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Cluster analysis of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder: clinical and genetic correlates
Comprehensive Psychiatry 46 (2005) 14 – 19 www.elsevier.com/locate/comppsych
Cluster analysis of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder: clinical and genetic correlates Christine Lochnera,*, Sian M.J. Hemmingsb, Craig J. Kinnearb, Dana J.H. Niehausa, Daniel G. Nelc, Valerie A. Corfieldb, Johanna C. Moolman-Smookb, Soraya Seedata, Dan J. Steina a
MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, University of Stellenbosch, PO Box 19063, Tygerberg, 7505, Cape Town, South Africa b MRC/US Center for Molecular and Cellular Biology, University of Stellenbosch, Tygerberg, 7505, Cape Town, South Africa c Center for Statistical Consultation, Department of Statistics & Actuarial Science, University of Stellenbosch, Stellenbosch, Matieland, 7602, South Africa
Abstract Background: Comorbidity of certain obsessive-compulsive spectrum disorders (OCSDs; such as Tourette’s disorder) in obsessivecompulsive disorder (OCD) may serve to define important OCD subtypes characterized by differing phenomenology and neurobiological mechanisms. Comorbidity of the putative OCSDs in OCD has, however, not often been systematically investigated. Methods: The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I DisordersPatient Version as well as a Structured Clinical Interview for Putative OCSDs (SCID-OCSD) were administered to 210 adult patients with OCD (N = 210, 102 men and 108 women; mean age, 35.7 F 13.3). A subset of Caucasian subjects (with OCD, n = 171; control subjects, n = 168), including subjects from the genetically homogeneous Afrikaner population (with OCD, n = 77; control subjects, n = 144), was genotyped for polymorphisms in genes involved in monoamine function. Because the items of the SCID-OCSD are binary (present/absent), a cluster analysis (Ward’s method) using the items of SCID-OCSD was conducted. The association of identified clusters with demographic variables (age, gender), clinical variables (age of onset, obsessive-compulsive symptom severity and dimensions, level of insight, temperament/character, treatment response), and monoaminergic genotypes was examined. Results: Cluster analysis of the OCSDs in our sample of patients with OCD identified 3 separate clusters at a 1.1 linkage distance level. The 3 clusters were named as follows: (1) breward deficiency Q (including trichotillomania, Tourette’s disorder, pathological gambling, and hypersexual disorder), (2) bimpulsivity Q (including compulsive shopping, kleptomania, eating disorders, self-injury, and intermittent explosive disorder), and (3) bsomaticQ (including body dysmorphic disorder and hypochondriasis). Several significant associations were found between cluster scores and other variables; for example, cluster I scores were associated with earlier age of onset of OCD and the presence of tics, cluster II scores were associated with female gender and childhood emotional abuse, and cluster III scores were associated with less insight and with somatic obsessions and compulsions. However, none of these clusters were associated with any particular genetic variant. Conclusion: Analysis of comorbid OCSDs in OCD suggested that these lie on a number of different dimensions. These dimensions are partially consistent with previous theoretical approaches taken toward classifying OCD spectrum disorders. The lack of genetic validation of these clusters in the present study may indicate the involvement of other, as yet untested, genes. Further genetic and cluster analyses of comorbid OCSDs in OCD may ultimately contribute to a better delineation of OCD endophenotypes. D 2005 Elsevier Inc. All rights reserved.
1. Introduction There is growing recognition that obsessive-compulsive disorder (OCD) is a heterogeneous disorder, with clinical subtypes that are characterized by differing pathophysio-
* Corresponding author. PO Box 19063, Tygerberg 7505, South Africa. Tel.: +27 21 938 9179; fax: +27 21 933 5790. E-mail address: [email protected] (C. Lochner). 0010-440X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.comppsych.2004.07.020
logical mechanisms and treatment outcomes [1,2]. In clinical practice, for example, only about 40% to 60% of patients respond to the first trial of any particular selective serotonin reuptake inhibitor (SSRI) [3]. Other neurotransmitter mechanisms may also be involved in OCD; dysregulation of the dopaminergic system, in particular, has been postulated as a crucial factor in treatment-resistant OCD [4,5]. Interestingly, the dopaminergic system may also be sensitized by repeated stress exposure [6,7]. Furthermore, it
C. Lochner et al. / Comprehensive Psychiatry 46 (2005) 14–19
has been suggested that patients with OCD who have particular variants of genes of the dopamine system are more likely to have tics [5,8], and the presence of tics predicts worse response to SSRIs [8,9]. A better understanding of subtypes of OCD might ultimately lead to new and more effective treatments [2]. One approach to subtyping OCD may be to consider issues of comorbidity. For instance, in their attempt to characterize psychopathological classes of disorders related to OCD to distinguish more homogeneous phenotypes with distinct etiologies, Nestadt et al [10] suggested that the OCD phenotype is expressed in 2 different subgroups on the basis of the presence of additional clinical syndromes that frequently accompany the condition. Moreover, OCD is commonly comorbid with obsessive-compulsive spectrum disorders (OCSDs; ie, conditions that share phenomenological and neurobiological features with OCD). For example, patients with comorbid OCD and Tourette’s disorder (TD) appear to be characterized by specific demographic features (they are more likely to be male) and clinical characteristics (they are less likely to respond to SSRIs) [9]. While most patients with OCD suffer from at least one comorbid OCD spectrum disorder [11], there has been relatively little systematic investigation of the structure and implications of such comorbidity. It is possible, however, that different dimensions of OCD spectrum comorbidity in OCD correspond to differential involvement of various neurochemical systems and neuroanatomical circuits [12]. In this study, we aimed to delineate the hypothesized spectrum of OCD-related disorders in OCD using cluster analysis. The association of identified clusters with demographic variables (age, gender), clinical variables (age of onset, obsessive-compulsive [OC] symptom severity and dimensions, level of insight, temperament/character, treatment response), and monoaminergic genotypes was examined.
2.2. Interview
2. Methods
2.3. Genotyping
2.1. Subjects Two hundred and ten adult patients with OCD (N = 210, 102 men and 108 women), with ages ranging between 18 and 75 years (35.7 F 13.3), took part in the study. To be eligible, patients had to meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV ) [13] criteria for a primary diagnosis of OCD on the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders–Patient Version (SCID-II/P) [14] and had to provide written informed consent for the study. A history of psychosis was an exclusion criterion. An experienced clinical researcher interviewed patients referred from a wide range of sources (the OCD Association of South Africa, community-based primary care practitioners, and specialist psychiatrists).
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The semistructured interview included questions on specific demographic data including current age, age of onset of OCD, and ethnicity. Clinical diagnoses were based upon data obtained with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders-Patient Version, selected parts of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis II Disorders-Patient Version (OC, avoidant, schizotypal, borderline personality disorders) [14], and the Structured Clinical Interview for Putative OCSDs (SCID-OCSD) [11] to assess putative OCSDs. In addition, the Yale-Brown Obsessive-Compulsive Scale (YBOCS) symptom checklist and severity rating scale were used, allowing assessment of the typology and severity of OC symptoms [15,16]. Patients’ level of insight into the senselessness or excessiveness of their OC symptoms was assessed using the relevant YBOCS item [15]. The presence/absence of tics (current and/or past) and their severity were assessed with the SCID-OCSD and the Yale Global Tic Severity Scale, respectively [17]. For patients who had received an adequate trial of pharmacotherapy with an SSRI and/or formal cognitive behavior therapy, response was assessed on the global improvement item of the Clinical Global Impression Scale; subjects with Clinical Global Impression Scale scores of 1 (bvery much improved Q) or 2 (b much improved Q) were defined as treatment responders (Clinical Global Impression of Change Scale) [18]. The Childhood Trauma Questionnaire [19] was used as a self-report questionnaire to assess the nature and severity of childhood trauma. Subscales of the Childhood Trauma Questionnaire include measures of emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. The Temperament and Character Inventory [20] was administered to measure behaviors associated with 4 temperament dimensions, namely, novelty seeking, harm avoidance, reward dependence, and persistence.
DNA was extracted from venous blood (10-30 mL) in a subset of Caucasian patients with OCD (n = 171) and control subjects (n = 168), including patients (n = 77) and control subjects (n = 144) from the genetically homogeneous Afrikaner population, and was genotyped for polymorphisms in genes involved in monoamine function, which had previously been hypothesized to be relevant to OCD [21]. The polymorphisms investigated were a 48-base pair (bp) variable number of tandem repeats in the third exon of dopamine receptor type 4 (DRD4) [22], a 40-bp variable number of tandem repeats in the 3V-untranslated region of the dopamine transporter (DAT) [23], a 44-bp insertion/deletion polymorphism in the promoter region of the serotonin receptor (5-HTT) [24], and single nucleotide polymorphisms in the serotonin receptor type 1B (5HT 1B ,
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previously referred to as 5-HT 1Db ; G861C) [25], the serotonin receptor type 2A (5-HT 2A ; T102C) [26], tyrosine hydroxylase (TH; Val81Met) [27], catechol-O-methyltransferase (COMT; Val158Met) [28], and monoamine oxidase A (MAOA; C1460T/EcoRV) [29]. Previously described genotyping protocols [21] were followed. 2.4. Data analysis First, because the items of the SCID-OCSD were binary (present/absent), a cluster analysis (Ward’s method)— appropriate for use with binary data [30]—was performed on the items (lifetime) of the SCID-OCSD for all patients with OCD. OCSDs were selected on the basis of previous literature and comprised TD, pathological gambling, hypersexual disorder, kleptomania, compulsive shopping, trichotillomania (TTM), intermittent explosive disorder (IED), eating disorders (including bulimia and anorexia nervosa), self-injury (ie, impulse control disorder not otherwise specified), body dysmorphic disorder (BDD), and hypochondriasis. For each respondent, cluster scores were obtained by calculation of the mean score for each cluster. The associations of cluster scores with demographic variables (age, gender), clinical variables (age of onset, OC symptom severity and dimensions, level of insight, temperament, treatment response), and genotypes were then examined using Pearson’s correlation coefficients and one-way analysis of variance as appropriate. Because the normal probability plots showed that the residuals were not normally distributed, a nonparametric bootstrap analysis of variance for multiple comparisons was used [31]. 3. Results 3.1. Cluster analysis At the 1.1 linkage distance level, the following 3 clusters were obtained (Fig. 1): (1)
(2)
(3)
Cluster I, subsequently named b reward deficiency,Q included TTM, pathological gambling, hypersexual disorder, and TD. Cluster II, subsequently named bimpulsivity,Q included compulsive shopping, kleptomania, eating disorders (including anorexia and bulimia nervosa), self-injury, and IED. Cluster III, subsequently named bsomatic,Q included BDD and hypochondriasis.
3.2. Comparison data The following significant results were found: (1)
Cluster I scores (ie, breward deficiency Q) were significantly associated with earlier onset of OCD (r = 0.17; P = .02) and the presence of tics (t = 3.26; P = .001). Cluster I scores were also significantly associated with harm-related (r =
Fig. 1. Cluster analysis results: tree diagram. TTM indicates trichotillomania; GAM, pathological gambling; SEX, hypersexual disorder; TD, Tourette’s disorder; SHOP, compulsive shopping; KLEP, kleptomania; EAT, eating disorders; SI, self-injury; IED, intermittent explosive disorder; BDD, body dysmorphic disorder; HYPOCH, hypochondriasis.
(2)
(3)
0.18; P = .01) and sexual/religious obsessions and compulsions (r = 0.21; P = .004). Cluster II scores (ie, bimpulsivityQ) were significantly associated with female gender (t = 2.45; P = .02), increased severity of OCD on the YBOCS (r = 0.18; P = .01), a history of childhood emotional abuse (r = 0.22; P = .03), and increased scores on the temperament trait of novelty seeking (r = 0.35; P b .001). Cluster III scores (ie, bsomaticQ) were significantly associated with deficits in insight (into the excessiveness or senselessness of OC symptoms) (r = 0.22; P = .02) and with somatic obsessions and compulsions (r = 0.22; P = .002).
The 3 identified clusters did not show significant associations with the other demographic and clinical variables (including treatment response), and there were no significant associations with the different genotypes. 4. Discussion Cluster analysis of the OCSDs in our sample of patients with OCD identified 3 separate clusters at the 1.1 linkage distance level. We labeled these clusters as (1) breward deficiency Q (including TTM, pathological gambling, hypersexual disorder, and TD), (2) bimpulsivity Q (including compulsive shopping, kleptomania, eating disorders, selfinjury, and IED), and (3) bsomatic Q (including BDD and hypochondriasis). A substantial literature has documented the comorbidity between OCD and TD, and the finding that TTM, pathological gambling, and hypersexual disorder clustered
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together with TD (in Cluster I, called b reward deficiency Q), is consistent with some previous evidence of comorbidity between these disorders. There is substantial evidence that tics in OCD are mediated in part by the dopaminergic system, and some evidence that this system also plays a role in the other conditions included this cluster [32-36]. Indeed, Blum and colleagues [37] have argued that a number of OCSDs are characterized by reward deficiency, pleasureseeking behavior, and dopaminergic deficits—hence, our use of the term breward deficiency Q to describe the cluster. The association of cluster I scores with earlier-onset OCD and with harm-related and sexual/religious obsessions and compulsions is consistent with previous data indicating that OCD with tics is characterized by early age of onset and by these symptom subtypes [38- 41]. The second identified cluster included compulsive shopping, kleptomania, eating disorders, self-injury, and IED, and because these conditions are associated with impaired impulse control, cluster II was termed bimpulsivity.Q Comorbidity of impulse control disorders in OCD is consistent with previous work noting that many patients with OCD manifest impulsive behavior or comorbid impulse control disorders [12,42-50]. The association between cluster II scores and increased severity of OCD is consistent with previous data indicating a link between impulsivity and OCD severity [48]. The association of cluster II scores with female gender and with emotional abuse is consistent with previous work linking a subset of patients with OCD, as well as eating disorders and selfinjurious behaviors in women, to early traumatic experiences [51-55]. Cluster II was also associated with increased novelty seeking, a temperament trait that is characterized by impulsivity and risk-taking behavior [56]. Impulsivity, whether in OCD or in other disorders, may be mediated by the serotonergic system [57] and may also be increased in the context of exposure to early maladaptive stressors. Body dysmorphic disorder, characterized by a preoccupation with imagined defects in appearance [13], and hypochondriasis, a disorder characterized by repeated concerns about illness, were included in cluster III, which we termed bsomatic.Q Obsessive-compulsive disorder is the most frequent comorbid diagnosis both in patients with BDD and those with subclinical BDD and their relatives [58]—supporting the idea of an OCD/somatic subtype. There is a substantial overlap in the phenomenology of OCD, BDD, and hypochondriasis insofar as patients with BDD and hypochondriasis also have OC traits (eg, recurrent intrusive thoughts—about bodily appearance or medical illness and ritualistic behaviors—mirror checking, reassurance seeking) [59,60]. On the other hand, patients with OCD also often have somatic concerns [61] including excessive or unfounded concerns about body defects, imagined defects in appearance, or concerns about illness (ie, somatic obsessions/related compulsions). Thus, it is not surprising that cluster III scores correlated with somatic obsessions and compulsions. The finding that cluster III
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scores were associated with less insight is consistent with work showing that patients with body dysmorphic concerns frequently have poor insight. We did not find a relationship between any of the identified clusters and the investigated dopaminergic and serotonergic polymorphisms, suggesting that variants in other genes in these systems should rather be explored. In conclusion, although aspects of the links discussed here have previously been described, to our knowledge, this is the first cluster analysis based on a prospective comprehensive interview investigating a range of OCSDs. The significant associations found between cluster scores and clinical variables suggest the value of delineating the dimensions along which comorbid OCSDs fall under OCD. Mood and anxiety disorders are also highly comorbid with OCD, suggesting that future work on the structure of comorbid disorders in OCD should address the inclusion of these conditions. Although there were no significant associations of cluster scores with the candidate genes investigated, it is possible that future work with larger samples and additional variants in other genes may ultimately show that examining comorbidity in OCD is helpful in delineating the endophenotypes that mediate the pathogenesis of this condition.
Acknowledgments This work was supported by the Medical Research Council of South Africa, the National Research Fund, and by a grant from the Obsessive-Compulsive Foundation. The help of the Obsessive-Compulsive Association of South Africa is gratefully acknowledged.
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Cluster analysis of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder: clinical and genetic correlates Christine Lochnera,*, Sian M.J. Hemmingsb, Craig J. Kinnearb, Dana J.H. Niehausa, Daniel G. Nelc, Valerie A. Corfieldb, Johanna C. Moolman-Smookb, Soraya Seedata, Dan J. Steina a
MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, University of Stellenbosch, PO Box 19063, Tygerberg, 7505, Cape Town, South Africa b MRC/US Center for Molecular and Cellular Biology, University of Stellenbosch, Tygerberg, 7505, Cape Town, South Africa c Center for Statistical Consultation, Department of Statistics & Actuarial Science, University of Stellenbosch, Stellenbosch, Matieland, 7602, South Africa
Abstract Background: Comorbidity of certain obsessive-compulsive spectrum disorders (OCSDs; such as Tourette’s disorder) in obsessivecompulsive disorder (OCD) may serve to define important OCD subtypes characterized by differing phenomenology and neurobiological mechanisms. Comorbidity of the putative OCSDs in OCD has, however, not often been systematically investigated. Methods: The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I DisordersPatient Version as well as a Structured Clinical Interview for Putative OCSDs (SCID-OCSD) were administered to 210 adult patients with OCD (N = 210, 102 men and 108 women; mean age, 35.7 F 13.3). A subset of Caucasian subjects (with OCD, n = 171; control subjects, n = 168), including subjects from the genetically homogeneous Afrikaner population (with OCD, n = 77; control subjects, n = 144), was genotyped for polymorphisms in genes involved in monoamine function. Because the items of the SCID-OCSD are binary (present/absent), a cluster analysis (Ward’s method) using the items of SCID-OCSD was conducted. The association of identified clusters with demographic variables (age, gender), clinical variables (age of onset, obsessive-compulsive symptom severity and dimensions, level of insight, temperament/character, treatment response), and monoaminergic genotypes was examined. Results: Cluster analysis of the OCSDs in our sample of patients with OCD identified 3 separate clusters at a 1.1 linkage distance level. The 3 clusters were named as follows: (1) breward deficiency Q (including trichotillomania, Tourette’s disorder, pathological gambling, and hypersexual disorder), (2) bimpulsivity Q (including compulsive shopping, kleptomania, eating disorders, self-injury, and intermittent explosive disorder), and (3) bsomaticQ (including body dysmorphic disorder and hypochondriasis). Several significant associations were found between cluster scores and other variables; for example, cluster I scores were associated with earlier age of onset of OCD and the presence of tics, cluster II scores were associated with female gender and childhood emotional abuse, and cluster III scores were associated with less insight and with somatic obsessions and compulsions. However, none of these clusters were associated with any particular genetic variant. Conclusion: Analysis of comorbid OCSDs in OCD suggested that these lie on a number of different dimensions. These dimensions are partially consistent with previous theoretical approaches taken toward classifying OCD spectrum disorders. The lack of genetic validation of these clusters in the present study may indicate the involvement of other, as yet untested, genes. Further genetic and cluster analyses of comorbid OCSDs in OCD may ultimately contribute to a better delineation of OCD endophenotypes. D 2005 Elsevier Inc. All rights reserved.
1. Introduction There is growing recognition that obsessive-compulsive disorder (OCD) is a heterogeneous disorder, with clinical subtypes that are characterized by differing pathophysio-
* Corresponding author. PO Box 19063, Tygerberg 7505, South Africa. Tel.: +27 21 938 9179; fax: +27 21 933 5790. E-mail address: [email protected] (C. Lochner). 0010-440X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.comppsych.2004.07.020
logical mechanisms and treatment outcomes [1,2]. In clinical practice, for example, only about 40% to 60% of patients respond to the first trial of any particular selective serotonin reuptake inhibitor (SSRI) [3]. Other neurotransmitter mechanisms may also be involved in OCD; dysregulation of the dopaminergic system, in particular, has been postulated as a crucial factor in treatment-resistant OCD [4,5]. Interestingly, the dopaminergic system may also be sensitized by repeated stress exposure [6,7]. Furthermore, it
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has been suggested that patients with OCD who have particular variants of genes of the dopamine system are more likely to have tics [5,8], and the presence of tics predicts worse response to SSRIs [8,9]. A better understanding of subtypes of OCD might ultimately lead to new and more effective treatments [2]. One approach to subtyping OCD may be to consider issues of comorbidity. For instance, in their attempt to characterize psychopathological classes of disorders related to OCD to distinguish more homogeneous phenotypes with distinct etiologies, Nestadt et al [10] suggested that the OCD phenotype is expressed in 2 different subgroups on the basis of the presence of additional clinical syndromes that frequently accompany the condition. Moreover, OCD is commonly comorbid with obsessive-compulsive spectrum disorders (OCSDs; ie, conditions that share phenomenological and neurobiological features with OCD). For example, patients with comorbid OCD and Tourette’s disorder (TD) appear to be characterized by specific demographic features (they are more likely to be male) and clinical characteristics (they are less likely to respond to SSRIs) [9]. While most patients with OCD suffer from at least one comorbid OCD spectrum disorder [11], there has been relatively little systematic investigation of the structure and implications of such comorbidity. It is possible, however, that different dimensions of OCD spectrum comorbidity in OCD correspond to differential involvement of various neurochemical systems and neuroanatomical circuits [12]. In this study, we aimed to delineate the hypothesized spectrum of OCD-related disorders in OCD using cluster analysis. The association of identified clusters with demographic variables (age, gender), clinical variables (age of onset, obsessive-compulsive [OC] symptom severity and dimensions, level of insight, temperament/character, treatment response), and monoaminergic genotypes was examined.
2.2. Interview
2. Methods
2.3. Genotyping
2.1. Subjects Two hundred and ten adult patients with OCD (N = 210, 102 men and 108 women), with ages ranging between 18 and 75 years (35.7 F 13.3), took part in the study. To be eligible, patients had to meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV ) [13] criteria for a primary diagnosis of OCD on the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders–Patient Version (SCID-II/P) [14] and had to provide written informed consent for the study. A history of psychosis was an exclusion criterion. An experienced clinical researcher interviewed patients referred from a wide range of sources (the OCD Association of South Africa, community-based primary care practitioners, and specialist psychiatrists).
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The semistructured interview included questions on specific demographic data including current age, age of onset of OCD, and ethnicity. Clinical diagnoses were based upon data obtained with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders-Patient Version, selected parts of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis II Disorders-Patient Version (OC, avoidant, schizotypal, borderline personality disorders) [14], and the Structured Clinical Interview for Putative OCSDs (SCID-OCSD) [11] to assess putative OCSDs. In addition, the Yale-Brown Obsessive-Compulsive Scale (YBOCS) symptom checklist and severity rating scale were used, allowing assessment of the typology and severity of OC symptoms [15,16]. Patients’ level of insight into the senselessness or excessiveness of their OC symptoms was assessed using the relevant YBOCS item [15]. The presence/absence of tics (current and/or past) and their severity were assessed with the SCID-OCSD and the Yale Global Tic Severity Scale, respectively [17]. For patients who had received an adequate trial of pharmacotherapy with an SSRI and/or formal cognitive behavior therapy, response was assessed on the global improvement item of the Clinical Global Impression Scale; subjects with Clinical Global Impression Scale scores of 1 (bvery much improved Q) or 2 (b much improved Q) were defined as treatment responders (Clinical Global Impression of Change Scale) [18]. The Childhood Trauma Questionnaire [19] was used as a self-report questionnaire to assess the nature and severity of childhood trauma. Subscales of the Childhood Trauma Questionnaire include measures of emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. The Temperament and Character Inventory [20] was administered to measure behaviors associated with 4 temperament dimensions, namely, novelty seeking, harm avoidance, reward dependence, and persistence.
DNA was extracted from venous blood (10-30 mL) in a subset of Caucasian patients with OCD (n = 171) and control subjects (n = 168), including patients (n = 77) and control subjects (n = 144) from the genetically homogeneous Afrikaner population, and was genotyped for polymorphisms in genes involved in monoamine function, which had previously been hypothesized to be relevant to OCD [21]. The polymorphisms investigated were a 48-base pair (bp) variable number of tandem repeats in the third exon of dopamine receptor type 4 (DRD4) [22], a 40-bp variable number of tandem repeats in the 3V-untranslated region of the dopamine transporter (DAT) [23], a 44-bp insertion/deletion polymorphism in the promoter region of the serotonin receptor (5-HTT) [24], and single nucleotide polymorphisms in the serotonin receptor type 1B (5HT 1B ,
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previously referred to as 5-HT 1Db ; G861C) [25], the serotonin receptor type 2A (5-HT 2A ; T102C) [26], tyrosine hydroxylase (TH; Val81Met) [27], catechol-O-methyltransferase (COMT; Val158Met) [28], and monoamine oxidase A (MAOA; C1460T/EcoRV) [29]. Previously described genotyping protocols [21] were followed. 2.4. Data analysis First, because the items of the SCID-OCSD were binary (present/absent), a cluster analysis (Ward’s method)— appropriate for use with binary data [30]—was performed on the items (lifetime) of the SCID-OCSD for all patients with OCD. OCSDs were selected on the basis of previous literature and comprised TD, pathological gambling, hypersexual disorder, kleptomania, compulsive shopping, trichotillomania (TTM), intermittent explosive disorder (IED), eating disorders (including bulimia and anorexia nervosa), self-injury (ie, impulse control disorder not otherwise specified), body dysmorphic disorder (BDD), and hypochondriasis. For each respondent, cluster scores were obtained by calculation of the mean score for each cluster. The associations of cluster scores with demographic variables (age, gender), clinical variables (age of onset, OC symptom severity and dimensions, level of insight, temperament, treatment response), and genotypes were then examined using Pearson’s correlation coefficients and one-way analysis of variance as appropriate. Because the normal probability plots showed that the residuals were not normally distributed, a nonparametric bootstrap analysis of variance for multiple comparisons was used [31]. 3. Results 3.1. Cluster analysis At the 1.1 linkage distance level, the following 3 clusters were obtained (Fig. 1): (1)
(2)
(3)
Cluster I, subsequently named b reward deficiency,Q included TTM, pathological gambling, hypersexual disorder, and TD. Cluster II, subsequently named bimpulsivity,Q included compulsive shopping, kleptomania, eating disorders (including anorexia and bulimia nervosa), self-injury, and IED. Cluster III, subsequently named bsomatic,Q included BDD and hypochondriasis.
3.2. Comparison data The following significant results were found: (1)
Cluster I scores (ie, breward deficiency Q) were significantly associated with earlier onset of OCD (r = 0.17; P = .02) and the presence of tics (t = 3.26; P = .001). Cluster I scores were also significantly associated with harm-related (r =
Fig. 1. Cluster analysis results: tree diagram. TTM indicates trichotillomania; GAM, pathological gambling; SEX, hypersexual disorder; TD, Tourette’s disorder; SHOP, compulsive shopping; KLEP, kleptomania; EAT, eating disorders; SI, self-injury; IED, intermittent explosive disorder; BDD, body dysmorphic disorder; HYPOCH, hypochondriasis.
(2)
(3)
0.18; P = .01) and sexual/religious obsessions and compulsions (r = 0.21; P = .004). Cluster II scores (ie, bimpulsivityQ) were significantly associated with female gender (t = 2.45; P = .02), increased severity of OCD on the YBOCS (r = 0.18; P = .01), a history of childhood emotional abuse (r = 0.22; P = .03), and increased scores on the temperament trait of novelty seeking (r = 0.35; P b .001). Cluster III scores (ie, bsomaticQ) were significantly associated with deficits in insight (into the excessiveness or senselessness of OC symptoms) (r = 0.22; P = .02) and with somatic obsessions and compulsions (r = 0.22; P = .002).
The 3 identified clusters did not show significant associations with the other demographic and clinical variables (including treatment response), and there were no significant associations with the different genotypes. 4. Discussion Cluster analysis of the OCSDs in our sample of patients with OCD identified 3 separate clusters at the 1.1 linkage distance level. We labeled these clusters as (1) breward deficiency Q (including TTM, pathological gambling, hypersexual disorder, and TD), (2) bimpulsivity Q (including compulsive shopping, kleptomania, eating disorders, selfinjury, and IED), and (3) bsomatic Q (including BDD and hypochondriasis). A substantial literature has documented the comorbidity between OCD and TD, and the finding that TTM, pathological gambling, and hypersexual disorder clustered
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together with TD (in Cluster I, called b reward deficiency Q), is consistent with some previous evidence of comorbidity between these disorders. There is substantial evidence that tics in OCD are mediated in part by the dopaminergic system, and some evidence that this system also plays a role in the other conditions included this cluster [32-36]. Indeed, Blum and colleagues [37] have argued that a number of OCSDs are characterized by reward deficiency, pleasureseeking behavior, and dopaminergic deficits—hence, our use of the term breward deficiency Q to describe the cluster. The association of cluster I scores with earlier-onset OCD and with harm-related and sexual/religious obsessions and compulsions is consistent with previous data indicating that OCD with tics is characterized by early age of onset and by these symptom subtypes [38- 41]. The second identified cluster included compulsive shopping, kleptomania, eating disorders, self-injury, and IED, and because these conditions are associated with impaired impulse control, cluster II was termed bimpulsivity.Q Comorbidity of impulse control disorders in OCD is consistent with previous work noting that many patients with OCD manifest impulsive behavior or comorbid impulse control disorders [12,42-50]. The association between cluster II scores and increased severity of OCD is consistent with previous data indicating a link between impulsivity and OCD severity [48]. The association of cluster II scores with female gender and with emotional abuse is consistent with previous work linking a subset of patients with OCD, as well as eating disorders and selfinjurious behaviors in women, to early traumatic experiences [51-55]. Cluster II was also associated with increased novelty seeking, a temperament trait that is characterized by impulsivity and risk-taking behavior [56]. Impulsivity, whether in OCD or in other disorders, may be mediated by the serotonergic system [57] and may also be increased in the context of exposure to early maladaptive stressors. Body dysmorphic disorder, characterized by a preoccupation with imagined defects in appearance [13], and hypochondriasis, a disorder characterized by repeated concerns about illness, were included in cluster III, which we termed bsomatic.Q Obsessive-compulsive disorder is the most frequent comorbid diagnosis both in patients with BDD and those with subclinical BDD and their relatives [58]—supporting the idea of an OCD/somatic subtype. There is a substantial overlap in the phenomenology of OCD, BDD, and hypochondriasis insofar as patients with BDD and hypochondriasis also have OC traits (eg, recurrent intrusive thoughts—about bodily appearance or medical illness and ritualistic behaviors—mirror checking, reassurance seeking) [59,60]. On the other hand, patients with OCD also often have somatic concerns [61] including excessive or unfounded concerns about body defects, imagined defects in appearance, or concerns about illness (ie, somatic obsessions/related compulsions). Thus, it is not surprising that cluster III scores correlated with somatic obsessions and compulsions. The finding that cluster III
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scores were associated with less insight is consistent with work showing that patients with body dysmorphic concerns frequently have poor insight. We did not find a relationship between any of the identified clusters and the investigated dopaminergic and serotonergic polymorphisms, suggesting that variants in other genes in these systems should rather be explored. In conclusion, although aspects of the links discussed here have previously been described, to our knowledge, this is the first cluster analysis based on a prospective comprehensive interview investigating a range of OCSDs. The significant associations found between cluster scores and clinical variables suggest the value of delineating the dimensions along which comorbid OCSDs fall under OCD. Mood and anxiety disorders are also highly comorbid with OCD, suggesting that future work on the structure of comorbid disorders in OCD should address the inclusion of these conditions. Although there were no significant associations of cluster scores with the candidate genes investigated, it is possible that future work with larger samples and additional variants in other genes may ultimately show that examining comorbidity in OCD is helpful in delineating the endophenotypes that mediate the pathogenesis of this condition.
Acknowledgments This work was supported by the Medical Research Council of South Africa, the National Research Fund, and by a grant from the Obsessive-Compulsive Foundation. The help of the Obsessive-Compulsive Association of South Africa is gratefully acknowledged.
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