0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

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

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
[+] Author Affiliations

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).


Arch Gen Psychiatry. 2009;66(11):1233-1241. doi:10.1001/archgenpsychiatry.2009.155.
Text Size: A A A
Published online

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.

Figures in this Article

Since the introduction of atypical antipsychotics (AAP), both case reports16 and clinical studies79 have described the de novo onset of obsessive-compulsive (OC) symptoms during treatment with these drugs. In a previous investigation, we screened 209 clinically stable outpatients with schizophrenia who were receiving AAP and found that 12.4% showed AAP-induced OC symptoms.10

It is widely accepted that genetic factors play an important role in an individual's susceptibility to various AAP adverse effects,11,12 and this assumption is the theoretical basis of pharmacogenetic studies. Nonetheless, heritability data for antipsychotic drug responses are extremely limited because of difficulties recruiting twin pairs who have received the same AAP treatment. We recently described clozapine-induced OC symptoms that emerged concordantly in a pair of monozygotic twins, which suggests the influence of genetic factors on this adverse effect.13 Strong evidence of heritability has been shown by family and twin studies of obsessive-compulsive disorder (OCD).1417 Considering the indirect evidence of genetic control on AAP-induced OC symptoms and difficulties in developing animal models and performing gene expression studies, genetic association studies with candidate genes could play a pivotal role in exploring the molecular mechanism of AAP-induced OC symptoms.

Implications of the glutamatergic system in the development of OC symptoms were suggested by a few biological studies of patients with OCD, including magnetic resonance spectroscopy studies.1820 The glutamate transporter gene SLC1A1 (OMIM 133550), which is located on chromosome 9p24, is regarded as a positional and functional candidate gene for vulnerability to OCD.21 Recently, polymorphisms in the SLC1A1 gene were reported to be associated with OCD by 3 independent studies.2224SLC1A1 codes for the glutamate transporter excitatory amino acid carrier 1 (EAAC1), which maintains extracellular glutamate concentrations by reuptake of synaptically released glutamate.25 Excitatory amino acid carrier 1 is highly expressed in the cerebral cortex, striatum, and thalamus, regions that might be involved in the pathogenesis of OC symptoms. Regarding the relationship between EAAC1 and AAP, significant downregulation of EAAC1 by chronic treatment with clozapine was observed in the cingulate cortex of the rat brain.26 Changes in transcript expression of excitatory amino acid transporter–interacting protein, which modulates subcellular localization and activity of the excitatory amino acid transporters, including EAAC1, were also described in clozapine-treated rats.27 In animal studies that investigated the effects of AAP on the glutamatergic system, clozapine treatment enhanced K+-stimulated glutamate release28 and upregulated N-methyl-D-aspartate receptor binding29 in the nucleus accumbens of rat brain. Increased expression of vesicular glutamate transporter mRNA30 and decreased N-methyl-D-aspartate binding31 by risperidone treatment were also reported. Considering the evidence of a biological relationship between the glutamatergic system and both OC symptoms and AAP, SLC1A1 is a promising candidate gene for susceptibility to AAP-induced OC symptoms.

This study aimed to determine whether polymorphisms in SLC1A1 are associated with AAP-induced OC symptoms in patients with schizophrenia. Genotype and haplotype frequencies were investigated in the OC and non-OC groups for 10 single-nucleotide polymorphisms (SNPs) in the 3′ region of SLC1A1 including SNPs that showed significant association with OCD in previous studies.2224 As AAP-induced OC symptoms are most frequently observed in clozapine-treated patients,1,8,10 we performed a subgroup analysis for clozapine-induced OC symptoms. To the best of our knowledge, this is the first pharmacogenetic study investigating AAP-induced OC symptoms.

SUBJECTS

Subjects consisted of an OC group (patients with schizophrenia with AAP-induced OC symptoms) and a non-OC group (patients with schizophrenia without OC symptoms). Subject recruitment was performed at the schizophrenia clinics of Samsung Medical Center, Seoul National University Hospital, and Asan Medical Center. Clinically stable patients with DSM-IV–diagnosed schizophrenia who were receiving AAP and were capable of providing reliable information regarding their symptoms were included in the screening of OC symptoms. At each center, 2 trained psychiatrists (of J.S.K., Y.H.J., M.L., M.H.J., J.-S.C., B.K., and K.S.H.) performed clinical interviews, and the assessment processes were standardized across sites. To screen for the presence of OC symptoms, direct interviews using the Korean version of the Structured Clinical Interview Schedule for DSM-IV Axis I Disorder32 and assessment using the Korean version of the Yale-Brown Obsessive Compulsive Scale3335 were performed for each patient by 2 psychiatrists independently. In addition, collateral information from available family members of the patients and hospital records were used to identify whether OC symptoms emerged de novo on AAP. The final decision on AAP-induced OC symptoms was made by consensus between the 2 raters and required the following criteria: (1) OC symptoms developed de novo while receiving AAP, (2) all of the criteria for DSM-IV-diagnosed OCD except for criteria C (description of severity) and E (exclusion of drug-induced cases) were met, and (3) OC symptoms were not the direct result of delusions, and their contents were clearly different from residual psychotic symptoms. Forty patients were included in the OC group. The non-OC group included 54 patients matched by sex and medicine (type of AAP) who had been receiving AAP for more than 24 months and had not developed any OC symptoms. One hundred controls were also included in this study to obtain data on Hardy-Weinberg equilibrium and haplotype structures of SNP markers. All of the subjects (OC and non-OC patient groups and controls) were ethnically Korean, which was ascertained by asking the ethnicity of both parents.

This study was approved by the institutional review boards of Samsung Medical Center, Seoul National University Hospital, and Asan Medical Center, and written informed consent was obtained from all subjects.

SNP SELECTION AND GENOTYPING

Thirteen SNPs spanning 25 kB toward the 3′ end of the SLC1A1 gene were selected for genotyping. Nine showed significant association with OCD in previous studies2224 (Figure 1). Four SNPs were additionally selected in this region considering minor allele frequencies (http://www.hapmap.org/, Release 22/Phase II, April 2007, on National Center for Biotechnology Information B36 Assembly) and intermarker distances between markers (http://genome.ucsc.edu/, March 2006 Assembly). Genomic DNA was extracted from peripheral blood using a Wizard Genomic DNA purification kit (Promega, Madison, Wisconsin) following the manufacturer's protocol. Three SNPs (rs10974625, rs3780412, and rs301430) were genotyped by single-base primer extension assay using the ABI PRISM SNaPshot Multiplex kit (Applied Biosystems, Foster City, California), and the other SNPs were genotyped by sequencing reaction using ABI PRISM BigDye Terminator v3.1 Cycle Sequencing Kits (Applied Biosystems). In both analyses, electrophoresis was done using the ABI PRISM 3100 Genetic Analyzer (Applied Biosystems). Genotypes were measured using Gene Scan analysis software (Applied Biosystems) for single-base primer extension assays, and Sequencher v4.1.4 software (Gene Codes, Ann Arbor, Michigan) for sequencing reactions. All markers were typed successfully in all subjects.

Place holder to copy figure label and caption
Figure 1.

SLC1A1 organization and single-nucleotide polymorphism (SNP) locations (from the University of California at Santa Cruz Genome Browser, March 2006 Assembly). The horizontal line represents the genomic sequence and vertical bars represent exons. Plus signs and circles denote SNPs significantly associated with obsessive-compulsive disorder in single-marker and haplotype analyses of previous studies,2224 respectively, with asterisks representing SNPs included in the current association study of atypical antipsychotics–induced obsessive-compulsive symptoms.

Graphic Jump Location
STATISTICAL ANALYSIS

Differences in demographic and clinical variables between OC and non-OC groups were tested using a t test or χ2 test. We evaluated the Hardy-Weinberg equilibrium of 13 SNPs using genotype data from controls. Because linkage disequilibrium (LD) analysis showed that 3 pairs of SNPs were in perfect linkage equilibrium, 1 from each pair (rs7871691, rs7042333, and rs301435) was excluded from the analysis. Ten SNPs were used in the final statistical analysis (Table 1; Figure 1).

Table Graphic Jump LocationTable 1. Characteristics of SNP Markers on SLC1A1

The allelic and genotypic association between SNPs and AAP-induced OC symptoms was initially tested using Pearson χ2 test or Fisher exact test (depending on the sample sizes of individual cells). Our main analysis used to test for association was logistic regression, which controls for possible confounding effects. In this analysis, sex, age, and medicine (type of antipsychotic drug) were used as model covariates. For the genetic model, we considered 4 types— additive, codominant, dominant, and recessive—based on the minor allele of each SNP. The inheritance model with the least Akaike Information Criterion36 was accepted as the best-fitting model.

Haploview v4.0 (http://www.broadinstitute.org/haploview/haploview)37 was used to estimate pairwise LD of SNP markers. The default confidence interval algorithm of the Haploview program identified 1 haplotype block consisting of SNP7 (rs301430) and SNP8 (rs301979) from the OC and non-OC patient group data (Figure 2). Another haplotype block consisting of SNP2 (rs2228622), SNP3 (rs3780413), and SNP4 (rs3780412) was added in the analysis, considering strong pairwise LD between markers (D′ ≥ 0.88) and results of single-marker analysis. In each of the 3 subject groups (OC, non-OC, and control), SNPs within the same haplotype block showed strong pairwise LD (D′ ≥ 0.79 for SNP2/SNP3/SNP4 block and D′ ≥ 0.84 for SNP7/SNP8 block) with a low LD gap between these 2 haplotype blocks. Haplotypes of individual subjects were estimated using SAS/Genetics haplotype procedure (SAS Institute Inc, Cary, North Carolina). Logistic regression was applied to test the association between haplotypes and AAP-induced OC symptoms. To use this regression model with haplotype data, ambiguity of haplotypes was additionally adjusted using each subject's probability of having a particular haplotype pair. The most frequent haplotype was automatically selected as the reference category, and rare haplotypes (haplotype frequency ≤0.05) were pooled together in a group.

Place holder to copy figure label and caption
Figure 2.

Linkage disequilibrium (LD) structure of the single-nucleotide polymorphisms and haplotype blocks analyzed in the current study. The number, in each LD indicates the value of D′ (D′ = 1 not shown) calculated from patient (both obsessive-compulsive [OC] and non-OC groups) data. Block 2 is determined using the default confidence interval algorithm of Haploview 4.0. Block 1 is an additional block including SNPs that show significant association with atypical antipsychotics–induced OC symptoms in single-marker analysis, and having high intermarker LD (D′ ≥ 0.88).

Graphic Jump Location

Considering multiple comparisons, we performed 10 000 permutations and obtained an adjusted P value for each analysis. We adopted the step-down minP multiple testing procedure proposed by Westfall and Young38 and Ge et al.39

Identical association tests were applied for a subgroup of patients receiving clozapine (32 in the OC group and 43 in the non-OC group).

Statistical analyses were performed using SAS version 9.1 (SAS Institute Inc). P values of less than .05 were considered statistically significant.

Demographic and clinical characteristics of the 2 patient groups are presented in Table 2. Patients in the OC group were younger than those in the non-OC group. There was no difference in duration of illness, clinical subtype, type of AAP, and mean maximum daily dose of each drug that has ever been reached between the OC and non-OC groups. The mean (SD) score of Yale-Brown Obsessive Compulsive Scale for the OC group was 14.89 (6.65).

Table Graphic Jump LocationTable 2. Demographic and Clinical Characteristics of Subjects

For all 10 SNPs used in the analysis, no significant deviation from Hardy-Weinberg equilibrium was observed in the controls (Table 1). Table 3 shows results of allelic and genotypic association analyses using a simple χ2 (or Fisher exact) test without controlling for possible confounding effects of demographic or clinical variables. Single nucleotide polymorphisms 2 (rs2228622) and 4 (rs3780412) showed an association with AAP-induced OC symptoms. However, no marker reached the level of significance after applying multiple test correction in the permutation tests.

Table Graphic Jump LocationTable 3. Genotypic and Allelic Association Analysis

In the logistic regression that controlled for confounding effects of age, sex, and medicine (Table 4), trends of association were observed in SNP2 (nominal P = .01; adjusted permutation P = .07) for dominant and codominant models (nominal P = .007; adjusted permutation P = .06) and SNP4 for dominant models (nominal P = .02; adjusted permutation P = .09). As represented in the Akaike Information Criterion values, the dominant model was accepted as the best inheritance model fitting our data for both SNP2 and SNP4. Other SNPs did not show any trend of association with AAP-induced OC symptoms.

Table Graphic Jump LocationTable 4. Association Analysis of AAP-Induced OC Symptoms With SNP2 and SNP4 on SLC1A1 Using Logistic Regression Model Adjusted for Age, Sex, and Type of Medicine

In the haplotype-based logistic regression analysis, an association with nominal P < .05 was observed for the A/C/G haplotype of the SNP2/SNP3/SNP4 block in additive, codominant, and dominant models (nominal P = .04, P = .006, and P = .01, respectively) (Table 5). The dominant model showed the lowest Akaike Information Criterion value and was accepted as the best inheritance model. The other haplotype block (SNP7/SNP8) did not show any association with AAP-induced OC symptoms. In permutation tests adjusting for multiple comparisons, the association between A/C/G haplotype of SNP2/SNP3/SNP4 and AAP-induced OC symptoms remained significant for dominant and codominant models.

Table Graphic Jump LocationTable 5. Association Analysis of AAP-Induced OC Symptoms With Haplotype (SNP2/SNP3/SNP4) Block on SLC1A1 Using Logistic Regression Model Adjusted for Age, Sex, and Type of Medicine

In the subgroup of patients receiving clozapine treatment, allelic and genotypic association was observed in SNP2 (χ2 = 4.906, P = .03 for allelic association; χ2 = 7.074, P = .02 for genotypic association) and SNP4 (χ2 = 5.900, P = .02 for allelic association; χ2 = 6.214, P = .04 for genotypic association). However, no marker reached statistical significance after applying multiple test correction. Regression analysis showed trends of association in SNP2 for dominant (nominal P = .01; adjusted permutation P = .07) and codominant (nominal P = .01; adjusted permutation P = .07) models (Table 4). In the haplotype-based analysis, association of the A/C/G haplotype of SNP2/SNP3/SNP4 block and clozapine-induced OC symptoms was observed in the additive, codominant, and dominant models (nominal P = .02, P = .008, and P = .02, respectively) (Table 5). After adjusting for multiple comparisons in the permutation test, significant association remained for the codominant model.

Several lines of evidence indicate that AAP induces or aggravates OC symptoms.19 To the best of our knowledge, however, there has been no pharmacogenetic study that explored candidate genes involved in this adverse drug reaction. In the present study, we investigated the relation between AAP-induced OC symptoms and 10 SNPs in the SLC1A1 gene that was recently reported to be associated with OCDs in 3 independent studies.2224

Obsessive-compulsive symptoms can be observed in patients in various stages of schizophrenia,40,41 ie, before the onset of illness, in the active psychotic phase, and after stabilization by pharmacotherapy. To limit the phenotype of the current study to drug-associated OC symptoms, we applied strict inclusion criteria, ie, de novo onset of OC symptoms during AAP treatment and OC symptoms of an ego-dystonic nature, reported by clinically stable patients, that could be clearly differentiated from delusions or other residual psychotic symptoms. According to a summary of 55 reported cases,1 the duration of AAP medication at the onset of AAP-induced OC symptoms ranged from a few weeks to 15 months. Therefore, we included patients who had been receiving AAP for more than 24 months without development of any OC symptoms in the non-OC group. Because AAP-induced OC symptoms showed preponderance in men and were most frequently observed in clozapine-treated patients,1,8,10 we tried to match sex and type of AAP between the OC and non-OC groups. We also controlled for these variables in the logistic regression model used in the analysis. In addition, we analyzed patients receiving clozapine separately.

Trends of association were detected between AAP-induced OC symptoms and SNP2 (rs2228622) and SNP4 (rs3780412). These 2 SNPs are tightly linked within the same haplotype block (SNP2/SNP3/SNP4) of SLC1A1, and the A/C/G haplotype of this block showed significant association with AAP-induced OC symptoms, which withstood multiple test correction. The haplotype association indicated that the odds of AAP-induced OC symptoms are 3.96 times higher in patients who have the A/C/G haplotype than in patients who have the reference haplotype (G/C/A, most frequent haplotype; frequency, 0.44) (odds ratio, 3.955; 95% confidence interval, 1.366-11.452). The same nature of association was observed in the separate analysis of the subgroup of patients receiving clozapine treatment.

Interestingly, the associated SNPs (SNP2 and SNP4) in the present study are identical to the SNPs that showed significant association with OCD in the investigation of Stewart et al,24 and one of them (SNP4) was also associated with OCD in another study.23 Single-nucleotide polymorphism 2 is a synonymous SNP located in exon 4, and SNP4 is an intronic SNP. The possible functional effects of these SNPs have not yet been investigated. If the polymorphisms do not directly confer susceptibility to AAP-induced OC symptoms, they might be in LD with nearby functional SNPs. Genotyping of additional polymorphisms and extensive sequencing in this region are warranted to clarify the causative variants. Given that clozapine showed the strongest potential to induce OC symptoms of the AAP and was reported to downregulate EAAC1 in the cingulate cortex of rat brain,26 and given the indirect evidence that other antipsychotic drugs also affect the glutamatergic system,29,42,43 the etiologic connection between the SLC1A1 gene and molecular mechanisms of AAP-induced OC symptoms needs to be more intensively pursued.

The present study has certain methodological limitations. First, the possibility that patients in the non-OC group (defined as lacking OC symptoms after 24 months of treatment) would later develop OC symptoms could not be ruled out because there has been no systematic evaluation of the duration of medication before the onset of AAP. Delayed onset of phenotypes might be an inevitable confounding factor in genetic studies. Second, considering the small sample size and adoption of multiple test corrections, this study might be vulnerable to type II error. Replication studies in independent samples are required. Third, we investigated only 1 gene implicated in OCD. There might be a large number of functional candidate genes for AAP-induced OC symptoms, eg, genes involved in the dopaminergic and serotonergic systems that are involved in the mechanism of action of AAPs. Association studies for those genes and evaluation of gene-gene interactions are needed in future studies. Because AAPs are used for the treatment of psychiatric disorders other than schizophrenia, association studies for a broader range of diagnoses are also warranted. Fourth, though all subjects in the OC and non-OC groups were ethnically Korean, population differences between the 2 groups have not been checked at the genetic level. Therefore, the possibility of a false-positive result originating from undetected population stratification could not be completely excluded.

Within the above discussed limitations, the findings in the current study suggest that SLC1A1 is involved in susceptibility to developing OC symptoms in patients with schizophrenia who are receiving AAP treatment. It is noteworthy that this is the first published pharmacogenetic study on this condition, and it provides preliminary evidence of the involvement of glutamatergic neurotransmission in the pathogenesis of AAP-induced OC symptoms.

Correspondence: Kyung Sue Hong, MD, PhD, Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea (hongks@skku.edu).

Submitted for Publication: October 6, 2008; final revision received February 25, 2009; accepted April 3, 2009.

Financial Disclosure: Dr Kwon reports having served as a consultant for Janssen, and has received research support or honoraria from Otsuka, Lilly Korea, Lundbeck, Dainippon Sumitomopharma, Janssen, Janssen Korea, AstraZeneca, and Pfizer. Dr Joo reports having served as a consultant for AstraZeneca and Pfizer, and has received research support or honoraria from AstraZeneca, Eli Lilly, SanofiAventis, GlaxoSmithKline, Otsuka, and Pfizer. Dr Hong reports having served as an advisor for AstraZeneca, and has received research support or honoraria from Otsuka, Pfizer, AstraZeneca, Janssen, SanofiAventis, and Eli Lilly.

Funding/Support: This study was supported by grant A030001 from the Korea Health 21 R&D Project, Ministry of Health, Welfare and Family Affairs, Republic of Korea; the In-SungFoundation for Medical Research; grant M10500000126 from the National Research Laboratory Program of Korea Science and Engineering Foundation (Dr Park); and the Brain Korea 21 Project of the Ministry of Education (Dr Park).

Lykouras  LAlevizos  BMichalopoulou  PRabavilas  A Obsessive-compulsive symptoms induced by atypical antipsychotics: a review of the reported cases. Prog Neuropsychopharmacol Biol Psychiatry 2003;27 (3) 333- 346
PubMed Link to Article
Alevizos  BPapageorgiou  CChristodoulou  GN Obsessive-compulsive symptoms with olanzapine. Int J Neuropsychopharmacol 2004;7 (3) 375- 377
PubMed Link to Article
Diler  RSYolga  AAvci  AScahill  L Risperidone-induced obsessive-compulsive symptoms in two children. J Child Adolesc Psychopharmacol 2003;13 ((suppl 1)) S89- S92
PubMed Link to Article
Ke  CLYen  CFChen  CCYang  SJChung  WYang  MJ Obsessive-compulsive symptoms associated with clozapine and risperidone treatment: three case reports and review of the literature. Kaohsiung J Med Sci 2004;20 (6) 295- 301
PubMed Link to Article
Ozer  SArsava  MErtugrul  ADemir  B Obsessive compulsive symptoms associated with quetiapine treatment in a schizophrenic patient: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2006;30 (4) 724- 727
PubMed Link to Article
Stamouli  SLykouras  L Quetiapine-induced obsessive-compulsive symptoms: a series of five cases. J Clin Psychopharmacol 2006;26 (4) 396- 400
PubMed Link to Article
Baker  RWChengappa  KNBaird  JWSteingard  SChrist  MASchooler  NR Emergence of obsessive compulsive symptoms during treatment with clozapine. J Clin Psychiatry 1992;53 (12) 439- 442
PubMed
de Haan  LLinszen  DHGorsira  R Clozapine and obsessions in patients with recent-onset schizophrenia and other psychotic disorders. J Clin Psychiatry 1999;60 (6) 364- 365
PubMed Link to Article
Ertugrul  AAnil Yagcioglu  AEEni  NYazici  KM Obsessive-compulsive symptoms in clozapine-treated schizophrenic patients. Psychiatry Clin Neurosci 2005;59 (2) 219- 222
PubMed Link to Article
Lim  MPark  DYKwon  JSJoo  YHHong  KS Prevalence and clinical characteristics of obsessive-compulsive symptoms associated with atypical antipsychotics. J Clin Psychopharmacol 2007;27 (6) 712- 713
PubMed Link to Article
Arranz  MJde Leon  J Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry 2007;12 (8) 707- 747
PubMed Link to Article
Malhotra  AK Pharmacogenetics to pharmacogenomics of psychotropic drug response. Lerer  BPharmacogenetics of Psychotropic Drugs. Cambridge, England Cambridge University Press2002;21- 35
Hong  KSNam  HJLim  M Emergence of obsessive-compulsive symptoms during clozapine treatment in a pair of monozygotic twins [eLetter]. Br J Psychiatry 2008;19081-a
do Rosario-Campos  MCLeckman  JFCuri  MQuatrano  SKatsovitch  LMiguel  ECPauls  DL A family study of early-onset obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2005;136B (1) 92- 97
PubMed Link to Article
Hanna  GLHimle  JACurtis  GCGillespie  BW A family study of obsessive-compulsive disorder with pediatric probands. Am J Med Genet B Neuropsychiatr Genet 2005;134B (1) 13- 19
PubMed Link to Article
Inouye  E Similar and dissimilar manifestations of obsessive-compulsive neuroses in monozygotic twins. Am J Psychiatry 1965;1211171- 1175
PubMed
van Grootheest  DSCath  DCBeekman  ATBoomsma  DI Twin studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet 2005;8 (5) 450- 458
PubMed Link to Article
Chakrabarty  KBhattacharyya  SChristopher  RKhanna  S Glutamatergic dysfunction in OCD. Neuropsychopharmacology 2005;30 (9) 1735- 1740
PubMed Link to Article
Starck  GLjungberg  MNilsson  MJonsson  LLundberg  SIvarsson  TRibbelin  SEkholm  SCarlsson  AForssell-Aronsson  ECarlsson  ML A 1H magnetic resonance spectroscopy study in adults with obsessive compulsive disorder: relationship between metabolite concentrations and symptom severity. J Neural Transm 2008;115 (7) 1051- 1062
PubMed Link to Article
Whiteside  SPPort  JDDeacon  BJAbramowitz  JS A magnetic resonance spectroscopy investigation of obsessive-compulsive disorder and anxiety. Psychiatry Res 2006;146 (2) 137- 147
PubMed Link to Article
Pauls  DL The genetics of obsessive compulsive disorder: a review of the evidence. Am J Med Genet C Semin Med Genet 2008;148C (2) 133- 139
Link to Article
Arnold  PDSicard  TBurroughs  ERichter  MAKennedy  JL Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch Gen Psychiatry 2006;63 (7) 769- 776
PubMed Link to Article
Dickel  DEVeenstra-VanderWeele  JCox  NJWu  XFischer  DJVan Etten-Lee  MHimle  JALeventhal  BLCook  EH  JrHanna  GL Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Arch Gen Psychiatry 2006;63 (7) 778- 785
PubMed Link to Article
Stewart  SEFagerness  JAPlatko  JSmoller  JWScharf  JMIllmann  CJenike  EChabane  NLeboyer  MDelorme  RJenike  MAPauls  DL Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2007;144B (8) 1027- 1033
Link to Article
Tzingounis  AVWadiche  JI Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat Rev Neurosci 2007;8 (12) 935- 947
PubMed Link to Article
Schmitt  AZink  MPetroianu  GMay  BBraus  DFHenn  FA Decreased gene expression of glial and neuronal glutamate transporters after chronic antipsychotic treatment in rat brain. Neurosci Lett 2003;347 (2) 81- 84
PubMed Link to Article
Huerta  I McCullumsmith  REHaroutunian  VGimenez-Amaya  JMMeador-Woodruff  JH Expression of excitatory amino acid transporter interacting protein transcripts in the thalamus in schizophrenia. Synapse 2006;59 (7) 394- 402
PubMed Link to Article
Yamamoto  BKCooperman  MA Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 1994;14 (7) 4159- 4166
PubMed
Schmitt  AZink  MMuller  BMay  BHerb  AJatzko  ABraus  DFHenn  FA Effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Neurochem Res 2003;28 (2) 235- 241
PubMed Link to Article
Moutsimilli  LFarley  SEl Khoury  MAChamot  CSibarita  JBRacine  VEl Mestikawy  SMathieu  FDumas  SGiros  BTzavara  ET Antipsychotics increase vesicular glutamate transporter 2 (VGLUT2) expression in thalamolimbic pathways. Neuropharmacology 2008;54 (3) 497- 508
PubMed Link to Article
Choi  YKGardner  MPTarazi  FI Effects of risperidone on glutamate receptor subtypes in developing rat brain. Eur Neuropsychopharmacol 2009;19 (2) 77- 84
PubMed Link to Article
Hahn  OSAhn  JHSong  SHCho  MJKim  JKBae  JNCho  SJJeong  BSSuh  DWHahm  BJLee  DWPark  JIHong  JP Development of Korean version of Structured Clinical Interview Schedule for DSM-IV Axis I Disorder: interrater reliability. J Korean Neuropsychiatr Assoc 2000;39 (2) 362- 372
Goodman  WKPrice  LHRasmussen  SAMazure  CDelgado  PHeninger  GRCharney  DS The Yale-Brown obsessive compulsive scale II: validity. Arch Gen Psychiatry 1989;46 (11) 1012- 1016
PubMed Link to Article
Kim  SJChoi  NKHong  HJHwang  YSKim  YKLee  HSKim  CH Dimensional analyses of the Yale-Brown obsessive-compulsive scale and Yale-Brown obsessive-compulsive scale checklist [in Korean]. Korean J Psychopharmacol 2004;15 (3) 339- 345
Lim  JSKim  CH Assessment of obsessive-compulsive symptoms and obsessive-compulsive disorder [in Korean]. Anxiety and Mood 2008;4 (1) 11- 18
Akaike  H A new look at the statistical model identification. IEEE Trans Automat Contr 1974;19 (6) 716- 723
Link to Article
Barrett  JCFry  BMaller  JDaly  MJ Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21 (2) 263- 265
PubMed Link to Article
Westfall  PHYoung  SS Resampling-Based Multiple Testing: Examples and Methods for P-value Adjustment.  New York, NY John Wiley & Sons1993;
Ge  YDudoit  SSpeed  TP Resampling-based multiple testing for microarray data analysis. TEST 2003;121- 77
Link to Article
Byerly  MGoodman  WAcholonu  WBugno  RRush  AJ Obsessive compulsive symptoms in schizophrenia: frequency and clinical features. Schizophr Res 2005;76 (2-3) 309- 316
PubMed Link to Article
Ongür  DGoff  DC Obsessive-compulsive symptoms in schizophrenia: associated clinical features, cognitive function and medication status. Schizophr Res 2005;75 (2-3) 349- 362
PubMed Link to Article
Bespalov  AJongen-Relo  ALvan Gaalen  MHarich  SSchoemaker  HGross  G Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs. J Pharmacol Exp Ther 2007;320 (2) 944- 950
PubMed Link to Article
De Souza  IE McBean  GJMeredith  GE Chronic haloperidol treatment impairs glutamate transport in the rat striatum. Eur J Pharmacol 1999;382 (2) 139- 142
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

SLC1A1 organization and single-nucleotide polymorphism (SNP) locations (from the University of California at Santa Cruz Genome Browser, March 2006 Assembly). The horizontal line represents the genomic sequence and vertical bars represent exons. Plus signs and circles denote SNPs significantly associated with obsessive-compulsive disorder in single-marker and haplotype analyses of previous studies,2224 respectively, with asterisks representing SNPs included in the current association study of atypical antipsychotics–induced obsessive-compulsive symptoms.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Linkage disequilibrium (LD) structure of the single-nucleotide polymorphisms and haplotype blocks analyzed in the current study. The number, in each LD indicates the value of D′ (D′ = 1 not shown) calculated from patient (both obsessive-compulsive [OC] and non-OC groups) data. Block 2 is determined using the default confidence interval algorithm of Haploview 4.0. Block 1 is an additional block including SNPs that show significant association with atypical antipsychotics–induced OC symptoms in single-marker analysis, and having high intermarker LD (D′ ≥ 0.88).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of SNP Markers on SLC1A1
Table Graphic Jump LocationTable 2. Demographic and Clinical Characteristics of Subjects
Table Graphic Jump LocationTable 3. Genotypic and Allelic Association Analysis
Table Graphic Jump LocationTable 4. Association Analysis of AAP-Induced OC Symptoms With SNP2 and SNP4 on SLC1A1 Using Logistic Regression Model Adjusted for Age, Sex, and Type of Medicine
Table Graphic Jump LocationTable 5. Association Analysis of AAP-Induced OC Symptoms With Haplotype (SNP2/SNP3/SNP4) Block on SLC1A1 Using Logistic Regression Model Adjusted for Age, Sex, and Type of Medicine

References

Lykouras  LAlevizos  BMichalopoulou  PRabavilas  A Obsessive-compulsive symptoms induced by atypical antipsychotics: a review of the reported cases. Prog Neuropsychopharmacol Biol Psychiatry 2003;27 (3) 333- 346
PubMed Link to Article
Alevizos  BPapageorgiou  CChristodoulou  GN Obsessive-compulsive symptoms with olanzapine. Int J Neuropsychopharmacol 2004;7 (3) 375- 377
PubMed Link to Article
Diler  RSYolga  AAvci  AScahill  L Risperidone-induced obsessive-compulsive symptoms in two children. J Child Adolesc Psychopharmacol 2003;13 ((suppl 1)) S89- S92
PubMed Link to Article
Ke  CLYen  CFChen  CCYang  SJChung  WYang  MJ Obsessive-compulsive symptoms associated with clozapine and risperidone treatment: three case reports and review of the literature. Kaohsiung J Med Sci 2004;20 (6) 295- 301
PubMed Link to Article
Ozer  SArsava  MErtugrul  ADemir  B Obsessive compulsive symptoms associated with quetiapine treatment in a schizophrenic patient: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2006;30 (4) 724- 727
PubMed Link to Article
Stamouli  SLykouras  L Quetiapine-induced obsessive-compulsive symptoms: a series of five cases. J Clin Psychopharmacol 2006;26 (4) 396- 400
PubMed Link to Article
Baker  RWChengappa  KNBaird  JWSteingard  SChrist  MASchooler  NR Emergence of obsessive compulsive symptoms during treatment with clozapine. J Clin Psychiatry 1992;53 (12) 439- 442
PubMed
de Haan  LLinszen  DHGorsira  R Clozapine and obsessions in patients with recent-onset schizophrenia and other psychotic disorders. J Clin Psychiatry 1999;60 (6) 364- 365
PubMed Link to Article
Ertugrul  AAnil Yagcioglu  AEEni  NYazici  KM Obsessive-compulsive symptoms in clozapine-treated schizophrenic patients. Psychiatry Clin Neurosci 2005;59 (2) 219- 222
PubMed Link to Article
Lim  MPark  DYKwon  JSJoo  YHHong  KS Prevalence and clinical characteristics of obsessive-compulsive symptoms associated with atypical antipsychotics. J Clin Psychopharmacol 2007;27 (6) 712- 713
PubMed Link to Article
Arranz  MJde Leon  J Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry 2007;12 (8) 707- 747
PubMed Link to Article
Malhotra  AK Pharmacogenetics to pharmacogenomics of psychotropic drug response. Lerer  BPharmacogenetics of Psychotropic Drugs. Cambridge, England Cambridge University Press2002;21- 35
Hong  KSNam  HJLim  M Emergence of obsessive-compulsive symptoms during clozapine treatment in a pair of monozygotic twins [eLetter]. Br J Psychiatry 2008;19081-a
do Rosario-Campos  MCLeckman  JFCuri  MQuatrano  SKatsovitch  LMiguel  ECPauls  DL A family study of early-onset obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2005;136B (1) 92- 97
PubMed Link to Article
Hanna  GLHimle  JACurtis  GCGillespie  BW A family study of obsessive-compulsive disorder with pediatric probands. Am J Med Genet B Neuropsychiatr Genet 2005;134B (1) 13- 19
PubMed Link to Article
Inouye  E Similar and dissimilar manifestations of obsessive-compulsive neuroses in monozygotic twins. Am J Psychiatry 1965;1211171- 1175
PubMed
van Grootheest  DSCath  DCBeekman  ATBoomsma  DI Twin studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet 2005;8 (5) 450- 458
PubMed Link to Article
Chakrabarty  KBhattacharyya  SChristopher  RKhanna  S Glutamatergic dysfunction in OCD. Neuropsychopharmacology 2005;30 (9) 1735- 1740
PubMed Link to Article
Starck  GLjungberg  MNilsson  MJonsson  LLundberg  SIvarsson  TRibbelin  SEkholm  SCarlsson  AForssell-Aronsson  ECarlsson  ML A 1H magnetic resonance spectroscopy study in adults with obsessive compulsive disorder: relationship between metabolite concentrations and symptom severity. J Neural Transm 2008;115 (7) 1051- 1062
PubMed Link to Article
Whiteside  SPPort  JDDeacon  BJAbramowitz  JS A magnetic resonance spectroscopy investigation of obsessive-compulsive disorder and anxiety. Psychiatry Res 2006;146 (2) 137- 147
PubMed Link to Article
Pauls  DL The genetics of obsessive compulsive disorder: a review of the evidence. Am J Med Genet C Semin Med Genet 2008;148C (2) 133- 139
Link to Article
Arnold  PDSicard  TBurroughs  ERichter  MAKennedy  JL Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch Gen Psychiatry 2006;63 (7) 769- 776
PubMed Link to Article
Dickel  DEVeenstra-VanderWeele  JCox  NJWu  XFischer  DJVan Etten-Lee  MHimle  JALeventhal  BLCook  EH  JrHanna  GL Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Arch Gen Psychiatry 2006;63 (7) 778- 785
PubMed Link to Article
Stewart  SEFagerness  JAPlatko  JSmoller  JWScharf  JMIllmann  CJenike  EChabane  NLeboyer  MDelorme  RJenike  MAPauls  DL Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2007;144B (8) 1027- 1033
Link to Article
Tzingounis  AVWadiche  JI Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat Rev Neurosci 2007;8 (12) 935- 947
PubMed Link to Article
Schmitt  AZink  MPetroianu  GMay  BBraus  DFHenn  FA Decreased gene expression of glial and neuronal glutamate transporters after chronic antipsychotic treatment in rat brain. Neurosci Lett 2003;347 (2) 81- 84
PubMed Link to Article
Huerta  I McCullumsmith  REHaroutunian  VGimenez-Amaya  JMMeador-Woodruff  JH Expression of excitatory amino acid transporter interacting protein transcripts in the thalamus in schizophrenia. Synapse 2006;59 (7) 394- 402
PubMed Link to Article
Yamamoto  BKCooperman  MA Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 1994;14 (7) 4159- 4166
PubMed
Schmitt  AZink  MMuller  BMay  BHerb  AJatzko  ABraus  DFHenn  FA Effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Neurochem Res 2003;28 (2) 235- 241
PubMed Link to Article
Moutsimilli  LFarley  SEl Khoury  MAChamot  CSibarita  JBRacine  VEl Mestikawy  SMathieu  FDumas  SGiros  BTzavara  ET Antipsychotics increase vesicular glutamate transporter 2 (VGLUT2) expression in thalamolimbic pathways. Neuropharmacology 2008;54 (3) 497- 508
PubMed Link to Article
Choi  YKGardner  MPTarazi  FI Effects of risperidone on glutamate receptor subtypes in developing rat brain. Eur Neuropsychopharmacol 2009;19 (2) 77- 84
PubMed Link to Article
Hahn  OSAhn  JHSong  SHCho  MJKim  JKBae  JNCho  SJJeong  BSSuh  DWHahm  BJLee  DWPark  JIHong  JP Development of Korean version of Structured Clinical Interview Schedule for DSM-IV Axis I Disorder: interrater reliability. J Korean Neuropsychiatr Assoc 2000;39 (2) 362- 372
Goodman  WKPrice  LHRasmussen  SAMazure  CDelgado  PHeninger  GRCharney  DS The Yale-Brown obsessive compulsive scale II: validity. Arch Gen Psychiatry 1989;46 (11) 1012- 1016
PubMed Link to Article
Kim  SJChoi  NKHong  HJHwang  YSKim  YKLee  HSKim  CH Dimensional analyses of the Yale-Brown obsessive-compulsive scale and Yale-Brown obsessive-compulsive scale checklist [in Korean]. Korean J Psychopharmacol 2004;15 (3) 339- 345
Lim  JSKim  CH Assessment of obsessive-compulsive symptoms and obsessive-compulsive disorder [in Korean]. Anxiety and Mood 2008;4 (1) 11- 18
Akaike  H A new look at the statistical model identification. IEEE Trans Automat Contr 1974;19 (6) 716- 723
Link to Article
Barrett  JCFry  BMaller  JDaly  MJ Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21 (2) 263- 265
PubMed Link to Article
Westfall  PHYoung  SS Resampling-Based Multiple Testing: Examples and Methods for P-value Adjustment.  New York, NY John Wiley & Sons1993;
Ge  YDudoit  SSpeed  TP Resampling-based multiple testing for microarray data analysis. TEST 2003;121- 77
Link to Article
Byerly  MGoodman  WAcholonu  WBugno  RRush  AJ Obsessive compulsive symptoms in schizophrenia: frequency and clinical features. Schizophr Res 2005;76 (2-3) 309- 316
PubMed Link to Article
Ongür  DGoff  DC Obsessive-compulsive symptoms in schizophrenia: associated clinical features, cognitive function and medication status. Schizophr Res 2005;75 (2-3) 349- 362
PubMed Link to Article
Bespalov  AJongen-Relo  ALvan Gaalen  MHarich  SSchoemaker  HGross  G Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs. J Pharmacol Exp Ther 2007;320 (2) 944- 950
PubMed Link to Article
De Souza  IE McBean  GJMeredith  GE Chronic haloperidol treatment impairs glutamate transport in the rat striatum. Eur J Pharmacol 1999;382 (2) 139- 142
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 35

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles