Sheng-Chang Wang

Association of Cerebrovascular Events With Antidepressant Use: A Case-Crossover Study

OBJECTIVE The authors sought to assess the risk of cerebrovascular events associated with use of antidepressant medications. METHOD The authors conducted a case-crossover study of 24,214 patients with stroke enrolled in the National Health Insurance Research Database in Taiwan from 1998 to 2007. The authors compared the rates of antidepressant use during case and control time windows of 7, 14, and 28 days. Adjustments were made for time-dependent variables, such as health system utilization and proposed confounding medications. Stratified analyses were performed for valuing the interaction between the stroke risk of antidepressant use and age, sex, presence of mood disorder, stroke type, severity of chronic illness, and duration of antidepressant treatment. A conditional logistic regression model was used to determine the odds of antidepressant use during case time windows. RESULTS The adjusted odds ratio of stroke risk with antidepressant exposure was 1.48 (95% confidence interval=1.37-1.59) using 14-day time windows. Stroke risk was negatively associated with the number of antidepressant prescriptions reported. Use of antidepressants with high inhibition of the serotonin transporter was associated with a greater risk of stroke than use of other types of antidepressants. CONCLUSIONS These findings suggest that antidepressant use may be associated with an increased risk of stroke. However, the underlying mechanisms remain unclear.

The association between dementia and long-term use of benzodiazepine in the elderly: nested case-control study using claims data.

OBJECTIVES The aim of this study was to examine the association between long-term benzodiazepines (BZDs) use and the risk of dementia. DESIGN Population-based nested case-control study of dementia. SETTING All subjects were aged 45 and older and enrolled in the National Health Insurance Research Database in Taiwan, 1997-2004. PARTICIPANTS Cases (N = 779) were patients who were identified with dementia at least two times in their outpatient claims. They were individually matched to six comparison subjects (N = 4,626) based on age and gender. MEASUREMENTS BZD usage (average dosage per year, average days per year, and cumulative dose and periods) and potential confounding comobidities, including cardiovascular and psychiatric diseases. RESULTS Subjects with dementia had higher cumulative dose, longer duration of BZDs exposure, and more likelihood to be long-term BZDs users. CONCLUSION Our findings suggest that long-term use of BZDs is associated with an increased risk for dementia, but the underlying mechanisms remain unclear, and further investigations are needed. Long-term use of BZDs should be avoided among the elderly, who may be at a higher risk for developing dementia, in addition to other health problems.

Concordance between patient self-reports and claims data on clinical diagnoses, medication use, and health system utilization in Taiwan

Purpose The aim of this study was to evaluate the concordance between claims records in the National Health Insurance Research Database and patient self-reports on clinical diagnoses, medication use, and health system utilization. Methods In this study, we used the data of 15,574 participants collected from the 2005 Taiwan National Health Interview Survey. We assessed positive agreement, negative agreement, and Cohens kappa statistics to examine the concordance between claims records and patient self-reports. Results Kappa values were 0.43, 0.64, and 0.61 for clinical diagnoses, medication use, and health system utilization, respectively. Using a strict algorithm to identify the clinical diagnoses recorded in claims records could improve the negative agreement; however, the effect on positive agreement and kappa was diverse across various conditions. Conclusion We found that the overall concordance between claims records in the National Health Insurance Research Database and patient self-reports in the Taiwan National Health Interview Survey was moderate for clinical diagnosis and substantial for both medication use and health system utilization.

Effect of Benzodiazepine Discontinuation on Dementia Risk

OBJECTIVES This study aimed to examine whether benzodiazepine (BZD) discontinuation would decrease the risk of dementia. DESIGN A population-based nested case-control study of dementia was used. SETTING All subjects aged 45 years or older and enrolled in the National Health Insurance Research Database in Taiwan between 1997 and 2007 were randomly selected. PARTICIPANTS A total of 8,434 cases had been identified with dementia at least three times in ambulatory claims or with one record in inpatient claims. They were individually matched with two comparison subjects (N = 16,706) by age, gender, and index date. MEASUREMENTS The lengths of discontinuation, cumulative BZD dose, and potential confounding factors, including medical and psychiatric disorders, were measured and used for further analysis. RESULTS Compared with nonusers, current users had an increased risk of dementia (adjusted odds ratio [aOR] = 2.71; 95% confidence interval [CI], 2.46-2.99). The dementia risk for former users was reduced as the duration of discontinuation lengthened (<1 month aOR = 2.40, 95% CI, 1.98-2.92; 1-3 months aOR = 1.93, 95% CI, 1.67-2.23; 3-6 months aOR = 1.49, 95% CI, 1.28-1.74; 6-12 months aOR = 1.43, 95% CI, 1.25-1.64; 1-2 years aOR = 1.23, 95% CI, 1.09-1.40; 2-3 years aOR = 1.22, 95% CI, 1.06-1.40; and >3 years aOR = 1.08, 95% CI, 0.98-1.20). The decreasing trend was significant (p < 0.001). CONCLUSION The risk of dementia was high for current users and decreased as the duration of BZD discontinuation lengthened. Further investigations are needed to replicate this association and explore the underlying mechanism that links long-term BZD use, BZD discontinuation, and the pathogenesis of neurocognitive dysfunction.

CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer.

Methadone is a racemic compound composed of the R-form and S-form enantiomers. The drug is usually used in maintenance therapy for the heroin-addicted patients. In our previous study, we found that the cytochrome P-450 (CYP) isozyme 2B6 preferentially metabolizes the S-methadone enantiomer. We thus tested whether CYP2B6 gene polymorphisms had any influence on the concentration or clearance of methadone. Ten single nucleotide polymorphisms within this gene region were evaluated in 366 patients undergoing methadone maintenance for at least 3 months. The plasma steady-state levels of racemic methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine were then measured in these individuals. The rs10403955 (T allele in intron 1), rs3745274 (G allele in exon 4), rs2279345 (T allele in intron 5), and rs707265 (A allele in exon 9) CYP2B6 allele types were found to be significantly associated with a higher clearance, a lower plasma concentration, and a lower concentration-to-dosage (C/D) ratio of (S)-methadone (P < 0.0017). Two haplotype blocks of a trinucleotide haplotype (rs8100458-rs10500282-rs10403955 in intron 1) and a hexanucleotide haplotype (rs2279342-rs3745274-rs2279343-rs2279345-rs1038376-rs707265 from intron 2 to exon 9) were constructed within CYP2B6. The major combinations of T-T-T and A-G-A-T-A-A of these particular haplotypes showed significant associations with the plasma concentrations of S-methadone and its C/D ratio (P < 0.0001, respectively). We conclude that genetic polymorphisms in the CYP2B6 gene may therefore be indicators of the clearance, plasma concentration and C/D ratio of S-methadone.

Genetic polymorphisms in CYP3A4 are associated with withdrawal symptoms and adverse reactions in methadone maintenance patients

AIM Methadone maintenance therapy is one of the standard treatments for heroin addiction. The isozyme CYP3A4 of the CYP system is one of the metabolic enzymes, as well as CYP2B6, responsible for the metabolism of methadone. The aim of the present study is to evaluate the potential use of genetic polymorphisms in CYP3A4 as biomarkers for the prediction of methadone treatment responses. MATERIALS & METHODS A total of 366 Han Chinese methadone maintenance treatment patients in Taiwan were recruited in this study. Main clinical assessments included the clinical opioid withdrawal scale (COWS), the treatment emergent symptom scale (TESS) and the plasma concentrations of methadone and its metabolites. Genetic associations of six SNPs in the CYP3A4 gene were calculated using a general linear model. RESULTS Genotypes and allele types of rs4646440 and rs2242480 were found to be significantly associated with the severity of withdrawal symptoms rated by COWS (p = 0.012, 0.0096, 0.017 and 0.012, respectively) as well as the side effects rated by TESS (p = 0.0089, 0.028, 0.0027 and 0.0085, respectively). The allele types associated with more severe withdrawal symptoms are also associated with more severe side effects and less betel nut (Areca catechu) use (p = 0.009 for rs4646440, p = 0.0063 for rs2242480). Further analyses on specific withdrawal symptoms in COWS showed that the genetic variants in rs4646440 are significantly associated with heart rate (allele type p = 0.0019). CONCLUSION These results suggested that genetic variants in the CYP3A4 gene may be useful indicators for the severity of side effects and withdrawal symptoms for methadone treatment.

Association of Stroke with the Receptor-Binding Profiles of Antipsychotics—A Case-Crossover Study

BACKGROUND Previous research suggests a link between antipsychotic use and stroke, but the relationships between receptor-binding profiles of antipsychotics and the risk of cerebrovascular events are unclear. METHODS A total of 14,584 patients with incident stroke were enrolled in the National Health Insurance Research Database in Taiwan from 1998 to 2007. We conducted a case-crossover study to compare the rates of antipsychotic use. The effects of receptor-binding profiles of antipsychotics on stroke risk were estimated, while the moderating effects of age, sex, presence of dementia, and duration of antipsychotic treatment were evaluated by stratified analyses. RESULTS The adjusted odds ratio of stroke risk with antipsychotics exposure was 1.60 (95% confidence interval, 1.51-1.69) using a 14-day time window. The use of antipsychotics with a high binding affinity of M1 muscarinic and α2 adrenergic receptors was associated with a greater risk of stroke than the use of other types of antipsychotics. An increased risk of stroke with antipsychotic use was noted in the patients who were older and/or who suffered from dementia. Moreover, our results showed that stroke risk with antipsychotic use was in a dose-related relationship. CONCLUSIONS Our findings suggest an association between stroke risk and high M1 muscarinic and α2 adrenergic affinity. The clinical implication is to start antipsychotics treatment at low dosages and to closely monitor the side effects in the initial treatment, particularly for individuals with older age and the presence of dementia.

Genetic polymorphisms in the opioid receptor mu1 gene are associated with changes in libido and insomnia in methadone maintenance patients

Methadone, a synthetic racemic opioid that primarily works as a μ-opioid receptor (OPRM1) agonist, is commonly used for the treatment of heroin addiction. Genetic association studies have reported that the OPRM1 gene is involved in the physiology of heroin and alcohol addiction. Our current study is designed to test the hypothesis that genetic polymorphisms in the OPRM1 gene region are associated with methadone dosage, plasma concentrations, treatment responses, adverse reactions and withdrawal symptoms in a methadone maintenance treatment (MMT) cohort from Taiwan. Fifteen OPRM1 single nucleotide polymorphisms (SNPs) were selected and genotyped using DNA samples from 366 MMT patients. The plasma concentrations of methadone and its metabolite were measured by high performance liquid chromatography. The results obtained using dominant model analysis indicate that the OPRM1 SNPs rs1074287, rs6912029, rs12209447, rs510769, rs3798676, rs7748401, rs495491, rs10457090, rs589046, rs3778152, rs563649, and rs2075572 are significantly associated with change-in-libido side effects (adjusted p<0.042). Using recessive model analysis, these SNPs were also found to be significantly associated with insomnia side effects in this cohort (p<0.009). The significance of the insomnia findings was mainly contributed by a subgroup of patients who had a positive urine morphine test (p<0.022), and by individuals who did not use benzodiazepine hypnotics (p<0.034). Our current data thus suggest that genetic polymorphisms in OPRM1 may influence the change-in-libido and insomnia side effects sometimes found in MMT patients.

OPRM1 genetic polymorphisms are associated with the plasma nicotine metabolite cotinine concentration in methadone maintenance patients: a cross sectional study

Majority of the heroin-dependent patients smoke cigarettes. Although it has been reported that the OPRM1 genetic polymorphism is associated with the brain mu-opioid receptor binding potential in cigarette smokers, there is no direct evidence showing the impact of plasma cotinine, a nicotine metabolite, on treatment responses to methadone maintenance treatment (MMT). In this study, we aimed to test the hypothesis that the genetic polymorphisms in the OPRM1 are associated with the methadone treatment responses and the severity of cigarette smoking directly measured by the plasma concentration of cotinine in a Taiwanese MMT cohort. Fifteen OPRM1 single-nucleotide polymorphisms (SNPs) were selected and genotyped on DNA samples of 366 MMT patients. Plasma concentrations of cotinine were measured by cotinine enzyme-linked immunosorbent assay. The plasma cotinine concentration had positive correlation with concentrations of methadone (P=0.042) and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine (P=0.037). Methadone treatment non-responders, defined by a positive urine morphine test, had a higher plasma concentration of cotinine (P=0.005), but a lower plasma concentration-to-dose ratio of both R- and S-methadone (P=0.001 and 0.012, respectively) than the responders. OPRM1 genetic variants, rs1074287, rs6912029, rs1799971, rs12209447, rs510769, rs3798676, rs553202, rs7748401, rs495491, rs10457090, rs589046, rs3778152 and rs563649, were significantly associated with the plasma concentration of cotinine when using recessive model for genotypes (general linear model (GLM), P<0.038; false discovery rate (FDR)<0.035) and additive model for allele types (GLM, P<0.03; FDR<0.049) in association analyses. The G allele carriers of SNP rs1799971 (A118G) on exon 1 of OPRM1 gene had a lower plasma cotinine concentration than the A allele carriers (GLM, P=0.029). OPRM1 genetic polymorphisms are associated with the plasma concentration of cotinine in a Taiwanese MMT cohort. Carriers with the major allele of SNP rs1799971 had a higher plasma cotinine concentration.

Development of a method to measure methadone enantiomers and its metabolites without enantiomer standard compounds for the plasma of methadone maintenance patients

A liquid chromatography-photodiode array (LC-PDA) method using a chiral analytical column was developed to determine the plasma levels of enantiomers of methadone and its chiral metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), without the standard compounds of R-form or S-form enantiomers. This method was established by the characteristics of recombinant cytochrome P-450 (CYP) isozymes, where CYP2C19 prefers to metabolize R-methadone and CYP2B6 prefers to metabolize S-methadone. We incubated the racemic methadone standard with either enzyme for 24 h. We identified the retention times of R- and S-methadone to be around 10.72 and 14.46 min, respectively. Furthermore, we determined the retention times of R- and S-EDDP to be approximately 6.76 and 7.72 min, respectively. No interferences were shown through the retention times of morphine, buprenorphine and diazepam. With the high recovery rate of a solid-phase extraction procedure, this method was applied in analyzing plasma concentrations of seven methadone maintenance patients where R- and S-methadone and R- and S-EDDP were 233.4 +/- 154.9 and 185.9 +/- 136.3 ng/mL and 84.4 +/- 99.4 and 37.6 +/- 22.9 ng/mL, respectively. These data suggest that the present method can be applied for routine assay for plasma methadone and EDDP concentrations for patients under treatment.