Manfred M. Fichter

Evidence for a Susceptibility Gene for Anorexia Nervosa on Chromosome 1

Eating disorders, such as anorexia nervosa (AN), have a significant genetic component. In the current study, a genomewide linkage analysis of 192 families with at least one affected relative pair with AN and related eating disorders, including bulimia nervosa, was performed, resulting in only modest evidence for linkage, with the highest nonparametric linkage (NPL) score, 1.80, at marker D4S2367 on chromosome 4. Since the reduction of sample heterogeneity would increase power to detect linkage, we performed linkage analysis in a subset (n=37) of families in which at least two affected relatives had diagnoses of restricting AN, a clinically defined subtype of AN characterized by severe limitation of food intake without the presence of binge-eating or purging behavior. When we limited the linkage analysis to this clinically more homogeneous subgroup, the highest multipoint NPL score observed was 3.03, at marker D1S3721 on chromosome 1p. The genotyping of additional markers in this region led to a peak multipoint NPL score of 3.45, thereby providing suggestive evidence for the presence of an AN-susceptibility locus on chromosome 1p.

Structured Interview for Anorexic and Bulimic disorders for DSM-IV and ICD-10: updated (third) revision.

OBJECTIVES Earlier versions of the Structured Interview for Anorexic and Bulimic Disorders (SIAB) were modified in order to include new research findings and to update the expert rating interview to the diagnostic criteria of DSM-IV and ICD-10. The semistandardized interview was developed for reliable and valid assessment of the specific as well as the general psychopathology of eating disorders. METHOD Data from SIAB-EX interviews (current and past/lifetime symptom expression) were available from three samples: (a) 330 eating-disordered patients assessed at the start of treatment, (b) 148 former eating-disordered patients with anorexia nervosa (AN) or bulimia nervosa (BN) assessed at follow-up, and (c) 111 community controls. Sixty-one of the 87 items of the SIAB-EX with a 5-point scale were factor analyzed. RESULTS Principal components analyses with varimax rotation produced the following six components of the SIAB-EX (lifetime): (I) Body Image and Slimness Ideal; (II) General Psychopathology; (III) Sexuality and Social Integration; (IV) Bulimic Symptoms; (V) Measures to Counteract Weight Gain, Fasting, and Substance Abuse; and (VI) Atypical Binges. The factor solution for the current symptom expression was very similar to that based on lifetime symptom expression. Average item and factor scores are given for six groups of eating-disordered patients and controls. High interrater reliability was established for both current and the past symptom expression. Cronbachs alpha coefficients indicated good internal consistency for five of the six components of the SIAB-EX. DSM-IV and ICD-10 diagnoses for eating disorders can be derived directly or by using a computer algorithm from the SIAB-EX. A detailed 90-page manual facilitates the training of interviewers. CONCLUSION The 87-item SIAB-EX was originally developed for detailed assessment of eating disorders cross-sectionally and longitudinally. The updated version which allows for diagnosis according to DSM-IV and ICD-10 is described here.

Temperament and character in women with anorexia nervosa

The present study examined temperament differences among anorexia nervosa (AN) subtypes and community controls, as well as the effect of body weight on personality traits in women with AN. Temperament and Character Inventory (TCI) scores were compared between 146 women with restrictor-type AN (RAN), 117 women with purging-type AN (PAN), 60 women with binge/purge-type AN (BAN), and 827 community control women (CW) obtained from an archival normative database. Women with AN scored significantly higher on harm avoidance and significantly lower on cooperativeness than CW. Subtype analyses revealed that women with RAN and PAN reported the lowest novelty seeking, RAN women the highest persistence and self-directedness, and PAN women the highest harm avoidance. Body mass index had a nominal effect on subgroup differences, suggesting that personality disturbances are independent of body weight. Findings suggest that certain facets of temperament differ markedly between women with AN, regardless of diagnostic subtype, and controls. More subtle temperament and character differences that were independent of body weight emerged that distinguish among subtypes of AN.

Six-year course and outcome of anorexia nervosa.

OBJECTIVE Since there are discrepant findings in the literature, we studied the longer-term course in a large sample of 103 DSM-IV anorexia nervosa (AN) patients. METHOD Assessments were made at four points of time: beginning of therapy, end of therapy, 2-year follow-up, and 6-year follow-up. Self-rating scales as well as expert-rating interview data were used. Eating disorder-specific and general psychopathology were assessed. These data were also compared with data on the 6-year course of patients with bulimia nervosa and binge eating disorder, respectively, who were treated at the same institution at about the same time. RESULTS The participation rate at the two follow-ups was high (97.9% of those alive). The general pattern of results over time of those alive at 6-year follow-up was as follows: substantial improvement during therapy, moderate (in many instances nonsignificant) decline during the first 2 years posttreatment, and further improvement from 3 to 6 years posttreatment. At the time of the 6-year follow-up, 26.8% had AN, 9. 9% had bulimia nervosa-purging type (BN-P), 2.0% were classified as eating disorder not otherwise specified (ED-NOS), all diagnosed according to DSM-IV criteria; more than one half (55.4%) showed no major DSM-IV eating disorder. Based on an operationalized global outcome score at 6-year follow-up, 34.7% had a good outcome, 38.6% an intermediate outcome, 20.8% a poor outcome, and 6 of 101 persons (5.9%) were deceased. Body mass index was 17.9 +/- 2.8 at the 6-year follow-up; amenorrhea was still found in 23.9%. DISCUSSION In comparison to samples with bulimia nervosa or binge eating disorder, the 6-year course of anorexia nervosa was less favorable. Mortality was rather high and symptomatic recovery protracted; predictors of unfavorable 6-year course were the presence of binges during 4 weeks before index treatment, psychiatric comorbidity, and low body weight at discharge from index treatment.

Twelve-year course and outcome of bulimia nervosa

BACKGROUND Since little is known about the long-term course and outcome of bulimia nervosa, the authors designed a 12-year prospective longitudinal study with five cross-sectional assessments based on a large sample of consecutively treated females with bulimia nervosa (purging type) (BN-P). METHOD One hundred and ninety-six females with BN-P were assessed (1) at the beginning of treatment, (2) at the end of treatment, (3) at 2-year follow-up, (4) at 6-year follow-up, and (5) at 12-year follow-up. In self-ratings as well as expert ratings based on interviews we assessed specific eating-disorder and general psychopathology. RESULTS The general pattern of results over time showed substantial improvement during treatment, slight (in most cases non-significant) decline during the first two years after the end of treatment, and further improvement and stabilization until 12-year follow-up. At that point the majority of patients (70.1 %) showed no major DSM-IV eating disorder, 13.2% had eating disorders not otherwise specified, 10.1 % had BN-P and 2% had died. Very few had undergone transition to anorexia nervosa or binge-eating disorders. Logistic regression analyses showed that psychiatric co-morbidity was the best and most stable predictor for eating-disorder outcome at 2, 6 and 12 years. CONCLUSIONS Course and outcome of BN-P was generally more favourable than for anorexia nervosa.

Weight loss causes neuroendocrine disturbances: experimental study in healthy starving subjects

A variety of endocrine dysfunctions have been reported for anorexia nervosa, protein caloric malnutrition, and depression. The effect of reduced caloric intake and weight loss on endocrine functions was assessed in an experiment with five healthy female subjects during an initial baseline phase, a 3-week phase of complete food abstinence, weight gain to the original level, and a final baseline phase. During fasting, disturbances in hypothalamic-pituitary-adrenal function were observed, with elevated plasma cortisol levels, increase in the number of secretory episodes, increase in cortisol plasma half-life, and insufficient suppression following 1.5 mg dexamethasone. While all dexamethasone suppression tests (DSTs) were normal at baseline, 7 of 14 DSTs showed insufficient suppression in the fasting phase. During fasting, basal thyroid-stimulating hormone (TSH) values were lowered and the TSH response to thyrotropin-releasing hormone (TRH) was blunted. The plasma level of growth hormone (GH) over 24 hours was elevated during fasting and administration of the alpha 2-adrenergic receptor agonist clonidine resulted in a subnormal GH response after restoration of original body weight. One of the five subjects showed increased irritability, distress, anxiety, and depression as measured by various psychological scales. The results show that reduced caloric intake, weight loss, or catabolic state have powerful effects on several endocrine systems. The specificity of measures of endocrine disturbances (DST, TRH tests, and clonidine tests) as biological markers for certain types of depression must be questioned, and the metabolic state should be given more consideration in future studies.

A controlled treatment study of somatoform disorders including analysis of healthcare utilization and cost-effectiveness

OBJECTIVE The purpose of this prospective study was to evaluate the effects of cognitive-behavioral treatment (CBT) on mental health status and healthcare utilization in patients with somatoform disorders (SFD) of a specialized tertiary care center. METHODS According to DSM-IV interviews, 54 patients had somatization disorder (SD), 51 abridged somatization syndrome (SSI-8) and 67 other defined SFD. A clinical non-SFD comparison group consisted of 123 patients. Treatment effects were controlled against the waiting list. Cost calculations for the 2-year periods before and after treatment were based on medical and billing records from health insurance companies. RESULTS The SFD patients improved significantly with respect to physical symptom distress, health anxieties, dysfunctional beliefs towards body and health, depression and psychosocial functioning. Their outpatient plus inpatient charges during the 2 years prior to treatment were about 2.2-fold higher than for average patients of the health system. At the 2-year follow-up, we found treatment-related cost offset of 382 (-24.5%) for outpatient and 1098 (-36.7%) for inpatient care. Indirect socioeconomic costs due to days lost from work decreased by 6702 (-35.3%). Per patient savings of 32,174 (-63.9%) were found in a subgroup of somatizing high-utilizers. CONCLUSION The results encourage including treatment strategies to reduce somatoform illness behavior into clinical practice.

Significant Linkage on Chromosome 10p in Families with Bulimia Nervosa

Bulimia nervosa (BN) is strongly familial, and additive genetic effects appear to contribute substantially to the observed familiality. In turn, behavioral components of BN, such as self-induced vomiting, are reliably measured and heritable. To identify regions of the genome harboring genetic variants conferring susceptibility to BN, we conducted a linkage analysis of multiplex families with eating disorders that were identified through a proband with BN. Linkage analysis of the entire sample of 308 families yielded a double peak, with the highest nonparametric multipoint maximum LOD score (MLS), of 2.92, on chromosome 10. Given the high heritability of self-induced vomiting and the reliability with which it can be measured, we performed linkage analysis in a subset (n=133) of families in which at least two affected relatives reported a symptom pattern that included self-induced vomiting. The highest MLS (3.39) observed was on chromosome 10, between markers D10S1430 and D10S1423. These results provide evidence of the presence of a susceptibility locus for BN on chromosome 10p. Using simulations, we demonstrate that both of these scores, 2.92 and 3.39, meet the widely accepted criterion for genomewide significance. Another region on 14q meets the criterion for genomewide suggestive linkage, with MLSs of 1.97 (full sample) and 1.75 (subset) at 62 centimorgans from p-ter.

A search for susceptibility loci for anorexia nervosa: methods and sample description

BACKGROUND Eating disorders have not traditionally been viewed as heritable illnesses; however, recent family and twin studies lend credence to the potential role of genetic transmission. The Price Foundation funded an international, multisite study to identify genetic factors contributing to the pathogenesis of anorexia nervosa (AN) by recruiting affective relative pairs. This article is an overview of study methods and the clinical characteristics of the sample. METHODS All probands met modified DSM-IV criteria for AN; all affected first, second, and third degree relatives met DSM-IV criteria for AN, bulimia nervosa (BN), or eating disorder not otherwise specified (NOS). Probands and affected relatives were assessed diagnostically with the Structured Interview for Anorexia and Bulimia. DNA was collected from probands, affected relatives and a subset of their biological parents. RESULTS Assessments were obtained from 196 probands and 237 affected relatives, over 98% of whom are of Caucasian ancestry. Overall, there were 229 relative pairs who were informative for linkage analysis. Of the proband-relative pairs, 63% were AN-AN, 20% were AN-BN, and 16% were AN-NOS. For family-based association analyses, DNA has been collected from both biological parents of 159 eating-disordered subjects. Few significant differences in demographic characteristics were found between proband and relative groups. CONCLUSIONS The present study represents the first large-scale molecular genetic investigation of AN. Our successful recruitment of over 500 subjects, consisting of affected probands, affected relatives, and their biological parents, will provide the basis to investigate genetic transmission of eating disorders via a genome scan and assessment of candidate genes.

Association of multiple DRD2 polymorphisms with anorexia nervosa.

To investigate whether the dopaminergic system plays a role in the etiology of anorexia nervosa (AN) via the dopamine D2 receptor, we investigated association and transmission disequilibrium at seven single-nucleotide polymorphisms (SNPs) spanning about 75 kbp of the gene DRD2. We studied 191 probands with a DSM-IV diagnosis of AN, 457 parents and affected relatives with a DSM-IV eating disorder diagnosis, and 98 unrelated, female, normal weight controls. The −141 C/− insertion/deletion (−141 Indel), previously shown to affect DRD2 transcription efficiency, and multiple exon seven polymorphisms, one of which has previously been shown to affect DRD2 transcript stability, exhibited statistically significant association with diagnosis in haplotype transmission disequilibrium and in haplotype case : control analyses. Significant linkage disequilibrium between the −141 Indel and two exon seven SNPs (939Y and 957Y) was observed over a distance of >50 kbp in the AN probands but not in the controls. Genetically transmitted variation in D2 dopamine receptor expression mediated by functional polymorphisms affecting transcription and translation efficiency may play a role in vulnerability to AN.