Common Genetic Variation and Age of Onset of Anorexia Nervosa.

Background: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche. Methods: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h 2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.

Long-term outcome in males with anorexia nervosa: A prospective, sex-matched study.

OBJECTIVE: The objective of this study is to report on the 5.5-years outcome of anorexia nervosa (AN) in male adolescent inpatients and compare it to the outcome of female adolescent inpatients with AN. METHOD: Diagnostic eating disorder outcome was assessed by the Structured Inventory of Anorexic and Bulimic Syndromes (DSM-IV) in 20 males and 20 females matched for AN diagnosis, age at treatment, and length of follow-up. For documentation, follow-up scores of the Eating Disorder Inventory and the Brief Symptom Inventory are reported. RESULTS: Diagnostic outcome did not differ between sexes. Four male and six female participants had AN at follow-up. One male and four females had crossed to bulimia nervosa, and five males and three females to eating disorder not otherwise specified. Remission was found in 10 males and 7 females. Effect sizes were mostly small. At follow-up females had higher scores than males with large effect sizes for drive for thinness (Cohen's d = 0.86) and body dissatisfaction (d = 1.07). DISCUSSION: Few significant sex differences were found. Additional research involving larger samples of males and a broader range of assessed outcomes (e.g., drive for muscularity) in both sexes is urgently needed.

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

[Eating and feeding disorders : New developments]. / Ess- und Fütterstörungen : Neue Entwicklungen.

An overview of eating and feeding disorders according to the future criteria of the International Classification of Diseases (ICD-11) is presented, including information on differential diagnosis, epidemiology, etiology, pathogenesis as well as therapy. Binge-eating disorder is new and the most frequent eating disorder. While anorexia nervosa and bulimia nervosa mostly affect women, the gender ratio in binge-eating disorder is more balanced. Concerning etiology, socio-cultural, biological and psychological factors are discussed. Cognitive behavioral psychotherapy is the best-validated treatment for all three eating disorders. According to the German guidelines for treatment (2019), focal psychodynamic psychotherapy is also a treatment option for anorexia nervosa. Evidence for the positive effect of psychopharmacologic drugs in the treatment of anorexia nervosa is still lacking. Fluoxetine has been shown to have a limited effect in the treatment of bulimia nervosa.

How precisely can psychotherapists predict the long-term outcome of anorexia nervosa and bulimia nervosa at the end of inpatient treatment?

OBJECTIVE: To assess the ability of psychotherapists to predict the future outcome for inpatients with anorexia nervosa (AN) and bulimia nervosa (BN). METHOD: Psychotherapists rated the prognosis of the patient's eating disorder on a five point Likert scale on several dimensions at the end of inpatient treatment. Actual outcome was assessed about 10 years after treatment. The sample comprised 1,065 patients treated for AN, and 1,192 patients treated for BN. RESULTS: Psychotherapists' rating of their patient's prognosis was not better than chance for good outcome in AN and BN and for poor outcome in BN. Prediction of poor outcome in AN was somewhat better with approximately two thirds of correct predictions. In logistic regression analysis, psychotherapists' rating of the patients' prognosis for AN contributed to the explained variance of long-term outcome, increasing the variance explained from 7% (by conventional predictors) to 8% after including psychotherapists' prognosis. In BN, there was no significant contribution of psychotherapists' prognosis to overall prediction. DISCUSSION: Our current knowledge of risk and protective factors for the course of eating disorders is unsatisfying. More specialized research is urgently needed.

Mortality in males as compared to females treated for an eating disorder: a large prospective controlled study.

PURPOSE: To report on the mortality of DSM-IV eating disorders and predictors of premature death in males compared to females after inpatient treatment. METHODS: Crude mortality rate (CMR) and standardized mortality ratio (SMR) were computed for a large sample of males aged at treatment 16-61 years [N = 66 anorexia nervosa (AN), 52 bulimia nervosa (BN), 70 eating disorder not otherwise specified (ED-NOS)] and females aged 14-65 years (N = 2066 AN, 1880 BN, 1350 ED-NOS). In addition, a survival analysis and Cox regression analyses for identifying predictors of death were computed. RESULTS: CMRs for males and females, respectively, were 15% and 5% in AN, 8% and 3% in BN, and 4% and 3% in ED-NOS. Compared to the general population, mortality was elevated in males with AN (SMR = 4.93) and in all female diagnostic groups (AN, BN, ED-NOS). No significant sex differences for SMR emerged in any diagnostic group. Compared to females with AN or BN, males with AN or BN showed a shorter survival time after onset (survival analysis). Being male, and having AN, increased the risk of premature death. CONCLUSION: Mortality in inpatients with eating disorder is high, especially in AN. Males appear to have about the same outcome in terms of mortality as females with AN, BN, and ED-NOS. However, long-term survival was shorter in males with AN or BN compared to females. The need for intensive treatment in both males and females with an eating disorder remains an important issue. LEVEL OF EVIDENCE: Level III, case-control analytic study.

Long-term outcomes in treated males with anorexia nervosa and bulimia nervosa-A prospective, gender-matched study.

OBJECTIVE: We report on the long-term outcome of males compared to females treated for anorexia nervosa (AN) or bulimia nervosa (BN). METHODS: A total of 119 males with AN and 60 males with BN were reassessed 5.8 ± 4.6 and 7.5 ± 5.9 years (respectively) after treatment and compared to matched female patients. RESULTS: At follow-up, males with AN had a higher body weight than females. For AN, remission rates (40% males vs. 41% females) did not differ at follow-up. And at follow-up, more males (34%) than females (19%) had an eating disorder not otherwise specified (ED-NOS; p < .01). At follow-up of AN, there was no binge-eating disorder (BED) and obesity was rare. For BN, remission rates (44% males vs. 50% females) and frequency of AN, BN, BED and ED-NOS did not differ at follow-up. Males with AN scored lower than females at follow-up on most subscales of the Eating Disorder Inventory (EDI) and on somatization, obsessive-compulsive symptoms, and depression (Brief Symptom Inventory). Males with BN scored lower than females with BN on perfectionism and higher on interpersonal distrust (EDI) at follow-up. DISCUSSION: Results from the scarce literature on males with ED are inconclusive regarding longer term outcome. In the present study, males with AN showed a slightly better outcome than females. In BN, outcome was about the same in males and females. According to our study, existing treatment is equally effective in both males and females. Additional research on the need of gender-specific diagnosis and therapy is required.

Mortality in males treated for an eating disorder-A large prospective study.

OBJECTIVE: To report on the long-term mortality of eating disorders in male inpatients. METHOD: Crude mortality rates (CMR) and standardized mortality ratios (SMR) were computed for a large sample of males (147 anorexia nervosa [AN], 81 bulimia nervosa [BN], 110 eating disorder not otherwise specified [ED-NOS]; DSM-IV). In addition, a survival analysis from onset of eating disorder to death or end of observation was computed. RESULTS: CMR was 12.9% in AN, 11.1% in BN, and 6.4% in ED-NOS. Standardized mortality was significantly elevated in males with AN (SMR = 5.91; 95% confidence interval 3.56-9.23) as well as ED-NOS (SMR = 3.40; 95% confidence interval 1.37-7.01) but not in males with BN (SMR = 1.88; 95% confidence interval 0.86-3.58). Males with AN died sooner after onset of eating disorder than males with BN or ED-NOS. DISCUSSION: Mortality in male inpatients with eating disorder is high, especially in AN. There is need for developing more effective treatments to achieve better outcome.

Long-term outcome of inpatients with bulimia nervosa-Results from the Christina Barz Study.

OBJECTIVE: To assess the long-term outcome and identify outcome predictors in a very large sample of inpatients treated for bulimia nervosa (BN). METHOD: Out of a total of 2,033 patients admitted consecutively to specialized treatment, 1,351 patients (mean age at treatment 25.94) were assessed for follow-up on average 11 (SD 6) years after admission. Also a very long-term (21 years) subsample (N = 147; mean age 25.92) was defined. Bivariate and logistic regression analyses identified predictors of poor outcome. RESULTS: For more than 70% of the patients follow-up information could be gathered. Severity of eating disorder (ED) and other symptoms decreased over time but remained higher than in healthy controls, using published normative data. Remission rate was 38% after 11 years and 42% in the subsample after 21 years. Out of the total sample of N = 2,033 patients, 49 had died (2.4%). Persistent BN was found in 14.2% and the most frequent crossover was to ED not otherwise specified. Predictors of poor outcome were fewer follow-up years, higher drive for thinness, higher age at treatment, and less global functioning. DISCUSSION: Based on clinical indicators, patients presented with a high level of ED and psychiatric symptomatology. With less than half of the patients remitted after 22 years, efforts are needed to improve treatment outcome.

Associations between dimensions of anorexia nervosa and obsessive-compulsive disorder: An examination of personality and psychological factors in patients with anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are highly comorbid. However, the factors that account for this comorbidity are poorly understood. We examined the core dimensions of AN and OCD and psychological and personality factors shared by both disorders. METHOD: In path analyses (N = 732 women with either current AN or recovered from AN), we examined which factors were uniquely and independently associated with the core dimensions of AN and OCD. We also examined recovery from AN as a moderator. RESULTS: When individuals with AN reported greater concern over mistakes, they endorsed more severity in both AN and OCD core dimensions. These unique associations existed above and beyond all other transdiagnostic personality and psychological factors and regardless of AN recovery status. CONCLUSIONS: Concern over mistakes partially accounts for severity in the core dimensions of both AN and OCD. Concern over mistakes may represent an important target in the aetiology of AN and OCD.

Short- and long-term outcome of males treated for anorexia nervosa: a review of the literature.

PURPOSE: To give an overview of existing studies on the short- and long-term outcome for males treated for anorexia nervosa and to compare the outcome between adolescents and adults as well as between males and females. METHODS: A systematic literature search was conducted in PubMed, PsycINFO and PSYNDEX and complemented by a manual search of the references from all relevant studies. RESULTS: Out of 1064 search results, 18 studies met our inclusion criteria. A combined total of 1129 males of varying age groups were followed 0.5-27 years post-treatment. For 1009 individuals, only vital status was ascertained. Length of follow-up and outcome definitions varied considerably. Limited data-especially in adults-prevented adequate age comparisons. In both adolescents and adults outcome and mortality differed widely across studies with no firm evidence for gender differences. Outcome in mixed samples of adolescents and adults was inconsistent. Studies rarely compared the genders statistically, and when they did, the results were nonsignificant. CONCLUSIONS: Knowledge on the outcome of males treated for anorexia nervosa is scarce. Only few studies comprising insufficient numbers of males exist. Results based on these findings are inconclusive and in part contradicting. Further research is needed, including large sample sizes of reliably diagnosed males, adequate follow-up intervals, follow-up assessments with carefully defined outcome criteria, and comparisons to matched female patient samples. LEVEL OF EVIDENCE: Level I, Systematic review.

RCT of a Video-based Intervention Program for Caregivers of Patients with an Eating Disorder.

OBJECTIVE: This paper presents the results of a randomized controlled trial measuring the efficacy of a video-based skills training to decrease burden and psychological distress in caregivers of inpatients treated for an eating disorder in specialized hospital units. METHOD: Two hundred eighty-five caregivers were randomized to either the video intervention (N = 147) or the control group (N = 138). Caregivers' primary outcomes were assessed via Eating Disorder Symptom Impact Scale, Accommodation and Enabling Scale and General Health Questionnaire-12 at baseline and three-months follow-up. RESULTS: Acceptability of the intervention was high. Receiving additional external professional help like psychotherapy or clinical counselling was identified as a moderator contributing to the efficacy of the intervention. Caregivers' burden (Eating Disorder Symptom Impact Scale) and psychological distress (General Health Questionnaire-12) were reduced by the intervention but not caregivers' accommodating behaviours (Accommodation and Enabling Scale). CONCLUSION: The video training is a promising approach and effective supplement for caregivers of patients with an eating disorder. Additional professional help to caregivers increases the effectiveness of the intervention. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Set-shifting and its relation to clinical and personality variables in full recovery of anorexia nervosa.

OBJECTIVE: First, this study aimed to explore whether set-shifting is inefficient after full recovery of anorexia nervosa (recAN). Second, this study wanted to explore the relation of set-shifting to clinical and personality variables. METHOD: A total of 100 recAN women were compared with 100 healthy women. Set-shifting was assessed with Berg's Card Sorting Test. Expert interviews yielded assessments for the inclusion/exclusion criteria, self-ratings for clinical and personality variables. RESULTS: Compared with the healthy control group, the recAN participants achieved fewer categories, showed more perseverations and spent less time for shifting set. Perfectionism is correlated with set-shifting but in converse directions in the two groups. DISCUSSION: Our study supports the findings of inefficiencies in set-shifting after full recovery from AN. Higher perfectionism in the recAN group is associated with better set-shifting ability, whereas higher perfectionism in the healthy control group is related to worse set-shifting ability.

The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa.

OBJECTIVE: Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN. METHOD: Our sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems. RESULTS: There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018). DISCUSSION: To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders.

Primary amenorrhea in anorexia nervosa: impact on characteristic masculine and feminine traits.

Animal studies indicate that gonadal hormones at puberty have an effect on the development of masculine and feminine traits. However, it is unknown whether similar processes occur in humans. We examined whether women with anorexia nervosa (AN), who often experience primary amenorrhea, exhibit attenuated feminization in their psychological characteristics in adulthood due to the decrease/absence of gonadal hormones at puberty. Women with AN were compared on a number of psychological characteristics using general linear models on the basis of the presence/absence of primary amenorrhea. Although women with primary amenorrhea exhibited lower anxiety scores than those without primary amenorrhea, in general, results did not provide evidence of attenuated feminization in women with AN with primary amenorrhea. Future research should utilize novel techniques and direct hormone measurement to explore the effects of pubertal gonadal hormones on masculine and feminine traits.

Factors associated with recovery from anorexia nervosa.

Previous studies of prognostic factors of anorexia nervosa (AN) course and recovery have followed clinical populations after treatment discharge. This retrospective study examined the association between prognostic factors--eating disorder features, personality traits, and psychiatric comorbidity--and likelihood of recovery in a large sample of women with AN participating in a multi-site genetic study. The study included 680 women with AN. Recovery was defined as the offset of AN symptoms if the participant experienced at least one year without any eating disorder symptoms of low weight, dieting, binge eating, and inappropriate compensatory behaviors. Participants completed a structured interview about eating disorders features, psychiatric comorbidity, and self-report measures of personality. Survival analysis was applied to model time to recovery from AN. Cox regression models were used to fit associations between predictors and the probability of recovery. In the final model, likelihood of recovery was significantly predicted by the following prognostic factors: vomiting, impulsivity, and trait anxiety. Self-induced vomiting and greater trait anxiety were negative prognostic factors and predicted lower likelihood of recovery. Greater impulsivity was a positive prognostic factor and predicted greater likelihood of recovery. There was a significant interaction between impulsivity and time; the association between impulsivity and likelihood of recovery decreased as duration of AN increased. The anxiolytic function of some AN behaviors may impede recovery for individuals with greater trait anxiety.

Cholecystokinin revisited: CCK and the hunger trap in anorexia nervosa.

OBJECTIVE: Despite a number of studies in the past decades, the role of Cholecystokinin (CCK) in anorexia nervosa (AN) has remained uncertain. In this study a highly specific assay for the biologically active part of CCK was used in patients with bulimic as well as with the restricting type of AN who were followed over the course of weight gain. METHODS: Ten patients with restricting and 13 with bulimic AN were investigated upon admission (T0), after a weight gain of at least 2 kg on two consecutive weighting dates (T1), and during the last week before discharge (T2) from inpatient treatment in a specialized clinic. Blood samples were drawn under fasting conditions and 20 and 60 minutes following a standard meal (250 kcal). Data were compared to those of eight controls matched for sex and age. Gastrointestinal complaints of patients were measured by a questionnaire at each of the follow-up time points. RESULTS: At admission, AN patients exhibited CCK-levels similar to controls both prior to and after a test meal. Pre and post-meal CCK levels increased significantly after an initial weight gain but decreased again with further weight improvement. CCK release was somewhat lower in bulimic than in restricting type AN but both subgroups showed a similar profile. There was no significant association of CCK release to either initial weight or BMI, or their changes, but CCK levels at admission predicted gastrointestinal symptom improvement during therapy. CONCLUSIONS: Normal CCK profiles in AN at admission indicates hormonal responses adapted to low food intake while change of eating habits and weight gain results in initially increased CCK release (counteracting the attempts to alter eating behavior) that returns towards normal levels with continuous therapy.

Central coherence in full recovery of anorexia nervosa.

OBJECTIVE: This study examined central coherence as a possible endophenotype in a large sample of women recovered from anorexia nervosa (rec AN). Recovery was defined by considering physiological, behavioural and psychological variables. METHOD: A total of 100 rec AN women and 100 healthy women completed the Rey Complex Figure Test, a measure for visual-spatial central coherence. The participants were matched 1:1 for age and educational level. RESULTS: Compared with the healthy control group, the rec AN group showed better accuracy in the copy condition. There was a trend for a local strategy in the rec AN group compared with a global strategy in the healthy control group. CONCLUSIONS: This sample of rec AN women showed no inefficiencies in global processing but a superior local processing after full recovery from AN.

Temporal sequence of comorbid alcohol use disorder and anorexia nervosa.

Women with eating disorders have a significantly higher prevalence of substance use disorders than the general population. The goal of the current study was to assess the temporal pattern of comorbid anorexia nervosa (AN) and alcohol use disorder (AUD) and the impact this ordering has on symptomatology and associated features. Women were placed into one of three groups based on the presence or absence of comorbid AUD and the order of AN and AUD onset in those with both disorders: (1) AN Only, (2) AN First, and (3) AUD First. The groups were compared on psychological symptoms and personality characteristics often associated with AN, AUD, or both using general linear models. Twenty-one percent of women (n=161) with AN reported a history of AUD with 115 reporting AN onset first and 35 reporting AUD onset first. Women with binge-eating and/or purging type AN were significantly more likely to have AUD. In general, differences were found only between women with AN Only and women with AN and AUD regardless of order of emergence. Women with AN and AUD had higher impulsivity scores and higher prevalence of depression and borderline personality disorder than women with AN Only. Women with AN First scored higher on traits commonly associated with AN, whereas women with comorbid AN and AUD displayed elevations in traits more commonly associated with AUD. Results do not indicate a distinct pattern of symptomatology in comorbid AN and AUD based on the temporal sequence of the disorders.