Jen-Yeu Chen

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

INTRODUCTIONnAdiponectin, 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.nnnMETHODSnAnthropometric 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.nnnRESULTSnThe 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).nnnCONCLUSIONnLower levels of adiponectin and weight gain after taking antipsychotics are associated with higher risk of metabolic syndrome in patients taking atypical antipsychotics.

Therapeutic effect of pirenzepine for clozapine-induced hypersalivation: a randomized, double-blind, placebo-controlled, cross-over study.

The objective of this study was to investigate the efficacy of pirenzepine in the treatment of clozapine-induced hypersalivation. Pirenzepine is reported to counteract hypersalivation by its selective antagonistic activity on the M 4 -muscarinic receptor, which is stimulated by clozapine. Twenty patients with clozapine-induced hypersalivation underwent a random-order, double-blind, placebo-controlled, cross-over trial which lasted 8 weeks each for the pirenzepine and placebo investigations, with a 4-week washout period in between. The severity of hypersalivation was assessed using an objective measure: saliva production monitored through the diameter of wetted surface on tissue paper placed over the patient’s pillow. Our study showed that pirenzepine had no significant therapeutic effect on hypersalivation compared with placebo, suggesting that hypersalivation induced by clozapine might have a neurobiological basis other than the M 4 -muscarinic receptor.

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

INTRODUCTIONnMetabolic 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.nnnMETHODnThis 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.nnnRESULTSnOne 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).nnnCONCLUSIONSnFor 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.

Artificial neural network prediction of clozapine response with combined pharmacogenetic and clinical data

Although one third to one half of refractory schizophrenic patients responds to clozapine, however, there are few evidences currently that could predict clozapine response before the use of the medication. The present study aimed to train and validate artificial neural networks (ANN), using clinical and pharmacogenetic data, to predict clozapine response in schizophrenic patients. Five pharmacogenetic variables and five clinical variables were collated from 93 schizophrenic patients taking clozapine, including 26 responders. ANN analysis was carried out by training the network with data from 75% of cases and subsequently testing with data from 25% of unseen cases to determine the optimal ANN architecture. Then the leave-one-out method was used to examine the generalization of the models. The optimal ANN architecture was found to be a standard feed-forward, fully-connected, back-propagation multilayer perceptron. The overall accuracy rate of ANN was 83.3%, which is higher than that of logistic regression (LR) (70.8%). By using the area under the receiver operating characteristics curve as a measure of performance, the ANN outperformed the LR (0.821+/-0.054 versus 0.579+/-0.068; p<0.001). The ANN with only genetic variables outperformed the ANN with only clinical variables (0.805+/-0.056 versus 0.647+/-0.066; p=0.046). The gene polymorphisms should play an important role in the prediction. Further validation of ANN analysis is likely to provide decision support for predicting individual response.

Risperidone for pre-existing severe tardive dyskinesia: a 48-week prospective follow-up study.

Atypical antipsychotics can alleviate the severity of tardive dyskinesia, but few studies have monitored their long-term effects. The present study investigated the effect of risperidone on pre-existing severe tardive dyskinesia among 40 patients with chronic schizophrenia over 48 weeks. The total Abnormal Involuntary Movement Scale (AIMS) score decreased in 35 patients (87.5%) and increased in three patients (7.5%). At the end of the 48-week trial, the mean total AIMS score decreased significantly, from 15.7±4.7 (baseline) to 10.6±4.4 (P<0.001), with a mean risperidone dosage of 3.6±1.5u2009mg/day. Twenty-three patients (57.5%) were responders with an average total AIMS score decrease of 8.0±2.7. Multiple logistic regression analysis controlling for age, gender, duration of illness, index hospitalization duration, risperidone dose, anticholinergic concomitant use and dystonia score change revealed that a change in the parkinsonism score was the most significant factor related to responders (odds ratio 3.476, 95% confidence interval 1.173–10.298). A significant improvement observed in tardive dyskinesia was noted at week 8, and this improvement persisted until week 48. The results show that the effect of risperidone on pre-existing tardive dyskinesia may be beneficial.

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

OBJECTIVEnClozapine 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.nnnMETHODSnPatients 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.nnnRESULTSnThe 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).nnnCONCLUSIONSnSimilar 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.

Support for an association of the C939T polymorphism in the human DRD2 gene with tardive dyskinesia in schizophrenia

Abstract Tardive dyskinesia (TD) is a movement disorder linked to long-term treatment with antipsychotic drugs. Since all typical antipsychotics are dopamine D2 receptor (DRD2) antagonists, it has been suggested that genetic variations in the human DRD2 gene might be associated with TD. Recently, one coding-synonymous polymorphism, C939T (rs6275) in exon 7 of the DRD2 gene, has been associated with TD in a Caucasian group. In the present study, we investigated whether this polymorphism is also associated with TD in a Chinese population. Three hundred and one patients (TD/non-TDxa0=xa0174/127) with schizophrenia being treated with long-term typical antipsychotics were enrolled in this study. There was no significant difference in the proportion of male and female participants or smokers and non-smokers, and no difference in the mean age, chlorpromazine equivalent doses or years of antipsychotic exposure. The C939T genotype and allele distribution differed significantly between the TD and non-TD groups ( p xa0=xa00.003 and p xa0=xa00.002, respectively). Patients homozygous for the 939T allele and the heterozygous carriers of CT had an increased risk of TD compared with 939C homozygotes (OR TT xa0=xa03.59, 95% CIxa0=xa01.71–7.53, p xa0=xa00.001; OR CT xa0=xa02.37, 95% CIxa0=xa01.21–4.66, p xa0=xa00.012). Therefore, our findings suggest that, similar to the findings in Caucasians, the C939T polymorphism in the DRD2 gene is associated with TD in a Chinese population. However, given the studys small sample size, the findings should be regarded cautiously. Further studies with larger sample sizes will be necessary before any firm conclusions can be drawn.

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/m2 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.

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.

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

BACKGROUNDnGrowing 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.nnnMETHODSnWe 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.nnnRESULTSnWe 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, Fishers exact test, one-tailed). In silico analysis showed that the R1024X and Q1091H mutations are possibly damaging.nnnCONCLUSIONSnAlthough 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.