Randomized, double-blind, placebo, and risperidone-controlled study of lurasidone in the treatment of schizophrenia: Results of an inconclusive 6-week trial.

OBJECTIVE: The efficacy and safety of lurasidone in schizophrenia has been demonstrated in multiple controlled trials, primarily in US and European populations. The aim of the current study was To evaluate lurasidone for the treatment of schizophrenia among patients in Japan, Korea, and Taiwan. METHODS: Hospitalized patients (N = 460) with schizophrenia were randomized to 6 weeks of fixed-dose lurasidone 40 mg/d, lurasidone 80 mg/d, risperidone 4 mg/d, or placebo. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). RESULTS: No significant endpoint differences in PANSS total score were found for lurasidone or risperidone vs placebo. Lurasidone was safe and well tolerated, with minimal effects on weight and metabolic parameters. DISCUSSION: The current study was inconclusive regarding the efficacy of lurasidone in schizophrenia but further confirmed its safety and tolerability.

Clozapine induces autophagic cell death in non-small cell lung cancer cells.

BACKGROUND/AIMS: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. METHODS: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. RESULTS: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. CONCLUSIONS: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

Assessment and classification of service learning: a case study of CS/EE students.

This study investigates the undergraduate students in computer science/electric engineering (CS/EE) in Taiwan to measure their perceived benefits from the experiences in service learning coursework. In addition, the confidence of their professional disciplines and its correlation with service learning experiences are examined. The results show that students take positive attitudes toward service learning and their perceived benefits from service learning are correlated with their confidence in professional disciplines. Furthermore, this study designs the knowledge model by Bayesian network (BN) classifiers and term frequency-inverse document frequency (TFIDF) for counseling students on the optimal choice of service learning.

Switching from clozapine to zotepine in patients with schizophrenia: a 12-week prospective, randomized, rater blind, and parallel study.

Clozapine is the most effective antipsychotic for patients with treatment-refractory schizophrenia, but many adverse effects are noted. Clinicians usually hesitate to switch from clozapine to other antipsychotics because of the risk of a re-emergence or worsening of the psychosis, although empirical studies are very limited. Zotepine, an atypical antipsychotic with a pharmacologic profile similar to clozapine, was found to be an effective treatment for patients with treatment-resistant schizophrenia in Japan. This 12-week study is the first prospective, randomized, and rater-blind study to investigate the efficacy and tolerability of switching from clozapine to zotepine. Fifty-nine patients with schizophrenia, who had taken clozapine for at least 6 months with a Clinical Global Impression-Severity score of at least 3, were randomly allocated to the zotepine and the clozapine groups. At the end of the study, 52 patients (88%) had completed the trial. The 7 withdrawal cases were all in the zotepine group. The final mean (SD) dose of zotepine and clozapine was 397.1 (75.7) versus 377.1 (62.5) mg/d, respectively. Patients in the zotepine group showed a significant increase in the Brief Psychiatric Rating Scale [mean (SD), 4.7 (8.7) vs -1.3 (6.3); P = 0.005], more general adverse effects as revealed by the Udvalg for Kliniske Undersogelser Rating Scale [mean (SD), 1.74 (3.9) vs -0.2 (2.8); P = 0.039], more extrapyramidal adverse effects as demonstrated by the Simpson and Angus Scale [mean (SD), 1.29 (3.5) vs 0.17 (2.1); P = 0.022], an increased use of propranolol (37.1% vs 0%, P < 0.0001) and anticholinergics (25.7% vs 0%, P = 0.008), and an increased level of prolactin (29.6 vs -3.8 ng/ mL, P < 0.0005), compared with the clozapine group. The results suggested that switching from clozapine to zotepine treatment should be done with caution.

Finding social phobia patients from the Internet.

Patients with social phobia commonly resist face-to-face assessments, and a number of alternative assessment methods based on the Internet are being developed. The aim of this study was to identify patients with social phobia on the Internet and characterize their condition, using the Social Phobia Inventory (SPIN). In Stage I, this study recruited 1307 participants from the Internet, most of whom were well-educated young females, who had remained unmarried and unemployed. The Internet-based SPIN demonstrated excellent internal consistency (Cronbach's α=0.937) and good test-retest reliability (intraclass correlation coefficient=0.942). In Stage II, we examined the discriminant validity of the SPIN via structured telephone interviews. The area under the receiver operating characteristic curve used to discriminate social phobia was 0.871 with an optimal cut-off point of 24 on the total score for the SPIN. According to the SPIN scores, 919 of Stage I participants (70.3%) reached the threshold of social phobia, 531 of which (57.8%) had never sought professional help. These results suggest that the Internet is a potential avenue through which to find untreated patients with social phobia.

Association of weight gain and metabolic syndrome in patients taking clozapine: an 8-year cohort study.

INTRODUCTION: Metabolic syndrome is an important side effect associated with clozapine. It has been hypothesized that weight gain contributes to the development of metabolic syndrome, but a direct diabetogenic effect has also been suggested. We conducted an 8-year cohort study to determine the association between weight gain and metabolic parameters among schizophrenic patients taking clozapine. METHOD: This study is a retrospective cohort study combining a cross-sectional survey of metabolic syndrome and retrospective chart review. The subjects were hospitalized schizophrenic patients (DSM-IV) who began to receive clozapine at least 3 months before the survey (March to September 2005) and subsequently had monthly body weight monitoring. Anthropometric and biochemical measurements were performed to determine the presence of metabolic syndrome. The chart reviews were conducted to obtain gender, age at initiation of clozapine treatment, baseline body mass index (BMI), BMI changes after the initiation of clozapine treatment, treatment duration with clozapine, and concomitant psychotropic medications. RESULTS: One hundred eighty-nine patients were maintained on clozapine for a mean ± SD treatment duration of 57.6 ± 27.3 months (range, 5-96). The prevalence of metabolic syndrome was 28.4%. The cohort regression models showed that baseline BMI (P < .01) and BMI change after clozapine treatment (P < .01) were significant factors for metabolic syndrome and 4 metabolic parameters except hyperglycemia, which was related to treatment duration (P < .05). CONCLUSIONS: For patients treated with clozapine, metabolic syndrome and most metabolic parameters were related to weight gain; however, glucose dysregulation was associated with treatment duration independent of weight gain. The results confirm that monitoring body weight is important, but periodic monitoring of blood sugar may also be required for clozapine patients who do not have significant weight gain.

Analysis of genetic variations in the human melatonin receptor (MTNR1A, MTNR1B) genes and antipsychotics-induced tardive dyskinesia in schizophrenia.

OBJECTIVES: Antipsychotics-induced tardive dyskinesia (TD) has been suggested to be related to altered dopaminergic neurotransmission in the striatum. Melatonin has a modulating effect on dopaminergic neurotransmission in the brain; therefore, the hypothesis of an association between the melatonin receptor genes (MTNR1A, MTNR1B) and antipsychotics-induced TD was examined in this study. METHODS: Schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale, and only patients who were either free of any abnormal involuntary movement (non-TD group) or who demonstrated persistent TD (TD group) were enrolled. Genotyping of six tagging single nucleus polymorphisms (SNPs) in the melatonin receptor genes (MRNR1A, MTNR1B) was then performed for each subject. RESULTS: Four hundred and eighteen inpatients (TD=256, non-TD=162) fitted the study criteria and underwent TD assessment and genotyping. Individual haplotype analysis showed that the haplotype ATG was significantly associated with non-TD (permutation P=0.037), and the association was also found to be significant by global haplotype analyses (permutation P=0.045). CONCLUSIONS: Our results indicated a significant association between the haplotype ATG in the MTNR1A gene and non-TD. Further replication in other countries or other populations is indicated.

Analysis of genetic variations in the dopamine D1 receptor (DRD1) gene and antipsychotics-induced tardive dyskinesia in schizophrenia.

BACKGROUND: Dyskinesia is a kind of abnormal involuntary movement disorder that increases with age. The pathogenesis of dyskinesia may result from divergent changes in dopamine D1 receptors (DRD1) and dopamine D2 receptors (DRD2) in the brain while aging. Tardive dyskinesia (TD), a kind of dyskinesia, may develop after long-term antipsychotic treatment. Because the prevalence of TD also steadily increased with age, TD has been suggested to be the consequence of an imbalance between DRD1 and DRD2. We supposed that patients who develop TD may have genetic variants of DRD1 that cause the excitatory effects of DRD1 overwhelming the attenuated inhibitory effects of DRD2 after antipsychotic treatment. METHODS: In the present study, schizophrenic inpatients receiving long-term antipsychotic treatment were first assessed using the Abnormal Involuntary Movement Scale (AIMS), and only patients who were either free of any abnormal involuntary movements (non-TD group, AIMS =0) or who showed persistent TD (TD group) were enrolled. Finally, 382 patients were recruited (TD=220, non-TD=162) and three single nucleus polymorphisms (SNPs; rs5326, rs4532 and rs265975) of DRD1 were genotyped for each subject. RESULTS: Genotype frequency (%; AA/AG/GG) of rs4532 (TD: non-TD) was 61.4/35.8/2.8: 74.2/24.5/1.3. After genetic analyses, genotype GG showed significant association with TD (if OR=2.0, power (%)=98.5; if OR=1.5, power (%)=63.7; P=0.033). Haplotype frequency (%) CGC of rs5326-rs4532-rs265975 (TD: non-TD) was 19.0:13.7; and after haplotype-based analyses, haplotype CGC also showed significant association with TD (OR=1.4, permutation P=0.027). CONCLUSION: Our results indicate that the genotypic variants of DRD1 might play a role in the susceptibility of TD. Further replication in other countries or other populations is highly expected.

Support for the involvement of the ERBB4 gene in schizophrenia: a genetic association analysis.

Cellular, animal and human studies support the involvement of aberrant NRG-ErbB signaling in the pathogenesis of schizophrenia. The aim of the present study was to examine whether genetic variation in the human ERBB4 gene is associated with susceptibility to schizophrenia. Two hundred and twenty-seven unrelated chronic inpatients with schizophrenia were enrolled in the study, and the genetic variation in the polymorphisms of the ERBB4 gene in the patients was compared with that of the control group, which consisted of 223 subjects free of psychiatric illness. The results showed that one coding-synonymous polymorphism (rs3748962, Val1065Val) was in genotypic (p=0.0027) and allelic (p=0.0007) association with schizophrenia. In comparison with subjects of the rs3748962-TT type, those of the rs3748962-CT and rs3748962-CC types were at 1.74- and 2.64-fold greater risk of schizophrenia (CT vs. TT: OR=1.71 (95% CI=1.15-2.53), p=0.0014; CC vs. TT: OR=2.64 (95% CI=1.37-5.23), p=0.0047), which supports the hypothesis of an additive model of transmission (p=0.0006). Furthermore, the frequency of haplotype ATC of rs3791709-rs2289086-rs3748962 was found to be significantly higher in the patients with schizophrenia than in the controls (case vs. control=36.0% vs. 24.4%, permutation p-value=0.0002). The findings support the involvement of the ERBB4 gene in schizophrenia in Han Chinese.

Resequencing of the vesicular glutamate transporter 2 gene (VGLUT2) reveals some rare genetic variants that may increase the genetic burden in schizophrenia.

OBJECTIVES: Vesicular glutamate transporters (VGLUT1-3) package glutamate into vesicles in the presynaptic terminal and regulate the release of glutamate. In mesencephalic dopamine neuron culture, the majority of isolated dopamine neurons express VGLUT2, but not VGLUT1 or 3, have been demonstrated. As related to the dysregulated glutamatergic hypothesis of schizophrenia, the gene encoding VGLUT2 is the most plausible candidate involved in the pathogenesis of this illness. METHODS: We searched for genetic variants in the promoter region and 12 exons (including UTR ends) of the VGLUT2 gene using direct sequencing in a sample of Han Chinese schizophrenic patients (n=375) and non-psychotic controls (n=366) from Taiwan, and conducted a case-control association study. RESULTS: We identified 8 common SNPs in the VGLUT2 gene. SNP and haplotype-based analyses showed no association with schizophrenia. Besides, we identified 9 rare variants in 13 out of 375 patients, including 3 variants located at the promoter region, 2 synonymous variants located at protein coding regions, and 4 variants located at UTR ends. No rare variants were found in the control subjects. Collectively, these rare variants were significantly overrepresented in the patient group (3.5% versus 0, p value of Fisher's exact test=2.3x10(-5)), suggesting they may contribute to the pathogenesis of schizophrenia. CONCLUSION: Although the functional significance of these rare variants remains to be characterized, our study may lend support to the multiple rare mutations hypothesis of schizophrenia, and may provide genetic clues to indicate the involvement of the glutamate transmission pathway in the pathogenesis of schizophrenia.

Genetic association between TNF-alpha -308 G>A polymorphism and longitudinal weight change during clozapine treatment.

OBJECTIVE: The aim of the study was to investigate the association between genetic variation in the tumor necrosis factor-alpha (TNF-alpha) gene and longitudinal weight change during long-term clozapine treatment. METHODS: Fifty-five patients with refractory schizophrenia treated with clozapine for 8 years were recruited. Gender, age, treatment response to clozapine in the first 14 months, baseline BMI, clozapine dose, concomitant use of mood stabilizers and other antipsychotics, and -308 G > A polymorphism in the human TNF-alpha gene were analyzed using generalized estimating equations. RESULTS: In addition to having a lower baseline BMI (p = 0.0013) and a longer treatment time (p = 0.050), the -308 GG carriers gained significantly more weight than the -308 A allele carriers (p = 0.0084) during 8 years of clozapine treatment, after controlling for other non-genetic factors. CONCLUSIONS: The -308 G > A genetic variant of the TNF-alpha gene is associated with longitudinal weight change during clozapine treatment. Follow-up duration is an important factor to consider when performing pharmacogenetic study of clozapine-induced weight gain.

Easy and low-cost identification of metabolic syndrome in patients treated with second-generation antipsychotics: artificial neural network and logistic regression models.

OBJECTIVE: Metabolic syndrome (MetS) is an important side effect of second-generation antipsychotics (SGAs). However, many SGA-treated patients with MetS remain undetected. In this study, we trained and validated artificial neural network (ANN) and multiple logistic regression models without biochemical parameters to rapidly identify MetS in patients with SGA treatment. METHOD: A total of 383 patients with a diagnosis of schizophrenia or schizoaffective disorder (DSM-IV criteria) with SGA treatment for more than 6 months were investigated to determine whether they met the MetS criteria according to the International Diabetes Federation. The data for these patients were collected between March 2005 and September 2005. The input variables of ANN and logistic regression were limited to demographic and anthropometric data only. All models were trained by randomly selecting two-thirds of the patient data and were internally validated with the remaining one-third of the data. The models were then externally validated with data from 69 patients from another hospital, collected between March 2008 and June 2008. The area under the receiver operating characteristic curve (AUC) was used to measure the performance of all models. RESULTS: Both the final ANN and logistic regression models had high accuracy (88.3% vs 83.6%), sensitivity (93.1% vs 86.2%), and specificity (86.9% vs 83.8%) to identify MetS in the internal validation set. The mean +/- SD AUC was high for both the ANN and logistic regression models (0.934 +/- 0.033 vs 0.922 +/- 0.035, P = .63). During external validation, high AUC was still obtained for both models. Waist circumference and diastolic blood pressure were the common variables that were left in the final ANN and logistic regression models. CONCLUSION: Our study developed accurate ANN and logistic regression models to detect MetS in patients with SGA treatment. The models are likely to provide a noninvasive tool for large-scale screening of MetS in this group of patients.

Improved body weight and metabolic outcomes in overweight or obese psychiatric patients switched to amisulpride from other atypical antipsychotics.

Switching to a different second-generation antipsychotic (SGA) with a lower risk of weight gain is recommended for overweight or obese psychiatric patients undergoing SGA treatment. However, there have been no complete reports regarding the long-term metabolic effects of switching to amisulpride. In this open-label 1-year study, we investigated the effects on body weight and other metabolic profiles when psychiatric patients treated with another SGA were switched to amisulpride treatment. Forty-six schizophrenia or schizoaffective inpatients with a body mass index greater than 27 kg/m were enrolled in the switch group. These patients were cross-titrated to amisulpride treatment and followed up for 1 year prospectively. Another 46 inpatients matched with the baseline body mass index of those in the switch group were enrolled as the control group retrospectively. The results showed that the switch group had greater weight loss than the control group (7.80 +/- 6.67 vs 2.60 +/- 6.23 kg, respectively; repeated-measure analysis of variance, P < 0.0005). During the treatment course, the amisulpride-treated patients showed significantly decreased fasting triglyceride, total cholesterol, glucose, and insulin resistance levels; decreased diastolic blood pressure and pulse rate; and a significant increase in high-density lipoprotein cholesterol levels after switching to amisulpride (all with a P < 0.05). The prevalence of metabolic syndrome in amisulpride-treated patients also decreased significantly from 65.2% to 30.4% (McNemar test, P < 0.0005). These findings suggest that switching to amisulpride could be an effective treatment of overweight or obese psychiatric patients treated previously with other SGAs.

Resequencing and association study of vesicular glutamate transporter 1 gene (VGLUT1) with schizophrenia.

Dysregulation of glutamate neurotransmission is implicated in the pathphysiology of schizophrenia. Vesicular glutamate transporters (VGLUTs) package glutamate into vesicles in the presynaptic terminal and regulate the release of glutamate. Abnormal VGLUT1 expression has been linked to schizophrenia in postmortem brain studies. The purpose of this study was to investigate the involvement of the human VGLUT1 in the susceptibility to schizophrenia. In this study, we searched for genetic variants in the putative core promoter region and 12 exons (including UTR ends) of the VGLUT1 gene using direct sequencing in a sample of Han Chinese schizophrenic patients (n=376) and non-psychotic controls (n=368) from Taiwan, and conducted a case-control association study. We identified two common SNPs (g.-248G>C (ss159695612) and c.2697C>A (rs1043558)) in the VGLUT1 gene. No differences in the allele and genotype frequencies were detected between the patients and control subjects. Besides, we identified eight patient-specific rare variants in 16 out of 376 patients, including two variants (g.-296A>G (ss159695611) and g.-32Cv>T (ss159695613)) at the core promoter region and 5'UTR, two missense variants (L516M (ss159695617) and P551S (ss159695618)) and three silent variants (E24E (ss159695614), L118L (ss159695615), and P133P (ss159695616)) at protein-coding regions, and one variant (c.2201G>A (ss159695619)) at the 3'UTR. No rare variants were found in 368 control subjects (4.3% versus 0, P=1.5x10(-5)). Although the functional significance of these rare variants remains to be characterized, our study may lend support to the multiple rare mutation hypothesis of schizophrenia, and may provide genetic clues to indicate the involvement of the glutamate transmission pathway in the pathogenesis of schizophrenia.

Exomic sequencing of the ionotropic glutamate receptor N-methyl-D-aspartate 3A gene (GRIN3A) reveals no association with schizophrenia.

BACKGROUND: Growing evidence suggests that dysregulation of N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate neurotransmission may be involved in the pathophysiology of schizophrenia. The NMDAR is a heteromeric protein complex consisting of subunits from three subfamilies (NR1, NR2A, 2B, 2C, 2D and NR3A, 3B). The unique ability of NR3A to modulate the NMDAR function makes it an attractive candidate gene of schizophrenia. The purpose of this study was to investigate the involvement of the gene encoding the human NR3A subunit (GRIN3A) in the liability to schizophrenia. METHODS: We searched for genetic variants in the putative core promoter region and all the exons (including UTR ends) of the GRIN3A gene in 333 Han Chinese patients with schizophrenia and 369 control subjects from Taiwan using direct polymerase chain reaction (PCR) autosequencing, and assessed their association with schizophrenia. RESULTS: We identified 22 single nucleotide polymorphisms (SNPs) in the GRIN3A gene in this sample. SNP- and haplotype-based analyses showed no association of these 22 SNPs with schizophrenia. Nevertheless, we identified two missense mutations (D133N and Q1091H), one nonsense mutation (R1024X), and two synonymous mutations (Y873Y and E889E) of the GRIN3A gene in 6 out of 333 (1.8%) patients, while no rare mutations were found in 369 control subjects (p=0.011, Fisher's exact test, one-tailed). In silico analysis showed that the R1024X and Q1091H mutations are possibly damaging. CONCLUSIONS: Although the functional significance of these mutations remains to be characterized, our study indicates that rare mutations in the GRIN3A gene may contribute to the pathogenesis of schizophrenia in certain patients.

Association of adiponectin and metabolic syndrome among patients taking atypical antipsychotics for schizophrenia: a cohort study.

INTRODUCTION: Adiponectin, an adipocyte-derived hormone controlling lipid and carbohydrate metabolism, has been suggested to be a biomarker for metabolic syndrome in the general population. This study investigated the association between adiponectin levels and metabolic syndrome in patients treated with atypical antipsychotics. METHODS: Anthropometric and metabolic parameters and serum adiponectin levels were assessed in hospitalized patients with schizophrenia who had used the same atypical antipsychotic for at least 3 months. Retrospective reviews of the patients' medical records were conducted to obtain demographic data and pretreatment characteristics. RESULTS: The study included 567 schizophrenia patients treated with clozapine (n=231), olanzapine (n=94) and risperidone (n=242), for an average of 45.8+/-27.8 months. The prevalence of metabolic syndrome among all subjects was 23.8%. The clozapine group had a higher prevalence of metabolic syndrome (28.7%) than did the olanzapine (24.2%) and risperidone groups (19.5%) (P=0.039), and the clozapine group had lower levels of adiponectin (8.46+/-6.02 mg/mL) than did the olanzapine (10.26+/-4. 9 mg/mL) and risperidone groups (10.69+/-7.43 mg/mL) (P=0.001). Adiponectin level was negatively correlated with body mass index (BMI) increase after initiation of antipsychotic treatment. Cross-sectional regression analysis showed that age (OR,=1.042, P=0.001), BMI (OR=1.404, P<0.0001), and adiponectin level (OR=0.862, P<0.0001) were significant factors in the presence of metabolic syndrome. Significant predictors of metabolic syndrome were age at initiation of antipsychotic treatment (OR=1.04, P=.007), BMI at initiation of antipsychotic treatment (OR=1.44, P<0.0001), BMI increase after initiation of antipsychotic treatment (OR=1.40, P<0.0001), and adiponectin level (OR=0.86, P<0.0001). CONCLUSION: Lower levels of adiponectin and weight gain after taking antipsychotics are associated with higher risk of metabolic syndrome in patients taking atypical antipsychotics.

Weight gain with clozapine: 8-year cohort naturalistic study among hospitalized Chinese schizophrenia patients.

OBJECTIVE: Clozapine is associated with significant weight gain. However, it is still debatable whether the majority of weight gain occurs in the early phase of treatment or if weight gain is a persistent side effect. The inconsistent results in previous outpatient studies may be due to many confounding factors, such as variations in drug adherence, diet content, activity level and environmental factors. The objective of this study was to investigate long-term weight changes in hospitalized Chinese schizophrenic patients treated with clozapine. METHODS: Patients were admitted at the largest mental hospital in Taiwan and had routine monthly body weight monitoring during the study period. Retrospective chart reviews were conducted to obtain demographic data, age at which clozapine treatment was initiated, and weight changes after the initiation of clozapine treatment. RESULTS: The study sample consisted of 349 hospitalized schizophrenic patients, including 204 males (58.8%), with an average age at clozapine initiation of 38.6+/-9.3 and an average clozapine dosage of 318+/-9.3 mg/day. Body weight increased over time, and reached a plateau at month 42. Younger age at clozapine initiation (P=0.0038) and lower baseline body mass index (BBMI) (P<0.0001) were associated with more weight gain. The patients with BBMI<25 gained significantly more weight (10.98+/-8.48 kg) compared to patients with BBMI>or=25 (1.17+/-13.29 kg) (P=0.004). CONCLUSIONS: Similar to reports on Caucasians, clozapine-associated weight gain in Chinese patients reached a plateau at month 42. Younger patients with normal BBMI were associated with higher risk of weight gain.

Analysis of genetic variations in the RGS9 gene and antipsychotic-induced tardive dyskinesia in schizophrenia.

Some patients treated chronically with antipsychotics develop tardive dyskinesia (TD), an abnormal involuntary movement disorder. Typical antipsychotics block D(2) dopamine receptors (D(2)DR) and produce D(2)DR supersensitivity. On contrary, regulators of G-protein signaling (RGS) can enhance the signal termination of G-protein-coupled D(2)DR. Besides, after prolonged inhibition of dopaminergic transmission, dopaminergic agonists induced severe dyskinesia only in RGS9 knock-out mice but not in normal mice. Therefore, variety in the human RGS9 gene may be related to susceptibility to TD. In this study, schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale twice over a 3-month interval. Only patients in whom abnormal involuntary movements were absent (non-TD group) and those who showed persistent TD (TD group) were enrolled. There were 407 patients in the study sample (TD = 252; non-TD = 155) and seven single nucleus polymorphisms (SNPs) in the RGS9 gene were genotyped for each subject. Genotype and allelic distributions of SNPs did not differ between the TD and non-TD groups in this study, with the exception that a weak trend of allelic association was seen with rs4790953 (P = 0.0399). In the haplotype analysis, a significant association of the AGG haplotype (rs8077696-rs8070231-rs2292593) of the RGS9 gene was found (permutation P = 0.007), and this is worthy of replication and further study.

Association study of HLA-A gene and schizophrenia in Han Chinese from Taiwan.

Dysregulation of the immune response has been proposed as a precipitating factor of schizophrenia, and human leukocyte antigens (HLA) play a critical role in regulating the cascade of immunological reaction. Hence, many studies have investigated the relationship between the HLA system and schizophrenia. HLA is a complex gene family that contains several highly polymorphic genes, while the HLA-A gene is the most often studied gene to be associated with schizophrenia in the literature. A recent study reported that the interaction of the HLA-A10 allele and Chlamydial infection was highly associated with schizophrenia in a German population, which prompted us to investigate whether the HLA-A gene was also associated with schizophrenia in our population. Using a sequencing-based HLA typing method, we determined the HLA-A genotypes in 377 Han Chinese patients with schizophrenia (214 males, 163 females) and 321 non-psychotic Han Chinese control subjects (164 males, 157 females) from Taiwan. In total, 26 DNA-defined HLA-A alleles were identified in this sample. However, no significant differences of these allelic frequencies were found between the patients and the control subjects, suggesting that the HLA-A gene was unlikely a major risk factor of schizophrenia in this sample. As different populations have different HLA polymorphisms, an examination of the relationship of other HLA genes and schizophrenia in our population, with a larger sample size, is warranted in the future.