Chi-Shin Wu

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.

Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response.

AIMS The antidepressant escitalopram (S-CIT) is metabolized by the cytochrome-P450 (CYP) enzymes CYP 2D6, 2C19 and 3A4. This study evaluated the impact of CYP2D6, 2C19 and 3A4 genetic polymorphisms on plasma concentrations of S-CIT and patient treatment response. MATERIALS & METHODS A total of 100 patients diagnosed with major depressive disorder were recruited to the study and their depression symptoms were assessed using the Hamilton Depression Rating Scale. The genetic polymorphisms *4, *5 and *10 on CYP2D6, *2, *3 and *17 on CYP2C19, and *18 on CYP3A4 were selected based on their function and respective allele frequencies in Asian populations. Polymorphisms were analyzed using the SNPstream genotyping system, PCR and direct sequencing methods. The steady-state serum concentrations of S-CIT and its metabolites S-desmethylcitalopram and S-didesmethylcitalopram were analyzed by HPLC. According to semiquantitative gene dose (SGD) and gene dose (GD) models for allele combinations of these polymorphisms, CYP2D6 was clustered into intermediate (0.5, 1 and 1.5 SGD) and extensive (2 SGD) metabolizers, while CYP2C19 was clustered into poor (0 GD) and extensive (1 and 2 GDs) metabolizers. RESULTS The group of patients with intermediate CYP2D6 metabolism (0.5 SGD) had a significantly higher frequency of remitters from major depressive disorder during the 8-week treatment (p = 0.0001). Furthermore, CYP2C19 poor metabolizers had significantly higher S-CIT serum levels than did extensive metabolizers at weeks 2, 4 and 8 (p < 0.05). The allele frequencies in CYP3A4*18 and CYP2C19*17 were too low to permit further subgroup analyses. CONCLUSION Our results suggest that the genetic polymorphisms in CYP2C19 may be influencing S-CIT serum concentrations, and that specific CYP2D6 polymorphisms may be predicting patient treatment outcomes based on gene dosage analyses.

ABCB1 gene polymorphisms are associated with the severity of major depressive disorder and its response to escitalopram treatment

Objective ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) is a drug transporter protein expressed on the epithelial cells of the intestine and the endothelial cells of the blood–brain barrier. Intestinal ABCB1 actively transports drugs from the cell membrane and prevents them from entering the blood stream whereas the blood–brain barrier ABCB1 prevents drugs from entering the central nervous system. In this study, we tested whether genetic polymorphisms within the ABCB1 gene are associated with the severity of depression and the effectiveness of the antidepressant, escitalopram (S-CIT), in treating major depressive disorder (MDD). Methods Twenty single nucleotide polymorphisms in the ABCB1 gene were selected and genotyped in 100 MDD patients who had undergone S-CIT treatment continuously for 8 weeks. The serum concentrations of S-CIT and its metabolites (S-desmethylcitalopram and S-didesmethylcitalopram) were then measured at weeks 2, 4, and 8. Results The ABCB1 genotypes of rs1922242 (P=0.0028) and rs1202184 (P=0.0021) showed significant association with the severity of depressive symptoms as assessed by the Hamilton Rating Scale for Depression adjusted with Hamilton Rating Scale for Anxiety. The haplotype block, rs1882478-rs2235048-rs2235047-rs1045642-rs6949448 (from intron 27 to intron 26), of ABCB1 was found strongly associated with the remission rate (global P=0.003, d.f.=69) in which haplotype T-T-T-C-C was associated with a slower remission rate on S-CIT treatment (P=0.001). The haplotypes may not be indicators of the severity of depression or anxiety. Conclusion Our findings suggest that single nucleotide polymorphisms in the ABCB1 gene may be indicators of the severity of depression and of the likely S-CIT treatment remission response in MDD.

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.

Multidimensional assessments of impulsivity in subjects with history of suicidal attempts

OBJECTIVE This study aimed to examine whether subjects with history of suicidal attempts had higher impulsivity as measured by neurocognitive tests and self-report questionnaires. The interrelationships among different impulsivity measures were also explored. METHODS Fifty-four nonpsychotic psychiatric inpatients, including 24 subjects with previous history of suicidal attempts and 30 comparison subjects without previous suicidal attempts, completed the self-report Barratt Impulsiveness Scale-11-Chinese version (BIS-11-CH) and 2 neuropsychologic tests of impulsivity: the immediate memory task/delayed memory task (IMT/DMT) and the single key impulsivity paradigm (SKIP). RESULTS The results indicated that subjects with previous suicidal attempts exhibited higher BIS-11-CH factor 2 (lack of self-control/attentional impulsivity) subscore (P = .02) and more commission errors in IMT (P = .03). However, BIS-11-CH scores and performance indices of IMT/DMT and of SKIP did not correlate with each other. CONCLUSIONS Our findings supported that subjects with previous suicidal attempts had higher impulsivity, which could be revealed by both self-report and neurocognitive measures. However, there is no correlation among self-report, IMT/DMT, and SKIP measures, indicating that they might be measuring different dimensions of impulsivity.

Antipsychotic drugs and the risk of ventricular arrhythmia and/or sudden cardiac death: a nation-wide case-crossover study.

Background Antipsychotics have been linked to prolongation of the QT interval. However, little is known about the risk of ventricular arrhythmia (VA) and/or sudden cardiac death (SCD) associated with individual antipsychotic drug use. This study was designed to investigate the association between specific antipsychotic drugs and the risk of VA and/or SCD. Methods and Results We conducted a case‐crossover study using a nation‐wide population‐based sample obtained from Taiwans National Health Insurance Research Database. A total of 17 718 patients with incident VA and/or SCD were enrolled. Conditional logistic regression models were applied to examine the effects of antipsychotic drug use on the risk of VA/SCD during various case and control time windows of 7, 14, and 28 days. The effect of the potency of a human ether‐à‐go‐go‐related gene (hERG) potassium channel blockade was also assessed. Antipsychotic drug use was associated with a 1.53‐fold increased risk of VA and/or SCD. Antipsychotic drugs with increased risk included clothiapine, haloperidol, prochlorperazine, thioridazine, olanzapine, quetiapine, risperidone, and sulpiride. The association was significantly higher among those with short‐term use. Antipsychotics with a high potency of the hERG potassium channel blockade had the highest risk of VA and/or SCD. Conclusion Use of antipsychotic drugs is associated with an increased risk of VA and/or SCD. Careful evaluations of the risks and benefits of antipsychotic treatment are highly recommended.

Increased risk of developing dementia in patients with bipolar disorder: a nested matched case-control study.

The association between bipolar disorder and subsequent dementia risk is not well established. The objective of this study was to investigate whether patients with bipolar disorder were at an increased risk for developing dementia.