Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.

[Internet-based approaches in the therapy of eating disorders]. / Internetbasierte Ansätze in der Therapie von Essstörungen.

Recent technological developments of communication media offer new approaches to diagnostic and therapeutic interactions with patients. One major development is Internet-based primary prevention in vulnerable individuals not yet suffering as well as the development of new therapeutic approaches for affected individuals based on the experiences of guided self-help through CD, DVD or bibliotherapy. The eating disorder literature shows several interesting, partly controlled and randomized, studies on bulimia nervosa, a few studies on binge eating disorder and no studies on anorexia nervosa. As part of the German Eating Disorder Network on Psychotherapy (EDNET) a 9-month Internet-based relapse prevention program for patients with anorexia nervosa after inpatient treatment was evaluated. Conception, first experiences and first results of the Internet-based relapse prevention program for anorexia nervosa are reported.

Twenty-five-year course and outcome in anxiety and depression in the Upper Bavarian Longitudinal Community Study.

OBJECTIVE: Assessment of 25-year course of pure and mixed anxiety and depression in a community sample. METHOD: Participants were grouped into pure anxiety, pure depression, mixed anxiety and depression, and no anxiety or depressive syndrome at baseline. Assessments consisted of a: i) baseline survey, ii) 5-year follow-up, iii) 25-year follow-up. Self-rating scales as well as expert-rating interviews yielded data on social and psychopathological risk factors and outcome measures. RESULTS: Baseline prevalence for mixed anxiety and depressive syndrome was 8.7%. Subjects with combined anxiety and depressive syndrome were more predisposed towards later adverse mental health outcomes and reduced functionality. The transition from anxiety syndrome (pure and mixed) to depressive syndrome over the 25-year study is more likely than the reverse. Logistic regression analysis emphasized the impact of early anxiety syndromes on later depression. CONCLUSION: Results underscore the long-term risks of suffering from a combined anxiety and depressive syndrome.

Is season of birth related to disordered eating and personality in women with eating disorders?

We assessed the relation between season of birth and eating disorder symptoms and personality characteristics in a sample of 880 women with eating disorders and 580 controls from two Price Foundation Studies. Eating disorder symptoms were assessed using the Structured Interview of Anorexic and Bulimic Disorders and the Structured Clinical Interview for DSM-IV. Personality traits were assessed using the Temperament and Character Inventory and the Frost Multidimensional Perfectionism Scale. Date of birth was obtained from a sociodemographic questionnaire. No significant differences were observed 1) in season of birth across eating disorder subtypes and controls; nor 2) for any clinical or personality variables and season of birth. We found no evidence of season of birth variation in eating disorders symptoms or personality traits. Contributing to previous conflicting findings, the present results do not support a season of birth hypothesis for eating disorders.

Gonadotropin secretion in bulimia nervosa.

Twenty-two normal weight women with bulimia nervosa (BN) were studied (mean age, 25 +/- 5 yr; body mass index, 20.2 +/- 2.6 kg/m2). Sixteen of them reported menstrual cycles in the range of 21-42 days, and 6 had experienced absence of menstruation for at least 3 months. Twenty-one healthy women with regular menstrual cycles (mean age, 23 +/- 2 yr; body mass index, 20.7 +/- 1.4) served as the control subjects. Frequent morning blood samples for estradiol (E2) and progesterone (P4) determinations were obtained for the duration of 1 menstrual cycle or for 6 weeks in the case of amenorrhea. LH, FSH, cortisol, and insulin secretion were studied on day 3, 4, or 5 after the onset of a menstrual cycle or on a random day in the 6 BN women with amenorrhea. Blood samples were collected at 15-min intervals from 1800-0600 h for LH and FSH and at 30-min intervals from 2400-0600 h for cortisol and insulin. Nineteen of the 21 controls, but only 10 of the 22 BN women, fulfilled the following standard criteria: maximum E2 above 440 pmol/L, maximum P4 above 19 nmol/L, and luteal phase length of 9 days or more. The 10 BN women with normal menstrual cycles had lower mean insulin concentrations than the controls (70 +/- 20 vs. 120 +/- 30 pmol/L; P less than 0.01), but gonadotropin secretion, cortisol, and T3 concentrations were similar. The 8 BN women with amenorrhea or ovulatory dysfunction (maximum E2, less than 440 pmol/L; maximum P4, less than 6 nmol/L) displayed decreased mean LH pulse frequency (2.6 +/- 2.4 vs. 5.7 +/- 2.0 pulses/12 h; P less than 0.01), increased mean cortisol (120 +/- 40 vs. 80 +/- 20 nmol/L; P less than 0.01), decreased mean insulin (90 +/- 40 vs. 120 +/- 30 pmol/L; P less than 0.05), and decreased mean T3 concentrations (1.5 +/- 0.3 vs. 1.8 +/- 0.2 nmol/L; P less than 0.01). The data suggest that BN in normal weight women is associated with an increased rate of ovarian dysfunction; decreased pulsatile LH secretion seems to be an important mechanism. Increased cortisol in the disturbed subgroup indicates that activation of the hypothalamic-pituitary-adrenal axis may play a role in the pathogenesis of gonadal dysfunction in bulimia nervosa.

Disturbances in the hypothalamo-pituitary-adrenal and other neuroendocrine axes in bulimia.

Disturbances in the hypothalamo-pituitary-adrenal (HPA) and other endocrine axes were assessed in 24 women with bulimia and healthy controls. Overnight blood samples for measuring nocturnal plasma cortisol, prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and follicle stimulating hormone (FSH) were obtained at 30-min intervals. A 1.5 mg dexamethasone suppression test (DST) and a TRH-test were performed. Patients were monitored closely while their nutritional intake was recorded over 21 days. Compared with healthy controls, nocturnal cortisol plasma levels were not elevated in the bulimics. There was a trend toward insufficient cortisol suppression in the DST in patients with bulimia, which was most pronounced in patients with signs of restricted caloric intake. Plasma dexamethasone levels were significantly reduced in bulimics compared with healthy controls. There was a trend for blunted thyrotropin stimulating hormone (TSH) responses to thyrotropin releasing hormone (TRH) in bulimia. The prolactin response to TRH was significantly reduced in bulimics with a history of anorexia nervosa. Plasma LH and plasma FSH were significantly reduced in bulimics with signs of reduced caloric intake [low T3, high levels of beta-hydroxy-butyric acid (BHBA), reduced daily caloric intake, high number of fasting days] as compared with healthy controls. Bulimics with high BHBA levels had significantly reduced nocturnal prolactin plasma levels. Results show that multiple neuroendocrine disturbances exist in bulimia in a milder form than in anorexia nervosa. Evidence for the impact of caloric intake on endocrine functions is presented. Endocrine dysfunctions in our bulimic sample did not show a positive association with the presence of depressive symptoms.

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.

Effect of experimental and pathological weight loss upon the hypothalamo-pituitary-adrenal axis.

Five healthy female subjects participated in a starvation experiment. After an initial baseline phase (A) they lost about 8 kg in a 3-week phase of complete food abstinence (B); thereafter they recovered to their original body weight (C) and kept this weight stable over more than 4 weeks (D). While all dexamethasone suppression tests (DST's) during the initial baseline were normal, half of the DST's (7/14) in the fasting phase showed insufficient suppression. In the following weight gain phase, all DST's were sufficiently suppressed. Twenty-four hour plasma cortisol patterns during fasting (B) showed a significant increase, as well as increased cortisol half-life, increased time in secretory activity, and increased number of secretory episodes. Administration of the alpha 2-adrenergic receptor agonist clonidine during fasting did not induce a further decrease in plasma cortisol level, whereas it did during baseline. The results demonstrate that weight loss, reduced caloric intake, and catabolic state have a very powerful influence on the hypothalamo-pituitary-adrenal (HPA) axis and other endocrine systems. The results shed new light on endocrine dysfunctions in mental disorders associated with reduced caloric intake, such as anorexia nervosa and depression, and question the specificity of certain endocrine dysfunctions for depression.

Cortisol levels and vigilance in eating disorder patients.

Elevated plasma levels of cortisol, as well as deficits in cognitive processes such as attention, have been observed in patients with eating disorders. The association between plasma cortisol and performance in vigilance task was studied in 17 patients with bulimia nervosa or anorexia nervosa during the acute phase of their eating disorder. In comparison to normal young women, the patients had a significantly lower hit rate in a discrimination task and showed an impaired perceptual sensitivity index. They also displayed significantly longer reaction times to hits, but not to false alarms. Cortisol levels of the patients were significantly higher than those of the normal controls. When patients were divided according to their median cortisol level, the patients with higher levels performed significantly more poorly than did the patients with lower levels. In the total patient sample, cortisol levels showed a significant negative correlation with hit-rate (r = -.54) and a significant positive correlation with reaction time to hits (r = .70). Other clinical characteristics were not related to cognitive performance. These results suggest a possible role of cortisol in the development of attentional deficits in eating disorder patients.

Circadian pattern of large neutral amino acids, glucose, insulin, and food intake in anorexia nervosa and bulimia nervosa.

Insulin, glucose, and large neutral amino acids (LNAA) were studied in 10 patients with anorexia nervosa, 13 patients with bulimia nervosa, and 15 healthy controls. Blood samples were collected at hourly intervals during the day and at two-hour intervals during the night over a 24-hour period. Ad libitum caloric and relative carbohydrate intake was significantly reduced in the anorectic and bulimic patients. Elevated concentrations of beta-hydroxybutyric acid (BHBA) were seen in the bulimic group, and low triiodothyronine (T3) concentrations in the anorectic group. Mean plasma glucose and insulin concentrations were significantly lowered in both groups. The tryptophan (Trp) to LNAA ratio was reduced in anorectic, but not in bulimic patients. These findings suggest that Trp influx into the brain is reduced in anorectic patients, possibly impairing central serotonergic function.

Anorexic syndromes in the male.

Forty-two male patients with an anorexic syndrome were assessed personally (n = 29) or by reviewing the case-notes. Twenty-nine male patients were classified as primary anorexia nervosa and they were compared to our series of atypical male patients and a series of 23 female anorexia nervosa patients. There was no difference between male and female patients in the age at onset. Male and female anorexia nervosa cases were very similar in their personality profile and symptomatology; however, male cases were more preoccupied in their thoughts with food, weight etc., and showed more hyperactivity, more achievement orientation and more sexual anxiety than female cases. The mothers' age at the male patients' birth was significantly younger than in the female group. Male anorexia nervosa patients were more extraverted and scored "superfeminine" on the masculinity vs feminity scale (FPI). A continuum from "true" anorexia nervosa to atypical cases and to secondary loss of appetite was observed.

The DSM-IV nosology of chronic pain: a comparison of pain disorder and multiple somatization syndrome.

This study evaluates the classification of pain from the perspective of the DSM-IV system. Of 60 in-patients with long-standing and disabling pain syndromes, 29 with pain disorder (PD) and 31 with pain as part of a multiple somatization syndrome (MSS) were compared before and after a structured cognitive-behavioral treatment. It was hypothesized that MSS patients show more psychological distress, are more severely disabled, and respond less to the treatment. Both groups were similar with respect to sociodemographic status, history of pain symptomatology and comorbidity with DSM-IV mental disorders. The results show that MSS patients had higher levels of affective and sensoric pain sensations as well as more pain-related disabilities. They were also less successful during treatment to reduce their pain-related depression and anxiety. Psychosocial functioning was improved only by PD patients, but remained almost unchanged in the MSS group. However, there were no group differences concerning general depression and hypochondriasis, dysfunctional attitudes towards body and health, and use of pain coping strategies. It is concluded that the DSM-IV distinction between 'pure' pain disorder and syndromes involving pain plus multiple somatoform symptoms cannot generally be confirmed, but further studies of validation are needed.

Effects on mortality of alcohol consumption, smoking, physical activity, and close personal relationships.

The study analyses the risks of mortality associated with alcohol consumption and smoking, as well as possible counteracting effects of physical activity and social support through close personal relationships. Data are based on the Upper Bavarian Study, a longitudinal epidemiological study of a representative community sample (n = 1668) in a rural area. Extensive semistructured psychiatric interviews by research physicians were conducted between 1975 and 1977 (n = 1536). Thirteen years after psychiatric assessment, information was obtained from the community register concerning death in the interval, data of death and cause of death according to ICD 9. This information could be ascertained for 93.1% (n = 1430) of those who had been interviewed, thus providing a good basis for generalizing the findings. Results indicate that alcohol intake and cigarette smoking increased mortality while physical activity and the availability of a steady partner had protective effects. There were no interactive effects between the four variables studied, except for a dramatically increased risk for women drinking more than 20 ml of pure alcohol a day and reporting no physical exercise at wave one assessment. The relative risks of alcohol intake and smoking, and the counteracting effects of physical activity and partnership, are exemplified in the cases of a 40-year-old female and a 40-year-old male. Specific analyses of the relationship between alcohol consumption, smoking, physical exercise and personal relationships, on the one hand, and, on the other, different causes of death, are presented.

How disabled are patients with somatoform disorders?

The purpose of this study was to evaluate the level and quality of psychosocial disabilities in patients suffering from somatoform disorders (SFD). Of 221 patients referred for psychiatric and cognitive-behavioral inpatient treatment, 37 were diagnosed according to DSM-IV as having SFD, 56 as pain disorder, 70 met the criteria for the subsyndromal form of SFD called the "Somatic Symptom Index" (SSI). The control group consisted of 58 patients with other mental disorders. All patients completed the Dysfunctional Analysis Questionnaire (DAQ) which measures social, vocational, personal, familial, and cognitive disabilities on psychometric scales. The results showed substantial disabilities in all somatoform subgroups; however, the levels and patterns of dysfunction in these patients were not statistically different from those in the control group. Impairment was generally more severe when patients had a comorbidity of somatoform and affective disorders. It is concluded that SFDs are associated with marked psychosocial disabilities similar to those seen in other mental disorders. The strongest predictor for psychosocial dysfunction is the comorbidity of somatoform with affective disorders, but not with anxiety disorders.

Binge eating disorder: treatment outcome over a 6-year course.

Little is known about the long-term course of binge eating disorder (BED). The aim of the study was to assess the 3- and 6-year course and outcome of 68 consecutively treated females with BED. Their mean age was 29.3 years and they were assessed longitudinally at four timepoints: (1) beginning of therapy; (2) end of therapy; (3) 3-year follow-up; and (4) 6-year follow-up. Self rating as well as expert ratings were used for assessment. Symptoms of specific eating disorder as well as general psychopathology were measured. The general pattern of results over time was as follows: substantial improvement during therapy; slight (in most cases nonsignificant) decline during the first 3 years after the end of treatment, and further improvement and stabilization in years 4, 5, and 6 after the end of treatment. At the 6-year follow-up, the majority showed no major DSM-IV eating disorder, 5.9% had BED, 7.4% had shifted to bulimia nervosa (purging type) (DSM-IV), 7.4% were classified as ED-NOS, and one patient died. Based on an operationalized global outcome score for the complete sample, 57.4% had good outcome, 35.3% intermediate outcome, 5.9% poor outcome, and one person (1.4%) died. BED and BNP patients showed very similar intermediate and long-term course in self ratings as well as expert ratings.

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.

Maintenance of weight loss after obesity treatment: is continuous support necessary?

OBJECTIVE: This study examined outcome differences of 109 obese subjects, who participated in a 10-week cognitive-behavioral inpatient treatment followed by either a weight maintenance program or a follow-up period without professional support. METHODS: Self-rated weight loss, eating behaviors, and general psychopathology were assessed several months before treatment, when subjects were admitted, at discharge, and at the 6-, 12-, and 18-month follow-ups. Structured interviews for mental disorders and eating pathology were conducted additionally. RESULTS: The mean weight of the sample at baseline was 127 kg. Weight loss of the total sample amounted to 8.0 kg (6.3%) and was completely maintained during the follow-up period. Significant reductions of eating and general psychopathology were observed at the 18-month follow-up. The outcome in the maintenance condition did not significantly differ from the outcome in the control condition. CONCLUSIONS: Weight regain after obesity treatment is not inevitable, but continuous patient-therapist contacts do not distinctly improve treatment effects.

The role of the general practitioner in the care of mentally disturbed subjects in the general population--results of the Upper Bavarian Study.

The role of the general practitioner in the care of mentally disturbed non-institutionalised persons aged 20 years and older was examined. Data were based on the representative community sample of the Upper Bavarian Field Study with a sample size of 1495 interviewees--aged 20 years and older. The 5-year prevalence of mental illness according to the definition used was 32.8%. 38.5% of all persons, identified as cases, consulted their general practitioner because of psychiatric or emotional problems. Females and the elderly were most likely to have received treatment by their general practitioner. The majority of treated persons were neurotic and psychosomatic patients. The general practitioner provided care for more psychiatric patients than the psychiatrist and for 25% of all "cases", without additional psychiatric consultation.

Improving social interaction in chronic psychotic using discriminated avoidance ("nagging"): experimental analysis and generalization.

Three social-interaction behaviors of a withdrawn chronic schizophrenic were increased using a discriminated avoidance ("nagging") procedure. The three behaviors were: (a) voice volume loud enough so that two-thirds of his speech was intellibible at a distance of 3m; (b) duration of speech of at least 15 sec; (c) placement of hands and elbows on the armrests of the chair in which he was sitting. "Nagging" consisted of verbal prompts to improve performance when the behaviors did not meet their criteria. A combined withdrawal and multiple-baseline design was used to evaluate the effectiveness of the procedure, and the contingency was sequentially applied to each of the three behaviors in each of four different interactions to determine the degree of stimulus and response generalization. Results indicated that the contingency was the effective element in increasing the patient's appropriate performance, and that there was a high degree of stimulus generalization and a moderate degree of response generalization. After the patient's discharge from the hospital, the durability of improvement across time and setting was determined in followup sessions conducted at a day treatment center and at a residential care home. Volume and duration generalized well to the new settings, while arm placement extinguished immediately.

[Diagnosis and treatment of somatoform disorders (functional physical complaints)]. / Diagnostik und Behandlung somatoformer Störungen (funktioneller körperlicher Beschwerden).

In modern classification systems, unexplained physical symptoms without an organic origin are labelled "somatoform disorders". This syndrome is very frequent and causes a lot of treatment costs as well as indirect costs (such as workers' compensation and others). In the past, effective treatment strategies were lacking. However, consideration of modern scientific results has made it possible to develop treatment approaches which find the acceptance of the patients and which are highly effective. A hierarchical approach is presented suggesting the following steps: a) Primary care: The consideration of management rules in primary care can prevent the chronicity of somatoform symptoms. b) Brief psychological and psychopharmacological treatments: Modern cognitive-behavioural approaches can help to cope with the symptoms and to improve the subjective well-being. First results for pharmacological treatments are encouraging. c) Integrative inpatient treatment including intense psychotherapeutic and psychosomatic ingredients. Experts' judgements of course and prognosis in somatoform disorders should consider the following features: Duration and multiplicity of the complaints; comorbidity with other psychiatric and physical disorders; disability in different areas of life such as at work, family, leisure time; individual coping strategies; treatment approaches in the past.