Hee Jung Nam

Association of the Glutamate Transporter Gene SLC1A1 With Atypical Antipsychotics-Induced Obsessive-compulsive Symptoms

CONTEXT Several studies have indicated that atypical antipsychotics (AAP) induce obsessive-compulsive (OC) symptoms. Research exploring the mechanism of this phenomenon, however, has been extremely limited. Considering the indirect evidence of genetic control and difficulties in developing animal models and performing gene expression studies, genetic association studies could be an important approach to understanding the molecular mechanism of AAP-induced OC symptoms. The glutamate transporter gene SLC1A1, which was recently reported to be associated with obsessive-compulsive disorder (OCD), is a promising candidate gene for susceptibility to AAP-induced OC symptoms. OBJECTIVE To determine whether polymorphisms in SLC1A1 are associated with AAP-induced OC symptoms in patients with schizophrenia. DESIGN A pharmacogenetic case-control association study. SETTING Outpatient schizophrenia clinics. PATIENTS Clinically stable patients with schizophrenia who were receiving AAP treatment (n = 94; OC group). The OC group consisted of 40 patients with AAP-induced OC symptoms, and the non-OC group consisted of 54 patients who had received AAP for more than 24 months without developing OC symptoms. MAIN OUTCOME MEASURES Allele, genotype, and haplotype frequencies. The association was tested with a logistic regression model using age, sex, and medication type as covariates. RESULTS Trends of association were observed in rs2228622 and rs3780412 (nominal P = .01; adjusted permutation P = .07) for the dominant model that was the inheritance model that best fit our data. In the haplotype -based analysis, the A/C/G haplotype at rs2228622-rs3780413-rs3780412 showed a significant association with AAP-induced OC symptoms; this association withstood multiple test correction (nominal P = .01; adjusted permutation P = .04; odds ratio, 3.955; 95% confidence interval, 1.366-11.452, for dominant model). CONCLUSIONS These results suggest that sequence variations in SLC1A1 are associated with susceptibility to AAP-induced OC symptoms. This is the first published pharmacogenetic study on this phenomenon and provides preliminary evidence of the involvement of glutamatergic neurotransmission in the pathogenesis of AAP-induced OC symptoms.

Interaction between genetic variants of DLGAP3 and SLC1A1 affecting the risk of atypical antipsychotics-induced obsessive-compulsive symptoms.

Adverse effects of atypical antipsychotics (AAP) can include obsessive–compulsive (OC) symptoms. Based on biological evidence of the relationship between the glutamatergic system and both OC disorder and AAP, this study aimed to determine whether DLGAP3, coding a post‐synaptic scaffolding protein of glutamatergic synapses, is associated with AAP‐induced OC symptoms. Furthermore, we explored the interactions between DLGAP3 and a previously reported susceptibility gene, the glutamate transporter gene SLC1A1, regarding this phenotype. Subjects were clinically stable schizophrenia patients receiving AAP treatment (n = 94), and they comprised an OC group (n = 40) and a non‐OC group (n = 54) (patients with and without AAP‐induced OC symptoms, respectively). We performed allelic/genotypic/haplotype association analyses for seven tag single‐nucleotide polymorphisms of DLGAP3 and gene–gene interaction analyses with rs2228622 of SLC1A1, observing a nominally significant association between AAP‐induced OC symptoms and rs7525948 in both simple chi‐square tests and the regression analyses (nominal P < 0.05). In the logistic regression analysis of gene–gene interaction, we found a significant interaction effect of rs7525948 of DLGAP3 and rs2228622 of SLC1A1 (permutation P = 0.036) on AAP‐induced OC symptoms, with a 30.2 times higher odds for individuals carrying risk genotypes at both loci in comparison with the reference group, which had no risk genotypes. This study provides suggestive evidence that DLGAP3 and its interactive effect with SLC1A1 might be involved in susceptibility to developing OC symptoms in schizophrenia patients receiving AAP treatment.

Cognitive profiles of healthy siblings of schizophrenia patients: Application of the cognitive domains of the MATRICS consensus battery

Even though a large body of data suggests the presence of various types of cognitive deficits in the unaffected relatives of schizophrenia patients, more study is needed to clarify the comparative sensitivities of specific cognitive measures for relative-control differences. In this study, the authors compared the cognitive profiles of unaffected siblings of schizophrenia patients and those of patients and normal controls, and attempted to identify cognitive markers that might be associated with genetic liability to schizophrenia. Eighty-eight clinically stable schizophrenia patients, 44 healthy patient siblings, and 100 normal controls were evaluated using comprehensive neuropsychological tests. The domain structure of the MATRICS consensus cognitive battery was adopted, and both domain scores and individual test scores were used in the analysis. Performances of the sibling group were intermediate between those of patients and controls on most measures. A significant difference between the sibling and control groups was observed only in the Category Fluency Test. This cognitive deficit might be caused by familial predisposition to schizophrenia and could be a candidate of endophenotype for schizophrenia.

Determination of pharmacokinetic properties of clozapine and norclozapine in Korean schizophrenia patients

There is a wide interethnic variance in the pharmacokinetic profile of clozapine (CLZ), but the accumulated data are limited to some regional populations. In this study, we investigated the pharmacokinetic profile of CLZ in Korean patients and examined the association between serum CLZ parameters and clinical outcome. We assessed 78 Korean patients with schizophrenia who had been taking CLZ medication for more than 6 months. The patients were classified into three groups (good, moderate, and poor responders) according to their Clinical Global Impressions-Improvement scores. The serum concentrations of CLZ and norclozapine were 610.7±368.4 and 314.5±163.0 ng/ml (mean±SD), respectively, showing a large interindividual variation that was affected by dose, age, smoking habits, and sex by variable degrees. The pharmacokinetic profiles of Koreans were similar to those observed in Asians but quite different from those in Caucasians. Investigation on clinical responses revealed that the good or moderate responders clinically improved at a relatively low serum CLZ levels, whereas the poor responders showed less improvement despite the higher doses and serum levels. The metabolic ratio of the good responders was 0.65±0.20, higher than the poor responders (P=0.033). In this study, we identified a pharmacokinetic profile of CLZ in Korean schizophrenia patients and found a wide interindividual difference affected by various factors.

Factor Structure of the Neurocognitive Tests: An Application of the Confirmative Factor Analysis in Stabilized Schizophrenia Patients

The purpose of the present study was to identify the factor structure of neurocognitive tests used on schizophrenia patients by using the confirmative factor analysis, and to assess the factor score differences of schizophrenia patients and healthy controls. Comprehensive neurocognitive tests were administered to stabilized schizophrenia patients (N=114) and healthy controls (N=120). In the results of factor analyses on patients, the multifactorial-6-factor model, which included the speed of processing, working memory, verbal learning and memory, visual learning and memory, attention/vigilance, and reasoning/problem solving as suggested by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), showed the better goodness of fit than any of the other models tested. And assessing the group differences of factor scores, we found the patients performed worse than the controls in all factors, but the result showed meaningful variations of impairments across the cognitive factors. Our study identifies the six major domains with multifactorial structure of cognitive abilities in schizophrenia patients and confirms the distinctive impairment patterns of each cognitive domain. These results may have utility in better understanding the pathology of schizophrenia as well as in genetic studies.

Prevalence of Metabolic Syndrome in Patients with Schizophrenia in Korea: A Multicenter Nationwide Cross-Sectional Study.

Objective We designed a nationwide study with limited exclusion criteria to investigate the prevalence of metabolic syndrome (MetS) in Korea and its relationship with antipsychotic medications. Methods This multicenter, cross-sectional, and observational study included patients diagnosed with schizophrenia or schizoaffective disorder. Sixteen hospitals enrolled 845 patients aged 18 to 65 years prescribed any antipsychotic medication between August 2011 and August 2013. MetS was diagnosed using the criteria of the modified Adult Treatment Panel III of the National Cholesterol Education Program with the Korean abdominal obesity definition (waist circumference ≥85 cm in women, ≥90 cm in men). Results The prevalence of MetS in all patients was 36.5% and was significantly higher in men than women (men, 40.8%; women, 32.2%) and was significantly correlated with age [odds ratio (OR) 1.02] and duration of illness (OR 1.03). The prevalence of MetS across antipsychotic drugs in the major monotherapy group was as follows: 18.8% for quetiapine, 22.0% for aripiprazole, 33.3% for both amisulpride and paliperidone, 34.0% for olanzapine, 35% for risperidone, 39.4% for haloperidol, and 44.7% for clozapine. Conclusion The prevalence of MetS is very high in patients with schizophrenia or schizoaffective disorder. Screening and monitoring of MetS is also strongly recommended.