Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Prevalence of psychiatric disorders among heroin users who received methadone maintenance therapy in Taiwan.

BACKGROUND: Many patients under methadone maintenance treatment are present with comorbid psychiatric symptoms. OBJECTIVE: We wish to examine the prevalence of psychiatric disorders among heroin users who received methadone maintenance therapy (MMT) in Taiwan. METHODS: By combining the National Health Insurance Research database and Center for Disease Control database, 18,271 heroin users who received MMT were defined as the subject group and after matching age and sex, 73,084 patients were randomly selected as the control group. RESULTS: The 1 year prevalence of any psychiatric disorder, any psychotic disorder, neurotic and other nonpsychotic disorder among MMT patients and control group were 13.14% versus 2.50% (OR 5.89, CI 5.53-6.27), 4.21% versus 1.29% (OR 3.38, CI 3.07-3.72), and 9.89% versus 1.31% (OR 8.25, CI 7.62-8.94), respectively. CONCLUSION: The prevalence of any co-morbid psychiatric disorder among MMT patients is almost six times higher than the control group. SCIENTIFIC SIGNIFICANCE: A thorough psychiatric screening and appropriate aggressive intervention should be incorporated into an effective methadone treatment program.

Suppression of antipsychotic-induced tardive dyskinesia with aripiprazole in an elderly patient with bipolar I disorder.

INTRODUCTION: Aripiprazole has a low risk for causing extrapyramidal syndrome and can remit neuroleptic-induced tardive dyskinesia (TD). Here, we presented a case in which TD was suppressed, but not cured, by long-term aripiprazole treatment. CASE: This 74-year-old male patient had bipolar I disorder and had developed TD many times after several antipsychotic treatments. The lowest chlorpromazine dose equivalent among the previous antipsychotic treatments was 25 mg/day of quetiapine. His TD always improved immediately after the dosage was shifted to aripiprazole. However, his insomnia or other psychiatric symptoms worsened the first three times when the treatment was shifted to aripiprazole, making the transition a failure. Before the fourth attempt of aripiprazole transition, the patient was in a euthymic state but again developed TD under olanzapine 10 mg/day treatment. During the fourth attempt of aripiprazole transition, his TD had remained in complete remission for more than 1 year after the dosage shifted to 10 mg/day of aripiprazole. He developed TD again when we tapered the aripiprazole dose to 5 mg/day, but his TD remitted when we restored his aripiprazole dose to 10 mg/day. CONCLUSION: Aripiprazole could be an effective drug in elderly bipolar patients with antipsychotic-induced TD while the patients are in a euthymic state. However, aripiprazole may only suppress TD rather than cure it.

Trends, correlates, and disease patterns of antipsychotic use among children and adolescents in Taiwan.

PURPOSE: We used Taiwan's population-based National Health Insurance database to investigate the trends, correlates, and disease patterns of antipsychotic use among children and adolescents. METHODS: The National Health Research Institutes provided a database of 1,000,000 random subjects for study. We chose subjects who were aged 18 years or younger during 1997-2005. In this sample, subjects who were given at least one antipsychotic prescription, including first-generation antipsychotics (FGAs) or second-generation antipsychotics (SGAs), were identified. Trends, prevalence, and associated factors of antipsychotic use were determined. The proportion of antipsychotic use for psychiatric and medical disorders was also analyzed. RESULTS: The 1-year prevalence of SGA use increased from 0.00 % in 1997 to 0.09 % in 2005, whereas the 1-year prevalence of FGA use ranged from 2.24 to 3.43 % during this same period, with no significant change. Age and male gender were associated with higher SGA use. Among SGA users, the greatest proportion suffered from psychiatric disorders, including tics, hyperkinetic syndrome of childhood, schizophrenia, affective disorders, and autism. Among FGA users, a larger proportion was for medical conditions, including diseases of the digestive and respiratory systems. CONCLUSION: The prevalence of pediatric SGA use increased greatly from 1997 to 2005. Among pediatric subjects using antipsychotics, SGAs were mostly used for psychiatric disorders, whereas FGAs were mostly prescribed for medical conditions. Future research will focus on indication, dosage, frequency, duration, adverse effects, and off-label use of antipsychotics in the pediatric population.

A multilevel analysis of regional and individual effects on methadone maintenance treatment in Taiwan.

OBJECTIVE: This study evaluated the direct and interactive effects of regional-level and individual-level characteristics on methadone maintenance treatment (MMT), after considering the individual characteristics in Taiwan. METHODS: This study utilized a survey research method. Opioid-dependent patients who participated in the outpatient MMT program in 2009 and met the eligibility criteria were recruited from five hospitals. The impact of MMT on self-perceived health was assessed by using questionnaires. This study assessed the participants' quality of life and treatment outcomes during 3-month follow-up visits, before evaluating the direct effects of regional and individual characteristics. Multilevel linear models were used to estimate whether regional levels influenced individual behavior and treatment outcomes. RESULTS: Three hundred thirty-four opioid-dependent patients agreed to participate in this study. After the follow-up period, 127 participants completed the study (completion rate = 38%). Participants receiving MMT demonstrated significant improvements in psychological state, HIV risk-taking behavior, social functioning, and health. Regional characteristics, such as the lower than junior high school rate, low-income family rate, and related crime rates, of the study regions were negatively associated with improvements in drug abuse behavior. CONCLUSIONS: This study shows that MMT can significantly improve the HIV risk-taking behavior and health of the study participants. Disadvantaged regions, however, exhibit poor treatment outcomes. This study suggests actions to minimize the treatment variations between regions.

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.

Effectiveness of a work-related stress management program in patients with chronic schizophrenia.

OBJECTIVE: The purpose of this study was to examine the effect of a work-related stress management program on perceived work-related stress in patients with chronic schizophrenia. METHOD: A single-blind, randomized crossover design was used. Twenty-nine patients undergoing vocational training while working at paid part-time jobs in a psychiatric center were randomly assigned to receive 12 weeks of a work-related stress management program followed by 12 weeks of no treatment, or the reverse. The Work-Related Stress Questionnaire for Chronic Psychiatric Patients (WSQP) was developed for this study and used to examine the treatment effect. RESULTS: The decrease in stress was significantly greater when the participants were undergoing the program compared to the decrease of stress when they were not (t = 2.93, p = .0034, r = .49). CONCLUSION: The results show that the work-related stress management program had large short-term positive effects on the patients' perceived work-related stress. These findings support providing this type of program to employed patients with chronic schizophrenia.

Posttraumatic stress disorder among professional and non-professional rescuers involved in an earthquake in Taiwan.

This study investigated the prevalence of posttraumatic stress disorder (PTSD) among professional and non-professional rescue workers involved in the 1999 Chi-Chi Earthquake in Taiwan. One month following the disaster, 252 rescue workers (167 professional rescue workers, 85 non-professional volunteers) were surveyed with the Chinese version of the Davidson Trauma Scale (DTS-C) and the Chinese version of the SPAN (SPAN-C). Non-professional rescuers had significantly higher scores than professional rescuers on both the DTS-C and the SPAN-C. The prevalences of PTSD, as defined by a DTS-C score > or = 44, among professional and non-professional rescuers were 19.8% and 31.8%, respectively. Among the three subscales of the DTS-C, only scores on the numbness/avoidance subscale were significantly higher in the non-professional than in the professional rescue workers. The results of this study suggest that disaster rescue work is associated with a high level of stress even for highly trained professionals and may lead to mental health problems.

Trends, correlates, and disease patterns of antidepressant use among children and adolescents in Taiwan.

The authors used a population-based database to investigate antidepressant use among children and adolescents in Taiwan. The National Health Research Institutes provided a database of 1 000 000 random subjects for study. The authors adopted this sample of subjects who were younger than 18 years during 1997 to 2005. Subjects with at least 1 antidepressant prescription were identified. Trends, prevalence, associated factors, and disease patterns of antidepressant use were detected. The 1-year prevalence of pediatric antidepressant use increased from 0.27% in 1997 to 0.47% in 2005. The 1-year prevalence of tricyclic antidepressant, selective serotonin reuptake inhibitor, and other antidepressant use among pediatric population was 0.23%, 0.20%, and 0.08%, respectively, in 2005. The prevalence of pediatric antidepressant use increased from 1997 to 2005. Among pediatric subjects with antidepressant use, selective serotonin reuptake inhibitors, and other antidepressants were used the most for psychiatric disorders, whereas tricyclic antidepressant was used the most for nonpsychiatric disorders.

Screening and confirmation of 62 drugs of abuse and metabolites in urine by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry.

An ultra-high-performance liquid chromatography--quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) method for the screening and confirmation of 62 drugs of abuse and their metabolites in urine was developed in this study. The most commonly abused drugs, including amphetamines, opioids, cocaine, benzodiazepines (BZDs) and barbiturates, and many other new and emerging abused drugs, were selected as the analytes for this study. Urine samples were diluted 5-fold with deionized water before analysis. Using a superficially porous micro-particulate column and an acetic acid-based mobile phase, 54 basic and 8 acidic analytes could be detected within 15 and 12 min in positive and negative ionization modes, respectively. The MS collision energies for the 62 analytes were optimized, and their respective fragmentation patterns were constructed in the in-house library for confirmatory analysis. The coefficients of variation of the intra- and inter-day precision of the analyte responses all were <17.39%. All analytes, except barbital, showed matrix effects of 77-121%. The limits of detection of the 62 analytes were between 2.8 and 187.5 ng/mL, which were lower than their respective cut-off concentrations (20-500 ng/mL). Ten urine samples from patients undergoing methadone treatment were analyzed by the developed UHPLC-QTOF-MS method, and the results were compared with the immunoassay method.

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.

Serum lipid profile could predict the inception and impacts of violent behaviors among acute psychiatric inpatients.

BACKGROUND: The prediction of violence among psychiatric inpatients using biophysiological indicators is warranted for re-examinations longitudinally. This study aims to explore factors associated with the occurrence of violence and subsequent medical impacts in psychiatric inpatients. METHODS: Inpatients diagnosed with either schizoaffective disorder or bipolar mania were admitted to acute wards in a professional psychiatric care setting. A longitudinal analysis was applied to construct predictive models with blood biochemistry tests upon admission. Medical records and an administrative database were used for analyses. RESULTS: Triglycerides were found to be a significant predictor of violence inception, which demonstrated a multivariate-adjusted odds ratio of 0.988 per mg/dL increment. Psychiatric inpatients with a higher level of triglycerides were less likely to have violent behaviors while more serious medical impacts were found once violence occurred. The elevated medical expenses derived from violence were negatively correlated with the level of cholesterol upon admission. A U-shape relationship was found between medical impacts and the combination of serum triglycerides and cholesterol. CONCLUSION: The study provides useful predictors for early pre-screening of potential violence cases among acute psychiatric inpatients and therefore offers various angles for future strategic management of care plans in psychiatric medical settings.

UGT2B7 genetic polymorphisms are associated with the withdrawal symptoms in methadone maintenance patients.

AIM: To test whether the genetic polymorphisms within the gene encoding the UGT2B7 gene may have an impact on methadone treatment. MATERIALS & METHODS: Twelve SNPs in UGT2B7 were selected. 366 methadone maintenance treatment patients in Taiwan were recruited and genotyped. RESULTS: In a genotype recessive model, rs6600879, rs6600880, rs4554144, rs11940316, rs7438135, rs7662029, rs7668258, rs7439366, rs4292394 and rs6600893 showed significant associations with severity of withdrawal symptoms (permutation p < 0.002), pupil size (permutation p < 0.048) and tremor (permutation p < 0.008). Haplotypes of GATCAGCCGC and CTCTGATTCT were significantly associated with pupil size score and tremor score (p < 0.034). CONCLUSION: These results suggest that SNPs of the UGT2B7 gene may play important roles in opiate withdrawal symptoms.

Alcohol use problem among patients in methadone maintenance treatment in Taiwan.

AIMS: To examine the prevalence rate and predictors of alcohol use problems among patients undergoing methadone maintenance treatment (MMT). DESIGN: This was a prospective follow-up study. PARTICIPANTS: Study population included 438 patients who underwent more than 6 months of MMT. MEASUREMENTS: Demographic and clinical characteristics were collected for each patient prior to treatment, and treatment-related variables were collected during treatment process. Hazardous drinking, alcohol abuse, and dependence were measured using a Chinese version of the Alcohol Use Disorders Identification Test (AUDIT) and by measuring breath alcohol concentration. FINDINGS: The prevalence rates of alcohol use problems, indicated by hazardous drinking are 31.4%. The protective predictors of alcohol use problems among MMT patients include an attendance rate of more than 90% (odds ratio [OR] = 0.54, 95% confidence interval [CI] = 0.30-0.97) and being older than 36 years (OR = 0.48, 95% CI = 0.27-0.86), and alcohol drinking problem at intake of study is a risk factor (OR = 5.30, 95% CI = 2.87-9.76). CONCLUSIONS: High attendance rate, which is regarded as a component of clinical policy and a key component of therapeutic context, should be incorporated with brief interventions to lower alcohol use problems among MMT patients.

Long-term psychological outcome of 1999 Taiwan earthquake survivors: a survey of a high-risk sample with property damage.

OBJECTIVE: Severe natural disasters can cause long-term psychological impact on the survivors. This study aimed to examine the prevalence and risk factors of posttraumatic stress symptoms and psychiatric morbidity among survivors of the severe earthquake that occurred in Chi-Chi, Taiwan, in September 21, 1999. METHODS: A total of 6412 earthquake survivors whose houses were destroyed by earthquake were recruited about 2 years after the disaster. They completed a self-report questionnaire assessing posttraumatic stress symptoms, psychiatric morbidity, and information of demographics, trauma exposure, and current living status. RESULTS: The estimated rates of posttraumatic stress disorder caseness and psychiatric morbidity were 20.9% and 39.8%, respectively. Psychiatric morbidity occurred mainly in survivors who were female, older, with low education level, and currently living in a prefabricated house. The risk factors for posttraumatic stress disorder caseness were female sex, currently living in a prefabricated house, low education level, and experienced complete destruction of property. CONCLUSION: These results showed that severe earthquake can cause long-term psychological impact in the survivors. The findings of risk factors suggest avenues for targeting postdisaster interventions.

The validation study and application of stratum-specific likelihood ratios in the Chinese version of SPAN.

The Davidson Trauma Scale (DTS) is a validated self-rating scale used in the diagnosis of post-traumatic stress disorder (PTSD). A shorter version of the DTS was developed to serve as a diagnostic screening tool. A four-item scale, the SPAN (named for its principal four items: Startle, Physiological arousal, Anger, and Numbness), was then developed. This report investigates the psychometric validation of the Chinese version of the SPAN (SPAN-C). Subjects were drawn from a sample of 210 survivors of the September 21, 1999 Chi-Chi Earthquake. The scale showed good internal consistency (Cronbach's alpha= 0.77) and test-retest reliability (r = 0.90). Concurrent validity was obtained against the clinical diagnostic interview, with a diagnostic accuracy of 0.8 at a SPAN-C score of 5. The recommended stratum-specific likelihood ratios were 0.04 (95% confidence interval [CI], 0.02 to 0.07) for the score range of 0 to 2, 0.93 (95% CI, 0.51 to 1.71) for the score range of 3 to 4, 2.31 (95% CI, 1.17 to 4.57) for the score range of 5 to 6, and 5.23 (95% CI, 3.12 to 8.78) for scores above 7. The psychometric strength of the SPAN-C indicates its reliability for future use, particularly for screening for subjects with a possible diagnosis of PTSD.