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Yu-Chun Hung,1 Hsi-Chung Chen,2 Po-Hsiu Kuo,2,3 Mong-Liang Lu,4,5 Ming-Chyi Huang,6 Chun-Hsin Chen,4,5 Sabrina Wang,7 Wei-Chung Mao,8 Chang-Shiann Wu,9 Tzu-Hua Wu1,5,10,11 1Division of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan; 2Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan; 3Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; 4Department of Psychiatry, Wan Fang Hospital & School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 5Psychiatric Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 6Department of Psychiatry, Taipei City Hospital, Songde Branch, Taipei, Taiwan; 7Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 8Department of Psychiatry, Cheng-Hsin General Hospital, Taipei, Taiwan; 9Department of Information Management, College of Management, National Formosa University, Huwei Township, Yunlin County, Taiwan; 10Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 11Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan;Correspondence: Tzu-Hua WuDivision of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 110, TaiwanTel +886-227361661 ext. 6172Email thwu@tmu.edu.twIntroduction: Efforts have been made in assessing efficacy and tolerability to various antidepressants, but understanding personalized chances of stability to medication switching sequence is still inconclusive. This study aimed to identify naturalistic switching patterns of medication in stratifying MDD patients.Methods: MDD patients were stratified based on treatment difficulty evaluated with the “Treatment Resistance to Antidepressants Evaluation Scale for Unipolar Depression” (TRADES). The duration of the time of diagnoses until the final switch to another class of antidepressants was used as prediction of unstable to drug therapy. ROC analysis was used to determine the cutoff values. A continuous temporal events function from the visual analytic tool was employed to perform patterns of switching between distinct pharmacological class such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).Results: TRADES scores of 4.5 and not-switching times of 12.5 months were used as cutoff values to divide patients into four subgroups: stable/easy-to-treat (SE), unstable/easy-to-treat (UE), stable/difficult-to-treat (SD) and unstable/difficult-to-treat (UD). A total of 80% and 76.9% of patients initially treated with the SSRIs paroxetine or fluoxetine, respectively, were predicted to be stable to drug therapy. Approximately 70%, 44.8% and 41.4% of patients initially treated with the SNRIs fluvoxamine, sertraline and venlafaxine, respectively, were predicted to be UD, and 60% of patients using duloxetine were predicted to be stable to drug therapy. Analysis of the switching phenomenon showed that SSRIs were the first prescribed medications and mostly taken by the stable subgroups, and SNRIs were the preferentially chosen switching alternative. Medication switching patterns in unstable MDD patients are discussed.Conclusion: Paroxetine, fluoxetine and duloxetine users were mostly stable among MDD patients in Taiwan with various stability and difficulty to treatments. Although responsiveness to specific medication sequence is likely required for clinical application, the results provide a baseline for such studies.Keywords: visualization, major depressive disorder, patterns of medication switching, antidepressants, stability

In this narrative review, we intended to summarize the evidence of pharmacological and somatic treatment choices for treatment-resistant depression (TRD). There are several types of therapeutic strategies to improve inadequate response to antidepressant treatment. The first step for patients with TRD is to optimize the dosage and duration of antidepressants as well as to ensure their drug compliance. The shift to antidepressant and antidepressant combination therapy for patients with TRD cannot be regarded as an evidence-based strategy. Only the combination of a monoamine reuptake inhibitor with a presynaptic α2-autoreceptor antagonist might have better efficacy than other antidepressant combinations. Currently, the most evidence-based treatment options for TRD are augmentation strategies. Among augmentative agents, second-generation antipsychotics and lithium have the strongest evidence for the management of TRD. Further studies are needed to evaluate the augmentative efficacy of anticonvulsants, thyroid hormone, glutamatergic agents, anti-inflammatory agents, and nutraceuticals for TRD. Among somatic therapies, electroconvulsive therapy and repetitive transcranial magnetic stimulation are effective for TRD. Further studies are warranted to provide clinicians with a better recommendation in making treatment choices in patients with TRD.

Background: Clozapine has been used in treatment-resistant patients with schizophrenia. However, only 40% of patients with treatment-resistant schizophrenia have response to clozapine. Many augmentation strategies have been proposed to treat those clozapine-resistant patients, but the results are inconclusive. In this review, we intended to review papers dealing with the augmentation strategies in the treatment of clozapineresistant patients with schizophrenia. Method: We reviewed randomized, double-blind, placebo- or sham-controlled trials (RCT) for clozapine-resistant patients with schizophrenia in Embase, PsycINFO, Cochrane, and PubMed database from January 1990 to June 2019. Results: Antipsychotics, antidepressants, mood stabilizers, brain stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation, and other strategies, were used as an augmentation in clozapine-resistant patients with schizophrenia. Except for better evidence in memantine with 2 RCTs and cognitive behavior therapy in 2 studies to support its effectiveness, we found that all the other effective augmentations, including sulpiride, ziprasidone, duloxetine, mirtazapine, ECT, sodium benzoate, ginkgo biloba, and minocycline, had only one RCT with limited sample size. Conclusion: In this review, no definite effective augmentation strategy was found for clozapine-resistant patients. Some potential strategies with beneficial effects on psychopathology need further studies with a larger sample size to support their efficacy.

Recent studies have suggested that gut–brain axis may be one of the mechanisms of major depression disorder (MDD). The current study aimed to investigate the effects of Lactobacillus plantarum PS128 (PS128) on psychophysiology in patients with MDD. We recruited 11 patients with MDD and gave them PS128 for 8 weeks. We compared depression symptoms, serum markers of inflammation and gut permeability, and gut microbiota before and after 8-week intervention and also explored the correlations among symptoms, biomarkers, and gut microbiota. After 8-week PS128 intervention, scores of Hamilton Depression Rating Scale-17 and Depression and Somatic symptoms Scale significantly decreased. Serum levels of high sensitivity c-reactive protein, interluekin-6, and tumor necrosis factor-α, zonulin and intestinal fatty acid binding protein, and the composition of gut microbiota did not significantly change after 8-week PS128 intervention. However, we found changes of some genera were correlated with changes of symptoms and biomarkers. In conclusion, this is an open trial with small sample size and has several limitations. The results need to be verified by randomized, double-blind, placebo-controlled trial with larger sample size.

The one-carbon metabolism pathway is a suitable candidate for studying the genetic and epigenetic factors contributing to metabolic abnormalities in patients with schizophrenia. We recruited 232 patients with schizophrenia and analyzed their serum folate, vitamin B12, and homocysteine levels and metabolic parameters to investigate the associations of genetic variants of methylenetetrahydrofolate reductase (MTHFR) and folate levels with metabolic parameters. MTHFR C677T and MTHFR A1298C were genotyped. Results showed that MTHFR 677T allele carriers had lower levels of total cholesterol and low-density lipoprotein cholesterol than those with the 677CC genotype. Metabolic parameters did not differ between MTHFR 1298C and 1298AA carriers. Patients with a low folate level had a lower high-density lipoprotein cholesterol level than those with a normal folate level, but the effect disappeared after adjustment for age, sex, and types of antipsychotics used. We found significant interactions between MTHFR A1298C and the folate level status (low vs. normal) in terms of body mass index and waist circumference. In conclusion, genetic variants in one-carbon metabolism might play a role in antipsychotic-induced metabolic abnormalities. Prospective studies on drug-naïve, first-episode patients with schizophrenia are warranted to identify key regions of DNA methylation changes accounting for antipsychotic-induced metabolic abnormalities.

The aim of the study was to assess the relationship between prolactin levels and sexual dysfunction in patients with schizophrenia who use olanzapine medication. The potential risk factors of hyperprolactinemia and sexual dysfunction were also investigated. Patients with schizophrenia undergoing olanzapine monotherapy were invited to participate in this cross-sectional study. The Arizona Sexual Experiences Scale (ASEX) and the Positive and Negative Syndrome Scale were used to evaluate subjective sexual dysfunction and psychopathology, respectively. Levels of prolactin and metabolic parameters were also measured. In total, 279 participants with schizophrenia were recruited. The overall incidences of hyperprolactinemia, sexual dysfunction, and metabolic syndrome were 51.6, 53.8, and 43.7%, respectively. Higher ASEX scores, higher insulin levels, female sex, and younger age were associated with hyperprolactinemia. Prolactin level was significantly correlated with ASEX score. Elevated prolactin levels, concomitant antidepressant, increased insulin resistance, longer illness duration, and female sex were associated with sexual dysfunction. Female participants recorded higher levels of sexual dysfunction than their male counterparts did, whereas male participants had comparatively lower prolactin levels and lower rates of spousal partnership. Hyperprolactinemia, metabolic syndrome, and sexual dysfunction are prevalent in patients with schizophrenia treated with olanzapine. Clinicians should maintain awareness of these problems and monitor them regularly with their patients.

Obsessive-compulsive symptoms (OCS) occur in a substantial portion of schizophrenia patients and have significant impacts on clinical course. This study was intended to investigate the relationships of OCS with pharmacological parameters of olanzapine, psychopathology, and quality of life. Totally 151 schizophrenia patients were recruited, and rated using Yale-Brown Obsessive-Compulsive scale (YBOCS), Positive and Negative Syndrome Scale (PANSS), Montgomery-Åsberg Depression Rating Scale (MADRS), and World Health Organization Questionnaire on Quality of Life: Short Form (WHOQOL-BREF). The concentrations of olanzapine and N-desmethylolanzapine were determined by HPLC. Twenty-five patients (16.6%) revealed the presence of OCS. OCS group had significantly higher olanzapine dose, more numbers of past hospitalizations, higher PANSS total, positive, negative, and general psychopathology scores, and higher MADRS score than those in non-OCS group. The WHOQOL-BREF physical subscale score in schizophrenia patients with OCS was significantly lower. Olanzapine dose, PANSS score, and MADRS score were significantly correlated with YBOCS score. Our findings highlight that OCS is highly prevalent in schizophrenia patients under olanzapine treatment, especially those at high doses. Schizophrenia patients with OCS had higher severity of psychotic and depressive symptoms and poorer quality of life. Clinicians should monitor OCS in patients with schizophrenia receiving olanzapine treatment.

Objectives: Both superoxide dismutase 2 gene (SOD2), encoding a free radical scavenger, and dystrobrevin-binding protein 1 gene (DTNBP1), a candidate gene for schizophrenia, have been implicated in methamphetamine (METH) psychosis. In this study, we intended to compare the distribution of those two genes between METH users with and without psychosis and to evaluate whether the length of time of METH exposure influenced such relationship. Methods: The study sample consisted of 84 cases of patients with METH-induced psychosis and 187 controls (METH users without psychosis). Five single-nucleotide polymorphisms (SNPs) in SOD2 and three SNPs in DTNBP1 were genotyped. We did both single-locus and haplotype analyses, and adjusted for multiple comparisons with an effective number of markers, and multivariable logistic regression analyses for adjusting for age, sex, and duration of METH use. Results: None of the individual SNPs were associated with METH-induced psychosis after adjustment for multiple comparisons. In the subgroup analysis, both rs4880 and rs2855116 in SOD2 were significantly associated with prolonged METH-induced psychosis (p < 0.01 and p < 0.01, respectively). Under the assumption of a codominant model, the CC genotype of rs4880 was significantly associated with METH-induced psychosis after adjustments for age, sex, and the duration of METH use (p < 0.01). This association was not supported by the haplotype analyses or gene–gene interactions between SOD2 and DTNBP1. Conclusion: Functional C-allele of rs4880 in SOD2 was associated with the prolonged subtype of METH-induced psychosis in Taiwanese population. Oxidative stress mechanisms show a rôle in the development of METH-induced psychosis.

Background: Several monotherapy and augmentation strategies have been introduced to improve the treatment of schizophrenia. The benefits of omega-3 polyunsaturated fatty acids in patients with mental disorders is becoming increasingly acknowledged. However, its role in the treatment of schizophrenia raises complex considerations about which there has been little consensus. The aim of this study was to synthesize the findings of randomized controlled trials that were conducted to determine the efficacy and safety of omega-3 polyunsaturated fatty acids in patients with schizophrenia. Methods: The MEDLINE, Embase, Cochrane, Scopus, and Web of Science databases were searched for relevant literature. The primary outcome was changes in psychopathology and the secondary outcomes were changes in metabolic parameters and safety profiles. Results: Twenty double-blind randomized controlled trials in 1494 patients were included. Omega-3 polyunsaturated fatty acids augmentation was associated with significantly improved psychopathology in patients with schizophrenia, particularly general psychopathology and positive symptoms but not negative symptoms. Patients who were severely ill and received omega-3 polyunsaturated fatty acids containing eicosapentaenoic acid >1 g/d showed significant improvement. A favorable effect of omega-3 polyunsaturated fatty acids supplements on serum triglycerides was also demonstrated. Omega-3 polyunsaturated fatty acids are well-tolerated and safe in patients with schizophrenia. Conclusions: These findings tentatively support the use of omega-3 polyunsaturated fatty acids as a potential augmentation strategy in schizophrenia. Further research in larger samples is warranted to clarify the optimal dosage and the correct proportions of omega-3 polyunsaturated fatty acids to administer, together with elucidation of the underlying mechanisms.

Antipsychotic-induced metabolic disturbance is a common adverse event occurring in patients treated with antipsychotic drugs. The mechanisms underlying metabolic dysregulation are complex, involving various neurochemical and hormonal systems, the interaction of genetic and lifestyle risk factors, and the antipsychotic drug prescribed. Recently, there has been increasing interest in the relationship between antipsychotic-induced metabolic disturbances and body weight regulatory hormones such as adiponectin. Adiponectin, an adipocyte-derived protein related to insulin sensitivity, weight gain, and anti-inflammation, has attracted great attention because of its potential role of being a biomarker to predict cardiovascular and metabolic diseases. Previous studies regarding the effects of antipsychotics on blood adiponectin levels have shown controversial results. Several factors might contribute to those inconsistent results, including different antipsychotic drugs, duration of antipsychotic exposure, age, sex, and ethnicity. Here we summarize the existing evidence on the link between blood adiponectin levels and metabolic disturbances related to antipsychotic drugs in patients with schizophrenia. We further discuss the effects of individual antipsychotics, patients' gender, ethnicity, age, and treatment duration on those relationships. We propose that olanzapine and clozapine might have a time-dependent biphasic effect on blood adiponectin levels in patients with schizophrenia.

Background The present study aimed to develop a new scale to evaluate the level of difficulty in treating major depressive disorder with antidepressants based on the lifetime treatment profile. Methods In addition to evaluating the difficulty of treatment with antidepressants (A subscale), the Treatment Resistance to Antidepressants Evaluation Scale (TRADES) is comprised of a subscale to account for the attributes that compromise the efficacy of treatment (B subscale). One hundred and six participants aged 18 to 65 years with remitted major depressive disorder were enrolled. Eligible cases were those with at least 2 years from disease onset until the scoring date of the TRADES (the index date), with a complete treatment record. Various psychosocial and clinical features, such as neuroticism, harm avoidance, and utilization of psychiatric services, were used to validate the TRADES. Results The mean duration of the course before and after the index date were 5.5 ± 3.5 and 3.1 ± 1.7 years, respectively. In a multiple regression analysis, the final total scores of the TRADES independently correlated with higher levels of neuroticism and harm avoidance. Total scores were also associated with a higher utilization of psychiatric outpatient and admission services before the index date. Furthermore, it is thought that total scores could predict a higher number of visits to psychiatric outpatient, emergency, and admission services following the index date. Conclusions The TRADES has acceptable validity and could help to quantify the level of treatment difficulty with antidepressants in major depressive disorder.

The authors aimed to evaluate whether the clinical phenotype of delirium differs if dichotomized either by sex or age (cutoff age, 65 years old) in a pooled sample of 406 nondemented adult patients with delirium as defined by DSM-IV criteria. Delirium characteristics were measured with the Delirium Rating Scale-Revised-98 (DRS-R-98). DRS-R-98 items were subgrouped to represent subscores representing the three core domains of delirium (cognitive, higher-order thinking, and circadian), noncore accessory symptoms (psychotic and affective), and diagnostic characteristics (temporal onset, fluctuation, and physical disorder). The authors compared means of the DRS-R-98 subscores and medians of individual items. Exploratory factor analyses evaluated delirium characteristics for each subgroup for each of the four groups-male, female, nongeriatric, and geriatric-while taking into account active medical diagnoses. Males had higher scores on motor agitation and affective lability (behavioral), whereas females had a higher frequency of hypoactive delirium. Delirium had a two-factor structure that emerged in all four study groups, and all its core domains loaded (i.e., correlated together) onto some of these two factors and with circadian domain correlating with accessory symptoms. Although the influence of a variety of active diagnoses on delirium was small and complex, traumatic brain injury had a clear influence on cognitive domain and abrupt onset. Age had a mild influence over delirium characteristics for both males and females. In conclusion, the authors confirmed a two-factor structure for delirium phenomenology, regardless of age and sex, with few significant differences between etiological groups.

Background: Ghrelin is a peptide hormone that mediates glucose homeostasis and lipid metabolism. Acylated ghrelin (AG) and desacylated ghrelin (DAG) are the two main forms of ghrelin, which have opposing roles in energy homeostasis. The AG/DAG ratio has been proposed to be associated with metabolic syndrome (MetS) in the general population. This study compared the relationships between MetS and ghrelin parameters in patients with schizophrenia. Methods: Patients diagnosed with schizophrenia and under olanzapine monotherapy were recruited. Fasting blood samples were collected for the analyses of metabolic and ghrelin parameters. The serum levels of total ghrelin and AG were measured by enzyme-linked immunosorbent assay kits. DAG level was calculated by subtracting the AG level from the total ghrelin level. Results: We recruited 151 subjects with schizophrenia, and classified them into those with MetS ( n = 41) and those without MetS ( n = 110). Subjects with MetS had a significantly higher AG/DAG ratio, as well as lower total ghrelin and DAG levels. There were no sex differences in ghrelin parameters. The AG/DAG ratio was significantly and positively correlated with weight, body mass index, waist circumference, insulin level, homeostasis model assessment of insulin resistance and number of MetS components. Multiple linear regression analysis indicated that the number of MetS components remained significantly associated with the AG/DAG ratio. Conclusions: Our results revealed that lower AG/DAG ratios were associated with better metabolic profiles in olanzapine-treated patients with schizophrenia. These observations suggest that the balance between AG and DAG plays a crucial role in the metabolic homeostasis among patients with schizophrenia.

Objective Leptin and adiponectin are adipokines which have opposing roles in the development of insulin resistance and metabolic syndrome (MetS). Leptin/adiponectin ratio (L/A ratio) has been proposed as a good biomarker for MetS in general population. This study aimed to compare the strength of association between MetS and leptin, adiponectin and L/A ratio, as well as to assess their performance to diagnose MetS in patients with schizophrenia. Methods Patients diagnosed with DSM-IV schizophrenia and under clozapine or olanzapine monotherapy for at least six months were recruited. We used the modified ATP III criteria for Asians to evaluate subjects for a diagnosis of MetS. Results We recruited 262 study subjects with schizophrenia, and classified them into those with MetS (n = 87) and those without MetS (n = 175). Leptin level was positively correlated with BMI, waist circumference, and insulin level. Adiponectin level was negatively correlated with most metabolic parameters, except glucose level. L/A ratio was positively correlated with most metabolic parameters, except levels of glucose and HDL-C. Significant gender differences existed in leptin levels, adiponectin levels, and L/A ratio. Without and with adjustment of age and gender, binary logistic regression analysis showed that leptin level, adiponectin level, and L/A ratio were significantly associated with MetS. The area under curve (AUC) of L/A ratio and leptin level for MetS was 0.744 (95% CI = 0.685–0.802) and 0.666 (95% CI = 0.601–0.731). The AUC of adiponectin level for the absence of MetS was 0.717 (95% CI = 0.655–0.780). The discriminative strength of L/A ratio for MetS was better in men than in women. Conclusions The present study results suggest that L/A ratio may be a preferential marker of metabolic syndrome in patients with schizophrenia compared to leptin or adiponectin alone.

Metabolic disturbance is a common side effect of olanzapine (OLZ); however, the relationships between plasma OLZ concentration (COLZ) and metabolic disturbance remain unclear. Our previous study revealed that COLZ ≧ 22.77 ng/mL was a positive predictor of therapeutic efficacy in patients with schizophrenia. This study aimed to investigate the roles of OLZ or N-desmethyl-olanzapine (DMO) in metabolic outcomes among OLZ-treated patients with schizophrenia. The metabolic syndrome (MS) was diagnosed based on the modified the National Cholesterol Education Program Adult Treatment Panel III criteria for Asians. HPLC-ECD analytical system was applied to determine the COLZ and DMO concentration (CDMO). The absolute drug levels and concentration-to-dose ratios (C/D ratios) were tested for their correlations to metabolic parameters. Total 151 fasting blood samples from patients with schizophrenia were collected. DMO C/D ratio negatively correlated with weight, body mass index, waist circumference, and C-peptide level. The receiver operator characteristic analysis determined a threshold CDMO > 5.63 ng/mL and DMO C/D ratio > 0.35 ng/mL/mg were negative predictors of MS. The COLZ/CDMO ratio > 6.03 was identified as positive predictor of MS. Combined with previous study result, we proposed that the optimal OLZ treatment should maintain COLZ/CDMO ratio between 3 and 6 to maximize the clinical efficacy and minimize the metabolic side effects. Our findings suggested that therapeutic drug monitoring on OLZ and DMO is a valuable tool to monitor metabolic side effects in OLZ-treated patients with schizophrenia.

Objective Numerous studies have demonstrated that fluvoxamine has considerable pharmacokinetic and pharmacodynamic interactions with clozapine. We conducted a 12-week, randomized, double-blind, placebo-controlled study to evaluate the effects of fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia. Methods We recruited 85 patients who received a DSM-IV diagnosis of schizophrenia. Eligible patients were randomized to receive fluvoxamine 50 mg/day plus clozapine 100 mg/day or clozapine 300 mg/day. We studied metabolic parameters, psychopathology, and drug levels at baseline and 4, 8, and 12 weeks after the intervention. Plasma levels of clozapine, norclozapine, clozapine N-oxide, and fluvoxamine were determined using high-performance liquid chromatography with ultraviolet detection. Results No significant difference was observed in baseline characteristics between the two groups. Clozapine–fluvoxamine combined treatment significantly attenuated the increments in body weight, insulin resistance, and levels of insulin, glucose, and triglycerides compared with clozapine monotherapy. Both groups exhibited significant improvements in their Positive and Negative Syndrome Scale (PANSS) total and negative scores. The combined treatment group showed significant reduction in the PANSS general psychopathology scores compared with the monotherapy group. No difference was observed in the plasma clozapine level between the two groups. The monotherapy group showed higher levels of norclozapine and clozapine N-oxide than the combined group. Conclusions Compared with clozapine monotherapy, treatment with adjunctive fluvoxamine with clozapine for 12 weeks can alleviate body weight gain and metabolic abnormalities in patients with schizophrenia, without sacrificing the clinical effect. Clinicians should interpret these findings cautiously considering the short duration of this study. The study was registered at www.clinicaltrials.gov ( NCT01401491 ).

Objectives: The association between older-age bipolar disorder and cognitive impairments may be mediated by vascular burden. The aim of the study was to examine the difference of cognitive function between older people with late-onset bipolar disorder (LOBD) and early-onset bipolar disorder (EOBD) by considering rigorous vascular risk burden evaluation, comprehensive cognitive tests, and relevant biochemistry data. Methods: We recruited 95 outpatients aged over 55 with a DSM-IV-TR diagnosis of bipolar I disorder. Fifty had LOBD, defined by age of onset after 40. Cognitive function was evaluated through a battery of tests assessing verbal memory, attention/speed, visuospatial function, verbal fluency, and cognitive flexibility. Vascular risk assessments included individual disorders, 10-year Framingham cardiovascular risk scores, and serum levels of homocysteine, vitamin B12, folate, and triiodothyronine. Results: No differences were observed between LOBD and EOBD on any cognitive test after adjusting for potential confounders. In addition to age and educational years, multiple linear regression analyses indicated significantly negative associations between serum homocysteine levels and cognitive performances in attention, psychomotor speed, verbal memory, and executive function. Conclusions: Among older people with bipolar disorder, LOBD is not associated with more cognitive dysfunction in this study. However, higher serum homocysteine levels were significantly associated with worse cognitive performance in this particular group. Clinicians therefore have to pay attention to the cognitive function in older bipolar patients with higher levels of homocysteine.

Differences in cognitive function have been suggested in people with late-life depression between those with early- (EOD) and late-onset (LOD), possibly reflecting different etiologies. The cutoff point for EOD and LOD was the first depressive episode before age 60 or later. However, depressive symptoms at the time of disorder are important confounders. The study aimed to compare cognitive function in older people with EOD and LOD in the euthymic state. A sample of 135 participants aged 60+ with a history of major depressive disorder in remission, received neuropsychological evaluation including tests of memory, attention, processing speed, visuospatial function, language, and executive function. Individual test scores and a derived composite score were investigated as dependent variables against age of onset using multiple linear regressions adjusted for potential confounders, including residual depressive symptoms. We found EOD (N = 67) and LOD (N = 68) groups did not differ significantly in overall composite cognitive scores after adjustment. Of individual test scores, only those for immediate recall were significantly lower in participants with EOD compared to LOD. In conclusion, the study found no associations between cognitive function and age of onset in this sample of people with depressive disorder in remission. Active or residual depressive symptoms might have confounded this relationship in previous research.

Accumulating data show that probiotics may be beneficial in reducing depressive symptoms. We conducted an updated meta-analysis and evaluated the effects of probiotics on depressive symptoms. A systematic search of six databases was performed, and the results were reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses, with the priori-defined protocol registered at PROSPERO (CRD42018107426). In total, 19 double-blind, randomized, placebo-controlled trials with a total of 1901 participants were included in the qualitative synthesis. Participants treated with probiotics showed significantly greater improvement in depressive symptoms than those receiving placebo. The clinical population was stratified by clinical diagnosis into those with major depressive disorder (MDD) and those with other clinical conditions. The beneficial effect of probiotics on depressive symptoms was significant in patients with MDD, but not in those with other clinical conditions and in the general population. In addition, multiple strains of probiotics were more effective in reducing depressive symptoms. In conclusion, altering the gut-brain axis with probiotics may be an approach to improve depression severity. It is essential to verify the efficacy of specific combinations or strains of probiotics for depressive symptoms by conducting studies with a larger sample size in the future.

Bipolar disorder (BD) is highly heritable and well known for its recurrent manic and depressive episodes. The present study focused on manic episode in BD patients and aimed to investigate state-specific transcriptome alterations between acute episode and remission, including messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and micro-RNAs (miRNAs), using microarray and RNA sequencing (RNA-Seq) platforms. BD patients were enrolled with clinical information, and peripheral blood samples collected at both acute and remission status spanning for at least 2 months were confirmed by follow-ups. Symptom severity was assessed by Young Mania Rating Scale. We enrolled six BD patients as the discovery samples and used the Affymetrix Human Transcriptome Array 2.0 to capture transcriptome data at the two time points. For replication, expression data from Gene Expression Omnibus that consisted of 11 BD patients were downloaded, and we performed a mega-analysis for microarray data of 17 patients. Moreover, we conducted RNA sequencing (RNA-Seq) in additional samples of 7 BD patients. To identify intraindividual differentially expressed genes (DEGs), we analyzed data using a linear model controlling for symptom severity. We found that noncoding genes were of majority among the top DEGs in microarray data. The expression fold change of coding genes among DEGs showed moderate to high correlations (∼0.5) across platforms. A number of lncRNAs and two miRNAs (MIR181B1 and MIR103A1) exhibited high levels of gene expression in the manic state. For coding genes, we reported that the taste function-related genes, including TAS2R5 and TAS2R3, may be mania state-specific markers. Additionally, four genes showed a nominal p-value of less than 0.05 in all our microarray data, mega-analysis, and RNA-Seq analysis. They were upregulated in the manic state and consisted of MS4A14, PYHIN1, UTRN, and DMXL2, and their gene expression patterns were further validated by quantitative real-time polymerase chain reaction (PCR) (qRT-PCR). We also performed weight gene coexpression network analysis to identify gene modules for manic episode. Genes in the mania-related modules were different from the susceptible loci of BD obtained from genome-wide association studies, and biological pathways in relation to these modules were mainly related to immune function, especially cytokine-cytokine receptor interaction. Results of the present study elucidated potential molecular targets and genomic networks that are involved in manic episode. Future studies are needed to further validate these biomarkers for their roles in the etiology of bipolar illness.

Weight gain is one of the most challenging issues in patients with schizophrenia treated with antipsychotics. Several meta-analyses have been conducted to review the efficacy of topiramate in reducing weight, however, several issues regarding the methodology had arisen of which make the results remain ambiguous.We conducted a meta-analysis of randomised controlled trials about the use of topiramate in patients with schizophrenia for weight reduction. Ten double-blinded randomised placebo-controlled trials and seven open-label randomised controlled trials included 905 patients.Patients treated with topiramate experienced a greater reduction in body weight and BMI. Patients in countries of the lower overweight population showed more significant BMI reduction. Besides, studies from the Middle East and South Asia showed the greatest effect in body weight change, followed by East Asia, then Europe/America. Topiramate group was outperformed control group with significant psychopathology improvement. No difference between two groups regarding the overall side effects.Topiramate was significantly superior to control group in mitigating weight gain and psychopathology in antipsychotic-treated patients with schizophrenia. The effects of topiramate augmentation need further investigations in larger definitive studies using methodological rigor and thorough assessments.

Background: High sedative use in a major depressive episode may imply specific clinical features. This study aims to examine the correlation between sedative use and clinical severity indicators in the initial treatment phase of first-onset major depressive disorder. Methods: A study cohort in the first episode of major depressive disorder was used to conduct pharmacological dissection. All participants had at least a 2-year follow-up period with a complete treatment record. The defined daily dose of antidepressants and augmentation agents were calculated as the antidepressant load and augmentation load, respectively. Sedative use, which was calculated as the equivalent dosage of lorazepam, were defined as the sedative load. These psychotropic loads were measured monthly and the averaged psychotropic loads for each day were obtained. Results: A total of 106 individuals (75.5% female) were included. The mean duration of disease course in participants was 5.5 ± 3.5 years. In the multiple regression analysis, after controlling for other classes of psychotropics and comorbid anxiety disorders, the sedative load independently correlated with higher number of antidepressants used, higher number of antidepressant used with an adequate dose and duration, more psychiatric emergency and outpatient visits within 2 years of disease onset. Conclusion: High loading of sedatives correlated with several indicators of clinical severity in major depressive disorder. The sedative load may be used as a specifier to identify subgroups in patients with major depressive disorder.

Background Seasonal Pattern (SP) was reported in depressive patients of both Bipolar Disorder (BD) and Major Depressive Disorder (MDD). In this study, we aimed to investigate genetic contributions of seasonal pattern of major depressive episodes in both BD and MDD patients, including genes in relevant biological pathways indicated in previous studies. To further clarify the roles of the variants in depression, we conducted analyses using a case-control study design to examine whether the genetic variants for SP also possess effects on susceptibility to depression. Methods We recruited 472 BD (83%) and MDD (17%) patients in Taiwan. SP of depressive episode were defined according to interview questions as “Which season do you feel the worst?” in their first, the most serious, and the most recent episode within a year. Subjects answered a specific season in two of the three episode categories were considered SP+, while others were categorized as non-SP (SP-). The other dataset for depression was obtained from the Taiwan biobank with about 10,000 people. Cases were defined by self-report MDD history or having the sum-score greater than 3 in the Patient Health Questionnaire-4. We examined 15 genes (824 single nucleotide variants) including the melatonin pathway (MTNR1a, MTNR1b, AANAT), serotonin pathway (TPH2, HTR2A, HTR2B, SLC6A4), circadian feedback loop (NPAS2, CRY2, ARNTL, ARNTL2, RORA, RORB, PER) and NF1A gene that identified from a previous genome-wide association study of seasonal mania. Association analyses were performed by multivariate logistic regression, adjusting for gender, age, and diagnosis. We corrected for multiple testings using false discovery rate method. Results After excluding subjects with missing covariates, there were a total of 464 subjects with 162 (35%) in the SP+ and 302 (65%) in the SP- groups. No differences were observed in gender, age or diagnosis distribution between the two SP groups. Nominal associations with p-value The 20 markers were tested again for depression in 9862 individuals from Taiwan biobank. Although none of them showed genome-wide significance, 6 SNPs had nominal p-values Discussion We found that NF1A gene maybe a susceptible gene for depression and modifiable gene for SP. Some genetic variants in this gene are related to both seasonal pattern of depressive episodes and depression with nominal significance, indicating partially shared genetic components between the development of mood symptoms and seasonality in depression. Further investigation is needed for replication with more stringent seasonal pattern evaluation, and for exploring the exact biological functions of the identified genetic variants.

Obesity-related genetic variants, including TMEM18 (rs6548238), SH2B1 (rs7498665), and GNPDA2 (rs10938397), have been shown to be associated with obesity in the general population. Our study aimed to test whether these genetic variants are associated with metabolic profiles and metformin treatment response in clozapine-treated schizophrenic patients. We recruited 107 clozapine-treated patients who were genotyped and measured their metabolic profiles. Fifty-five subjects, who had at least 1 metabolic abnormality in a range of measures, were subsequently randomized to a 24-week trial of metformin (n = 28) or placebo (n = 27). We examined the associations between TMEM18, SH2B1, GNPDA2 genetic variants and metabolic profiles at baseline in all patients and metabolic changes in the trial groups. We found a significant association between SH2B1 and blood pressure at baseline in all patients. In the metformin group, TMEM18 minor allele carriers had a greater reduction in insulin levels (P = 0.04). A significantly higher proportion of TMEM18 and GNPDA2 minor allele carriers (60% and 40%) lost more than 7% of their body weight after metformin treatment as compared with their homozygous counterparts (21.7% and 15.4%, P = 0.02 and 0.004, respectively).There were trends toward favorable metabolic changes in minor allele carrier groups. In the placebo group, no association between genetic variants and changes in metabolic profiles was found. In conclusion, the study results suggest that these genes might be associated with metabolic abnormalities and response to metformin in clozapine-treated patients with schizophrenia.

Background Ketamine has been used to probe the biology of psychosis and cognitive dysfunction in humans. High levels of ketamine abuse are associated with persisting psychosis (KPP) in a minority of users. However, relatively little is known about cognitive function among KPP patients and whether the cognitive impairments associated with KPP resemble those of schizophrenia (SZ). Methods We recruited 149 treatment-seeking patients, including nonpsychotic ketamine users (KNP, n = 51), KPP (n = 23), and SZ (n = 75) patients. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate psychopathology and the Cogstate Brief Battery to assess cognitive function including psychomotor processing speed, attention, working memory, verbal and visual learning and memory, spatial problem solving, and social-emotional cognition. Results Ketamine-dependent patients had an extensive history of ketamine use (average duration = 7.1 ± 4.2 years, average consumption = 3.8 ± 2.7 g per day). Although KPP patients used relatively less average ketamine daily dose than KNP patients, KPP patients exhibited significantly greater total PANSS score and subscale scores, while these scores in KPP and SZ patients did not differ significantly. After adjusting for demographic characteristics and antipsychotic dose, KPP and SZ patients showed impairments in spatial problem solving and verbal memory compared to KNP patients, but KPP and SZ patients did not significantly differ from each other. Conclusion These data suggest that the symptom profile and cognitive impairments associated with persisting psychosis due to chronic heavy ketamine abuse resemble those of schizophrenia, while KNP patients showed significantly less severe symptom profile and cognitive impairment than KPP and SZ.

Alcohol withdrawal syndrome is associated with increased central N-methyl-D-aspartate (NMDA) glutamate transmission. Medications that reduce glutamate release or block NMDA overactivation have shown efficacy for treating alcohol withdrawal syndrome. Dextromethorphan (DXM), a widely used antitussive drug, is a low-affinity, noncompetitive NMDA antagonist with potential neuroprotective properties. This study, using a randomized, double-blind, placebo-controlled study design, examined the benefit of DXM in the management of acute alcohol withdrawal. Alcohol-dependent patients admitted for detoxification treatment and experiencing moderate alcohol withdrawal, as measured by a score greater than 10 on the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), were randomly assigned to receive either DXM 360 mg/d or an identical placebo for 7 days in a double-blind manner. All subjects received a concurrent dose of lorazepam 2 mg along with the initial administration of DXM or placebo and were given additional lorazepam (1 mg) as a rescue medication according to the symptom-triggered detoxification protocol. Outcome measures consisted of the mean total dose of lorazepam received, the sequential scores on the CIWA-Ar, and craving assessed by the Obsessive-Compulsive Drinking Scale. Forty subjects completed the study, 18 in the DXM group and 22 in the placebo group. We found that compared with placebo, DXM use was not associated with lower lorazepam doses to control alcohol withdrawal symptoms. The progression in CIWA-Ar and Obsessive-Compulsive Drinking Scale scores was also comparable between the 2 groups. Our preliminary results do not support the efficacy of high-dose DXM in reducing the need of benzodiazepines to treat withdrawal symptoms in alcohol-dependent patients.

BACKGROUND:This therapeutic drug monitoring (TDM) study aimed to determine the role of olanzapine (OLZ) and N-desmethyl-OLZ (DMO) levels in the therapeutic efficacy of OLZ in patients with schizophrenia. METHOD:Plasma concentrations of OLZ (COLZ) and DMO (CDMO) in schizophrenic patients 12 hours post-dose were assessed. The correlations of COLZ and CDMO with the various scores of the Positive and Negative Syndrome Scale (PANSS) were evaluated. A receiver operating characteristic curve (ROC) was utilized to identify the threshold COLZ and COLZ/CDMO ratio for maintenance of satisfactory efficacy. RESULTS:A total of 151 samples from patients with schizophrenia were analyzed for individual COLZ and CDMO levels. The mean COLZ and CDMO levels were 37.0 ± 25.6 and 6.9 ± 4.7 ng/mL, respectively, and COLZ was ~50% higher in female or nonsmokers (p

Background: Lower concentrations of n23 PUFAs have been reported to be associated with cognitive impairment and dementia, but also with depression—itself a potential risk factor for cognitive decline. Objective: The aims of this study were to investigate associations between n23 PUFA concentrations in erythrocyte membrane or plasma and cognitive function in an at-risk sample of older people with previous major depression and to explore specificity with respect to cognitive domains. Design: A cross-sectional sample of 132 eligible participants who had recovered from major depression (mean 6 SD age: 67.8 6 6.6 y) were enrolled from outpatient psychiatric services. A series of cognitive tests and a structured questionnaire were administered. Fasting blood samples were collected for n23 PUFA measurements. Results: Higher EPA and total n23 PUFA concentrations and a lower ratio of arachidonic acid to EPA in erythrocyte membranes were associated with a higher cognitive composite score: independent of age and sex, but no longer significant after adjustment for education. No associations were found with plasma concentrations of any fatty acid. Considering individual cognitive tests, the strongest and most consistent correlations were found between immediate recall and concentrations of total n23 PUFAs and a-linolenic acid (ALA) in erythrocytes, which were observed only in participants with recurrent depression. Conclusions: Total erythrocyte n23 PUFA concentrations are positively associated with cognitive function, particularly immediate recall, in older people with previous depression. Lower concentrations of n23 PUFAs or ALA in erythrocyte membranes may be good predictors for cognitive impairment in older people with previous recurrent depression. Am J Clin Nutr 2012;95:420–7.

Objective Metabolic adversities are prevalent in patients with schizophrenia. Retinol-binding protein 4 (RBP4) and high molecular weight (HMW) adiponectin have been recently found to be associated with metabolic features in non-psychiatric population. The study aimed to evaluate the associations between metabolic features and RBP4, total adiponectin, and HMW adiponectin in patients with schizophrenia. Methods We recruited 109 patients with schizophrenia treated with clozapine or haloperidol and evaluated their body mass index (BMI), waist circumference, blood pressure, and fasting triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose, insulin, RBP4, total adiponectin, and HMW adiponectin levels. Results We found that patients with metabolic syndrome (MS) had higher RBP4 level, and lower total adiponectin and HMW adiponectin levels than those without MS. There were no significant differences in metabolic features and adipocytokine levels between patients treated with clozapine and haloperidol. Most of the metabolic indexes were significantly correlated with the levels of adipocytokines. After adjusting the effects of age, gender, and BMI, marginal significant correlations existed between TG and RBP4 levels; HDL-C and total adiponectin and HMW adiponectin; insulin and HOMA-IR and HMW adiponectin. Receiver operating curve analysis showed that all of the three adipocytokines could differentiate patients with MS from those without MS. Meanwhile, total adiponectin and HMW adiponectin, but not RBP4, had the differentiating power for insulin resistance. Conclusion Higher RBP4 and lower total adiponectin and HMW adiponectin levels were observed in schizophrenic patients with MS. Only HMW adiponectin is marginally correlated with insulin sensitivity. The finding that metabolic profiles, but not the antipsychotic types, are associated with adipocytokine levels should be confirmed in longitudinal studies.

Schizophrenic patients have a high prevalence of metabolic adversities. Previous studies have suggested some candidate genes for obesity- and metabolic-related traits, including the insulin-induced gene (INSIG2), melanocortin 4 receptor gene (MC4R), and leptin and leptin receptor genes (LEP and LEPR). We aimed to investigate the associations between these genes and metabolic disturbances in patients with schizophrenia in Taiwan.Patients with a diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were recruited from 36 community psychiatric rehabilitation centers or hospitals in Taipei. A total of 650 subjects were enrolled, and 577 were included in the genetic analyses. The anthropometric (body mass index, waist circumference [WC], and blood pressure) and biochemical measurements (fasting plasma glucose, insulin, triglyceride, high-density lipoprotein cholesterol, and Homeostasis Model of Assessment - Insulin Resistance index [HOMA-IR]) were assessed. Seven loci in the 4 genes were genotyped using standard TaqMan assays. Genetic association analyses were conducted for binary and quantitative measurements of the previously mentioned traits. Obese patients with schizophrenia exhibited more metabolic disturbances than nonobese patients.Our data showed that INSIG2 was significantly associated with fasting plasma glucose (for rs17587100, P0.0001), MC4R was associated with WC (for rs2229616, P = 0.005), and LEP was associated with body mass index and WC (for rs7799039, P0.01). In addition, these loci showed suggestive associations with traits including high-density lipoprotein cholesterol and triglyceride, metabolic syndrome, insulin level, and HOMA-IR index (P = 0.05). In addition to the effect from antipsychotic medications and an unhealthy lifestyle, genetic factors also contribute to the high prevalence of obesity and metabolic disturbances in patients with schizophrenia, especially genes involved in metabolic-related pathways.

’Background: Oxidative stress has been proposed as one of the mechanisms of alcohol-induced brain shrinkage and alcohol-induced hepatotoxicity. The aim of this study was to assess the correlations between liver function and brain volume (BV) measurements in patients with alcohol dependence. Methods: We recruited 124 patients with alcohol dependence and 111 healthy control subjects from National Institute of Health, National Institute on Alcohol Abuse and Alcoholism inpatient alcohol treatment program. Gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as hematocrit (Hct) and albumin were assayed shortly after admission. Magnetic resonance imaging examination was conducted in both groups (after 3-week abstinence in the patient group). We used stepwise linear regression analyses to determine the variables most strongly correlated with brain shrinkage. Results: Patients with alcohol dependence had lower BV, and greater brain shrinkage as measured by gray matter ratio (GMR), white matter ratio (WMR), brain ratio (BR), and higher cerebrospinal fluid ratio ratio (CSFR) compared with their healthy counterparts. Age and sex were significantly correlated with some BV measurements in both patient and control groups. Body mass index (BMI) was significantly correlated with CSFR, BR, GMR, and WMR; Hct with CSFR and BR; serum GGT level with BV, CSFR, BR, GMR, and WMF in the patient group. No biological variables were correlated with BV indices in the control group. In gender-stratified analysis, age was significantly correlated with brain shrinkage in male patients but not in female patients. Serum GGT level in male and female patients, Hct in male patients, and AST levels in female patients were significantly correlated with brain shrinkage. Conclusions: Our results showed that the higher levels of liver function indices, especially GGT, correlated with BV shrinkage as measured using CSFR, BR, GMR, and WMR in patients with alcohol dependence but not in controls. Serum GGT level outweighed aging effect on brain

Increasing attention has been paid recently to the potential diabetogenic effect of second-generation antipsychotics (SGAs). The objective of this prospective study was to evaluate the effects of quetiapine treatment on pancreatic beta-cell function in SGA-naïve schizophrenic patients. Seventeen schizophrenic subjects completed an eight-week trial. The metabolic parameters were assessed at weeks 0, 2, 4, and 8. We measured glucose homeostasis with the intravenous glucose tolerance test. After the eight-week treatment, body weight and body mass index showed to be significantly increased compared to those at baseline. No significant changes were found in serum levels of fasting glucose, insulin, total cholesterol, and high-density lipoprotein. Insulin resistance and insulin secretion were significantly increased. Incidences of clinically significant weight gain and treatment-emergent metabolic syndrome were 11.8% and 11.8%, respectively. This study result confirms the association of quetiapine treatment and impairment of glucose homeostasis in schizophrenic patients.

Objective Metabolic syndrome (MS) is a major health problem in schizophrenic patients. Peroxisome proliferator-activated receptor γ2 (PPARγ2) is one of the candidate genes responsible for the liability to metabolic problems. In this study, we investigated the effect of the PPARγ2 gene Pro12Ala and C161T polymorphisms on metabolic adversities in patients with schizophrenia or schizoaffective disorder. Methods Metabolic profiles and PPARγ2 gene polymorphisms were determined in 600 patients (309 men and 291 women) with a clinical diagnosis of schizophrenia or schizoaffective disorder. Metabolic indices and components of MS were compared between patients with different Pro12Ala or C161T genotypes. Results In the whole population, the allele frequency of 12Ala and 161T was 4.4% and 24.7% respectively. Both polymorphisms had no significant effect on obesity or metabolic-related traits. However, following gender stratification of the data, we found female 12Ala allele carriers were at greater risk of developing abdominal obesity (OR = 4.0, 95% CI = 1.1–14.2, p = 0.04) and hypertension (OR = 2.9, 95% CI = 1.2–7.4, p = 0.02) than female 12Ala allele non-carriers. Male 161T allele carriers had lower insulin levels ( p = 0.02) and lower high-density lipoprotein cholesterol (HDL-C) ( p = 0.05) levels than male 161T allele non-carriers. Moreover, female 161T allele carriers had higher body weight ( p = 0.04), waist circumference ( p = 0.05), and systolic blood pressure ( p = 0.01), and were at greater risk of developing hypertension (OR = 2.0, 95% CI = 1.1–3.5, p = 0.02). Haplotype analyses showed that PPARγ2 gene polymorphisms were significantly associated with HDL-C level in men and blood pressure in women. Conclusions We did not find an association of PPARγ2 gene polymorphisms with MS or obesity in our schizophrenia sample. But further analyses by gender stratification revealed gender-specific differences in the effect of different PPARγ2 genotypes on certain metabolic adversities in these patients.

Background: Chronic and excessive alcohol consumption enhances the formation of reactive oxygen species (ROS) and ethanol-derived free radicals. 8-Hydroxy-2′-deoxyguanosine (8-OHdG) is a marker to estimate ROS-induced DNA damage. The study objective was to compare serum 8-OHdG levels between patients with alcohol dependence and healthy controls and to investigate the correlation between this marker and the severity of alcohol withdrawal syndrome (AWS). Methods: We recruited 79 patients with alcohol dependence and 63 healthy control subjects. The severity of AWS was evaluated using the Chinese version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar-C) every 8 hours. Levels of 8-OHdG, malondialdehyde (MDA), and other biologic indexes were assayed at baseline for patient and control groups, and after 1-week detoxification for the patient group. Results: The 8-OHdG and MDA levels in the alcoholic group were significantly higher than those in the control group (0.34 vs. 0.27 ng/ml and 13.5 vs. 10.1 μM, respectively). Both 8-OHdG and MDA were significantly correlated with the highest CIWA-Ar-C (correlation coefficient = 0.39, p

Background: Brain-derived neurotrophic factor (BDNF) is associated with alcohol addiction and withdrawal-related neurotoxicity. Delirium tremens (DT) is the most serious complication of alcohol withdrawal syndrome (AWS). In this study, we explored the differences in serum BDNF levels, measured at baseline and 1 week after alcohol withdrawal among alcoholic patients with and without DT. Methods: Sixty-five inpatients, fulfilling the DSM-IV criteria of alcohol dependence and admitted for alcohol detoxification, as well as 39 healthy control subjects were enrolled. The alcoholic patients were divided by the appearance of DTs into the DT group (n = 25) and non-DT group (n = 40). We collected blood samples of the patient groups on the first and seventh days of alcohol withdrawal and measured serum BDNF levels by sandwich enzyme-linked immunosorbent assay. Results: Serum BDNF levels differed significantly among the three groups: (i) control group 14.8 ± 4.7 ng/ml; (ii) non-DT group 12.3 ± 3.3 ng/ml; (iii) DT group 6.2 ± 2.6 ng/ml (p

Background: There are clear interactions between chronic alcohol consumption and circadian rhythmicity that is regulated by several circadian clock genes. The altered expressions of these genes have been mainly described in animals. The mammalian master clock in the suprachiasmatic nuclei orchestrates the biological rhythms in peripheral tissues. As peripheral blood mononuclear cells (PBMCs) are the most accessible tissue clinically, we assessed the mRNA levels of these genes in patients with alcohol dependence (AD) undergoing alcohol-withdrawal (AW) treatment. Methods: Twenty-two male patients fulfilled the DSM-IV diagnostic criteria of AD, and 12 comparison healthy control subjects were recruited. The patients with AD were further divided by the presence of delirium tremens (DTs), the most severe form of AW syndrome, into DT group and non-DT group. All the participants received blood withdrawal at 9 am, while the patients with AD had blood collection twice: on the next morning of admission (baseline) and on the seventh day. PBMCs were isolated from whole blood, and the mRNA expression profiles of hClock1, hBmal1, hPer1, hPer2, hCry1, and hCry2 were determined by quantitative real-time PCR. Results: The baseline mRNA levels of the target circadian clock genes were markedly lower in patients with AD than in control subjects. After 1 week of alcohol detoxification, there were very limited restorations of discrete circadian gene expressions. DT group did not differ in the expression patterns of circadian clock genes from non-DT group. Conclusions: This is the first study demonstrating the overall lowering of circadian clock genes among patients with AD. The expression pattern is comparable between patients with and without DTs. Although preliminary with data at only one single time point, the observation of strikingly reduced mRNA levels supports the association between circadian clock gene dysregulation and chronic alcohol intake.

The second generation antipsychotic drugs (SGAs) are effective in treating patients with schizophrenia and have been considered as the first line therapy. Recently, increasing attention has been drawn to the potential diabetogenic effect of these novel antipsychotics. The goal of this study was to evaluate the time-dependent effects of olanzapine treatment on pancreatic beta cell function in SGA-naive schizophrenic patients. Forty-two schizophrenic subjects received olanzapine therapy for 8 weeks and thirty-three of them completed the trial. Of whom 33 completers (21 male, mean ± SD age: 37.6 ± 8.0 years) were inpatients and unexposed to SGA. The metabolic parameters were quantitatively assessed at weeks 0, 2, 4, and 8 by the intravenous glucose tolerance test. After 56-day olanzapine treatment, subjects had significant increases in body weight and as well as in the levels of triglyceride, total cholesterol, and low-density lipoprotein. Insulin secretion significantly decreased at week 2, returned to baseline at week 4, and significantly increased at week 8. Of the total samples, 18.2% and 33.3% of them met the criteria for significant weight gain and metabolic syndrome after 8-week olanzapine treatment, respectively. This study indicates that olanzapine-treated schizophrenic patients displayed biphasic changes in insulin secretion to a hyperglycemic challenge. The results of this study support that olanzapine might directly influence pancreatic beta cell function.

Objective: Because of ethnic differences in metabolic syndrome (MS) criteria, this study aimed to investigate the MS prevalence among patients with schizophrenia or schizoaffective disorder in Taiwan. Method: We recruited 650 patients with schizophrenia or schizoaffective disorder from 36 psychiatric institutions. The MS prevalence was assessed based on the modified Adult Treatment Panel (ATP) III criteria for Asians. Results: The overall MS prevalence was 34.9%, with 38.9% in female and 31.5% in male patients respectively. The difference of MS prevalence between our sample and the general population was marked in male patients under 40 years of age and in female patients under 50 years old. Body mass index ≥24 and age over 40 years old are two important risk factors of MS. Female and polypharmacy had marginal significance with the presence of MS. Conclusion: Patients with schizophrenia or schizoaffective disorder in Taiwan had a high prevalence of MS, which appeared early in their lives.

Aims: This 12-week open-label study was designed to investigate the pharmacokinetics and efficacy of a direct switch from a conventional depot to long-acting injectable risperidone in patients with schizophrenia and schizoaffective disorder. Methods: Men or women from 18 to 65 years old with a diagnosis of schizophrenia or schizoaffective disorder were eligible for participation if they had been treated with conventional depot for at least 8 weeks before study entry. Intramuscular long-acting risperidone was administered starting from 25 mg, with the dose flexibly adjusted every two weeks for 12 weeks from week 4. Results: Of the 25 patients enrolled in this study, 21 completed at least one post-baseline assessment and were thus included in the analysis. The mean serum concentration of risperidone plus 9-hydroxyrisperidone was 29.1 ng/mL at the 12th week after switching, with an average injection dose of 31.25 mg long-acting risperidone every two weeks. The levels of active moiety of risperidone seemed to be higher in Chinese patients compared to those in Caucasian patients. Positive and Negative Syndrome Scale total scores (from 67.5 to 56.4; P = 0.002), scores for negative symptoms (P = 0.006) and general symptoms (P = 0.001) were improved significantly 12 weeks after the switch. Mean Extrapyramidal Symptom Rating Scale scores were improved significantly from 20.1 to 5.5 (P

Aims: A higher prevalence of alcohol use disorders (AUD) among psychiatric patients has been reported previously and the identification rate is relatively low. This study was designed to investigate the prevalence and identification of AUD among acute psychiatric inpatients with severe mental illness in a psychiatric hospital in Taiwan. Methods: In a two-phase case identification strategy, the Alcohol Use Disorders Identification Test (AUDIT) was used as the first phase screening tool and the Structured Clinical Interview for DSM-IV-TR as the second phase diagnostic interview. The definition of identification was diagnosis of AUD on medical record at discharge. Results: Of 400 respondents, 42 screened positive and 358 screened negative. All screen-positive respondents and 35 screen-negative respondents entered the second phase interview. The weighted lifetime prevalence of alcohol dependence was 8.3% (95% confidence interval [CI]: 4.6–11.9%); alcohol abuse, 1.5% (95%CI: 0.2–2.8%); and AUD, 9.8% (95%CI: 5.7–13.8%). The overall identification rate of AUD by medical staff was 28.2% (0% for alcohol abuse and 33.3% for alcohol dependence). Patients with mood disorders were prone to being undetected as having AUD. Conclusion: AUD comorbidity was common among inpatients with severe mental illness in Taiwan and was easily neglected by medical staff. It is necessary to use a validated screening questionnaire, such as AUDIT, to detect high-risk patients and then give appropriate interventions to enhance treatment outcome.

The second generation antipsychotic drugs, such as risperidone, olanzapine, and quetiapine, are effective in treating patients with schizophrenia and have been considered as the first line therapy. Recently, increasing attention has been drawn to the potential diabetogenic effect of these novel antipsychotics. The goal of this study was to evaluate the effect of metformin treatment on the olanzapine-induced metabolic disturbance in schizophrenic patients. Twenty-four schizophrenic subjects who had received olanzapine treatment at least 3 months were assigned to the therapy with metformin 1500 mg/day for 8 weeks. The metabolic parameters were quantitatively assessed at baseline, weeks 2, 4, and 8 by using the intravenous glucose tolerance test. After an 8-week treatment with metformin, the body weight, fasting levels of glucose, triglyceride, and insulin, insulin secretion, and insulin resistance significantly decreased. Half of study subjects with metabolic syndrome obtained improvement after the metformin trial. Subjects' psychopathological condition remained unchanged during the study period. The olanzapine-induced metabolic disturbance could be reversed after 8-week metformin treatment. Based on the results of this study, we hypothesize that metformin could modulate the effect of olanzapine-induced metabolic disturbance.

Nasopharyngeal carcinoma (NPC) is an epithelial cancer that metastasizes predictably to cervical lymph nodes or distant organs. To assess whether the chemokine receptors of NPC cells play important roles in metastasis and are associated with radiotherapy history, the significance of various chemokine receptors (CCR1-10, CXCR1-6, XCR1, and CX3CR1) in NPC cell lines (TW01, TW04, HONE1, BM1, and AS1) and 52 NPC tumour biopsies from 48 patients with NPC was evaluated by mRNA and cytometric analyses, chemotaxis and actin polymerization assays, and immunohistochemical staining. Quantitative real-time reverse transcription-polymerase chain reaction revealed substantial expression of CCR7, CCR9, CXCR4, and CXCR6 mRNA in all the NPC cell lines. Of these, however, only CCR7, CXCR4, and CXCR6 were functional in NPC cells. Negative immunoreactivity for CCR7, CXCR4, and CXCR6 was demonstrated in almost all nasopharyngeal (NP) specimens from patients with primary NPC (n = 12) and in those with regional metastatic NPC (n = 15). However, expression of two or three of these chemokine receptors was demonstrated in NP specimens from patients with liver metastasis. Strong positivity was demonstrated for all three of these chemokine receptors in almost all of the regional and distant metastasis specimens. Significant differences in the expression of CCR7, CXCR4, and CXCR6 were found between primary tumours and metastases (p < 0.001, p < 0.001, and p < 0.002, respectively). This observation was further confirmed by laser capture microdissection of freshly frozen tumours from primary (n = 5) and metastatic (n = 8) NPC sites (p = 0.04, 0.03, and 0.03 for CCR7, CXCR4, and CXCR6, respectively). Finally, significant differences in CXCR4 expression were demonstrated between de novo and post-radiotherapy groups (1/22 vs. 5/8; p < 0.003). It appears reasonable to conclude, therefore, that CCR7, CXCR4, and CXCR6 are expressed and active in human NPC metastases, while CXCR4 expression is associated with radiotherapy history.

Aims: Alcoholic energy drinks (AEDs) have been popular among Taiwanese manual workers. Study results concerning increased health risks of AED consumption relative to alcohol alone have been inconsistent, and the risk for potential work-related injury or disease has not been studied. Our study goal was to evaluate the association between AED consumption and work-related injury or disease in manual workers in Taiwan. Methods: Nationalsurvey data oftheworking population in 2007wasutilized. Atotal of1192 manual workers, who drank alcohol more than once per week, were divided into AED-drinkers and non-AED drinkers. We compared AED drinking behaviors and risk of work-related injury or disease between the two groups. Results: AED drinkers had a higher risk of work-related injury or disease, with an odds ratio of 1.48 (95% CI: 1.14–1.93), after controlling demographic, smoking and drinking characteristics. The presence of problem drinking (defined by CAGE score equal to or higher than two) was another risk factor of having work-related injury or disease. Compared to non-AED counterparts, AED drinkers had a significantly higher prevalence of work-related injury or disease in the strata of CAGE score of 1 and 2. Conclusion: AED consumers presented increased risks of work-related injury or disease compared with non-AED drinkers among manual workers in Taiwan. In order to conduct an effective intervention program to protect Taiwanese manual workers from potential risks, the reasons for this increased risk among AED drinkers need to be further studied.

Background Chronic and excessive alcohol consumption increases oxidative stress. We previously found that levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, are elevated in alcohol-dependent patients without delirium tremens (DTs). The aim of this study was to compare serum 8-OHdG levels between alcohol-dependent patients with and without DTs. Methods We recruited 16 alcohol-dependent patients with DTs (DTs group) and 58 patients without DTs (non-DTs group). Alcohol withdrawal severity was evaluated using the Chinese version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar-C) every 8 hours. Serum levels of 8-OHdG and other biological indices were assayed at baseline and after 1 week of detoxification. Results The mean 8-OHdG level in the DTs group was significantly higher than that in the non-DTs group (0.50 vs. 0.34 ng/ml, p

Background Metformin has been used for alleviating metabolic abnormalities in patients with schizophrenia. The lowest dose of metformin to treat metabolic abnormalities in clozapine-treated patients is 1000 mg/d. This study was designed to determine whether metformin at 500 mg/d and 1000 mg/d is effective in improving the metabolic profiles of clozapine-treated patients with pre-existing metabolic abnormalities, and whether its effectiveness depends on metformin dosage. Methods In this 12-week, randomized, double-blind, placebo-controlled trial, metformin at 500 mg/d or 1000 mg/d was prescribed to clozapine-treated patients with schizophrenia who had pre-existing metabolic abnormalities. The recruited patients underwent physical and laboratory evaluations at weeks 4, 8, and 12. The outcomes were any changes in metabolic traits. Results Among the 96 clozapine-treated patients with schizophrenia screened for the trial, 55 patients with pre-existing metabolic abnormalities were randomly assigned to placebo (n = 18), metformin dosage at 500 mg/d (n = 18), and metformin dosage at 1000 mg/d (n = 19) groups. The body weight (BW) of patients in the metformin 1000 mg/d group significantly decreased, by a mean of 0.97 kg over the 12 week trial period. Moreover, patients in the metformin at 500 mg/d and 1000 mg/d groups had a significant decrease in body mass index (BMI) after 12 weeks, with the mean decrease being 0.70 and 0.50 kg/m2, respectively. No significant changes were observed in the other metabolic parameters of patients in the three groups. Conclusions Our results demonstrated that a low metformin dosage of either 500 mg/d or 1000 mg/d for 12 weeks slightly reduced the BW and BMI of clozapine-treated patients with pre-existing metabolic abnormalities. A longer period of treatment with a larger sample is warranted to determine the factors that influence the metformin treatment response. Trial Registration ClinicalTrials.gov NCT02751307

Introduction Hyperprolactinemia is a well-recognized side effect of antipsychotic treatment. Cabergoline, a dopamine agonist, has been introduced on the market to treat hyperprolactinemia, even secondary to antipsychotic use. Case report In this article, we described two schizophrenic patients who received cabergoline to treat their antipsychotic-induced hyperprolactinemia and developed a subsequent psychotic exacerbation. The first patient received amisulpride as antipsychotic medication, and the second one took risperidone and fluoxetine for her psychotic and depressive symptoms, respectively. Both patients improved significantly their psychotic symptoms in 1 week without changing their former antipsychotic regimens. Discussion To the best of our knowledge, we found no previous report of cabergoline-induced psychotic exacerbation in schizophrenic patients who received antipsychotics. We brought up questions whether schizophrenic patients on amisulpride or with the addition of fluoxetine may have higher risk to experience psychotic worsening. We also highlighted the possible role of dose-dependent nature in cabergoline-induced psychotic exacerbation, suggesting that the single starting dose of 0.5 mg or higher might be unsafe in schizophrenic patients. Conclusion These cases suggest that cabergoline, like other dopaminergic agents, should be used with caution in psychotic patients and the dose should be as low as possible.

Objective: Many studies have shown that metformin can decrease body weight and improve metabolic abnormalities in patients with schizophrenia. Whether or not the beneficial effects can be sustained after discontinuation of metformin needs to be evaluated. We conducted a 24-week randomized, double-blind, placebo-controlled study to evaluate the effect of metformin on metabolic features in clozapine-treated patients with schizophrenia and followed their body weight after stopping the intervention for at least 24 weeks. Method: The study was conducted between September 2008 and July 2011. We recruited patients with DSM-IV diagnosis of schizophrenia or schizoaffective disorder who had been taking clozapine for more than 3 months, were overweight or obese, or fulfilled at least 1 criteria of metabolic syndrome. Eligible patients were randomized to receive metformin 1,500 mg/d or placebo. We followed metabolic features at baseline and at weeks 2, 4, 8, 16, and 24 and rechecked body weight when the patients stopped the trial after at least 24 weeks. Results: A total of 55 subjects (28 in the metformin and 27 in the placebo group) were enrolled. There were no significant differences in all baseline characteristics between the 2 groups, except that patients in the metformin group had higher fasting plasma glucose levels (P = .03). After the 24-week intervention, body weight (P < .0001), body mass index (P < .0001), fasting plasma glucose (P < .0001), highdensity lipoprotein cholesterol (P = .03), insulin level (P = .01), and homeostasis model assessment index (P = .02) had significant changes in the metformin group. At the end of the intervention, 8 patients (28.57%) lost more than 7% of their body weight in the metformin group. Mean body weight returned to baseline after patients stopped the intervention in the metformin group. Conclusions: Metformin can significantly reduce body weight and reverse metabolic abnormalities in clozapine-treated patients with schizophrenia and preexisting metabolic abnormalities. However, the beneficial effects of metformin on body weight disappeared after discontinuing this medication. Trial Registration: ClinicalTrials.gov identifier: NCT01300637

Aims: Alcohol withdrawal-enhanced neurotoxicity contributes to the addictive process. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity and learning. In this study, we explored the changes of serum BDNF levels in alcoholic patients at baseline and after one-week alcohol withdrawal. Methods: Twenty-five alcoholic patients were admitted for alcohol detoxification treatment, and 22 healthy control subjects were also enrolled. We collected blood samples of the patient group on the first and seventh day of alcohol withdrawal, and measured serum BDNF level with sandwich enzyme-linked immunosorbent assay. The severity of withdrawal symptoms was evaluated by the Clinical Institute Withdrawal Assessment-Alcohol, Revised every eight hours. Results: Serum BDNF levels did not differ significantly between alcoholic patients and control subjects. But BDNF levels were found to be significantly increased one week after alcohol withdrawal (from 13.9 ± 3.8 ng/ml to 15.4 ± 3.8 ng/ml, P = 0.03). A significant positive correlation was found between baseline BDNF level and baseline withdrawal severity ( r = 0.45, P = 0.03). Conclusions: The present study suggests that elevated serum BDNF levels were found in early alcohol withdrawal, implying that BDNF may involve in neuroadaptation during the period.

Alcohol use disorders (AUDs) are common among inpatients in general hospitals and often cause excess mortality. This study investigates the prevalence of AUDs among nonpsychiatric inpatients in one general hospital and evaluates the ability of medical staff to identify such morbidity. A two-phase case-identification strategy was employed utilizing the Alcohol Use Disorders Identification Test as the first-phase screening tool and the Schedules for Clinical Assessment in Neuropsychiatry as the second-phase diagnostic interview. Among 538 eligible patients, a total of 422 (78.4%) completed the first-phase screening. A subsample (20%) of those screened negative and 90% of those screened positive were interviewed at the second phase. The weighted 1-year prevalence rates of alcohol abuse and alcohol dependence were 3.9% and 12.6%, respectively. The overall identification rate of AUDs by medical staff was 25.4% (0% for alcohol abuse and 30% for alcohol dependence). In conclusion, approximately one sixth of nonpsychiatric inpatients in a general hospital have AUDs and have been neglected substantially by medical staff. Implications of the findings for the prevention of AUDs and their physical complications are discussed.