Chih-Ken Chen

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.).

Psychiatric comorbidity and gender differences of persons incarcerated for methamphetamine abuse in Taiwan

Abstract  Methamphetamine (MAP) abuse has been common in Taiwan for the past decade. The purpose of the present study was to investigate MAP abuse in Taiwan, with specific attention to psychiatric comorbidity and gender differences. A total of 325 MAP abuse subjects (180 male, 145 female) from a detention center in Taipei were assessed with the Diagnostic Interview for Genetic Studies. The following were studied: drug use behavior, treatment‐seeking behavior, lifetime prevalence of mood disorders, MAP psychosis, alcohol use disorders, pathological gambling and antisocial personality. The MAP‐abuse subjects in Taiwan had high psychiatric morbidity and low access to mental health services. There also exist certain differences in the prevalence of psychiatric illnesses and treatment‐seeking behavior between male and female subjects. Compared with their male counterparts, more female subjects reported experience of mental disturbance and experience of psychiatric treatment. The female subjects more commonly reported suicidal behaviors than the male subjects.

Psychiatric comorbidity and gender difference among treatment-seeking heroin abusers in Taiwan

Abstract  The objectives of the present study were to estimate the psychiatric comorbidity of Taiwanese heroin users seeking treatment and to identify the gender differences in psychiatric comorbidity and drug use behavior. Subjects were interviewed using a structured questionnaire on drug use behavior and the Mini International Neuropsychiatric Interview for psychiatric disorders. Of the subjects, 58.5% of the male and 62.5% of the female subjects had at least one non‐substance‐use axis I psychiatric disorder or antisocial personality disorder. Compared to male subjects, female subjects were younger, were less educated, had higher rates of unemployment and had earlier onset of illicit drug use. Female subjects were 11‐fold more likely than male subjects to exhibit suicidal behavior. Among heroin abusers in the present study, female subjects were more widely exposed to unfavorable social factors and had substantially higher incidence of suicidal behavior than male subjects. Drug treatment centers should be aware of these gender differences and pay particular attention to comorbid depressive disorders and suicidal behavior of female heroin abusers.

Family-based association study between brain-derived neurotrophic factor gene polymorphisms and attention deficit hyperactivity disorder in UK and Taiwanese samples†

Brain‐derived neurotrophic factor (BDNF) plays an important role in normal neuronal development. Several lines of evidence implicate the involvement of BDNF in attention‐deficit hyperactivity disorder (ADHD). This study investigated the role of two common BDNF variants (Val66Met, C270T) in two samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212). We found evidence of increased transmission of the C allele of the C270T in Taiwanese samples (TDT: χ2 = 6.78, P = 0.009) and the two samples pooled together (TDT: χ2 = 7.24, P = 0.007). No association was found between the Val66Met polymorphism and ADHD in either of the two populations. Analysis of haplotypes demonstrated a significant decreased transmission of haplotypes containing the Val66 allele and the 270T allele in the Taiwanese samples (TDT: χ2 = 4.57, P = 0.032) and the pooled sample set (TDT: χ2 = 5.82, P = 0.016). This study provides evidence for the possible involvement of BDNF in susceptibility to ADHD.

Association study between the monoamine oxidase A gene and attention deficit hyperactivity disorder in Taiwanese samples.

BackgroundAttention deficit hyperactivity disorder (ADHD) is a common and highly heritable disorder of childhood characterized by inattention, hyperactivity and impulsivity. Molecular genetic and pharmacological studies suggest the involvement of the dopaminergic, serotonergic and noradrenergic neurotransmitter systems in the pathogenesis of ADHD. Monoamine oxidase A (MAO-A) encodes an enzyme that degrades biogenic amines, including neurotransmitters such as norepinephrine, dopamine and serotonin. In this study we examined a 30 bp promoter variable number tandem repeat (VNTR) and a functional G/T single nucleotide polymorphism (SNP) at position 941 in exon 8 (941G/T) of MAO-A for association with ADHD in a Taiwanese sample of 212 ADHD probands.MethodsWithin-family transmission disequilibrium test (TDT) was used to analyse association of MAO-A polymorphisms with ADHD in a Taiwanese population.ResultsA nominally significant association was found between the G-allele of 941G/T in MAO-A and ADHD (TDT: P = 0.034. OR = 1.57). Haplotype analysis identified increased transmission of a haplotype consisting of the 3-repeat allele of the promoter VNTR and the G-allele of the 941G/T SNP (P = 0.045) to ADHD cases which the strong association with the G-allele drove.ConclusionThese findings suggest the importance of the 941G/T MAO-A polymorphism in the development of ADHD in the Taiwanese population. These results replicate previously published findings in a Caucasian sample.

Effects of a 10-week weight control program on obese patients with schizophrenia or schizoaffective disorder: A 12-month follow up

Aims:  Weight gain secondary to antipsychotic medication is associated with many serious conditions, including type II diabetes mellitus, hypertension, and coronary heart disease, and also with poor medication compliance. Weight control programs may be of benefit to outpatients with schizophrenia, but also raise an issue of cost‐effectiveness. We aimed to evaluate the effectiveness of a 10‐week weight control program for outpatients taking atypical antipsychotics for treatment of schizophrenia, and to follow up the effects of this weight control program in controlling weight gain after termination of the program.

Differential add-on effects of aripiprazole in resolving hyperprolactinemia induced by risperidone in comparison to benzamide antipsychotics

UNLABELLED Hyperprolactinemia is associated with typical antipsychotic agents and atypical antipsychotics such as risperidone and amisulpride. This study investigates the effects of 8-week adjunctive treatment with aripiprazole in patients with hyperprolactinemia induced by risperidone in comparison to benzamide antipsychotics (amisulpride and sulpiride). Aripiprazole was administered to 24 patients with antipsychotic-induced hyperprolactinemia. The doses of pre-existing antipsychotics were fixed, while the aripiprazole dose was 5-20 mg/day during the 8-week study period. Serum prolactin levels were measured at weeks 4 and 8. Symptoms and side effects were assessed using the Positive and Negative Syndrome Scale (PANSS), Arizona Sexual Experience Scale, Abnormal Involuntary Movement Scale, Simpson-Angus Scale, Barnes Akathisia Scale, and metabolic measures at weeks 2, 4 and 8. Mean (standard error) prolactin levels decreased from 77.0±13.3 ng/mL to 18.3±2.1 ng/mL (p<0.001 vs. baseline), from 144.9±24.4 ng/mL to 127.5±21.7 ng/mL (p=0.099 vs. baseline) and 71.4±24.6 ng/mL to 43.3±14.7 ng/mL (p=0.106 vs. baseline) for those taking risperidone, amisulpride, and sulpiride, respectively. For those who took risperidone before the study started, 14 of 15 (93.3%) patients had normalized prolactin levels, while only 1 of 10 (10%) taking benzamide antipsychotics had normalized prolactin levels. The PANSS score improved significantly, and aripiprazole had no significant influence on metabolic measures or scales of movement side effects. Adjunctive aripiprazole treatment reversed effectively hyperprolactinemia induced by risperidone, but was less effective for that induced by benzamide antipsychotics. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00541554.

Persistence of psychotic symptoms as an indicator of cognitive impairment in methamphetamine users

BACKGROUND Prolonged exposure to methamphetamine (meth) has neurotoxic effects and impairs neurocognitive functions. This study aims to ascertain whether meth users who experience persistent psychosis suffer more severe cognitive impairment than those not experiencing persistent psychosis. METHODS This cross-sectional study includes 252 participants: 25 meth users without psychosis (METH-P), 50 with brief psychosis (METH+BP), and 56 with persistent psychosis (METH+PP), as well as 54 patients with schizophrenia and 67 healthy controls. The neurocognitive function and clinical psychopathology of each patient were evaluated with the Brief Assessment of Cognition in Schizophrenia (BACS) and the Brief Psychiatric Rating Scale (BPRS), respectively. RESULTS All cognitive domains evaluated with BACS (verbal memory, working memory, motor speed, verbal fluency, attention and processing speed, executive function, and composite scores) in METH+PP patients were similar to those in the schizophrenia patients and were worse than those in METH-P, METH+BP, and the healthy control subjects. Furthermore, cognitive functioning in meth users that did not experience persistent psychosis showed no statistically significant difference compared with the healthy control subjects. Among the meth users in this study, the negative symptom scores in the BPRS correlated to cognitive performance on the BACS, with the exception of motor speed. CONCLUSIONS Meth users display heterogeneity in their psychotic symptoms and cognitive profiles. Therefore, persistent psychotic symptoms may denote a risk for cognitive decline among meth users. Further longitudinal studies should be performed in the future to clarify the causal relationship between cognitive deficits and the development of persistent psychosis.

Obesity in schizophrenic outpatients receiving antipsychotics in Taiwan

Abstract  This investigation estimates and compares, for the first time, the distribution of body mass index (BMI: kg/m2) and the prevalence of obesity among Chinese outpatients with schizophrenia treated with antipsychotics. The BMI of 201 outpatients with schizophrenia‐spectrum disorders was studied via a cross‐sectional naturalistic study. This investigation also compared the BMI of the subjects with a Taiwanese reference population. This investigation found no significant difference in the prevalence of obesity between male and female subjects. The prevalence of obesity among male and female patients in this investigation was, respectively, 2.74‐ and 2.51‐fold greater than the Taiwanese reference population, and the prevalence of severe obesity among male and female patients was 4.66‐ and 3.53‐fold greater than that in the Taiwanese reference population, respectively. The rate of severe obesity was especially high in patients treated with olanzapine. Atypical antipsychotics other than olanzapine did not seem to be more closely associated with obesity or severe obesity compared to typical antipsychotics.

Adjunctive effects of aripiprazole on metabolic profiles: Comparison of patients treated with olanzapine to patients treated with other atypical antipsychotic drugs ☆

Metabolic abnormalities are serious adverse effects of atypical antipsychotic treatment. This study aims to determine the effects of adjunctive aripiprazole on metabolic profiles among patients receiving treatment with atypical antipsychotics, and to examine whether these effects are different from that of pre-existing atypical antipsychotics. In the 8-week open-label trial, aripiprazole was added to patients who were receiving treatment with atypical antipsychotics and had experienced weight gain or dyslipidemia. The dosage of pre-existing atypical antipsychotics was fixed, while the dosage of aripiprazole ranged from 5 to 20 mg/day during the study period. Metabolic profiles, including body weight, body mass index (BMI), plasma levels of fasting glucose, triglycerides, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and adiponectin, were measured at baseline and week 8. As a result, 43 subjects (16 males and 27 females, mean age: 37.8±10.8 years) completed the study. The pre-existing antipsychotics were olanzapine (n=12), risperidone (n=19), quetiapine (n=6) and amisulpiride (n=6). The mean dosage of adjunctive aripiprazole was 9.9±3.2 mg/day. After the aripiprazole-augmented regimen for 8 weeks, patients treated with olanzapine had significant decreases in body weight, BMI and triglyceride levels, and had significant increases in adiponectin levels. For patients treated with other atypical antipsychotics, none of the metabolic parameters significantly changed after administering aripiprazole. In conclusion, aripiprazole-augmented treatment might be beneficial for the metabolic regulation of patients being treated with a stable dose of olanzapine, but not for those treated with other atypical antipsychotics. A long-term, randomized, double-blind controlled design is suggested to confirm these findings.