with convenient sampling was used for this study. The data were collected using the Chineseversion SPQ-B between October 2008 and June 2009. Participants included 513 male and 675 female undergraduate students in Taiwan. The factor construct validity of the scale was examined by confirmatory factor analysis using structural equation modeling with SPSS AMOS version 17 software. Results: The results show that the three-factor model fits the data better than the one-factormodel for both male and female participants. The male participants scored significantly higher than their female counterparts in terms of total scale, interpersonal subscales, and disorganized subscales. Conclusions/Implications for Practice: The Chinese version of the SPQ-B adequately achieves three-factor construct validity for undergraduate students. The scalemay be used to screen for the schizotypal personality trait in both male and female college students to identify those at an elevated risk for mental illness.

Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Doctors must prescribe antidepressants based on educated guesses due to the fact that it is unmanageable to predict the effectiveness of any particular antidepressant in an individual patient. With the recent advent of scientific research, the genome-wide association study (GWAS) is extensively employed to analyze hundreds of thousands of single nucleotide polymorphisms by high-throughput genotyping technologies. In addition to the candidate-gene approach, the GWAS approach has recently been utilized to investigate the determinants of antidepressant response to therapy. In this study, we reviewed GWAS studies, their limitations and future directions with respect to the pharmacogenomics of antidepressants in MDD.

Schizophrenia is an illness that impairs a person's social cognition. The Mayer Salovey Caruso Emotional Intelligence Test (MSCEIT) is the most well-known test used to measure emotional intelligence (EI), which is a major component of social cognition. Given the absence of EI ability-based scales adapted to Chinese speakers, we translated the MSCEIT into a Traditional Chinese version (MSCEIT-TC) and validated this scale for use in schizophrenia studies. The specific aims were to validate the MSCEIT-TC, to develop a norm for the MSCEIT-TC, and use this norm to explore the EI performance of schizophrenic individuals. We included in our study seven hundred twenty-eight healthy controls and seventy-six individuals with schizophrenia. The results suggest that the MSCEIT-TC is reliable and valid when assessing EI. The results showed good discrimination and validity when comparing the two study groups. Impairment was the greatest for two branches Understanding and Managing Emotions, which implies that the deficits of schizophrenia individuals involve ToM (theory of mind) tasks. Deficits involving the negative scale of schizophrenia was related to impaired performance when the MSCEIT-TC was used (in branch 2, 3, 4, and the area Strategic). Our findings suggest that the MSCEIT-TC can be used for emotional studies in healthy Chinese and in clinical setting for investigating schizophrenic individuals.

Objective: Researchers, by studying first-generation antipsychotics, have established an early prediction model, which had a favorable specificity but a low sensitivity. This study aims to optimize early prediction of treatment response for schizophrenia using a novel statistic method that can be done even under the Microsoft Excel system of a personal computer. Methods: One hundred twenty-three inpatients with acutely exacerbated schizophrenia were given optimal therapy of risperidone, a commonly used second-generation antipsychotic agent. Response was defined as a reduction of 20% or more in the Positive and Negative Syndrome Scale total score. We applied the generalized estimating equation method's logistic regression to establish an early prediction model based on the treatment results of the first and the second weeks. Results: The proposed method correctly predicted nonresponse at 4 and 6 weeks in 80.8% and 81.8% of the patients, respectively. The method also identified responder at 4 and 6 weeks in 80.0% and 82.8%, respectively. The predictive powers (or correct prediction rates) at 4 and 6 weeks were 80.3% and 82.4%, respectively. In addition, the results based on the responses in Positive and Negative Syndrome Scale scores were slightly better than those in Brief Psychiatric Rating Scale scores. Conclusions: Using the first 2 weeks' treatment results to predict the fourth or sixth week's treatment response is acceptable in terms of specificity, sensitivity, and predictive power. Further studies are needed. Moreover, whether this model could be applied to establish a prediction system for other psychotropics, such as antidepressants, also deserves research.

Objective: Glutamate decarboxylase (GAD), the rate-limiting enzyme in the synthesis of γ-aminobutyric acid (GABA), may be involved in the development of alcoholism. This study examined the possible roles of the genes that code for 2 forms of GAD (GAD1 and GAD2) in the development of alcoholism. Method: An association study was conducted among 140 male alcoholic subjects meeting the DSM-III-R criteria for alcohol dependence and 146 controls recruited from the Han Taiwanese in community and clinical settings. Psychiatric assessment of drinking conditions was conducted using a Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry. The SHEsis and Haploview programs were used in statistical analyses. Results: Nine single-nucleotide polymorphisms (SNPs) at the GAD1 gene were valid for further statistics. Between alcoholic subjects and controls, significant differences were found in genotype distributions of SNP1 (p=0.000), SNP2 (p=0.015), SNP4 (p=0.015), SNP5 (p=0.031), SNP6 (p=0.012), and SNP8 (p=0.004) and in allele distributions of SNP1 (p=0.001), SNP2 (p=0.009), and SNP8 (p=0.009). Permutation tests of SNP1, SNP2, and SNP8 demonstrated significant differences in allele frequencies but not in 2 major haplotype blocks. Three valid SNPs at the GAD2 gene demonstrated no associations with alcoholism. Further permutation tests in the only 1 haplotype block or individual SNPs demonstrated no significant differences. Conclusions: This is the first report indicating a possible significant role of the GAD1 gene in the development of alcohol dependence and/or the course of alcohol withdrawal and outcome of alcoholism.

Background Agonists at the N-methyl-D-aspartate (NMDA)-glycine site (D-serine, glycine, D-alanine and D-cycloserine) and glycine transporter-1 (GlyT-1) inhibitor (N-methylglycine, or called sarcosine) both improve the symptoms of stable chronic schizophrenia patients receiving concurrent antipsychotics. Previous studies, however, found no advantage of D-serine, glycine, or D-cycloserine added to clozapine. The present study aims to determine the effects of sarcosine adjuvant therapy for schizophrenic patients receiving clozapine treatment. Methods Twenty schizophrenic inpatients enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/day) which was added to their stable doses of clozapine. Measures of clinical efficacy and side-effects were determined every other week. Results Sarcosine produced no greater improvement when co-administered with clozapine than placebo plus clozapine at weeks 2, 4, and 6. Sarcosine was well tolerated and no significant side-effect was noted. Conclusions Unlike patients treated with other antipsychotics, patients who received clozapine treatment exhibit no improvement by adding sarcosine or agonists at the NMDA-glycine site. Clozapine possesses particular efficacy, possibly related to potentiation of NMDA-mediated neurotransmission. This may contribute to the clozapine’s unique clinical efficacy and refractoriness to the addition of NMDA-enhancing agents.

Electroacupuncture (EA) is widely used to treat disorders of the nervous system, such as stroke. The aim of the present study was to investigate the effect of EA on cerebral blood flow (CBF) in cerebral ischemic rats. We developed an animal model of cerebral ischemia (CI) by occluding the blood flow of both common carotid arteries in Sprague-Dawley (SD) rats; 2 or 15 Hz EA was applied to both Zusanli acupoints. The levels of nitric oxide (NO) in the peripheral blood and amounts of calcitonin gene-related peptide (CGRP) in the cerebral cortex and thalamus were measured. In addition, L-N (G)-nitro arginine methyl ester (L-NAME) was used to measure the changes in CBF induced by EA in rats with and without CI. The results indicated that both 2 and 15 Hz EA increase the mean CBF in rats with and without CI. However, neither 2 nor 15 Hz EA induced changes in levels of NO in peripheral blood or changes in CGRP levels in cerebral cortex and thalamus. In addition, L-NAME did not change the increase in CBF. We concluded that both 2 and 15 Hz EA at both Zusanli acupoints induced the increase of CBF in rats with and without CI. Whether the effect of EA is related to NO or CGRP will be investigated in a future study.

Background: Polymorphisms within intron 7 of the tryptophan hydroxylase (TPH1) gene were found to be associated with alcohol dependence in different ethnic groups, including the aboriginal Bunun group in Taiwan. This study aimed to identify genetic variants at the TPH1 locus and to examine their associations with alcoholism. We hypothesized that the polymorphism of TPH1 gene is functional and influences the human circadian rhythm to contribute to the pathophysiology of alcohol dependence. Methods: DNA from the Taiwanese Han and Bunun was subjected to sequence for screening genetic variation in the coding and promoter regions of the TPH1 locus. Polymorphisms among individuals with alcohol dependence and control subjects in two ethnic groups in Taiwan were investigated. Results: Three variants in the TPH1 promoter region were identified, and the markers are in complete linkage disequilibrium in both populations. Positive associations at both allelic and genotypic levels were obtained between case and control groups in the Bunun. Expression studies demonstrated that the variants indeed affected reporter gene activity in human choriocarcinoma and colon adenocarcinoma cell lines. Conclusions: Polymorphisms in the promoter region may influence the function of the TPH1 gene and further influence the proclivity of alcohol dependence in one ethnic group in Taiwan. The associations between TPH1 genotypes and alcoholism may deserve further investigation.

BACKGROUND Adjunctive fluvoxamine inhibits clozapine metabolism and decreases plasma norclozapine (a toxic metabolite of clozapine) to clozapine ratios. This study aimed to demonstrate the effects of fluvoxamine on clozapine-related weight gain, hyperglycemia, and lipid abnormalities. METHOD Sixty-eight treatment-resistant inpatients with a DSM-IV diagnosis of schizophrenia were randomly assigned to 2 treatment groups for 12 weeks. The monotherapy group (N = 34) received clozapine (< or = 600 mg/day). The coadministration group (N = 34) received fluvoxamine (50 mg/day) plus low-dose clozapine (< or = 250 mg/day). The study was conducted from August 1999 to October 2002. RESULTS The 2 groups were similar in demographic data; baseline body weight and body mass index (BMI); baseline serum glucose, triglyceride, and cholesterol levels; and steady-state plasma clozapine concentration. The monotherapy patients (but not the coadministration patients) had significantly higher (p < .05) body weight, BMI, and serum glucose and triglyceride levels after treatment than at baseline. At week 12, the monotherapy patients also had significantly higher glucose (p = .035), triglyceride (p = .041), and norclozapine (p = .009) (and numerically higher cholesterol) levels than the cotreatment patients. The changes in weight and serum glucose and triglyceride levels were significantly correlated (p = .026, p = .005, and p = .028, respectively) with the plasma concentration of norclozapine but not with plasma levels of clozapine. CONCLUSION These results suggest that fluvoxamine cotreatment can attenuate weight gain and metabolic disturbances in clozapine-treated patients. Plasma levels of norclozapine, but not clozapine, are associated with increases in weight and serum glucose and triglyceride levels. Of note, coadministration of fluvoxamine could increase plasma clozapine levels markedly and carry the risk of adverse events. If this combined treatment is applied, conservative introduction with reduced clozapine dosage and careful therapeutic drug monitoring of clozapine concentration is recommended.

Background Hypofunction of N-methyl-D-aspartate glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine or glycine, endogenous full agonists of the glycine site of N-methyl-D-aspartate receptor, or D-cycloserine, a partial agonist, improve the symptoms of schizophrenia. N-methylglycine (sarcosine) is an endogenous antagonist of glycine transporter-1, which potentiates glycine's action on N-methyl-D-aspartate glycine site and can have beneficial effects on schizophrenia. Methods Thirty-eight schizophrenic patients were enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/d), which was added to their stable antipsychotic regimens. Twenty of them received risperidone. Measures of clinical efficacy and side effects were determined every other week. Results Patient who received sarcosine treatment revealed significant improvements in their positive, negative, cognitive, and general psychiatric symptoms. Similar therapeutic effects were observed when only risperidone-treated patients were analyzed. Sarcosine was well-tolerated, and no significant side effect was noted. Conclusions Sarcosine treatment can benefit schizophrenic patients treated by antipsychotics including risperidone. The significant improvement with the sarcosine further supports the hypothesis of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Glycine transporter-1 is a novel target for the pharmacotherapy to enhance N-methyl-D-aspartate function.

There is strong evidence to suggest that genetic variation plays an important role in inter-individual differences in medication response and toxicity. Most of the previous pharmacogenetic studies, however, cannot be reconfirmed. Of note, drug efficacy or side effects depend not only on genetic factors but also on nongenetic factors, such as illness duration, past treatment history, and drug dosage or blood concentration. However, most pharmacogeneticists did not consider or control the possible impact of the nongenetic factors. Schizophrenia is a severe neuropsychiatric disorder with a polygenic mode of inheritance that is also governed by nongenetic factors. Schizophrenia's symptoms are principally subdivided into two subtypes, positive and negative. The positive symptoms include delusions and hallucinations; the negative symptoms, blunted affect and social withdrawal. Atypical antipsychotics are usually superior in the treatment of negative symptoms than typical agents. Although atypical agents are becoming the mainstay for schizophrenia treatment, what makes an antipsychotic “atypical” remains unclear. One of our recent studies have simultaneously evaluated the effects of genetic and nongenetic determinants on the efficacy of risperidone (a widely used atypical antipsychotic agent). We found that 5-HT2A receptor 102-T/C polymorphism could predict clinical response (mainly for negative symptoms rather than positive symptoms) in schizophrenia. Among nongenetic factors, fewer previous hospitalizations and higher risperidone dosage also predicted better treatment response after control for the 102-T/C polymorphism and other confounders. It is hoped that this novel study model could revolutionize future research in pharmacogenetics or other fields of genetics. Drug Dev. Res. 60:164–171, 2003. © 2003 Wiley-Liss, Inc.

Background: Predictors for risperidone-related weight gain remain unclear. This study aimed to identify clinical factors influencing body weight in risperidone-treated patients. Method: One hundred forty-six newly hospitalized DSM-IV schizophrenia patients with acute exacerbation entered this prospective, 6-week, repeated-measures trial. The mean ± SD risperidone dose was 4.3 ± 1. 4 mg/day at week 6. Efficacy, body weight, and tolerability were measured biweekly. Efficacy was assessed with the Positive and Negative Syndrome Scale (PANSS) and the Nurses' Observation Scale for Inpatient Evaluation (NOSIE). For determining the impacts of possible prognostic factors on body weight, we utilized generalized estimating equation methods to control for other variables and the within-subject dependence over repeated assessments. Results: After the effects of other factors (including baseline body weight) were adjusted, every 1-week increase in treatment duration raised body weight by 0.442 kg (p

Response predictors of risperidone or other newer atypical antipsychotics for schizophrenia treatment remain unclear. This study aimed to investigate the influence of patient demographics on risperidone efficacy for schizophrenia. One hundred twenty-one newly hospitalized patients who had schizophrenia with acute exacerbation entered this prospective, 6-week risperidone trial. The target dose was 6 mg/day, or lower in case of side effects. Consequently, the mean +/- SD dose remained quite stable after week 2 and reached 4.4 +/- 1.3 mg/day at week 6. Efficacy and side effect assessments were conducted biweekly. The mean total score of the Positive and Negative Syndrome Scale (PANSS) declined during the trial, particularly within the first 4 weeks. Further, of the various efficacy scores (and their natural logarithm values) collected, only the logarithm of the PANSS total score was selected to serve as the response value, because it was normally distributed and thus suitable for regression analyses. After adjusting the effects of treatment duration (weeks 0-6) and other patient-related variables with the generalized estimating equation method, each 1-week increase in duration of prior hospitalizations raised the PANSS total by 0.04% (p = 0.002) and each 1-year increment in the education duration decreased the PANSS by 0.94% (p = 0.04). Gender, age, age at illness onset, duration of illness, diagnosis subtype, or number of prior hospitalizations, however, did not significantly impact the response value. These preliminary results suggest that longer hospitalization duration and shorter education predict higher symptomatology. Further studies with longer observation and larger samples in not only acutely ill patients but also other populations (e.g., first-episode patients) are warranted.

For agitated dementia showing insufficient response to conventional antipsychotics, the feasibility of transition to atypical agents remains unknown. Sixty-two Chinese inpatients with dementia and disruptive behaviors were recruited into an 8-week screening trial of haloperidol. Thirty-five (56%) of them responded insufficiently. They then entered a prospective, 16-week, open-labeled study. Haloperidol was abruptly shifted to risperidone 0.5 mg/day at weeks 1 to 4 and then 1 mg/day at weeks 5 to 12. At weeks 13 to 16, the regimen was shifted back to haloperidol at previous doses, mostly 1 mg/day. Safety, efficacy, cognition, and moods were evaluated at least every 4 weeks. Generalized estimating equation methods were used for determining the effects of the prognostic variables on the outcome values. Risperidone, particularly at 0.5 mg/day, was generally tolerable. The Brief Psychiatric Rating Scale (BPRS) score decreased progressively under risperidone treatment; at week 12, 16 (46%) patients showed response (>or=25% reduction in the BPRS). Patients with vascular dementia were more likely to respond than those with Alzheimer's disease ( p = 0.02). Haloperidol reinstitution resulted in no further improvement, except trend increments in motor symptoms. Risperidone also tended to benefit the performance on the Behavioral Pathology in Alzheimer's Disease Rating Scale. Six (17%) patients improved on moods and self-care with risperidone. These preliminary results suggest that crossover from haloperidol to risperidone is generally safe and effective and may produce favorable moods in agitated dementia patients. Vascular dementia is a predictor of treatment response. In contrast to the dose (1 mg/day) recommended for most white individuals, 0.5 mg/day could be tried at first in Chinese patients. Because of the design's limitations, further controlled studies are warranted.

Patients with schizophrenia are susceptible to low bone mineral density (BMD). Many risk factors have been suggested. However, it remains uncertain whether the risk factors differ between men and women. In addition, the study of bone density in men is neglected more often than that in women. This study aims to examine specific risk factors of low BMD in different sexes. Men (n=80) and women (n=115) with schizophrenia, similar in demographic and clinical characteristics, were enrolled in three centers. Clinical and laboratory variables (including blood levels of prolactin, sex and thyroid hormones, cortisol, calcium, and alkaline phosphatase) were collected. BMD was measured using a dual-energy X-ray absorptiometer. Men had lower BMD than women. Predictors for BMD in men included hyperprolactinemia (B=-0.821, P=0.009), body weight (B=0.024, P=0.046), and Global Assessment of Functioning score (B=0.027, P=0.043); in women, BMD was associated with menopause (B=-1.070, P

Background Late-life depression is common among elderly patients. Ignorance of the health problem, either because of under-diagnosis or under-treatment, causes additional medical cost and comorbidity. For a better health and quality of life (QoL), evaluation, prevention and treatment of late-life depression in elderly patients is essential. Methods This study examined (1) the differences of clinical characteristics, degree of improvement on QoL and functionality on discharge between non-depressed and depressed elderly inpatients and (2) factors associated with QoL on discharge. Four hundred and seventy-one elderly inpatients admitted to a geriatric evaluation and management unit (GEMU) from 2009 to 2010 were enrolled in this study. Comprehensive geriatric assessment including the activities of daily living (ADL), geriatric depression scale, and mini-mental state examination were conducted. QoL was assessed using the European Quality of Life-5 Dimensions and the European Quality of Life-5 Dimensions Visual Analog Scale on discharge. Information on hospital stay and Charlson comorbidity index were obtained by chart review. Chi-square tests, independent t-tests, Mann–Whitney U tests and multiple linear regressions were used in statistical analysis. Results Worse QoL and ADL on discharge were found among the depressed. Depressive symptoms, female gender, duration of hospital stay, and rehabilitation were significant factors affecting QoL on discharge in linear regression models. Conclusions The importance of the diagnosis and treatment of depression among elderly inpatients should not be overlooked during hospital stay and after discharge. Greater efforts should be made to improve intervention with depressed elderly inpatients.

Background Facial emotion perception (FEP) can affect social function. We previously reported that parts of five tested single-nucleotide polymorphisms (SNPs) in the MET and AKT1 genes may individually affect FEP performance. However, the effects of SNP-SNP interactions on FEP performance remain unclear. Methods This study compared patients with high and low FEP performances (n = 89 and 93, respectively). A particle swarm optimization (PSO) algorithm was used to identify the best SNP barcodes (i.e., the SNP combinations and genotypes that revealed the largest differences between the high and low FEP groups). Results The analyses of individual SNPs showed no significant differences between the high and low FEP groups. However, comparisons of multiple SNP-SNP interactions involving different combinations of two to five SNPs showed that the best PSO-generated SNP barcodes were significantly associated with high FEP score. The analyses of the joint effects of the best SNP barcodes for two to five interacting SNPs also showed that the best SNP barcodes had significantly higher odds ratios (2.119 to 3.138; P

Schizophrenic patients suffer from more metabolic or sleep problems. Little is known about risk factors. We recruited 17 patients with chronic schizophrenia from the rehabilitation center in a medical center in Taiwan and measured their demographic data, cognitive performance, and physical fitness, metabolic profiles and sleep parameters. They were divided into two groups according to clinical severity, then compared in terms of metabolic and sleep parameters. Those with more severe symptomatology had more metabolic abnormality and shorter slow wave sleep (SWS). Our findings suggest clinical symptoms as linked with heavier body weight, wider neck circumference, elevated blood pressure, and shorter SWS. Further studies are warranted to confirm the preliminary finding and to elucidate the underlying mechanism.

This open-label trial examined the efficacy and safety of a glycine transporter I inhibitor, sarcosine, in the 24-week treatment of high-functioning children with autistic disorder. Four children (three boys, one girl, 9-11 years of age; average intelligence quotient 80.5) completed the 24 weeks of study. Sarcosine administration was at 30 mg/kg/day in the form of a capsule in two divided doses. The outcome measures were. Autism Diagnostic Observation Schedule (Module 3), parent and teacher-reported Adaptive Behavior Assessment System-II, parenting stress index, Conners’ Continuous Performance Test, Wisconsin Card Sorting Test, child behavior checklist and Swanson, Nolan and Pelham IV hyperactivity attention scales. Safety assessments included monthly recorded vital signs, body weight, body height and adverse events. Statistical analysis found no significant treatment effect on all the outcome measures using the Wilcoxon Signed Rank test and generalized estimating equations analysis. However, an activation effect was reported by caregivers, and was corroborated by clinician’s observation. Details were reported as a case-series in the text. We concluded that sarcosine was well tolerated. Though the data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, and worthy of a double-blind placebo-controlled study with a focus on a certain subgroup of children with autism spectrum disorders.

Background Concomitant fluvoxamine use can potentially reduce the dosage of clozapine needed in treatment-refractory patients with schizophrenia. Previous reports have shown that fluvoxamine can increase plasma clozapine concentrations by inhibition of cytochrome P450 (CYP) 1A2. We evaluated the safety and efficacy of fluvoxamine, 50 mg/day, coadministration with clozapine, 100 mg/day, in refractory schizophrenic patients. Method In this prospective study, 18 treatment-refractory patients with DSM-IV schizophrenia (10 nonsmokers and 8 smokers) were treated with clozapine at a target dose of 100 mg h.s. After steady-state conditions of clozapine had been reached, 50 mg/day of fluvoxamine was then added. Plasma levels of clozapine, norclozapine, and clozapine N-oxide were measured prior to fluvoxamine addition and on days 14 and 28 during combined treatment. Side effects and efficacy were monitored with standardized rating instruments. Results After 14 days of combined treatment, the mean +/- SD plasma clozapine level increased 2.3-fold to 432.4+/-190.9 ng/mL without further elevation on day 28. All patients completed the study without significant adverse side effects. Twelve of the 18 patients achieved plasma clozapine concentrations of at least 350 ng/mL. While plasma norclozapine levels also rose (but to a smaller extent), plasma clozapine N-oxide levels remained unchanged after the add-on therapy. Patients who smoked had 34% lower plasma clozapine concentrations than nonsmokers (NS). Three of the 4 patients who did not reach clozapine plasma levels of at least 300 ng/mL were smokers. Plasma norclozapine/clozapine ratios, especially in smokers, declined significantly with fluvoxamine addition. Conclusion The addition of fluvoxamine, 50 mg/day, to low-dose clozapine, 100 mg/day, can raise plasma clozapine levels to at least 300 ng/mL in most patients. Only slight dosage adjustments with clozapine may be needed after fluvoxamine coadministration in some patients who smoke. Plasma clozapine levels remained stable after 14 days of fluvoxamine addition. The combined treatment was well tolerated, and clinical improvement was observed in our patients. Further long-term studies with this drug combination are needed to determine its economic impact.

Introduction: Pretreatment plasma homovanillic acid (HVA) levels have been reported to be a correlate of clinical response to typical antipsychotics for schizophrenic, bipolar manic, and mixed groups of psychotic patients. Biological markers of clinical response to antipsychotics could be useful for optimizing drug treatment. Method: Thirty-one consenting acute inpatient subjects between ages 19 and 66 years with a DSM-III-R clinical diagnosis of bipolar disorder, manic with psychotic features were entered into this double-blind study and were randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg for the 3-week study. Subjects also received one of the following concomitant medications: standard lithium, lorazepam 4 mg/day, or placebo. Results: The primary multiple regression analysis, including all subjects on both haloperidol doses, yielded a significant main effect for pretreatment plasma HVA ( n =31, F =5.7, P =0.025), indicating that higher pretreatment plasma HVA was predictive of better clinical response. In addition, the interaction between haloperidol dose and pretreatment plasma HVA was also significantly associated with clinical response ( F =12.59, P =0.0015). When the two haloperidol doses were analyzed separately, we found that pretreatment plasma HVA was only correlated with clinical response in the low haloperidol 5 mg/day group ( n =18, F =11.73, P =0.0038) and was unrelated to clinical response to the high haloperidol 25 mg/day group. Limitations: The sample size was small. Results may have been confounded by prior antipsychotic treatment and concomitant use of lithium or lorazepam. Discussion: These results suggest that pretreatment plasma HVA could be useful for dosing antipsychotics. Patients with high plasma HVA levels would be good candidates for low-dose treatment because they are more likely to improve on such a dose, while patients with low plasma HVA levels might warrant more rapid dosage escalation.

The drug-drug interaction between fluvoxamine (FLV) and clozapine (CLZ) was evaluated by in-vitro and in-vivo methods. In-vitro studies were conducted using human hepatic microsomal preparations with standard chemical inhibitors of the cytochrome P450 (CYP 450) isozyme system. Furafyline, FLV, troleandomycin (TAO) and erythromycin were used as the chemical inhibitors. For the in-vivo study, nine male schizophrenic patients were administered a single dose of CLZ 50 mg on two separate occasions with a 2-week FLV treatment of 50 mg twice a day in between each CLZ dose. Blood samples were obtained over 48 h following CLZ administration. CLZ and its two principle metabolites, clozapine N-oxide (CNO) and desmethylclozapine (DCLZ), were measured by high performance liquid chromatography with ultraviolet detection for both in-vitro and in-vivo studies. The in-vitro formation of DCLZ was inhibited by furafyline and FLV by 42.0% and 48.5% (P < 0.01), respectively. TAO and erythromycin had only modest inhibition effects on DCLZ formation of 18.3% and 21.0% (P = NS), respectively. CNO in-vitro formation was significantly reduced by TAO and erythromycin by 44.5% and 45.0% (P < 0.01), respectively. Furafyline and FLV had only modest effects of 19.2% and 8.5% (P = NS), respectively. In schizophrenic patients, FLV resulted in a pronounced increased in CLZ plasma concentrations with the total mean CLZ AUC increased by a factor of 2.58 from 780.8 ng/ml per hour to 2218.0 ng/ml per hour (P < 0.001). All patients were sedated during combined FLV and CLZ use. During FLV treatment, CNO and DCLZ AUC both decreased by 18.8% (P = 0.07) and 9.0% (P = NS), respectively. These results indicate that in-vitro evaluations may not always accurately reflect changes in drug-drug interaction observed in-vivo. Careful patient monitoring is recommended during FLV/CLZ co-administration.

Background Previous reports concerning the effects of gender and age on steady-state plasma concentrations of clozapine and its major metabolites, norclozapine and clozapine-N-oxide, have been controversial. Since the frequency distribution of the plasma levels is asymmetrical and skewed to the right, the statistical methods (such as analysis of variance and regression analysis) used earlier are actually inappropriate for analyzing the effects of the variables on the concentrations and might contribute to the inconsistent results. The goal of the present study, with befitting statistics, is to measure the potential effect of dose, gender, age, and body weight on plasma levels of clozapine and its 2 major metabolites. Method We retrospectively analyzed data from a therapeutic drug monitoring study for steady-state plasma clozapine, norclozapine, and clozapine-N-oxide levels that was conducted in a large group of Chinese schizophrenic inpatients (male:female ratio = 83:79; age range, 33.8 +/- 9.3 years). The daily doses of clozapine had ranged from 100 to 900 mg, with a mean +/- SD value of 379.5 +/- 142.2 mg. Plasma concentrations had been measured using high-performance liquid chromatography with ultraviolet detection. Multiple linear regression was adopted to quantify the effects of various factors on the plasma levels. The natural logarithm of the plasma level was used as the dependent variable to overcome the skewness problem. Results After adjusting the effects of gender, age, and body weight by multiple linear regression, each 1-mg increment in the daily dose could raise the clozapine level by 0.31%, norclozapine by 0.27%, and clozapine-N-oxide by 0.16%. Female patients had 34.9% higher clozapine levels and 36.3% higher norclozapine, with other variables being controlled. No sex differences were demonstrated for clozapine-N-oxide levels. Each 1-year increment in age would elevate the clozapine level by 1.1%, norclozapine by 1.0%, and clozapine-N-oxide by 1.0%. Body weight could not influence the levels of these compounds. Conclusion The present results suggest that women possess higher plasma levels (about one third higher) of clozapine and norclozapine, but not the N-oxide metabolite. Each addition of 1 year in age elevated clozapine and either metabolite's levels by about 1%. Furthermore, every 1-mg increase in the daily dose raised clozapine and norclozapine concentrations by approximately 0.3%. These findings could assist clinicians in optimizing clozapine dosing strategies.

Plasma reduced haloperidol (RH) concentrations or RH to haloperidol (HL) ratios have been suggested to be important in determining the clinical efficacy and extrapyramidal side effects of HL. In this study, we measured the steady-state plasma HL and RH levels by high performance liquid chromatography and analyzed the effects of various variables (dose, gender, age, and body weight) on RH/HL ratios in four dose groups of Chinese schizophrenic inpatients: 10 mg/day (n = 84), 20 (n = 111), 30 (n = 29), and 60 (n = 55). In addition, the polymorphic distribution of RH/HL ratios, suggested by previous investigators, was further tested in each dosage group (for controlling the potential dosage effect on RH/HL ratios). As a result, both age and body weight could influence RH/HL ratios. Each year increase in age (after adjusting the effects of gender, body weight, and dosage) would elevate the RH/HL ratio by 0.0067 (P0.0001). On the other hand, after adjusting gender, age, and dosage effects, each kg increment in body weight would decrease the RH/HL ratio by 0.0044 (P0.01). Gender did not influence the ratio. Furthermore, the high dosage groups had higher RH/HL ratios (even with other variables being controlled). In comparison with the 10 mg group, the 60 mg group exhibited a higher mean RH/HL ratio by 0.84 (P0.0001) and the 30 mg group did by 0.31 (P0.0001). The 20 mg group was almost equal to the 10 mg group in RH/HL ratios. Besides, at each dosage group, the frequency distribution of RH/HL ratios seemed to be predominantly unimodal with a small proportion of extreme outliers. The results of this study clearly indicate that aging or a high dose (or = 30 mg/day) of HL could raise the plasma RH/HL ratio, while an increasing body weight would reduce that. In contrast, gender does not affect the ratios.

Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment.We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample.Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing.Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

We have previously found that sarcosine, a glycine transporter I inhibitor, can improve the psychiatric symptoms of schizophrenia. In this study, we aimed to investigate whether the agent can also ameliorate neuropsychiatric symptoms of Parkinson's disease (PD) patients with dementia.An 8-week, double-blind, placebo-controlled trial was conducted in patients who had PD with dementia (PD-D). Neuropsychiatric manifestations were measured before and at week 2 (V1), week 4 (V2) and week 8 (V3) after treatment. Linear regression with the generalized estimating equations was applied for data analysis.Fifteen patients were randomized into a sarcosine group; the other 15 into a placebo group. The generalized estimating equations model revealed significant differences in Hamilton Depression Rating Scale score (P = 0.049) at V1 and Neuropsychiatry Inventory (P = 0.039) at V2 between the treatment and placebo groups. By excluding the advanced patients from analysis, there were significant differences in Unified Parkinson's Disease Rating Scale V2 (P = 0.004) and V3 (P = 0.040), Hamilton Depression Rating Scale V1 (P = 0.014) and V2 (P = 0.047), Neuropsychiatry Inventory V1 (P = 0.002) and V2 (P 0.001) and Behavior Pathology in Alzheimer's Disease Rating Scale V2 (P = 0.025) in favor of sarcosine.Sarcosine temporally improved depression and neuropsychiatric symptoms in PD-D patients without exacerbating the motor or cognitive features; the beneficial effects were more prominent in patients with mild-moderate severity. Enhancement of N-methyl-D-aspartate receptor-glycine cascade may lead to a novel path for the management of PD-D.

The prevalence of Alzheimer's disease (AD) in the elderly is growing rapidly worldwide, and the deteriorating clinical course of AD places a heavy burden on both the patients and their families. Early detection and intervention of mild cognitive impairment in the early phase of AD is vital for the purpose of improving the cognitive performance of patients and preventing the existing deficits from worsening. However, the main compounds currently used to treat early AD, acetylcholinesterase inhibitors (AChEIs), are unsatisfactory in efficacy and safety. Moreover, evidence indicates that AChEIs are ineffective in treating AD at extremely early stages, which implies that mechanisms other than those targeted by AChEIs underlie the pathogenesis of AD. Dysfunctional glutamatergic neurotransmission, particularly that mediated by the N-methyl-D-aspartate (NMDA) receptor, has been reported to play a role in the pathophysiology of AD. The NMDA receptor (NMDAR) regulates synaptic plasticity, memory, and cognition, and the attenuation of NMDAR-mediated neurotransmission can result in impaired neuroplasticity and cognitive deficits in the aging brain. Furthermore, NMDARs also interact with amyloid beta peptide/amyloid precursor protein and tau protein, whose production represents the main manifestations of AD. In this paper, we review the evidence supporting NMDA dysfunction in both animal models of AD and patients afflicted with AD, and we also review the literature that suggests that NMDA-enhancing agents such as glycine and D-cycloserine can improve cognitive functions. The benefits and limitations of NMDAR antagonists that can diminish the excitatory neurotoxicity triggered by glutamate are also addressed in relation to AD. We propose that enhancing glutamatergic neurotransmission by activating the NMDAR may be effective in treating the cognitive decline that occurs in AD. Prospective studies on AD in which NMDA-enhancing agents are used are required to verify this hypothesis and confirm the long-term efficacy and safety of the treatment agents.

Schizophrenia is a serious neuropsychiatric disease characterized by positive symptoms, negative symptoms and cognitive impairment. Evidence have shown that cognitive impairment sustains in every clinical stage, may relate with the liability, may predict functional outcome in schizophrenia and could be the core symptom of schizophrenia. The treatment of cognitive impairment in schizophrenia could alleviate the burden of the illness and has become the subject of intensive research. In this review, we synthesize current advances of assessing strategies, pharmacological and non-pharmacological treatments of cognitive impairment in schizophrenia. According to the registered records of ClinicalTrials.gov, the most widely studied strategies have aimed at modifying neurochemical mechanisms of dopamine metabolism, glutamate metabolism, γ-aminobutyric acid (GABA) metabolism, serotonin metabolism, acetylcholine metabolism, and oxytocin. Despite preclinical data for putative pro-cognitive drugs, their clinical benefits for schizophrenia patients have been limited. The small sample sizes and the short treatment duration could be related with the suboptimal results. Evidence supported the short-term benefits of cognitive remediation therapy on cognitive domains with small to moderate effects; however, the small sample sizes and the characteristics of subjects limited the generalization of the positive results and the long-term functional outcome is not clear. Combination therapy is promising, by integrating pro-cognitive agents and cognitive rehabilitation programs or combining two kinds of pro-cognitive agents via different mechanisms. Future studies should investigate the pro-cognitive drugs' long-term efficacy, rebound deterioration in psychosis/cognition following discontinuation, and related biomarkers of functional outcome.

Schizophrenia, a multifactorial mental disorder with polygenic inheritance as well as environmental influences, encompasses a characteristic group of symptoms. Negative and cognitive symptoms which respond poorly to currently available antipsychotics remain a great clinical challenge. Aggressive studies are ongoing to explore the etiological mechanisms of this disease. Among them, one of the primary causal factors is dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews the clinical manifestations of the disease, limitations of current antipsychotics and reconceptualization of the nature of disease and treatment modalities based on the evidence provided by drug models, genetic studies, and clinical trials. The NMDA receptor (NMDAR) model plays a critical role in the revolution of pharmaceutical industry as a new set of drug targets is proposed. Investigations on the modulation of glutamatergic system, particularly the intrinsic NMDA glycine modulatory site, exhibit encouraging results. A group of "NMDA-enhancing agents" either acts directly or indirectly on the glycine modulatory site, showing therapeutic efficacy in preclinical and early clinical trials. A new generation of therapeutic agents targeting the NMDAR shows promise as the next wave of drug development for schizophrenia.

OBJECTIVE Previous studies suggested that antidepressants augmented with second-generation antipsychotics (SGAs), including aripiprazole, olanzapine, quetiapine, and risperidone, resulted in better treatment response or higher rates of remission in patients with major depressive disorder (MDD). However, population-based study on SGA augmentation for patients with MDD remains limited. The purpose of this study was to investigate the effectiveness of SGA augmentation for treatment of MDD using the National Health Insurance Research Database in Taiwan. METHOD The subjects were patients with MDD (ICD-9-CM code: 296.2 and 296.3) who were initially admitted to psychiatric inpatient settings for the first time between January 1, 1996, and December 31, 2007, and could be tracked until December 31, 2011. To assess the treatment effect of SGA augmentation, 993 MDD patients who received aripiprazole, olanzapine, quetiapine, or risperidone augmentation treatment for 8 weeks or more were included in this 1-year mirror-image study. Outcome measures included length of psychiatric hospitalization and number of psychiatric admissions and emergency room (ER) visits. RESULTS After patients received SGA augmentation treatment, key psychiatric service use (including length of psychiatric hospitalization [P < .0001], number of psychiatric admissions [P < .0001], and ER visits [P = .0006]) due to MDD diagnosis was significantly reduced. Subgrouping analysis for each SGA drug also showed significant reduction in number of psychiatric admissions for MDD patients who received aripiprazole (P < .0001), olanzapine (P = .003), quetiapine (P < .0001), and risperidone (P < .0001). CONCLUSIONS The study provides support that aripiprazole, olanzapine, quetiapine, and risperidone augmentation therapy could be effective in reducing psychiatric service utilization among MDD patients.

Betel-quid (BQ) contains biologically psychoactive ingredients; however, data are limited concerning the symptoms and syndrome of BQ dependence among chewers. The aims of this study were to evaluate the ingredients-associated BQ dependence syndrome and country-specific chewing features and behaviour for BQ dependence among chewers from six Asian communities.An intercountry Asian Betel-quid Consortium study.Six Asian general communities in Taiwan, Mainland China, Indonesia, Malaysia, Sri Lanka and Nepal.Six multi-stage random samples of BQ chewers in the Asian Betel-quid Consortium study (n = 2078).All chewers were evaluated for BQ dependence using the DSM-IV and ICD-10 criteria.The 12-month BQ dependence rate was 12.5-92.6% and 47.9-99.3% (P = 0.023) among tobacco-free and tobacco-added BQ chewers across the six Asian communities, with a higher dependence rate in chewers who used tobacco-free BQ with lime added than without (23.3-95.6% versus 4.0%, P ≤ 0.001). Taiwanese and Hunanese BQ chewers both notably endorsed the dependency domain of 'time spent chewing'. 'Tolerance' and 'withdrawal' were the major dependence domains associated with the Nepalese and Indonesian chewers, with high BQ dependence rates. Malaysian and Sri Lankan chewers formed a BQ dependence cluster linked closely to 'craving'. In Sri Lanka, the quantity consumed explained 90.5% (P 0.001) of the excess dependence risk for tobacco-added use, and could be a mediator between tobacco-derived psychoactive effect and BQ dependence development.DSM-IV criteria for dependence apply to a significant proportion of betel quid users in Asian communities, more so if they use it with tobacco or lime.

Whether genetic factors affect social cognition, particularly emotion management, requires elucidation. This study investigates whether social cognition varies with genetic variations of COMT and tryptophan hydroxylase-2 (TPH2), which modulate dopamine and serotonin neurotransmissions respectively, and thereby emotion regulation. NIMH-recommended "managing emotions branch and 2 subtasks" of MSCEIT and six neurocognition domains, and genotypes of COMT Val158Met and TPH2 G703T were measured in 150 Han-Chinese healthy adults. Subjects carrying the M allele (M group) of COMT exceeded Val/Val homozygotes (V group) in managing emotions branch (p = 0.032) and emotional relation subtask (p = 0.037). TPH2 T/T homozygotes (T group) excelled those with the G allele (G group) in emotional management subtask (p = 0.025). Subjects with M+T variation surpassed the other 3 groups (M+G, V+T and V+G) in managing emotion branch (p = 0.002), emotional relation subtask (p = 0.023), and emotional management subtask (p = 0.002). The findings remained after control for gender, age, education, and neurocognitive functions. Synergistically, the effect size of COMT-TPH2 combination surmounted the sum of separate effect sizes of COMT and TPH2. The findings suggest that genetic variations of COMT and TPH2 have synergistic effects on social cognition in the general population.

Distinctively higher plasma G72 protein levels in patients with schizophrenia than in healthy individuals

The use of antipsychotic combination has been increasing during the last decade. This study aimed to compare the efficacy and safety of low-dose amisulpride plus low-dose sulpiride with full-dose amisulpride in the treatment of acute schizophrenia. In this 6-week, double-blind, fixed-dose study, patients were randomized to antipsychotic combination (400 mg/day amisulpride plus 800 mg/day sulpiride, N=46) or monotherapy (800 mg/day amisulpride, N=46) groups. Efficacy measurements included the Positive and Negative Syndrome Scale (PANSS) and subscales, and other scales. Safety and quality of life were also assessed. Response was defined as a 30% reduction in the PANSS total score. Both groups were similar in terms of the following: (a) clinical characteristics at baseline, (b) response rates, and (c) score changes in all psychopathology measures, quality of life, and all side-effect scales after 6 weeks of treatment. There were also no significant between-group differences in changes in other safety measurement. However, the combination strategy did reduce treatment costs. The current study suggests that an antipsychotic combination of low-dose antipsychotics is as efficacious and safe as, but cheaper than, optimal-dose monotherapy in the treatment of schizophrenia.

A growing body of evidence indicates that caveolin-1 (CAV1) may influence the development of human cancer. However, the exact role of CAV1 in childhood leukemia is still controversial. We investigated six novel polymorphic variants of CAV1, namely C521A (rs1997623), G14713A (rs3807987), G21985A (rs12672038), T28608A (rs3757733), T29107A (rs7804372), and G32124A (rs3807992), and analyzed the association of each specific genotype with susceptibility to childhood leukemia.In total, 266 patients with childhood leukemia and 266 age-matched healthy controls, recruited from two major medical centers in Taiwan, were genotyped investigating the association of these polymorphisms with childhood leukemia.We found that there were significant differences between childhood leukemia and control groups in the distributions of their genotypes (p=4.1×10(-8) and 0.0167) and allelic frequencies (p=4.9×10(-10) and 3.7×10(-3)) in the CAV1 G14713A and T29107A polymorphisms, respectively. As for the haplotype analysis, those who had GG/AT or GG/AA at CAV1 G14713A/T29107A had a reduced risk of childhood leukemia compared to those with GG/TT, while those with any other combinations were at increased risk.The A allele of CAV1 G14713A is risky, while the A allele of CAV1 T29107A is protective for the development of childhood leukemia and these may be novel useful genomic markers for the early detection of childhood leukemia.

Methadone is a widely used substitution therapy for opioid addiction. Large inter-individual variability has been observed in methadone maintenance dosages and P-glycoprotein (P-gp) was considered to be one of the major contributors. To investigate the mechanism of P-gp’s interaction with methadone, as well as the effect of genetic variants on the interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established in the present study. The RNA and protein expression levels of human P-gp were confirmed by real-time quantitative RT-PCR and western blot, respectively. Utilizing rhodamine 123 efflux assay and calcein-AM uptake study, methadone was demonstrated to be an inhibitor of wild-type human P-gp via non-competitive kinetic (IC50 = 2.17±0.10 µM), while the variant-type human P-gp, P-gp with 1236T-2677T-3435T genotype and P-gp with 1236T-2677A-3435T genotype, showed less inhibition potency (IC50 = 2.97±0.09 µM and 4.43±1.10 µM, respectively) via uncompetitive kinetics. Methadone also stimulated P-gp ATPase and inhibited verapamil-stimulated P-gp ATPase activity under therapeutic concentrations. These results may provide a possible explanation for higher methadone dosage requirements in patients carrying variant-type of P-gp and revealed the possible drug-drug interactions in patients who receive concomitant drugs which are also P-gp substrates.