Chay Hoon Tan

Antipsychotic drug prescription for schizophrenia in East Asia: rationale for change

Abstract  The purpose of this international collaborative study was to investigate the prescription patterns of antipsychotic drugs for schizophrenia in East Asia and to analyze factors that affect these patterns. Prescription patterns for patients admitted for treatment of schizophrenia were surveyed using a standardized protocol from six East‐Asian region/countries: China, Hong Kong, Japan, Korea, Singapore and Taiwan. Patients’ social and clinical characteristics, psychiatric symptoms, course of illness, and adverse effects of medications were systematically assessed and recorded. Prescriptions of the first‐ and second‐generation antipsychotic drugs were compared. A total of 2399 patients were recruited. The second‐generation drugs comprised 28.1% of all prescribed antipsychotics, and 46% of the antipsychotic prescriptions were in the context of polypharmacy. The mean dosage of antipsychotics for the whole sample was 675.3 + 645.1 mg chlorpromazine equivalents. Japan had a high frequency of prescribing high doses and polypharmacy; Singapore had a high utilization of depot injections while China had a higher prescription of clozapine. Using multiple logistic regression analysis, distinctions in the prescription patterns of antipsychotic drugs were found: first‐generation drugs were mainly for controlling aggressive behavior, while second‐generation drugs were targeted at the alleviation of positive, negative psychotic symptoms as well as disruptive behavior in schizophrenia. The present collaborative study highlighted differences in the prescription patterns, especially the under‐utilization of second‐generation antipsychotic drugs in East Asia. The pattern of antipsychotic medication use varied from country to country and is likely to be influenced by the prevailing health‐care system, the availability and cost of the drugs.

Physical, social and productive leisure activities, cognitive decline and interaction with APOE-ε4 genotype in Chinese older adults

BACKGROUND We evaluated the combined and differential effects of physical, social and productive activities on cognitive decline and whether they were modified by the presence of the APOE-epsilon 4 allele. METHODS In a prospective cohort study of 1635 community-dwelling Chinese older adults aged 55 or older participating in the ongoing Singapore Longitudinal Aging Study, physical, social and productive leisure activities were assessed at baseline, and cognitive decline (at least one point drop) in MMSE scores between baseline and follow-up after one year. RESULTS Cognitive decline was observed in 30% of the respondents. Controlling for age, gender, education and other risk factors, odds ratios (ORs) were significantly reduced in those with medium (OR: 0.60, 95% CI: 0.45-0.79) and high activity levels (OR: 0.62, 95% CI: 0.46-0.84). A stronger association was shown for productive activity (OR = 0.36), than for physical (OR = 0.78) and social activities (OR = 0.85). These associations showed statistically significant interactions with APOE genotype, being more pronounced in those with the APOE-epsilon 4 allele. CONCLUSION Increased leisure activity, especially productive activities more than physical or social activities, was associated with a lowered risk of cognitive decline. APOE-epsilon 4 genotype individuals appeared to be more vulnerable to the effects of low and high levels of leisure activities.

Susceptibility to neuroleptic-induced tardive dyskinesia and the T102C polymorphism in the serotonin type 2A receptor

BACKGROUND Genetic factors have been implicated in the pathophysiology of the movement disorder tardive dyskinesia, which may involve dopamine-serotonin interaction. Case-control association studies have identified the T102C polymorphism of the 5-HT2A receptor gene as being associated with schizophrenia and responsiveness to clozapine. In this study, we examine the association of this polymorphism in the 5-HT2A receptor gene as a risk factor for developing schizophrenia and tardive dyskinesia from prolonged treatment with neuroleptics. METHODS Ninety-seven healthy control subjects with no history of mental illness and 221 schizophrenic patients (87 with tardive dyskinesia, 134 without) were genotyped by PCR-RFLP. RESULTS Comparison between cases and control subjects revealed no significant association between the C allele and schizophrenia. There was significant difference in allele frequency (p = .044, OR = 1.54 95% CI = 1.02-2.33) between patients who developed tardive dyskinesia and those who did not. Significant difference remains even after adjusting for age and neuroleptic dosage (p = .041) with the odds ratio at 1.64 (95% CI = 1.02-2.62). CONCLUSIONS A genetic variant of the 5-HT2A receptor may be associated with neuroleptic-induced tardive dyskinesia in schizophrenia. Further studies are needed to replicate the finding. The role of 5-HT2A receptor in the etiology of tardive dyskinesia or treatment-resistant schizophrenia should be further investigated.

Polymorphisms of dopamine receptors and tardive dyskinesia among Chinese patients with schizophrenia

The putative role of dopamine in the pathophysiology of tardive dyskinesia (TD) makes the genes coding for dopamine receptors the appropriate candidates for study. We investigate the association of the polymorphism of the Ser311Cys and Ser9Gly of the dopamine D2 (DRD2) and D3 receptor (DRD3) genes respectively with TD in Chinese patients with schizophrenia. In a case‐control study, 117 Chinese patients with TD were compared to 200 patients without TD. Patients were diagnosed to have schizophrenia according to DSM‐IV criteria. Dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS), whereas extrapyramidal side‐effects (EPSE) were assessed by the Simpson‐Angus Rating Scale. Genotype groups were comparable in age, gender, duration of illness, daily neuroleptic and benzodiazepine dose as well as the mean scores for EPSE. We failed to find an association between the polymorphism of the DRD2 gene with TD but found an increased risk of developing TD among those with D3 serine/serine genotype. Our results did not indicate that the D2 genotype has a role in the pathophysiology of TD in Chinese patients with schizophrenia. The association of TD with the serine/serine genotype of the DRD3 may be an epiphenomenon of patients with a subtype of schizophrenia who had more exposure to neuroleptics.

Long-Term Metformin Usage and Cognitive Function among Older Adults with Diabetes

Evidence strongly supports the important role of insulin resistance in cognitive decline and dementia and suggests that insulin sensitizers may protect against cognitive decline in diabetic and pre-diabetic individuals. Inconclusive results have been reported in clinical trials of rosiglitazone, an insulin sensitizer that also increases cardiovascular mortality risks. No study has yet reported a protective cognitive effect of metformin, an insulin-sensitizing biguanide widely used in diabetic patients. We studied 365 older persons aged 55 and over in the population-based Singapore Longitudinal Aging Study with diabetes who were followed up over 4 years. The odds ratios (OR) of association of metformin use (n = 204) versus non-use (n = 161) with cognitive impairment (Mini-Mental State Exam ≤ 23), and by duration: up to 6 years (n = 114) and more than 6 years (n = 90) were evaluated in cross-sectional and longitudinal multivariate analyses. Controlling for age, education, diabetes duration, fasting blood glucose, vascular and non-vascular risk factors, metformin use showed a significant inverse association with cognitive impairment in longitudinal analysis (OR = 0.49, 95% CI 0.25-0.95). Metformin use showed significant linear trends of association across duration of use in cross-sectional and longitudinal analyses (p = 0.018 and p = 0.002, respectively), with use for more than 6 years significantly associated with lowest risk of cognitive impairment in both cross-sectional analysis (OR = 0.30, 95% CI 0.11-0.80) and in longitudinal analysis (OR = 0.27, 95% CI 0.12-0.60). No significant interactive effects of metformin use with APOE-ε4, depression, or fasting glucose level were observed. Among individuals with diabetes, long-term treatment with metformin may reduce the risk of cognitive decline. Further studies should establish the role of hyperglycemia and insulin resistance, and the protective role of metformin in the risk of cognitive decline and dementia.

Genetic analysis of the thermolabile methylenetetrahydrofolate reductase variant in schizophrenia and mood disorders.

Objective An elevated homocysteine level has been reported for patients with schizophrenia and depression. We investigated the frequency of the common C667 T variant of the enzyme methylenetetrahydrofolate reductase in controls and patients of Chinese descent. Methods Controls with no history of mental disorder and patients diagnosed with schizophrenia, bipolar and unipolar disorders were recruited. Genomic DNA from all were genotyped for the C667 T polymorphism by polymerase chain reaction-restriction fragment length polymorphism. Results There was no significant difference in genotype distributions or allele frequencies between controls and any of the diagnostic groups, although the frequency of the T allele was higher for all diagnostic groups and for both the male and female genders. When data was analyzed with the minor T allele as dominant, there was an excess of the T-containing genotypes in each of the patient groups compared with controls. For the difference between controls and all cases combined it almost reached statistical significance (P=0.077), with an odds ratio of 1.46 (95% confidence interval, 0.96–2.22). Conclusions Although there was no significant association as measured by the P value, the odds ratio and confidence interval provided some evidence of increased risk for individuals with the T-containing genotypes. A minor role for this polymorphism in the pathogenesis of schizophrenia and depression could not be ruled out and would warrant further investigation.

Attempted suicide and polymorphism of the serotonin transporter gene in Chinese patients with schizophrenia

Abnormalities of serotonin synthesis and metabolism may be associated with suicidality. The serotonin transporter gene (5-HTT) is one of the important genes involved in the regulation of serotonin neurotransmission. We examined the association of suicidal behavior in Chinese schizophrenic patients with a functional polymorphism of the promoter region of the 5-HTT gene (5-HTTLPR). The 5-HTTLPR genotype was determined by polymerase chain reaction for 76 suicidal and 262 non-suicidal patients with a diagnosis of schizophrenia (DSM-IV criteria). All subjects were unrelated to each other, and all were Chinese. There was no significant genotypic or allelic association of the 5-HTTLPR polymorphism with history of attempted suicide. From our results, this 5-HTTLPR polymorphism is unlikely to have a major effect on suicidal behavior in Chinese patients with schizophrenia.

Pharmacotherapy for schizophrenic inpatients in East Asia – Changes and challenges

Objectives: (1) to review characteristics of prescription patterns of antipsychotic medication in China, Hong Kong, Japan, Korea, Singapore and Taiwan, (2) to examine the changes of prescriptions brought about by the introduction of second generation psychotropic drugs (SGA) in East Asia, (3) to analyse factors contributing to the characteristic use of antipsychotics, and (4) to suggest ways and means to improve the prescription practice of antipsychotics in East Asia. Methods: Authors of this study collaborated with psychiatrists in East Asia to undertake an international survey reviewing prescription patterns of psychotropic medications in East Asia. The REAP (Research on Asian psychotropic prescription patterns) study reviewed the prescription of a large number of schizophrenic inpatients in China, Hong Kong, Japan, Korea, Singapore and Taiwan in 2001 and 2004 using a unified research protocol and questionnaire. Results: Prescription patterns of antipsychotic drugs differ greatly country by country and have recently experienced rapid changes. Our survey shows second generation antipsychotics are frequently used in East Asia. The introduction of SGA resulted in the combined use of first generation psychotropic drugs (FGA) and SGA in East Asia. These changing prescription patterns have created many challenges for psychiatrists in East Asia.

International study on antidepressant prescription pattern at 20 teaching hospitals and major psychiatric institutions in East Asia: Analysis of 1898 cases from China, Japan, Korea, Singapore and Taiwan

Abstract  The purpose of the present study was to review the prescription patterns of antidepressants in different countries in East Asia. The survey was conducted in China, Japan, Korea, Singapore and Taiwan from October 2003 to March 2004 using the unified research protocol and questionnaire. Twenty teaching hospitals and major psychiatric hospitals participated and a total of 1898 patients receiving antidepressants were analyzed. The survey provided a number of interesting characteristics on the prescription patterns of antidepressant in East Asia. Out of 56 antidepressants listed in the Anatomical Therapeutic Chemical Classification (ATC) index by the World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology (Oslo), only 26 antidepressants were prescribed in participating countries in East Asia. On average 38.4% of prescriptions of antidepressants were for patients with diagnoses other than depressive disorders. The availability and commonly prescribed antidepressants varied greatly by country. The selective serotonin re‐uptake inhibitors (SSRI) and other newer antidepressants were prescribed in approximately 77.0% of all cases. At the time of the survey, only two SSRI medications were available in Japan. However, five types of SSRI were available and were often prescribed in Korea.

Antipsychotic polypharmacy in inpatients with schizophrenia in Asia (2001−2009)

OBJECTIVE This study aimed to identify trends in the use of antipsychotic polypharmacy (APP) and their demographic and clinical correlates in the treatment of schizophrenia in Asia between 2001 and 2009. METHOD A total of 6,761 schizophrenia inpatients in 9 Asian countries and territories were examined; 2,399 in 2001, 2,136 in 2004, and 2,226 in 2009. Patients’ socio-demographic and clinical characteristics and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. RESULTS The proportion of APP prescription decreased from 46.8 % in 2001, to 38.3 % in 2004, and increased to 43.4 % in 2009, with wide intercountry variations at each survey. Multiple logistic regression analysis of the whole sample revealed that patients on APP were younger, had a higher dose of antipsychotics in chlorpromazine equivalents, and more severe positive and negative symptoms. They were also more likely to receive depot and fi rst-generation antipsychotic drugs. CONCLUSIONS The frequency of APP prescription varied between countries and territories, suggesting that a host of clinical and socio-cultural factors played a role in determining APP use in Asia. To resolve the discrepancy between treatment recommendation and clinical practice, regular reviews of prescription patterns are needed.