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Jun Soo Kwon, MD, PhD; Yeon Ho Joo, MD, PhD; Hee Jung Nam, MD; Meerae Lim, MD; Eun-Young Cho, MS; Myung Hun Jung, MD; Jung-Seok Choi, MD; Byungsu Kim, MD, PhD; Do-Hyung Kang, MD; Sohee Oh, MS; Taesung Park, PhD; Kyung Sue Hong, MD, PhD

Arch Gen Psychiatry. 2009;66(11):1233-1241.

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.

Author Affiliations: Department of Neuropsychiatry, Seoul National University College of Medicine, Seoul National University Hospital (Drs Kwon, Jung, Choi, and Kang); Brain and Cognitive Sciences, WCU Program, College of Natural Sciences, Seoul National University (Dr Kwon); Department of Psychiatry, University of Ulsan College of Medicine, Asan Medical Center (Drs Joo and Kim); Department of Psychiatry, Sungkyunkwan University School of Medicine (Drs Nam, Lim, and Hong) and Samsung Biomedical Research Institute, Samsung Medical Center (Ms Cho and Dr Hong); and Department of Statistics, Seoul National University, Seoul, Korea (Ms Oh and Dr Park).

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