Pre-morbid Psychiatric Morbidity, Comorbidity and Personality in Patients with Anorexia Nervosa Compared to their Healthy Sisters

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1 European Eating Disorders Review Eur. Eat. Disorders Rev. 10, (2002) Published online in Wiley InterScience ( DOI: /erv.476 Paper Pre-morbid Psychiatric Morbidity, Comorbidity and Personality in Patients with Anorexia Nervosa Compared to their Healthy Sisters Andreas Karwautz 1,4 *, Sophia Rabe-Hesketh 2, David A. Collier 3 and Janet L. Treasure 1 1 Eating Disorders Unit, Institute of Psychiatry, London, UK 2 Department of Biostatistics and Computing, Institute of Psychiatry, London, UK 3 Department of Psychological Medicine, Institute of Psychiatry, London, UK 4 University Clinic of Neuropsychiatry of Childhood and Adolescence, University of Vienna, Austria Anorexia nervosa (AN) has been linked with pre-morbid disorders, comorbidity, and specific personality traits in between-family case control studies. However, these findings have not been replicated in within-family studies, and it is not known whether these factors are linked specifically with AN or are shared familial factors. We aimed to compare pre-morbid disorders, comorbidity, and specific personality traits between sister-pairs discordant for AN. Forty-five families with two sisters discordant for AN were retrospectively assessed by interview and questionnaires. The proband with AN had mood disorders and personality disorders (PDs) more frequently than their sister and had lower scores of novelty seeking, self-directedness and cooperativeness, and higher scores of harm avoidance, persistence, self-transcendence and of all EDI-2 scales. In conclusion, major depression, cluster C PDs, persistence, harm avoidance, and self-transcendence appear to be specifically linked to AN and to be *Correspondence to: Dr A. Karwautz, Consultant Psychiatrist, Eating Disorders Unit, University Clinic of Neuropsychiatry of Childhood and Adolescence, University of Vienna Medical School, Waehringer Guertel 18 20, A-1090 Vienna, Austria. Tel: Fax: Andreas.Karwautz@univie.ac.at Contract/grant sponsor: Austrian Science Foundation, Vienna. Contract/grant number: J-1608-MED, Contract/grant sponsor: University of Vienna, Austria. Contract/grant sponsor: Austrian Ministry of Science. Contract/grant sponsor: Action Research. Contract/grant sponsor: European Community Framework V. Contract/grant number: QLK European Eating Disorders Review Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 10(4), (2002)

2 A. Karwautz et al. Eur. Eat. Disorders Rev. 10, (2002) individual-specific in nature. Major depression seems to be a risk factor for AN. Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. Keywords: anorexia nervosa; sister-pairs; personality; comorbidity INTRODUCTION Between family case control studies with unrelated subjects are an important tool for the identification of risk factors and related traits important in psychological disorders. However, associations might be confounded by between-family differences such as socioeconomic status, family structure, and cultural values which are often unmeasured and ignored (Dick, Johnson, Viken, & Rose, 2000). The use of discordant siblings (as close as possible in age) is a powerful tool to replicate and clarify associations in disorders such as anorexia nervosa (AN). AN is strongly associated with pre-morbid psychiatric disorders (e.g. Fairburn, Cooper, Doll, & Welch, 1999; Gillberg, Rastam, & Gillberg, 1995; Karwautz et al., 2001a), comorbidity with mood disorders (e.g. Halmi et al., 1991; Herzog, Keller, Sacks, Yeh, & Lavori, 1992), anxiety disorders (Braun, Sunday, & Halmi, 1994; Bulik, Sullivan, Fear, & Joyce, 1997), substance use disorders (Herzog et al., 1992), and personality disorders (e.g. Rosenvinge, Martinussen, & Ostensen, 2000; Wonderlich, Swift, Slotnick, & Goodman, 1990). Patients with AN score at the extremes of some temperament and personality dimensions (Klump et al., 2000; Vitousek & Manke, 1994). In the present study we used a within-family design of discordant sister-pairs for anorexia nervosa, to (1) control for unmeasured potentially confounding factors and (2) to examine whether these risk factors (premorbid axis-i disorders, PDs, personality traits) are linked specifically to the sibling with AN. SUBJECTS AND METHODS Design A case control design was used to compare 45 sister pairs discordant for AN. The part of the study relating to specific genetic and environmental risk factors has been previously described elsewhere (Karwautz et al., 2001a). Recruitment We approached women with AN who had volunteered to participate in research and current patients with AN at the South London and Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 256

3 Eur. Eat. Disorders Rev. 10, (2002) Comorbidity in Anorexia Nervosa Maudsley NHS Trust. To be included in the study the probands had to have AN and have a sister who did not have any form of an eating disorder (either AN, BN nor EDNOS). The sisters had to be less than 10 years apart in age and to have lived in the same family for a minimum of 8 years. If the patient had more than one sister, the sister closest in age was approached. Of 50 subjects with sisters that we approached, two declined to ask their sister to participate. Of those who were interviewed two pairs were excluded because the unaffected sister had a covert eating disorder. One pair was excluded because it became apparent during the interview that they were not full biological siblings. Due to incomplete interview schedules or insufficiently scored questionnaire measures, data on PDs, temperament and character are available only for 43 and 40 pairs, respectively. Of the 45 patients recruited 28 were research volunteers and 17 were current in- and outpatients at the hospital. The protocol for the study was reviewed by the Research Ethics Committee of the Bethlem and Maudsley Trust. Patients and their sisters gave written informed consent before inclusion in the study. Assessment measures A lifetime eating disorder history was assessed using a European adaptation of the Longitudinal Interval Follow-up Evaluation (LIFE Keller et al., 1987). AN (restricting versus binge/purging subtype), and lifetime status for major axis I disorders were diagnosed using the Structured Clinical Interview for Mental Disorders, research version 2.0 (SCID-I). The reliability and validity of the SCID-I has been documented with inter-rater agreement ranging from a kappa of 0.7 to 1.0. In order to document a premorbid occurrence of psychiatric disorders we used the method developed by Fairburn et al. (1999) to define onset of the eating disorder as the age of the first persistent symptoms of the disorder (called index age) and we asked the patients about the time before the eating disorder started in order to get a measure of risk. We used the criterion of 3 years without any episodes of binge eating to define the restricting subtype of AN (as set by The Price Foundation Collaborative Group, 2001). In order to assess axis II diagnoses we used the International Personality Disorder Examination ICD-10 module (Loranger, Janca, & Sartorius, 1997), which is a structured interview with an inter-rater reliability between 0.65 and 0.72 and a temporal stability between 0.53 and 0.54 (Lenzenweger, 1999; Loranger et al., 1994, 1997). The following self-report measures were used. Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 257

4 A. Karwautz et al. Eur. Eat. Disorders Rev. 10, (2002) Eating Disorders Inventory The Eating Disorders Inventory-2 (EDI-2; Garner, 1991) is a widely used self-report measure of eating disorder symptoms and putative vulnerability factors with excellent internal consistency, content validity, criterion based validity, and construct validity and good test retest reliability in eating disordered and healthy control subjects (Garner, 1991). Five of the dimensions in this instrument were designed to measure the underlying personality traits. Temperament and Character Inventory The Temperament and Character Inventory (TCI) (Cloninger, Przybeck, Svrakic, & Wetzel, 1994) is a self-report instrument with 225 items which measures dimension of temperament (novelty seeking, harm avoidance, reward dependence, and persistence) and character (self-directedness, cooperativeness, and self-transcendence). The internal consistency of the composite scales is high (ranging from 0.76 to 0.87 for the temperament scales and 0.84 to 0.89 for the character scales) (Cloninger et al., 1994). Procedure Eighty-six per cent of the subjects were interviewed in person and the remainder over the telephone. Each sister was interviewed independently. The senior author re-rated the taped interviews blind to case status. The questionnaires were filled in after having the interviews keeping the interviewer blind to the TCI and EDI-2 scores. Data analysis The clinical and demographic data from the two phenotypic extremes (þ/ anorexia) was compared using paired t-tests. The sisters were compared regarding the occurrence of the axis-i and axis-ii disorders using McNemar s tests and regarding personality dimensions and eating disorder-related psychopathology using paired t-tests. The comorbidity and personality traits were compared by chi-squared or t-tests between the AN subtypes. All main test results (e.g. the variable any mood disorder, any PD ) were considered as statistically significant at the 1 per cent level (p < 0.01). Because a difference in comorbidity and PDs was found within the literature consistently in one direction when comparing AN patients with unrelated controls, we used tests with one-tailed p-values for these items when comparing AN patients with related controls. Because the reports on the TCI scales in Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 258

5 Eur. Eat. Disorders Rev. 10, (2002) Comorbidity in Anorexia Nervosa AN were not of such a consistent pattern (in particular for the character scales which have been reported in few studies only) we used tests with two-tailed p-values for those. If there were significant differences between the groups on a domain level, a level of significance of p < 0.05 was accepted for additional analyses on an item level. All analysis was carried out using SPSS-PC. RESULTS Clinical and demographic characteristics of the sister-pairs The sisters were similar in age with a mean age gap of 3.2 þ/ 1.9 years. The affected subjects had a mean age of 27.7 þ/ 8.5 years, the unaffected sisters 27.4 þ/ 9.7 years. The mean age of first established symptoms of an eating disorder (index age) was 15.3 þ/ 3.2 years. The affected subject was the youngest of the pair in 49 per cent of the cases. At the time of the interview the affected subjects had a mean BMI of 17.7 þ/ 3.7 kg/m 2, whereas the unaffected sisters had a mean BMI of 22.4 þ/ 3.8. The minimum BMI of the affected sister was 13.1 þ/ 2.2 and the median duration of the illness was 3 years (interquartile range (IQR) ). Fifty-seven per cent of the fathers had professional occupations. Eighteen per cent of the affected sisters were not working because of medical reasons in comparison to 2 per cent (n ¼ 1) of the unaffected sisters. Overall the affected subjects had a poorer level of career adjustment than their sisters. Inter-rater reliability The raters, both unblinded (primary investigator) and blinded (senior investigator) to case status, agreed in their ratings with a mean kappa (SD) of 0.85 (0.2). Premorbid axis-i morbidity (Table 1) Forty per cent (n ¼ 18) of the anorexic patients had a diagnosis of any DSM-IV mood disorder (versus 7 per cent (n ¼ 3) of the sisters, chi 2 ¼ 12.2, p < 0.001) prior to the onset of their eating disorder. Major depressive episodes were present in 29 per cent (n ¼ 13) of the group with AN and in 7 per cent (n ¼ 7) of their sisters (p ¼ 0.02). Anxiety disorders were present equally (7 per cent (n ¼ 3) in both groups). Substance-related disorders were rare in both sister groups. Separation anxiety disorder was present in 11 per cent (n ¼ 5) in AN versus 2 per cent (n ¼ 1) in their sisters (n.s.). Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 259

6 A. Karwautz et al. Eur. Eat. Disorders Rev. 10, (2002) Table 1. Distribution of premorbid and lifetime rates of axis-i psychiatric disorders among subjects with anorexia nervosa and their sisters (n ¼ 45; McNemar s test, two-tailed p-values) Diagnosis Patient Sister Test statistics n ¼ 45 (%) n ¼ 45 (%) p (one-tailed) Axis-I disorders (premorbid occurrence) Mood disorders Any mood disorder ð 2 Þ 18 (40) 3 (7) < (12.2) Any major depressive episode 13 (29) 3 (7) 0.01 Major depressive disorder, single episode 10 (8) 3 (7) n.s. Major depressive disorder, recurrent episodes 3 (7) 0 (0) n.s. Dysthymia 4 (8) 0 (0) n.s. Depressive disorder NOS 0 (0) 0 (0) Anxiety disorders Any anxiety disorder ð 2 Þ 3 (7) 3 (7) n.s. Panic disorder without agoraphobia 0 (0) 0 (0) Panic disorder with agoraphobia 0 (0) 0 (0) Specific phobia 1 (2) 0 (0) n.s. Social phobia 0 (0) 0 (0) Obsessive compulsive disorder 2 (4) 2 (4) n.s. Posttraumatic stress disorder 1 (2) 0 (0) n.s. Generalized anxiety disorder 0 (0) 1 (2) n.s. Substance-related disorders Any substance-related disord. (Fisher s exact) 0 (0) 0 (0) Alcohol abuse 0 (0) 0 (0) Alcohol dependence 0 (0) 0 (0) Abuse of other substances 0 (0) 0 (0) Dependence on other substances 0 (0) 0 (0) Disorders of infancy, childhood and adolescence Separation anxiety disorder 5 (11) 1 (2) n.s. Axis-I disorders (lifetime occurrence) Mood disorders Any mood disorder ð 2 Þ 34 (76) 11 (24) < (21.5) Any major depressive episode 26 (58) 9 (20) < Major depressive disorder, single episode 14 (31) 6 (13) 0.03 Major depressive disorder, recurrent episodes 12 (27) 3 (7) 0.01 Dysthymia 14 (31) 1 (2) < Depressive disorder NOS 9 (20) 1 (2) 0.01 Anxiety disorders Any anxiety disorder ð 2 Þ 22 (49) 11 (24) 0.02 (4.79) Panic disorder without agoraphobia 6 (13) 2 (4) 0.15 Panic disorder with agoraphobia 8 (18) 5 (11) 0.28 Specific phobia 3 (7) 1 (2) 0.32 Social phobia 3 (7) 1 (2) 0.25 Obsessive compulsive disorder 5 (11) 2 (4) 0.23 Posttraumatic stress disorder 2 (4) 0 (0) 0.25 Generalized anxiety disorder 2 (4) 1 (2) 0.5 Continues Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 260

7 Eur. Eat. Disorders Rev. 10, (2002) Comorbidity in Anorexia Nervosa Table 1. Continued Diagnosis Patient Sister Test statistics n ¼ 45 (%) n ¼ 45 (%) p (one-tailed) Separation anxiety disorder 5 (11) 1 (2) 0.11 Substance-related disorders Any substance-related disord. (Fisher s exact) 8 (18) 1 (2) 0.02 Alcohol abuse 6 (13) 1 (2) 0.03 Alcohol dependence 3 (7) 0 (0) 0.13 Abuse of other substances 2 (4) 0 (0) 0.25 Dependence on other substances 0 0 (0) Lifetime axis-i psychopathology (Table 1) Seventy-six per cent (n ¼ 34) of the anorexic patients had a lifetime diagnosis of any DSM-IV mood disorder (versus 24.4 per cent (n ¼ 11) of the sisters, p < 0.001). Forty-nine per cent (n ¼ 22) of the anorexic subjects had any form of anxiety disorder (versus 24 per cent (n ¼ 11) of the sisters n.s.), and 18 per cent (n ¼ 8) had any substance-related disorder (versus 2 per cent (n ¼ 1) of the sisters; n.s.). Comorbid axis-ii psychopathology (Table 2) Fifty-four per cent (n ¼ 23) of the women with AN had at least one PD diagnosis, compared to 7 per cent (n ¼ 3) of the sisters, p < ). Thirty-four per cent (n ¼ 15) fulfilled criteria of one PD, 7 per cent (n ¼ 3) had two, and 12 per cent (n ¼ 5) had three PD diagnoses. The sister-pairs Table 2. Distribution of personality disorder diagnoses among subjects with anorexia nervosa and their sisters (McNemar s test with n ¼ 43 for Axis II disorders; two-tailed p-values) Personality disorder Patients Sisters Test statistics (IPDE definite diagnoses) n ¼ 43 (%) n ¼ 43 (%) p (one-tailed) Any personality disorder (Fisher s exact test) 23 (54) 3 (7) < Schizoid 4 (9.1) 1 (2.3) 0.13 Paranoid 1 (2.3) 0 (0) 0.5 Emotional unstable, impulsive type 3 (6.8) 0 (0) 0.13 Emotional unstable, borderline type 2 (4.5) 0 (0) 0.25 Dissocial 0 (0) 0 (0) Histrionic 0 (0) 0 (0) Dependent 6 (13.6) 0 (0) 0.02 Anankastic 10 (22.7) 2 (4.7) 0.01 Anxious 9 (20.5) 1 (2.3) 0.02 Unspecific 1 (2.3) 0 (0) 0.5 Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 261

8 A. Karwautz et al. Eur. Eat. Disorders Rev. 10, (2002) differed significantly in particular in the frequency of anankastic PD (n ¼ 10 versus n ¼ 2), anxious PD (n ¼ 9 versus n ¼ 1) and dependent PD (n ¼ 6 versus n ¼ 0) (Cluster C diagnoses). All other PD diagnoses were very rare in the patient group and nearly absent in the controls. Temperament and character dimensions, and personality traits: comparing the sister-pairs The sisters differed in their temperament and character pattern (TCI) apart from the reward dependence dimension. The subjects with AN were lower in novelty seeking (t ¼ 4.36, df ¼ 39, p < ), selfdirectedness (t ¼ 9.38, df ¼ 39, p < ), and cooperativeness (t ¼ 2.61, df ¼ 39, p ¼ 0.013), and higher in harm avoidance (t ¼ 7.88, df ¼ 39, p < ), persistence (t ¼ 3.82, df ¼ 39, p < ), and selftranscendence (t ¼ 2.64, df ¼ 39, p ¼ 0.012) than their non-eating disordered sisters. The women with eating disorders had higher scores on all of the personality subscales of the EDI-2 (all paired samples t-tests, df ¼ 39, p < 0.001). Defining the subgroups Sixty-four per cent (n ¼ 29) of the probands fulfilled the criterion for restricting AN i.e. 3 years without any episodes of binge eating. The restricting and the bingeing subgroup were similar in age, age at first symptoms, birth weight, age at lowest maintained weight, and BMI at the time of the interview. However, the restricting subgroup reached significantly lower BMI scores during the course of their disorder (AN/ RES AN/BP: mean BMI (SD); 12.4 (2.1) 14.4; t ¼ 3.22, p ¼ 0.002) and reported lower scores in the bulimia subscale of the EDI-2 (mean 2.0 þ/ 2.9 versus 8.1 þ/ 6.6; t ¼ 4.21; df ¼ 40; p < 0.001). There were no significant differences either for premorbid or lifetime diagnoses within the domains of any mood, anxiety, substance-related disorder, and PD. The subgroups did not significantly differ in the scores on the TCI or the personality dimensions of the EDI-2. DISCUSSION All human psychological traits and psychiatric disorders are composed of both genetic and environmental risk factors in varying proportions. Environmental factors can be shared (such as parental divorce) on nonshared (such as individual experience of abuse). Except for general cognitive ability, there is good evidence from twin studies that Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 262

9 Eur. Eat. Disorders Rev. 10, (2002) Comorbidity in Anorexia Nervosa psychopathology and personality are composed almost entirely of nonshared environment and genetic factors (Plomin, defries, McClearn, & McGuffin, 2000), with shared environment playing a minor role. It is thus important to focus on individual-specific environments in determining the risk factors which lead to psychiatric morbidity, and twins or siblings discordant for a disease or trait are a powerful approach to measuring this. Case control studies with unrelated controls cannot determine whether risk factors and behavioural associations are a result of shared environment, non-shared environment and/or genetic factors. Twin studies and model fitting have demonstrated that overall, shared family environment is not of major importance to the aetiology of eating disorders (Bulik, Sullivan, Wade, & Kendler, 2000b; Pike & Plomin, 1996; Plomin, Asbury, & Dunn, 2001), but are weak for AN because of lack of statistical power. Most recently, a twin-study in anorexic syndromes reported that additive genetic and non-shared environmental factors in the best-fitting model accounted for 74 and 26 per cent, respectively of the variance of broadly defined AN-syndromes (Klump, Miller, Keel, McGue, & Iacono, 2001). Twin studies also do not address whether risk factors such as pre-morbid depression and PDs, which are not unique to eating disorders, are shared or non-shared risk factors. Even obviously shared factors such as parental divorce affect children differently, and it is important to assess differences between siblings in this context. Strength of the study design It was Strober (1991) who recognized the value of a behavioural genetic approach for an aetiological model of AN integrating genetics, biology, and psychology and focusing on individual differences. The present study was designed to find individual-specific differences between sisters discordant for AN both before the onset and after the onset of the eating disorder, since these factors will be important in triggering and maintaining the state of disease. We specifically focused on individual differences in psychiatric comorbidity and temperamental and character traits between the two sisters discordant for AN. The use of agedisplaced sister-pairs discordant for the outcome of interest is seen as powerful tool (Dick et al., 2000) (a) to replicate associations of AN and behavioural risk factors seen in between-family studies in a withinfamily design, i.e. examining whether the risk factors and related traits are individual-specific or partly shared familial factors present also in sisters without an eating disorder; (b) to clarify associations for uncommon disorders such as AN, where even large twin registries cannot provide enough power for risk-factor analyses (Bulik et al., Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 263

10 A. Karwautz et al. Eur. Eat. Disorders Rev. 10, (2002) 2000b); and (c) to control for unmeasured potentially confounding variables like socioeconomic status, family structure, religious, and cultural values. Limitations of the study The study has several limitations. The primary investigator was not blind to the eating disorder diagnosis. However, there was good reliability of the ratings made by the blind assessor. Furthermore, a meta-analysis on assessment of PDs described only minor differences between blinded and unblinded ratings in eating disordered samples (Rosenvinge et al., 2000). A small proportion of subjects were interviewed by telephone. Although this limits access to non-verbal cues, studies have found that telephone interviews can be as reliable as face-to-face interviews in making axis-i and axis-ii diagnoses (Colombotos, 1969; Rhode, Lewinsohn, & Seeley, 1997). The sample size was too small to give definitive information about AN subtypes. Another limitation is the retrospective account of pre-morbid psychiatric morbidity, thus causing possible recall bias. However, Brewin, Andrews and Gotlib (1993) found retrospective data reliable when they were assessed via personal interviews and the items were behaviourally described. Furthermore, it remains unclear, whether personality traits are completely stable over time (e.g. before illness, during illness). However, there has been some evidence that IPDE ratings of personality are relatively stable over a 4-year period of time (Lenzenweger, 1999). The two sources of recruitment tapped into a broad spectrum of cases. The hospital sample has cases at the severe end of the spectrum as the South London and Maudsley NHS Trust is both a tertiary referral service as well as providing local services for the 2 million community in Southeast London. The volunteers were recruited from a variety of sources and this group had a broad range of severity and utilization of services. Comparison with previous work on premorbid morbidity and axis-i comorbidity We found that the women with AN had higher rates of mood disorders, in particular major depressive episodes before the age at which AN developed. Also the lifetime occurrence of mood disorders (in particular recurrent major depressive episodes, dysthymia, and DEPNOS) was significantly higher in the AN group. The percentages found are in line with the literature reporting approximately one-third of patients with AN having a mood disorder prior to onset (Braun et al., 1994; Fairburn Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 264

11 Eur. Eat. Disorders Rev. 10, (2002) Comorbidity in Anorexia Nervosa et al., 1999; Gillberg et al., 1995; Karwautz et al., 2001a). The lifetime prevalence rate of mood disorders we found is within the range reported in several other studies which report rates between 36 and 82 per cent (Braun et al., 1994; Halmi et al., 1991; Herzog et al., 1992). Anxiety disorders tended to be more common in the patient group and substance-related disorders were rarely found in the sister-pairs studied. There is little information on the premorbid occurrence of anxiety disorders although in those comorbid for social phobia, the anxiety disorder preceded onset in 79 and 90 per cent of cases respectively (Braun et al., 1994; Bulik et al., 1997). The lifetime prevalence rate of anxiety disorders given in the literature lies between 20 and 60 per cent (Braun et al., 1994; Bulik et al., 1997; Herzog et al., 1992), and that of substance use disorders between 0 and 36 per cent (Braun et al., 1994; Herzog et al., 1992). Our data is in keeping with these rates. Comparison with previous work on axis-ii comorbidity Personality disorders (especially those in cluster C) were significantly more prevalent in the patient group. The rates and the distribution found in our sample is in keeping with the literature which reports that between 22 and 80 per cent of patients with AN also fulfil the criteria for a personality disorder (PD) (average proportion of any PD in AN: 0.50 according to Inceoglu, Franzen, Backmund, & Gerlinghoff, 2000; Rosenvinge et al., 2000). The average proportion of cluster C PDs in AN according to the meta-analysis is 0.45 (Rosenvinge et al., 2000), thus dominating in AN. In particular, the frequency of anankastic PD, which we found to be the most common of the PDs in our sample, lies within the range of 10 and 60 per cent for restricting AN patients (Rastam & Gillberg, 1992; Wonderlich et al., 1990). These PDs (and/or the traits that underpin them) may precede onset (Gillberg et al., 1995) and persist after recovery (Gillberg et al., 1995; Halmi et al., 1991; Srinivasagam et al., 1995; Wentz-Nilsson, Gillberg, Gillberg, & Rastam, 1999). Indeed it has been suggested that anankastic PD may be the broader phenotype that is present in the families of people with an eating disorder (Lilenfeld et al., 1998). Comparison with previous work on temperament, character, and personality traits It was Strober (1991) who first integrated the organismic approach to temperament by Cloninger into a model of aetiology for AN focusing on self-development (Karwautz et al., 2001b). In terms of these dimensions Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 265

12 A. Karwautz et al. Eur. Eat. Disorders Rev. 10, (2002) of personality (temperament and character) the women with AN differed markedly from their sisters, scoring lower in novelty seeking, self-directedness, and cooperativeness, and higher in harm avoidance, persistence, and self-transcendence and higher in all the dimensions of the EDI-2. The data on temperamental traits are fairly consistent over the existing studies and our data (most recently: Diaz-Marsa, Carrasco, & Saiz, 2000; Klump et al., 2000; The Price Foundation Collaborative Group, 2001). Women with AN consistently have high scores for harm avoidance and persistence. After recovery, harm avoidance remains high (Casper, 1990; Kleifield, Sunday, Hurt, & Halmi, 1994) and novelty seeking remains low (Casper, 1990). To our knowledge, data on the character dimensions of personality (measured by TCI ratings) has been reported in AN in detail in only two studies, showing high harm avoidance and low self-directedness being associated with chronicity, and high self-directedness and high cooperativeness scores with full recovery (Bulik, Sullivan, Fear, & Pickering, 2000a; Klump et al., 2000). Overall the differences we found between AN patients and their noneating disordered sisters are similar to those of other published samples comparing AN patients and unrelated controls in terms of clinical and demographic features, axis-i, axis-ii comorbidity, temperamental, and character traits, thus replicating by and large the findings of studies using between-family designs. What has this study comparing patients and their sisters added to the knowledge derived from case control studies assessing differences between patients and unrelated controls? (1) Our study suggests that the differences found in morbidity prior to onset are non-shared rather than shared risk factors. The premorbid and comorbid disorders we found would be encompased in Fairburns domain of personal vulnerability (Fairburn et al., 1999). (2) Our study suggests further, that the lifetime occurrence of comorbid psychiatric disorders are non-shared markers of disease, which may contribute to the maintenance of AN. (3) Concerning PDs and personality traits, and given their relative stability (Lenzenweger, 1999), our study suggests the non-shared nature of those disorders and traits as factors of personal vulnerability. (4) The use of healthy sisters as controls meant that many cultural and family factors were accurately matched as studies using unrelated case control samples are by definition not able to distinguish whether the vulnerability factors are shared or individual-specific factors (Dick et al., 2000). Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 266

13 Eur. Eat. Disorders Rev. 10, (2002) Comorbidity in Anorexia Nervosa Further research One major implication of this study is that mood disorders and temperament and character traits are linked to the development of AN and are not-shared factors. From the present data it is uncertain to what extent these risk factors arise both from a general genetic predisposition to psychopathology and from non-shared events. In support of a pleiotropic genetic factor (i.e. one which increases general risk of psychiatric illness) is the finding that there is an overlap of the heritability between AN and depression (Wade, Bulik, Neale, & Kendler, 2000). ACKNOWLEDGEMENTS We are grateful to all sufferers and their sisters for volunteering for this study and to Ms Joyce Ballantyne for giving financial support. This study was supported in part by an Erwin Schrödinger Fellowship (J-1608-MED, 1998) from the Austrian Science Foundation, Vienna, Austria, a grant from the University of Vienna, Austria, a grant from the Austrian Ministry of Science to AK, a grant from Action Research and a grant from European Community Framework V (QLK ) to AK, DAC, and JLT. REFERENCES Braun, D. L., Sunday, S. R., & Halmi, K. A. (1994). Psychiatric comorbidity in patients with eating disorders. Psychological Medicine, 24, Brewin, C. R., Andrews, B., & Gotlib, I. H. (1993). Psychopathology and early experience: a reappraisal of retrospective reports. Psychological Bulletin, 113, Bulik, C. M., Sullivan, P. F., Fear, J. L., & Joyce, P. R. (1997). Eating disorders and antecendent anxiety disorders: a controlled study. Acta Psychiatrica Scandinavica, 96, Bulik, C. M., Sullivan, P. F., Fear, J. L., & Pickering, A. (2000a). Outcome of anorexia nervosa: eating attitudes, personality, and parental bonding. International Journal of Eating Disorders, 28, Bulik, C. M., Sullivan, P. F., Wade, T. D., & Kendler, K. S. (2000b). Twin studies of eating disorders: a review. International Journal of Eating Disorders, 27, Casper, R. C. (1990). Personality features of women with good outcome from restricting anorexia nervosa. Psychosomatic Medicine, 52, Cloninger, C. R., Przybeck, T. R., Svrakic, D. M., & Wetzel, R. D. (1994). The Temperament and Character Inventory (TCI): a guide to its development Copyright # 2002 John Wiley & Sons, Ltd and Eating Disorders Association. 267

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