Preliminary evidence for an association between a dopamine D3 receptor gene variant and obsessive-compulsive personality disorder in patients with major depression.код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 141B:409 –413 (2006) Preliminary Evidence for an Association Between a Dopamine D3 Receptor Gene Variant and Obsessive-Compulsive Personality Disorder in Patients With Major Depression Katrina J. Light,1* Peter R. Joyce,1 Suzanne E. Luty,1 Roger T. Mulder,1 Christropher M.A. Frampton,1 Laura R.M. Joyce,1 Allison L. Miller,2 and Martin A. Kennedy2 1 Department of Psychological Medicine, Christchurch School of Medicine & Health Sciences, Christchurch, New Zealand Department of Pathology, Christchurch School of Medicine & Health Sciences, Christchurch, New Zealand 2 We have previously reported that the Ser9Gly dopamine D3 receptor (DRD3) polymorphism was associated with increased rates of obsessivecompulsive personality disorder (OCPD) symptomology. We tested the replicability of this association within a further two independent groups of individuals with a history of depression, from a clinical sample (n ¼ 149) and a family study (n ¼ 213). The data from the replication samples and the original sample, within which the association was found, were compiled within a metaanalysis. Although the independent samples did not replicate the original finding, the metaanalysis elucidated significant evidence supporting the association. An individual with Gly/Gly genotype is 2.4 (P ¼ 0.017) times more likely to be diagnosed with OCPD. Male gender was also found to be a significant predictor of OCPD diagnosis (OR ¼ 2.82, P ¼ 0.001). An exploration of an association of DRD3 with Axis I anxiety disorder diagnoses and Temperament and Character Inventory (TCI) traits, in particular persistence, revealed no support for an association. We conclude that DRD3 may contribute to the development of OCPD. ß 2006 Wiley-Liss, Inc. KEY WORDS: dopamine D3 receptor gene; obsessive-compulsive personality disorder Please cite this article as follows: Light KJ, Joyce PR, Luty SE, Mulder RT, Frampton CMA, Joyce LRM, Miller AL, Kennedy MA. 2006. Preliminary Evidence for an Association Between a Dopamine D3 Receptor Gene Variant and Obsessive-Compulsive Personality Disorder in Patients With Major Depression. Am J Med Genet Part B 141B:409–413. INTRODUCTION As a constituent of the dopaminergic system, the dopamine D3 receptor (DRD3) has been recognized as a candidate locus for voluntary behavior for sometime, however, as yet no consistent association has emerged. One of the more common DRD3 polymorphisms involves a residue change from serine to glycine at position 9 of the N-terminal extracellular domain of the receptor [Lannfelt et al., 1992]. The polymorphism can be identified by the resultant creation of a BalI restriction enzyme site and alteration of a MscI recognition site [Lannfelt et al., 1992; Wong et al., 2000]. Knockout mice, in accordance with dopaminergic agonists and antagonists that have a preferred affinity for the D3 receptor, support the notion that the DRD3 gene is involved in the control of locomotor activity [Daly and Waddington, 1993; Waters et al., 1994; Svensson et al., 1994a,b; Accili et al., 1996]. Similarly, downregulation of D3 receptor expression via the administration of an antisense oligodeoxynucleotide results in increased locomotor activity within rats [Menalled et al., 1999]. Czermak et al.  identified a significant negative correlation between the expression of DRD3 (in peripheral blood lymphocytes) and the personality trait of persistence. The trait ‘persistence’ (using Cloninger’s Temperament and Character Inventory (TCI)) is weakly correlated with obsessive-compulsive personality disorder (OCPD) symptoms, as measured by the Structured Clinical Interview for DSM-III-R Axis II Personality Disorders (SCID-II) [Mulder and Joyce, 1997]. Joyce et al.  recently reported a novel association of DRD3 with OCPD, which has yet to be replicated. The primary purpose of this study is to attempt to replicate the finding using two independent samples of depressed individuals. To identify a consistent trend in association across the three samples, a meta-analysis, with the benefit of its increased power, was undertaken. OCPD is regarded as an ‘anxious’ personality disorder [Samuels et al., 2000], consistent with increased comorbidity of anxiety disorders, such as phobia and obsessivecompulsive disorder [Nestadt et al., 1991]. The secondary aims of this study were to explore the possibility of an association of DRD3 with Axis I anxiety diagnoses (including obsessivecompulsive disorder, panic disorder, simple and social phobia) and also Cloninger’s temperament traits, in particular, persistence. METHODS Grant sponsor: Health Research Council of New Zealand. *Correspondence to: Katrina J. Light, Department of Psychological Medicine, Christchurch School of Medicine & Health Sciences, PO Box 4345, Christchurch, New Zealand. E-mail: email@example.com Received 27 September 2005; Accepted 5 January 2006 DOI 10.1002/ajmg.b.30308 ß 2006 Wiley-Liss, Inc. Patient selection, assessment, and demographic information for the original sample are reported by Joyce et al. . The sample of 157 individuals included 151 New Zealand (NZ) Europeans, 3 Maoris, 2 Asians, and 1 who identified as ‘other.’ This sample was recruited as part of a Christchurch Outcome of Depression study examining predictors of outcome in patients randomized to treatment with either fluoxetine or nortriptyline [Joyce et al., 2002]. 410 Light et al. Replication Sample 1 (Clinical Sample) Patients. The depressed patients within this clinical sample were recruited for a study examining predictors of response to interpersonal psychotherapy (IPT) and cognitivebehavioral therapy (CBT). This study was approved by the Canterbury (New Zealand) Ethics Committee. Individuals were 18 years or older, with a principal current diagnosis of major depression. Patients were excluded if they had a history of mania (i.e., bipolar I disorder) or schizophrenia, or a severe current alcohol or drug dependence as their principal diagnosis. Patients were required to be physically healthy and to be free of psychotropic drugs for a minimum of 2 weeks or five drug half lives. Assessment. After giving informed consent, the patients attended a detailed clinical and neurobiological assessment, which included giving a blood sample for DNA extraction. The clinical assessment was conducted by a psychiatrist or clinical psychologist using the Structured Clinical Interview for DSMIV (SCID) [Spitzer et al., 1992]. Ratings on the Hamilton and Montgomery–Asberg [Montgomery and Asberg, 1979] depression rating scales were also made. Patients completed a series of self-report questionnaires, including the SCID Personality Questionnaire (SCID-PQ) and the TCI [Cloninger et al., 1993]. After these baseline assessments, patients were randomized to treatment with either IPT or CBT. After commencing treatment, a trained psychiatrist or clinical psychologist completed the SCID-II for DSM-IV [Spitzer et al., 1987] to assess the presence of Axis II personality disorders. The mean age of the sample was 34.8 years (SD, 10.3 years) and 72.5% were female. Eighty-nine percent of the sample were NZ Europeans, 5% were Asian, 5% were Maori, 2% identified as ‘other,’ and one individual was a Pacific Islander. The mean Montgomery–Asberg depression score was 23.8 (6.4), 72% had recurrent depression and 38% met DSM-IV criteria for melancholia. Of the 177 depressed patients, DRD3 genotyping data and OCPD data were available for 152 individuals. This included three individuals who were part of the sample in the original study, so their data were excluded, yielding a final sample of 149 individuals. Replication Sample 2 (Depressed Individuals From a Family Study) Patients. Subjects were recruited for a family study examining the molecular genetics of mood disorders and personality. Recruitment was via an advertisement for subjects who had received treatment for a major depressive episode (regardless of a history of mania or hypomania), and had two parents and/or siblings who were willing to be involved in the study. The full sample consisted of 127 probands, 98 mothers, 56 fathers, 67 sisters, and 30 brothers. To ensure consistency with the other two samples, which were composed solely of depressed individuals, only individuals in this study who had received a principal affective diagnosis of major depressive disorder, bipolar II or bipolar not otherwise specified, were included as depressed individuals. This was to have diagnostic consistency with the original and first replication studies (which excluded bipolar I disorder). Of the total 378 individuals, 237 had a history of non-bipolar I major depression—this included 110 probands, 56 mothers, 16 fathers, 39 sisters, and 16 brothers. Only these 237 depressed individuals were included in the analyses. This study was approved by the Canterbury Ethics Committee, Christchurch, New Zealand. Assessment. Subjects gave written informed consent for the study and were then interviewed by a trained research interviewer. For Axis I diagnoses the major interview schedule was the Mini-International Neuropsychiatric Interview (MINI) [Sheehan et al., 1998], although the alcohol and drug section of the MINI was replaced by the comparable modules of the Structured Clinical Interview for DSM-III-R (SCID) [Spitzer et al., 1992]. For selected Axis II personality disorders, the interviewer asked structured questions about personality traits and associated impairment, followed by the SCID-II interview for DSM-IV [Spitzer et al., 1987] for all disorders except paranoid and narcissistic personality disorders. After each interview, a psychiatrist (PRJ) reviewed the interview plus any other relevant diagnostic information (i.e., medical records), from which DSM-IV diagnoses were assigned. Further to this, individuals completed the TCI [Cloninger et al., 1993]. Each individual provided a blood sample, from which genomic DNA was extracted by the method of Ciulla et al. . The mean age of the sample was 44.3 years (SD, 15.02). Seventy-seven percent of the sample were females. Ninty-four percent of the sample were NZ European, 4% were non-NZ European, and 2% identified as being of ‘other’ ethnicity. Within this sample, 42% had recurrent depression and 54% met DSM-IV criteria for melancholia. Of the 237 depressed individuals, DNA was available for 228. Fifteen of these 228 individuals had already been included within the original study or replication sample 1. As such, replication sample 2 included 213 depressed individuals for whom complete genetic and personality data were available. Laboratory Methodology As described in Joyce et al. , the DRD3 Ser9Gly polymorphism was assayed by a polymerase chain reaction followed by digestion with MscI. This identified three genotypes (Ser/Ser, Ser/Gly, and Gly/Gly). Based on the original findings, the following analyses characterized individuals by the presence or absence of the Gly/Gly genotype. Statistical Methods Preliminary univariate analyses to identify differences in age, gender, genotype, and OCPD diagnosis across the three studies, were conducted. A one-way analysis of variance (ANOVA) was used to evaluate age, while w2-tests were used for the other three analyses. An association of age with rate of OCPD diagnosis was examined using a one-way ANOVA. Similarly, gender and rate of OCPD diagnosis were evaluated using a chi-squared or Fisher’s exact test as appropriate, in each of the three samples. An association of the Gly/Gly genotype with OCPD was examined using a Fisher’s exact test, within both replication samples. A meta-analysis across the three samples was conducted using Breslow-Day and Tarone’s homogeneity w2tests, Cochran’s and Mantel–Haenszel conditional independence w2-tests, and Mantel–Haenszel common odds ratio estimate. Logistic regression was undertaken using the presence or absence of OCPD as the dependent variable, and age, gender, and presence or absence of the Gly/Gly genotype as potential predictors. To identify the effect of more substantial changes in age (i.e., per decade), the logistic regression calculations utilized the following age groupings: 18–29 years, 30–39 years, 40–49 years, and 50þ years. A meta-analysis of the logistic regression results used a combined dataset (incorporating the three samples) and included the above predictors, along with gender sample and genotype samsample. On the basis that these interactions were not significant, just sample, age, gender, and genotype were entered into the regression model. An ANOVA was utilized to examine associations of the dimensional measures of OCPD symptoms and TCI temperament traits with the Gly/Gly genotype in the individual replication samples. The presence or absence of APA-defined Axis I anxiety disorder diagnoses were each evaluated with Dopamine D3 Receptor and Obsessive-Compulsive Personality Disorder respect to the genetic polymorphism using a chi-squared or Fisher’s exact test, in each replication sample. RESULTS Sample Characteristics Within the original sample, the mean age was 32.4 years (SD, 11.5 years), 43% were male and 96% were Caucasian. The Ser9 and Gly9 allele frequencies were 66% and 34%, respectively. 8.3% (n ¼ 13) had been diagnosed with OCPD, of whom the mean age was 32.5 years (SD, 14.9 years) and 76.9% were male. The first replication sample had a mean age of 35.3 years (SD, 10.3 years), 26% were males and 88% were Caucasian. Within this sample, the Ser9 allele occurred in 69% and the Gly9 allele 31%. 12.1% (n ¼ 18) of this sample had OCPD, the mean age was 39.0 years (SD, 10.7 years) and 38.9% were male. Within the second replication sample, the mean age was 44.8 years (SD, 15.0 years), 21.1% were male and 93% were Caucasian. The allele frequencies of the Ser9 and Gly9 alleles were 69% and 31%, respectively. 10.3% (n ¼ 22) had received the diagnosis of OCPD, the mean age was 44.2 years (SD, 13.2 years) and 40.9% were male. The three samples significantly differed in age (F ¼ 48.16, df ¼ 2,516, P < 0.001) and gender distribution (w2 ¼ 22.5, df ¼ 2, P < 0.001). Conversely, rate of OCPD diagnosis and presence of Gly/Gly genotype was not significantly different across the three samples. The allele frequencies of the three samples were each in Hardy–Weinberg equilibrium and are comparable with other studies [Lannfelt et al., 1992; Henderson et al., 2000; Jonsson et al., 2003]. Age was not significantly associated with rate of OCPD diagnosis across the three studies, while gender was associated (OR ¼ 2.9, 95% CI ¼ 1.6–5.4, P < 0.001). There was a significantly greater propensity for males to have been diagnosed with OCPD in the original (OR ¼ 4.9, 95% CI ¼ 1.3–18.7, P ¼ 0.011) and second replication samples (OR ¼ 2.9, 95% CI ¼ 1.2–7.5, P ¼ 0.025). This trend was also present within the first replication sample, but was not significant (OR ¼ 2.0, 95% CI ¼ 0.7–5.5, P ¼ 0.251). DRD3 Polymorphism and Obsessive-Compulsive Personality Disorder No support for an association of OCPD diagnosis with the presence of the Gly/Gly genotype was found in either of the replication samples (Table I). However, tests for homogeneity of the odds ratios illustrated that the three samples did not significantly differ with respect to the association of an OCPD diagnosis with the presence of a Gly/Gly genotype (w2 ¼ 3.12, df ¼ 2, P ¼ 0.210). Further to this, Cochran’s and Mantel– Haenszel tests of conditional independence indicated an 411 overall significant association across the studies (Cochran’s: w2 ¼ 6.13, df ¼ 1, P ¼ 0.013; Mantel–Haenszel: w2 ¼ 4.99, df ¼ 1, P ¼ 0.025). Therefore, although the two replication samples did not individually contribute support, a meta-analysis of these samples as well as the original sample identified a consistent association of the Gly/Gly genotype with the presence of an OCPD. Multivariate logistic regression analyses were applied to each of the three samples, incorporating age, gender, and Gly/ Gly genotype as potential predictors of OCPD diagnosis (Table II). The original sample identified the presence of homozygous glycine alleles and male gender as being significant predictors (OR ¼ 7.30, 95% CI ¼ 1.9–28.2, P ¼ 0.004 and OR ¼ 5.37, 95% CI ¼ 1.3–21.7, P ¼ 0.018, respectively). Similarly, the second replication sample identified the male gender as a significant predictor of OCPD diagnosis (OR ¼ 3.0, 95% CI ¼ 1.2–7.7, P ¼ 0.020). The proposed multivariate model showed no significant effects within the first replication sample. A meta-analysis of the three studies elucidated the Gly/Gly genotype (OR ¼ 2.53, 95% CI ¼ 1.2– 5.4, P ¼ 0.016) and male gender (OR ¼ 2.82, 95% CI ¼ 1.5–5.1, P ¼ 0.001) as significant predictors, independent of study, for occurrence of OCPD. Exclusion of non-Caucasian individuals did not alter the results for either the individual studies or the meta-analysis. Although the number of OCPD symptoms was significantly associated with presence of the Gly/Gly genotype (F (1,155) ¼ 4.85, P ¼ 0.029) within the original sample, no support for such an association was found in either of the replication samples. DRD3 Polymorphism and Axis I Anxiety Disorder Diagnoses and TCI Temperament Traits Within the original sample, DRD3 genotype was significantly associated with obsessive-compulsive disorder (OCD) diagnosis (w2 ¼ 6.21, df ¼ 2, P ¼ 0.045), yet the presence of a Gly/Gly genotype did not appear to be associated. Similarly, Gly/Gly genotype was not significantly associated with OCD diagnosis in either of the replication samples. None of the phobic disorders or panic disorder were found to be associated with Gly/Gly genotype. Furthermore, both replication samples failed to find support for a significant association of Gly/Gly genotype with any of Cloninger’s temperament measures, including persistence. DISCUSSION In this study we set out to replicate an association of the DRD3 Gly/Gly genotype with OCPD. Two independent TABLE I. DRD3 Ser9Gly Genotype Frequency Among Individuals With and Without Obsessive-Compulsive Personality Disorder (OCPD) Diagnosis, in Three Independent Samples Genotype Previous study Without OCPD (n ¼ 144) With OCPD (n ¼ 13) Replication sample 1 Without OCPD (n ¼ 131) With OCPD (n ¼ 18) Replication sample 2 Without OCPD (n ¼ 191) With OCPD (n ¼ 22) Meta-analysis Without OCPD (n ¼ 466) With OCPD (n ¼ 53) Ser/Ser Ser/Gly Gly/Gly Presence of Gly/Gly genotype OR (95% CI) P-value 46% (66) 15% (2) 45% (65) 46% (6) 9% (13) 38% (5) 6.30 (1.8–22.08) 0.008 50% (66) 44% (8) 39% (51) 39% (7) 11% (14) 17% (3) 1.67 (0.43–6.5) 0.435 48% (91) 50% (11) 43% (82) 36% (8) 9% (18) 14% (3) 1.52 (0.41–5.63) 0.462 48% (223) 40% (21) 42% (198) 40% (21) 10% (45) 21% (11) 2.44 (1.18–5.05) 0.017 412 Light et al. TABLE II. Multivariate Logistic Regression Predicting Obsessive-Compulsive PD Diagnosis in Three Samples Adjusting for Age and Gender and a Meta-Analysis Previous study Predictor Gly/Gly genotype Age (per decade) Male Sample 1 Sample 2 Meta-analysis OR P-value OR P-value OR P-value OR P-value 7.298 1.071 5.374 0.004 0.819 0.018 2.010 1.470 2.224 0.329 0.148 0.137 1.340 0.965 3.023 0.671 0.871 0.020 2.527 1.113 2.821 0.016 0.462 0.001 samples of depressed individuals failed to individually yield support for a previously identified association; however, a meta-analysis of the three samples elucidated an overall significant association, whereby an individual with Gly/Gly genotype is 2.4 times more likely to be diagnosed with OCPD. As with all single-gene association studies, our findings need to be interpreted tentatively within the broader context of OCPD etiology. The DRD3 provides just one explanation for OCPD behavior and hypothesizing how it does so is complicated by the paucity of research relating to this personality disorder. The DRD3 Ser9Gly mutation does not affect the insertion of the receptor into the membrane [Lundstrom and Turpin, 1996]. Instead the mutation, although it occurs within the extracellular N-terminus and hence is unlikely to affect agonist or antagonist binding, has demonstrated significantly higher affinity for dopamine [Lundstrom and Turpin, 1996]. The specific influence of this polymorphism on an animal behavior has yet to be modeled. However, functional analyses using knockout mice, DRD3 agonists and antagonists suggest that this receptor is involved in locomotor inhibition [Daly and Waddington, 1993; Waters et al., 1994; Svensson et al., 1994a,b; Accili et al., 1996]. This is corroborated by the finding of functional D3 receptors specifically throughout the ‘‘motor’’ circuit [Larson and Ariano, 1995]. Clarification is required regarding the etiology of obsessivecompulsive behavior. For example, based on our findings implicating DRD3 as a risk factor for OCPD, it could be suggested that such behavior arises from impairment in one’s motor control, utilization of sensory information, and/or reward system. Firstly, evidence for impaired motor control, as a result of DRD3, has been presented above. Consistent with this, Villemarette-Pittman et al. , based on findings of cooccurrence of OCPD with impulsive aggression, proposed that OCPD may be a compensatory mechanism for some individuals that have innate behavioral disinhibition. Secondly, DRD3 mRNA has been identified within the sensory relay nuclei, suggesting a possible role in modality-specific sensory processing [Sokoloff et al., 1990; Suzuki et al., 1998]. Sachdev and Malhi , in their proposal of obsessive-compulsive disorder (OCD) as a disorder of decision-making, suggested that sensory-perceptual evidence is ineffective within individuals with OCD. While there is only partial phenotypic overlap between OCD and OCPD, it is possible that OCPD individuals may have impaired sensory information processing. Thirdly, mice mutant for the D3 receptor, as well as DRD3 agonists and antagonists, have suggested an inhibitory influence of the receptor on reward mechanisms [Caine and Koob, 1993; KlingPetersen et al., 1995; Xu et al., 1997]. Individuals with OCPD are characterized by unrelenting perfectionism, which is evident in their excessive devotedness to work and selfcriticalness [Villemarette-Pittman et al., 2004]. In addition to our finding of an association of DRD3 with OCPD, we also found gender to be a significant predictor of OCPD within the original and second replication sample, and a trend towards an effect was present within the first replication sample. In the meta-analysis, male gender increased risk of OCPD 2.8 times. The finding of an increased prevalence in males is concordant with the findings of an epidemiological survey conducted in Baltimore, MD [Nestadt et al., 1991]. Within this community-based survey, there were five times more males than females who had received the DSM-III diagnosis of compulsive personality disorder. A strength of this study is its incorporation of a metaanalysis. The probabilistic, rather than deterministic, nature of genetic effects within psychiatric disorders brings about small, inconsistent effect sizes when undertaking association studies. This study presents findings from two previously unpublished, independent samples and utilizes a metaanalysis to elucidate a consistent trend. One limitation of the study may be the inclusion of just three samples, all of which originated from the same outpatient clinical unit. However, the samples were ascertained for different purposes and all clinical data were collected using a validated structured clinical interview. A second limitation of this study is that, although subjects were asked to respond in accordance with how they usually are, it is not possible for us to identify the existence of these traits independent of clinical depression. This association of DRD3 with OCPD needs to be replicated among individuals who have never been diagnosed with depression. Finally, this study is limited by the relatively small number of individuals within each of the samples that had been diagnosed with OCPD. This article presents data supporting an association of DRD3 with OCPD, which although not significant in two of the three samples, is consistent overall. Although OCPD is a relatively narrowly defined diagnosis, it still encompasses an admixture of symptom criteria. Specifically how the DRD3 is a risk factor for some or all of these behaviors, remains to be understood. Analyses directly examining the biological basis of OCPD have generally been non-existent, possibly due to the difficulty of representing OCPD behaviors within an animal model. Instead, inferences have been made based on the proposed obsessive-compulsive spectrum, yet, to date, the dopamine system has not primarily been implicated [Villemarette-Pittman et al., 2004]. ACKNOWLEDGMENTS We thank Elisabeth Wells for her statistical assistance. For both clinical samples, we thank Robyn Abbott, Isobel Stevens, and Andrea Bartram. For the family study, we thank Andrea Bartram, Sarah Rowe, and other interviewers. REFERENCES Accili D, Fishburn CS, Drago J, Steiner H, Lachowicz JE, Park B-H, Gauda EB, Lee EJ, Cool MH, Sibley DR, et al. 1996. A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice. PNAS 93:1945–1949. Caine SB, Koob GF. 1993. Modulation of cocaine self-administration in the rat through D-3 dopamine receptors. Science 260:1814–1816. Ciulla TA, Sklar RM, Hauser SL. 1988. A simple method for DNA purification from peripheral blood. Anal Biochem 174:485–488. Cloninger CR, Svrakic DM, Przybeck TR. 1993. A psychobiological model of temperament and character. Arch Gen Psychiatry 50:975–990. Dopamine D3 Receptor and Obsessive-Compulsive Personality Disorder Czermak C, Lehofer M, Renger H, Wagner EM, Lemonis L, Rohrhofer A, Schauenstein K, Liebmann PM. 2004. Dopamine recpetor D3 mRNA expression in human lyphocytes is negatively correlated with the personality trait of persistence. J Neuroimmunol 150:145– 149. Daly SA, Waddington JL. 1993. Behavioural effects of the putative D-3 dopamine receptor agonist 7-OH-DPAT in relation to other ‘‘D-2-like’’ agonists. Neuropharmacology 32:509–510. Henderson AS, Korten AE, Jorm AF, Jacomb PA, Christensen H, Rodgers B, Tan X, Easteal S. 2000. COMT and DRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders. Am J Med Genet 96:102–107. Jonsson EG, Burgert E, Crocq MA, Gustavsson JP, Forslund K, MattilaEvenden M, Rylander G, Flyckt LK, Bjerkenstedt L, Wiesel FA, et al. 2003. Association study between dopamine D3 receptor gene variant and personality traits. Am J Med Genet Part B Neuropsychiatr Genet 117B:61–65. Joyce PR, Mulder RT, Luty SE, Sullivan PF, McKenzie JM, Abbott RM, Stevens IF. 2002. Patterns and predictors of remission, response and recovery in major depression treated with fluoxetine or nortriptyline. Aust N Z J Psychiatry 36:384–391. 413 Nestadt G, Romanoski AJ, Brown CH, Chahal R, Merchant A, Folstein MF, Gruenberg EM, McHugh PR. 1991. DSM-III compulsive personality disorder: An epidemiological survey. Psychol Med 21:461–471. Sachdev PS, Malhi GS. 2005. Obsessive-compulsive behaviour: A disorder of decision making. Aust N Z J Psychiatry 39:767–773. Samuels J, Nestadt G, Bienvenu OJ, Costa PT Jr, Riddle MA, Liang KY, Hoehn-Saric R, Grados MA, Cullen BA. 2000. Personality disorders and normal personality dimensions in obsessive-compulsive disorder. Br J Psychiatry 177:457–462. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59:22–33; quiz 34–57. Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz J-C. 1990. Molecular cloning and characterisation of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–150. Spitzer RL, Williams JBW, Gibbon M. 1987. Structured Clinical Interview for DSM-III-R Personality Disorders. New York: Biometrics Research Department, New York State Psychiatric Institute. Joyce PR, Rogers GR, Miller AL, Mulder RT, Luty SE, Kennedy MA. 2003. Polymorphisms of DRD4 and DRD3 and risk of avoidant and obsessive personality traits and disorders. Psychiatry Res 119:1–10. Spitzer RL, Williams JB, Gibbon M, First MB. 1992. The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry 49:624–629. Kling-Petersen T, Ljung E, Wollter L, Svensson K. 1995. Effects of dopamine D3 preferring compounds on conditioned place preference and intracranial self-stimulation in the rat. J Neural Transm Gen Sect 101:27–39. Suzuki M, Hurd YL, Sokoloff P, Schwartz JC, Sedvall G. 1998. D3 dopamine receptor mRNA is widely expressed in the human brain. Brain Res 779:58–74. Lannfelt L, Sokoloff P, Martres M-P, Pilon C, Giros B, Jonsson E, Sedvall G, Schwartz JC. 1992. Amino acid substitution in the dopamine D3 receptor as a useful polymorphism for investigating psychiatric disorders. Psychiatr Genet 2:249–256. Svensson K, Carlsson A, Huff RM, Kling-Petersen T, Waters N. 1994a. Behavioral and neurochemical data suggest functional differences between dopamine D2 and D3 receptors. Eur J Pharmacol 263:235–243. Larson ER, Ariano MA. 1995. D3 and D2 dopamine receptors: Visualization of cellular expression patterns in motor and limbic structures. Synapse 20:325–337. Lundstrom K, Turpin MP. 1996. Proposed schizophrenia-related gene polymorphism: Expression of the Ser9Gly mutant human dopamine D3 receptor with the Semliki Forest virus system. Biochem Biophys Res Commun 225:1068–1072. Menalled LB, Dziewczapolski G, Garcia MC, Rubinstein M, Gershanik OS. 1999. D3 receptor knockdown through antisense oligonucleotide administration supports its inhibitory role in locomotion. Neuroreport 10:3131– 3136. Montgomery SA, Asberg M. 1979. A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389. Mulder RT, Joyce PR. 1997. Temperament and the structure of personality disorder symptoms. Psychol Med 27:99–106. Svensson K, Carlsson A, Waters N. 1994b. Locomotor inhibition by the D3 ligand R-(þ)-7-OH-DPAT is independent of changes in dopamine release. J Neural Transm Gen Sect 95:71–74. Villemarette-Pittman NR, Stanford MS, Greve KW, Houston RJ, Mathias CW. 2004. Obsessive-compulsive personality disorder and behavioral disinhibition. J Psychol 138:5–22. Waters N, Lofberg L, Haadsma-Svensson S, Svensson K, Sonesson C, Carlsson A. 1994. Differential effects of dopamine D2 and D3 receptor antagonists in regard to dopamine release, in vivo receptor displacement and behaviour. J Neural Transm Gen Sect 98:39–55. Wong AH, Buckle CE, Van Tol HH. 2000. Polymorphisms in dopamine receptors: What do they tell us? Eur J Pharmacol 410:183–203. Xu M, Koeltzow TE, Santiago GT, Moratalla R, Cooper DC, Hu XT, White NM, Graybiel AM, White FJ, Tonegawa S. 1997. Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors. Neuron 19:837–848.