Identity, stigma, and HIV risk among transgender women: a qualitative study in Jiangsu Province, China.

BACKGROUND: Transgender women have multiple disparities globally, including social rejection and stigma, HIV infection and untreated mental health problems. However, few data on transgender women are available in China. Therefore, this study aimed to explore transgender women's experiences on gender identity, disclosure, discrimination, transgender-specific medical care, and perceptions of HIV and sexually transmitted infections (STI) risk in China. METHODS: A qualitative study was conducted in Nanjing and Suzhou city, China in 2018. Key informant interviews (n = 14) and focus group discussions (n = 2) with diverse transgender women were implemented. Text was transcribed and translated, and Dedoose™ software was used for coding, analysis and interpretation by the research team. RESULTS: Chinese transgender women share experiences with transgender women worldwide, including a long and challenging identity search, stigma and discrimination, poor access to trans-specific services and unmet needs for mental health care. Features unique to them include terms used for self-identification, culturally-shaped expectations for reproduction, and ideals of placing the familial and societal welfare over personal fulfillment. Social networks of this population appear sparse, scattered, and underground. Familial rejection was experienced by nearly all respondents. Perceptions of HIV and STI risk and history of HIV testing were notably low. CONCLUSIONS: Transgender women in China face high social rejection and discrimination along with unmet need for various types of healthcare. Scaling up transgender-specific services including gender-affirming medical care, mental health care and HIV/STI prevention are warranted to address the social, medical and mental health of transgender women in China.

Effects of genetic variants of ADH1B and ALDH2 and social network on continued alcohol drinking among young adolescents in Taiwan.

BACKGROUND: This study aimed (i) to evaluate the effects of genetic variants of ADH1B and ALDH2 and social network position on continued alcohol use in early adolescence, and (ii) to explore possible moderating role of pubertal development on genetic effects. METHODS: The sample comprised 496 children who ever drank alcohol before the ages of 10-12. Information pertaining to sociodemographic background, pubertal development, parental drinking, alcohol and tobacco use, alcohol-metabolizing genes, and nominated best friends was collected in four waves of assessment. Polymorphisms of ADH1B (rs1229984) and ALDH2 (rs671) were genotyped. The latent class analysis was first used to characterize longitudinal alcohol use pattern, followed by the multinomial logistic regression analyses to assess its association with genes, pubertal development, and social network. RESULTS: Three distinct classes of alcohol users (i.e. ex-drinkers, sporadic drinkers, and continued drinkers) were derived from alcohol-experienced children. Both alcohol-metabolizing genes appear to have protective effects, yet such relationships were only significant for youngsters in pre-to-early pubertal stage: the adjusted odds ratio (aOR) of ADH1B fast-genotype for sporadic drinkers was 0.46 and that of ALDH2 slow-genotype for both sporadic and continued drinkers was 0.47 and 0.42, respectively. Children having the bridge position in their peer network were more likely to be sporadic drinkers (aOR=4.15) and continued drinkers (aOR=3.16). CONCLUSIONS: Our results illustrate a potential moderating effect of pubertal development on the protective influence of alcohol-metabolizing genes on subsequent alcohol use among alcohol-experienced children as well as the independent contribution of early life's social network to their alcohol involvement.

Assessment of CYP450 genetic variability effect on methadone dose and tolerance.

AIM: Methadone dose is related to treatment success in individuals under methadone maintenance treatment (MMT). We constructed a gene matrix using previously identified genetic polymorphisms in CYP450 and determined their genetic influence on methadone dose or tolerance. MATERIALS & METHODS: The allelic combinations of CYP450 genetic variants (two from CYP2C19, four from CYP2B6 and five from CYP3A4) were analyzed in 366 MMT heroin dependent patients as possible determinants of methadone dose and tolerance using analysis of covariance. RESULTS: Methadone dose (p = 0.007) and tolerance (p = 0.06) were mainly influenced by CYP2C19 gene dose. Moreover, dominant influence of the CYP2C19 gene dose on methadone dose and tolerance was only found among MMT patients with negative urine morphine test results, but not among those with positive results. CONCLUSION: The findings suggest that CYP2C19 gene dose may serve as a potential indicator for assessing methadone dose and tolerance in MMT patients.

The association of genetic polymorphisms in the κ-opioid receptor 1 gene with body weight, alcohol use, and withdrawal symptoms in patients with methadone maintenance.

Methadone is a synthetic opioid that binds to the κ-opioid receptor with a low affinity. This study tested the hypotheses that the genetic polymorphisms in the κ-opioid receptor 1 (OPRK1) gene region are associated with methadone treatment responses in a Taiwan methadone maintenance treatment (MMT) cohort. Seventeen single nucleotide polymorphisms (SNPs) in OPRK1 were selected and genotyped on DNA of 366 MMT patients. Six SNPs from rs7843965 to rs1051660 (intron 2 to exon 2) were significantly associated with body weight (P < 0.007). A haplotype of 4 SNPs rs7832417-rs16918853-rs702764-rs7817710 (exon 4 to intron 3) was associated with bone or joint aches (P ≤ 0.004) and with the amount of alcohol use (standard drinks per day; global P < 0.0001). The haplotype rs10958350-rs7016778-rs12675595 was associated with gooseflesh skin (global P < 0.0001), yawning (global P = 0.0001), and restlessness (global P < 0.0001) withdrawal symptoms. The findings suggest that genetic polymorphisms in OPRK1 were associated with the body weight, alcohol use, and opioid withdrawal symptoms in MMT patients.

Functional genetic polymorphisms in CYP2C19 gene in relation to cardiac side effects and treatment dose in a methadone maintenance cohort.

Abstract Methadone maintenance therapy is an established treatment for heroin dependence. This study tested the influence of functional genetic polymorphisms in CYP2C19 gene encoding a CYP450 enzyme that contributes to methadone metabolism on treatment dose, plasma concentration, and side effects of methadone. Two single nucleotide polymorphisms (SNPs), rs4986893 (exon 4) and rs4244285 (exon 5), were selected and genotyped in 366 patients receiving methadone maintenance therapy in Taiwan. The steady-state plasma concentrations of both methadone and its EDDP metabolite enantiomers were measured. SNP rs4244285 allele was significantly associated with the corrected QT interval (QTc) change in the electrocardiogram (p=0.021), and the Treatment Emergent Symptom Scale (TESS) total score (p=0.021) in patients who continued using heroin, as demonstrated with a positive urine opiate test. Using the gene dose (GD) models where the CYP2C19 SNPs were clustered into poor (0 GD) versus intermediate (1 GD) and extensive (2 GD) metabolizers, we found that the extensive metabolizers required a higher dose of methadone (p=0.035), and showed a lower plasma R-methadone/methadone dose ratio (p=0.007) in urine opiate test negative patients, as well as a greater QTc change (p=0.008) and higher total scores of TESS (p=0.018) in urine opiate test positive patients, than poor metabolizers. These results in a large study sample from Taiwan suggest that the gene dose of CYP2C19 may potentially serve as an indicator for the plasma R-methadone/methadone dose ratio and cardiac side effect in patients receiving methadone maintenance therapy. Further studies of pharmacogenetic variation in methadone pharmacokinetics and pharmacodynamics are warranted in different world populations.

CYP1A2 genetic polymorphisms are associated with early antidepressant escitalopram metabolism and adverse reactions.

AIM: The liver CYP1A2 enzyme may metabolize antidepressant escitalopram (S-CIT) to S-desmethylcitalopram (S-DCIT) and S-didesmethylcitalopram (S-DDCIT). This study tested whether genetic polymorphisms in the CYP1A2 gene are associated with the treatment responses to S-CIT. MATERIALS & METHODS: Ten SNPs in CYP1A2 were selected and genotyped in 158 patients under S-CIT treatment. The serum levels of S-CIT and its metabolites were measured by HPLC. RESULTS: CYP1A2 SNPs rs2069521, rs2069526, rs4646425 and rs4646427 are significantly associated with the metabolic ratios of S-DDCIT/S-DCIT (p = 0.002, 0.018, 0.008 and 0.004, respectively) at week 2 of treatment. Carriers of the allele types associated with higher S-DDCIT/S-DCIT ratios had more severe side effects. CONCLUSION: These results suggest that genetic variants in CYP1A2 may be indicators for S-CIT metabolism and that the fast metabolizers may experience more severe adverse reactions in the early stages of S-CIT treatment. Original submitted 27 December 2012; Revision submitted 15 May 2013.

Comparison of escitalopram and paroxetine in the treatment of major depressive disorder.

This is a single-blind, parallel, flexible-dose study to compare the efficacy and tolerability of escitalopram and paroxetine in the treatment of patients with major depressive disorder. We recruited 399 patients from the outpatient clinics of five hospitals in northern Taiwan. Patients were administered either escitalopram (10-30 mg) or paroxetine (20-40 mg) according to the judgment of clinicians. These patients were assessed using the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety at weeks 0, 1, 2, 4, 6, and 8. A total of 302 patients fulfilled the evaluation criteria and were included in a statistical analysis. We found that escitalopram induced more significant symptom reduction and response rate in terms of the mean HAM-D scores at week 6 (P<0.05) and week 8 (P<0.05) than paroxetine, but that there were no significant differences between the two groups in the remission rate. Escitalopram induced significantly less frequency of adverse effects of weakness (P<0.01), nausea and vomiting (P<0.001), drowsiness (P<0.01) as well as somnolence (P<0.01) than paroxetine, although all these side effects were mild and tolerable. However for a more definitive result, future prospective trials with the inclusion of a placebo group and a double-blind design are needed. In patients who did not have severe depression (HAM-D score at baseline<21), but not in severely depressed patients, escitalopram was statistically superior to paroxetine, as shown by the mean change in the HAM-D score.

Response to citalopram is not associated with SLC6A4 genotype in African-Americans and Caucasians with major depression.

AIMS: Ethnic differences in genotype frequency provide a natural condition for assessing the contribution of gene variations to the causes and treatments of disease. Accordingly, the purpose of this study was to determine whether ethnic variations in allele frequencies of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) of the SLC6A4 gene were related to the response to the treatment of depression. MAIN METHODS: African-Americans (n=101) and Caucasians (n=100) with major depressive disorder were treated with the antidepressant citalopram (20-60mg/day) for 8weeks. Genotyping for the long (L) and short (s) alleles (LL, Ls, and ss) of the SLC6A4 gene was performed and the association between genotype and treatment response was assessed. KEY FINDINGS: Subjects in both ethnic groups showed a significant reduction in depression scores over time (p<.0001). However, in spite of a significantly greater frequency of the L allele in African-Americans as compared to Caucasians, a comparable clinical response between the two groups was found with 5-HTTLPR polymorphism not significantly associated with clinical response in either ethnic group. SIGNIFICANCE: The results are consistent with a previous finding and in accord with most of the results obtained in Caucasian subjects that SLC6A4 genotype is not related, at least by itself, to a response to treatment in either ethnic group to any clinically significant degree.

Psychotropic drugs and risk of motor vehicle accidents: a population-based case-control study.

AIM: To examine comprehensively the relationship between exposure to four classes of psychotropic drugs including antipsychotics, antidepressants, benzodiazepines (BZDs) and Z-drugs, and motor vehicle accidents (MVAs). METHOD: The authors conducted a matched case-control study of 5183 subjects with MVAs and 31 093 matched controls, identified from the claims records of outpatient service visits during the period from 2000 to 2009. Inclusion criteria were defined as subjects aged equal to or more than 18 years and involved in MVAs. Conditional logistic regressions with covariates adjustment (including urbanity, psychiatric and non-psychiatric outpatient visits and Charlson comorbidity score) were applied to examine the effect of four classes of psychotropic drugs on MVAs. RESULTS: Significant increased risk of MVAs was found in subjects taking antidepressants within 1 month (adjusted odds ratio (AOR) 1.73, 95% confidence interval (CI) 1.34, 2.22), 1 week (AOR 1.71, 95% CI 1.29, 2.26), and 1 day (AOR 1.70, 95% CI 1.26, 2.29) before MVAs occurred. Similar results were observed in subjects taking benzodiazepines (BZDs) (AOR 1.56, 95% CI 1.38, 1.75 for 1 month; AOR 1.64, 95% CI 1.43, 1.88 for 1 week, and AOR 1.62, 95% CI 1.39, 1.88 for 1 day) and Z-drugs (AOR 1.42, 95% CI 1.14, 1.76 for 1 month, AOR 1.37, 95% CI 1.06, 1.75 for 1 week, AOR 1.34, 95% CI 1.03, 1.75 for 1 day), but not antipsychotics. Moreover, significant dose effects of antidepressants (equal to or more than 0.6-1.0 DDD), BZDs (equal to or more than 0.1-0.5 DDD) and Z-drugs (more than 1 DDD) were observed, respectively, on the risk of experiencing an MVA. CONCLUSION: Taken together, subjects taking antidepressants, BZDs and Z-drugs, separately, should be particularly cautioned for their increasing risk of MVAs.

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.

Pharmacogenomics study in a Taiwan methadone maintenance cohort.

Pharmacogenomics is research to study the drug treatment responses in subgroups of patients according to their genetic variants or genetic expression information. Methadone maintenance treatment, which is usually prescribed for patients with heroin dependence, was launched in Taiwan by the government in 2006. In this study, 366 patients who had taken methadone continually in the previous 7 days were examined. Data from administration of the Treatment Outcomes Profile (TOP), Severity of Dependence Scale (SDS), Clinical Opioid Withdrawal Scale (COWS), and Treatment Emergent Symptoms Scale (TESS) were obtained from patients' report records. Genes encoding the liver cytochrome P-450 (CYP) enzymes that are involved with the metabolism of methadone (CYP2B6, 3A4 and 2C19) were selected and genotyped in this cohort. We found that the SNPs on CYP2B6 were associated with plasma S-methadone concentration; SNPs on CYP3A4 were associated with withdrawal symptoms and side effects; and SNPs on CYP2C19 were associated with methadone dose. SNPs in the genes encoding the morphine phase II metabolic enzyme, UGT2B7, were associated with withdrawal symptom scores. In pharmacodynamic genes, the SNPs on OPRM1 were associated with insomnia and change in libido side effects. We conclude that SNP markers may be useful for future methadone dosage adjustment and to reduce adverse reactions.

Overlapping Prescriptions of Stimulants for Children and Adolescents With Attention-Deficit Hyperactivity Disorder.

OBJECTIVES: The study aimed to assess the occurrence of overlapping prescriptions for methylphenidate among children and adolescents with newly diagnosed attention-deficit hyperactivity disorder (ADHD) and to evaluate the extent to which physician-level and patient-level characteristics affected the risk of prescription overlap during a one-year treatment period. METHODS: The analytic sample comprised 3,081 incident cases of ADHD in 2002 involving children aged 17 years or younger from a retrospective cohort study in Taiwan. Medical and pharmacy claims data from 1999 to 2002 were retrieved from the National Health Insurance Program. All records of methylphenidate prescriptions within a year of treatment initiation were retrieved for each patient, and the number of overlapping days for any two successive prescriptions (new, renewal, or refill) was measured. Multilevel analyses were performed to identify predictors of methylphenidate prescription overlap. RESULTS: Within a year of treatment initiation, approximately 3% to 4% individuals with a new diagnosis of ADHD had experienced methylphenidate prescription overlap. Youngsters who resided in a rural region (adjusted odds ratio [AOR]=2.68) or who had ever changed prescribing doctors (AOR=3.04) were more likely to have visits with a methylphenidate prescription overlap. Receiving methylphenidate from physicians aged 46 or older was associated with 3.6-fold increased odds of prescription overlap. CONCLUSIONS: In an effort to improve the quality and safety of prescription of controlled substances in younger populations, interventions or policies should be devised to target both the service providers and the patients.

Comparison of symptoms in African-American, Asian-American, Mexican-American and Non-Hispanic White patients with major depressive disorder.

The study compared depressive and associated psychopathological symptoms in 17 African-American, 19 Asian-American, 22 Mexican-American and 41 Non-Hispanic White patients with unipolar major depressive disorder. Overall, severity of depression was comparable among the groups both on clinician-rated and subject-rated measures. However, ethnic-minority groups were more likely to experience diurnal variation of mood, with worsening in the evening. Furthermore, Asian-Americans and Mexican-Americans reported greater severity of anxiety and somatic symptoms. The findings suggest that clinicians should be aware of potential differences in symptom presentation when assessing and treating depressed patients from different ethnic groups.

Gender differences in widowhood effects among community-dwelling elders by causes of death in Taiwan.

PURPOSE: We sought to determine whether widowhood-associated excess mortality differs by gender in terms of causes of death. METHODS: Data were collected from a five-wave interview of approximately 2500 community-dwelling elders in the Survey of Health and Living Status of the Nearly Elderly and Elderly. Baseline characteristics were used to derive the risk score (RS) to reflect individual's baseline pre-widowhood vulnerability. Time-dependent Cox regression analyses were used to estimate spousal loss-related mortality by causes. RESULTS: For males, the adjusted hazard ratios (aHRs) of widowhood for all-cause and some major causes of death (e.g., neoplasm) increased inversely with RS: the aHRs for all-cause death were 4.81 and 1.76 in the lowest and highest RS groups, respectively. In contrast, the corresponding aHRs were relatively homogeneous for women (1.52 and 1.70). CONCLUSIONS: Identifying gender heterogeneity in widowhood effects can guide further efforts to devise gender-tailored programs to enhance healthy aging.

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.

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.

Five-year trajectories of long-term benzodiazepine use by adolescents: patient, provider, and medication factors.

OBJECTIVES: This study sought to understand the stability of and change in benzodiazepine use among incident long-term benzodiazepine users over a five-year period and to investigate predictors of variation in use patterns from adolescence into adulthood. METHODS: Long-term use was defined as receipt of benzodiazepine prescriptions for 31 or more cumulative days in a calendar year. Data for 1999-2005 were obtained from the National Health Insurance Research Database in Taiwan. Two age groups of incident long-term users in 2000 were identified--1,758 aged 12-15 and 5,265 aged 16-19-and their benzodiazepine prescription records from 2001 to 2005 were retrieved. Group-based trajectory analyses and polytomous logistic regression were performed to evaluate differential risk of benzodiazepine use over time. RESULTS: From 3% to 5% of the incident benzodiazepine users were long-term users. Four distinct groups of users emerged from the five years of study data: occasional, decelerating, accelerating, and chronic users. Overall, one-quarter were accelerating or chronic users. A history of psychosis or epilepsy, prescription by providers from multiple specialties, and receipt of benzodiazepines with a long half-life or mixed indications significantly increased one's risk of becoming a chronic or accelerating user (range of adjusted odds ratios from 2 to 6). CONCLUSIONS: Patient characteristics and attributes of service providers and pharmacological agents played significant roles in benzodiazepine use patterns. Prescribers can reduce the risk of long-term use by assessing whether pediatric patients have received benzodiazepines from multiple doctors for various medical conditions.

Differential effects of predictors on methylphenidate initiation and discontinuation among young people with newly diagnosed attention-deficit/hyperactivity disorder.

OBJECTIVE: Previous population-based studies have identified factors accounting for differential utilization of psychotropic medications among young patients with attention-deficit/hyperactivity disorders (ADHDs); yet, few analyses have addressed changes in such factors that can occur in the help-seeking process. The aim of this study was to examine patient- and service provider-level predictors for methylphenidate (MPH) initiation and discontinuation. METHOD: This cohort study included 10,153 newly diagnosed ADHD patients under 18 years of age in 2000, identified from the National Health Insurance Research Database. The risk association was estimated by time-dependent survival analyses, as indexed by hazard ratio. RESULTS: Approximately 30% of young people received MPH treatment within the year of their ADHD diagnosis, and virtually none remained in treatment beyond 12 months. Regardless of co-morbidity status, the following were significantly associated with earlier initiation of MPH treatment: older age (e.g., adjusted hazard ratio [aHR] for age 12-17 = 4.5-7.6), lower socioeconomic status (aHR = 1.2-1.4), southern residence (aHR = 1.4-1.6), receiving the diagnosis while school was in session (aHR = 1.3-1.4), receiving the diagnosis from a physician specializing in pediatrics or psychiatry (aHR = 7.3-16.8), and receiving the diagnosis in a district hospital/clinic (aHR = 1.3-1.7). However, once treatment started, older ages appeared to increase the risk of early discontinuation by 15%, and the corresponding estimates for receiving initial MPH in a regional hospital or district hospital/clinic were 27% and 32%, respectively. Change in treatment location upon subsequent visit was associated with a 58% reduction in early discontinuation. CONCLUSIONS: This information about time-varying predictors for MPH utilization throughout treatment may provide insight into the delivery of pediatric mental health services and has important implications for the design of clinical treatment programs.

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.