Correspondence : Jun Soo Kwon, MD, PhD, Department of Psychiatry, Seoul National University College of Medicine, 28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Korea
Tel : +82-2-2072-2972, Fax : +82-2-747-9063, E-mail: kwonjs@plaza.snu.ac.kr

Introduction

Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by intrusive and distressing thoughts, urges, and images as well as repetitive behaviors. As the serotonin reuptake inhibitor (SRI) has been effective in the treatment of OCD, serotonin and serotonin associated genes have begun to be considered as important factors in the pathology of OCD. More recently, 5-HT_2A receptor gene has become the focus of increasing research attention, as a factor which is significantly related to OCD.¹
Neurocognitive dysfunction is considered to be the core pathological factor in OCD. Some studies reported the contribution of 5-HT_2A receptors on neurocognitive functions.^2,3 However, little is known about the influence of the 5-HT_2A receptors polymorphism on neurocognitive function in OCD.
The objective of this study was to evaluate the possibility of an association between the T102C polymorphism of the 5-HT_2A receptor and neurocognitive function in OCD.

Methods

Subjects
Fifty four subjects, all of whom fulfilled the DSM-IV diagnostic criteria for OCD, were recruited into this study. Symptom severity was measured by Yale-Brown Obsessive Compulsive Scale (Y-BOCS). All the OCD patients were medicated at the time of the study. The medications were as follows: Mean daily dosage was fluoxetine 66.7 mg (n=10), fluvoxamine 192.9 mg (n=11), paroxetine 53 mg (n=7), setraline 163.16 mg (n=23) and clomipramine 55.0 mg (n=3). All patients also provided written informed consent for the taking blood samples. The protocols of this study were approved by the Institutional Review Board of the Seoul National University Hospital.

Genotyping
Genomic DNA was extracted from the peripheral whole blood of each subject using a Qiagen DNA extraction kit (Qiagen, Hilden, Germany). Polymorphisms in 5-HT_2A gene were assessed via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, as has been reported previously.⁴

Neurocognitive function test
All the subjects completed neuropsychological function tests (NCFT). The Rey-Osterrieth Complex Figure Test (RCFT), Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT), Controlled Oral Word Association Test (COWA) and Korean version of the Wechsler Adult Intelligence Scale (K-WAIS) were conducted.

Statistical analysis
Chi-square test and Analysis of variance (ANOVA) test were employed in the statistical analysis of the data. Bonferroni correction was used for multiple testing. The significance level was set at α=0.05.

Results

The genotypic patterns of T102C were divided into T/T genotype (n=16, 30.8%), T/C genotype (n=28, 53.8%) and C/C genotype (n=10, 15.4%). The frequency of the C allele and T allele were 55.6% and 44.4%, respectively. There were no statistically significant differences among three genotypic groups with regard to age, gender, education, age of onset, duration of illness, IQ and symptoms (Table 1).
ANOVA after Bonferroni correction showed statistical significances in immediate recall (F_2,48=3.558, p=0.036) and delayed recall (F_2,197=3.492, p=0.038) of RCFT, which was found between the T/C genotype and C/C genotype. The group of patients with C/C genotype demonstrated significantly delayed response times in immediate recall and delayed recall on RCFT (Figure 1). We also noted no statistically significant differences among genotypic groups with regard to the results of NCFT, including the WCST, TMT, COWA and K-WAIS (Table 1).

Discussion

Neurocognitive function is considered to be the core factor in the pathophysiology of OCD. The 5-HT_2A may exert some effect on neurocognitive function.^2,3 Our results showed that the group of patients with homozygous mutant-type of 5-HT_2A receptor polymorphism demonstrated significant delayed response time in immediate recall and delayed recall of RCFT, a test used to evaluate visuospatial memory. Poyurovsky et al. demonstrated that the speed and the accuracy of task performance in visual immediate memory and visuospatial processing were improved in 5-HT_2A antagonist mianserin-treating group, as compared to the placebo group.² This result suggested that the 5-HT_2A receptor does exert some effects on the visuo-spatial memory. Our result is consistent with the previous study. In addition, we suggest that the T102C polymorphism of the 5-HT_2A receptor contributes to neurocognitive function in OCD.
This study suffered, however, from some limitations. First, the sample size was fairly small. Second, the role of the 5-HT_2A receptor gene in OCD remains to be clarified.^5,6 We hope that future studies, including large sample size, will provide additional information regarding to the role of 5-HT_2A receptor gene polymorphisms in OCD, and should help to clarify the relationship between 5-HT_2A receptor gene polymorphisms and neurocognitive functions. In summary, we suggest that the T102C genotype may be important factor in neurocognitive functioning, and neurocognitive functions may prove a good candidate phenotype for use in OCD association or linkage studies.

1. Marek GJ, Carpenter LL, McDougle CJ, Price LH. Synergistic action of 5-HT_2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 2003;28:402-412.

2. Poyurovsky M, Koren D, Gonopolsky I, Schneidman M, Fuchs C, Weizman A, et al. Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia patients: an add-on, double-blind placebo-controlled study. Eur Neuropsychopharmacol 2003;13:123-128.

3. Williams GV, Rao SG, Goldman-Rakic PS. The physiological role of 5-HT_2A receptors in working memory. J Neurosci 2002;22:2843-2854.

4. Warren JT Jr, Peacock ML, Rodriguez LC, Fink JK. An MspI polymorphism in the human serotonin receptor gene (HTR_2A): detection by DGGE and RFLP analysis. Hum Mol Genet 1993;2:338.

5. Tot S, Erdal ME, Yazici K, Yazici AE, Metin O. T102C and -1438 G/A polymorphisms of the 5-HT_2A receptor gene in Turkish patients with obsessive-compulsive disorder. Eur Psychiatry 2003;8:249-254.

6. Huang Y, Liu X, Li T, Guo L, Sun X, Xiao X, et al. Cases-Control association study and transmission disequilibrium test of T102C polymorphism in 5HT_2A and Tourette syndrome. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2001;18:11-13.