Catechol-O-Methyl Transferase Gene Polymorphism and Treatment Response to Clozapine in Refractory Schizophrenia / 대한정신약물학회지

OBJECTIVE: Disturbances in the biogenic amine pathways have been hypothesized to be the biochemical basis of schizophrenia. Catechol-O-methyl transferase (COMT) gene is an important candidate gene due to its function to metabolically inactivating these amines. We investigated the association between 472 G/A (158val/met) and -287 A/G polymorphisms of COMT gene with response to clozapine treatment in refractory schizophrenia. METHODS: One hundred twenty patients of refractory schizophrenia, who were treated with clozapine longer than six months, were participated in this study. We evaluated treatment response on the basis of the difference of re-hospitalization frequency and hospitalization duration before and after the first clozapine administration day. Genotyping of the 472 G/A and -287 A/G polymorphisms was performed by SNapShot method. RESULTS: In 472 G/A polymor-phism, there were no significant differences of the re-hospitalization frequency and the hospitalization duration between the A (-) group and A (+) group, and also no differences among GG, GA, and AA groups. In -287 A/G polymorphism, there were no significant differences between G (-) group and G (+) group. However, we observed significant differences in the re-hospitalization frequency (F=4.38, p=0.015) and in the hospitalization duration (F=3.90, p=0.024) among three genotype groups. CONCLUSION: We found that the treatment response to clozapine was not associated with COMT 472 G/A polymorphism but was positively associated with -287 A/G polymorphism in refractory schizophrenia. However, This association is not strong enough to conclude the association between -287 A/G polymorphism in COMT gene and clozapine response. Further studies with a large sample are required to verify this positive finding more clearly.

Genetic Association between Single Nucleotide Polymorphisms on COMT Gene and Schizophrenia in Korean Population / 대한정신약물학회지

OBJECTIVE: This study aimed to explore genetic relation between schizophrenia and COMT gene which plays an important role in metabolizing dopamine, one of the most intriguing neuro-transmitters for schizophrenia. METHODS: 1) Single Nucleotide Polymorphism (SNP) on exons of COMT gene was searched by F-CSGE (Fluorescent-Conformation Sensitive Gel Electrophoresis) method with 50 patients with schizophrenia to look for any SNP unique to Korean patients with schizophrenia. 2) Genotyping was done for five SNPs on COMT gene for 218 patients with schizophrenia and 199 normal controls by SNaPShot method. Allele frequencies, genotype frequencies and simulated haplotype frequencies were compared between patients with schizophrenia and normal controls. RESULTS: 1) No unique SNPs for Koreans was found on exons of COMT gene and seven SNPs were found, all of them are already reported to be found in other ethnic groups. 2) No significant difference between patients with schizophrenia and normal controls in terms of allele frequencies, genotype frequencies and haplotype frequencies was found in our sample. CONCLUSION: Genetic association between five SNPs on COMT gene and DSM-IV diagnosis of schizophrenia among Koreans was not able to be found in this study.

Minor Physical Anomalies in Patients with Schizophrenia

OBJECT AND METHOD: Minor physical anomalies(MPAs) are frequently seen in patients with schizophrenia. MPAs are considered to arise from the anomalous development of ectoderm-originated tissues in the developing fetus. Since the central nervous system originates from ectoderm, MPAs can be regarded as externally observable and objective indicators of the aberrant development which might have taken place in the central nervous system. To investigate whether MPAs are more frequent in schizophrenic patients, the frequencies of MPAs were compared between schizophrenic patients and normal controls. Total 245 schizophrenic patients diagnosed with DSM-IV(male : 158, female : 87), and 418 normal control subjects(male : 216, female : 202) were included in this study. The MPAs were measured using the modified Waldrop scale with fifteen items in six bodily regions; head, eye, ear, mouth, hand, and foot. RESULT: The total scores of Waldrop scale were 4.40+/-1.93(mean+/-standard deviation) in patients and 3.43+/- 1.68 in controls for females, and for males, 4.58+/-1.75 in patients and 4.28+/-1.59 in controls. For females, the excess of MPAs in schizophrenic patients was statistically significant(t-test : p<0.001). For males, schizophrenic patients also showed more MPAs than normal controls, but this tendency did not reach statistical significance (t-test : p=0.094). When the modified Waldrop total scores excluding head circumference were compared, the total scores in schizophrenic patients were significantly higher for both male and female subjects(t-test : male p<0.001, female p=0.001). The individual anomaly items included in Waldrop scale were also investigated. The items of epicanthus, hypertelorism, malformed ears, syndactylia were significantly more frequent in schizophrenic patients. In contrast, the items of adherent ear lobes, asymmetric ears, furrowed tongue, curved fifth finger, single palmar crease and big gap between toes did not show any differences in frequency between schizophrenic patients and normal controls. Since a lot of statistical analyses showed different results between male and female subjects, it seems to be necessary to consider gender as an important controlling variable for the analysis, however only the item of head circumference showed statistically significant gender-related difference according to log-linear analysis. CONCLUSION: With a relatively large sample size, the frequencies of MPAs enlisted in Waldrop scale were compared between schizophrenic patients and normal controls in this study. MPAs were more frequently seen in schizophrenic patients and, especially, several specific items in the Waldrop scale showed prominent excess in schizophrenic patients. Although definite conclusions cannot be drawn due to the inherent limitation of the study using Waldrop scale, these results seem to support the possibility that aberrant neurodevelopmental process might be involved in the pathogenesis of schizophrenia in some of the patients.