Dysregulation of soluble epoxide hydrolase and lipidomic profiles in anorexia nervosa.

Individuals with anorexia nervosa (AN) restrict eating and become emaciated. They tend to have an aversion to foods rich in fat. Because epoxide hydrolase 2 (EPHX2) was identified as a novel AN susceptibility gene, and because its protein product, soluble epoxide hydrolase (sEH), converts bioactive epoxides of polyunsaturated fatty acid (PUFA) to the corresponding diols, lipidomic and metabolomic targets of EPHX2 were assessed to evaluate the biological functions of EPHX2 and their role in AN. Epoxide substrates of sEH and associated oxylipins were measured in ill AN, recovered AN and gender- and race-matched controls. PUFA and oxylipin markers were tested as potential biomarkers for AN. Oxylipin ratios were calculated as proxy markers of in vivo sEH activity. Several free- and total PUFAs were associated with AN diagnosis and with AN recovery. AN displayed elevated n-3 PUFAs and may differ from controls in PUFA elongation and desaturation processes. Cytochrome P450 pathway oxylipins from arachidonic acid, linoleic acid, alpha-linolenic acid and docosahexaenoic acid PUFAs are associated with AN diagnosis. The diol:epoxide ratios suggest the sEH activity is higher in AN compared with controls. Multivariate analysis illustrates normalization of lipidomic profiles in recovered ANs. EPHX2 influences AN risk through in vivo interaction with dietary PUFAs. PUFA composition and concentrations as well as sEH activity may contribute to the pathogenesis and prognosis of AN. Our data support the involvement of EPHX2-associated lipidomic and oxylipin dysregulations in AN, and reveal their potential as biomarkers to assess responsiveness to future intervention or treatment.

Elasticity in portion selection is predicted by severity of anorexia and food type in adolescents.

The size of portions that people select is an indicator of underlying mechanisms controlling food intake. Fears of eating excessive portions drive down the sizes of portions patients with anorexia nervosa (AN) can tolerate eating significantly below those of healthy controls (HC) (Kissileff et al., 2016). To determine whether patients with AN will also reduce the sizes of typical or ideal portions below those of controls, ANOVA was used to compare maximum tolerable, typical, and ideal portions of four foods (potatoes, rice, pizza, and M&M's) in the same group of 24 adolescent AN patients and 10 healthy adolescent controls (HC), on which only the maximal portion data were previously reported. Typical and ideal portion sizes did not differ on any food for AN, but for HC, typical portions sizes (kcals) became larger than ideal as the energy density of the food increased, and were significant for the most energy dense food. Ideal portions of low energy dense foods were the same for AN as for in HC. There was a significant 3-way (group × food × portion type) interaction, such that HC selected larger maximum than typical portions only for pizza. We therefore proposed that individuals of certain groups, depending on the food, can be flexible in the amounts of food chosen to be eaten. We call this difference between maximum-tolerable, and typical portion sizes selected "elasticity." Elasticity was significantly smaller for AN patients compared to HC for pizza and was significantly inversely correlated with severity of illness. This index could be useful for clinical assessment of AN patients, and those with eating problems such as in obesity and bulimia nervosa and tracking their response to treatment.

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.

A 1-year follow-up of a multi-center treatment trial of adults with anorexia nervosa.

OBJECTIVE: To examine maintenance of recovery following treatment in an adult anorexia nervosa (AN) population. METHOD: One year follow-up of a randomized clinical trial with 122 participants treated with: cognitive behavioral therapy (CBT), drug therapy (fluoxetine), or a combination (CBT+fluoxetine) for 12 months. Participants were assessed at baseline, end of treatment, and follow-up. The primary outcomes were weight and the global scores from the Eating Disorder Examination (EDE) separately and combined. RESULTS: Fifty-two participants completed the follow-up. Mean weight increased from end of treatment to follow-up. Seventy-five percent (75%) of those weight recovered at end of treatment maintained this recovery at follow-up. Recovery of eating disorder psychopathology was stable from end of treatment to follow-up, with 40% of participants with a global EDE score within normal range. Using the most stringent criteria for recovery, only 21% of the completer sample was recovered. DISCUSSION: The findings suggest that while adults with AN improve with treatment and maintain these improvements during follow-up, the majority is not recovered. Additionally, further research is needed to understand barriers to treatment and assessment completion.

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 response to LH-RH in anorexia nervosa.

The gonadotropin-ovary axis of patients with anorexia nervosa was assessed with the aim of distinguishing between an intrinsically hypophysial deficiency and pituitary malfunction secondary to hypothalamic impairment. The most consistent endocrine abnormality was low serum luteinizing and follicle stimulating hormone (LH and FSH) levels associated with depressed serum estradiol levels. Gonadotropin levels responded to luteinizing hormone-releasing hormone (LH-RH), thus indicating a primarily hypothalamic dysfunction. The increase in serum FSH was at least as great as that of LH. The LH levels were additionally depressed and their increase after LH-RH injection somewhat blunted by three-day treatment with ethinyl estradiol.

Treatment of anorexia nervosa with behavior modification. Effectiveness of formula feeding and isolation.

Anorexia nervosa has been treated with a variety of therapies. One seemingly successful modality, behavioral modification, has in most cases been used concurrently with various drugs, making the contributions of each impossible to separate. Eight patients meeting rigorous criteria for anorexia nervosa were treated in this study exclusively with behavioral therapy (reward contingent on weight gain). All had a substantial weight gain while hospitalized, and on short-term follow-up are maintaining or continuing to gain toward their normal weight range on individualized positive-reinforcement programs.

Activity measures in anorexia nervosa.

Twenty-four-hour measurements of wrist and ankle kinetic energy expenditures were obtained on 20 hospitalized female anorectics during the first two weeks of their hospitalization. Kinetic energy was examined against measures of weight, depression, and Minnesota Multiphasic Personality Inventory scores in a regression analysis. Effect of cyproheptadine hydrochloride, amitriptyline hydrochloride, and placebo on activity was assessed. The results supported previous studies showing a positive relationship between weight gain and motor activity and challenge the commonly held notion that activity decreases in anorectics as their clinical condition improves. Motor activity was initially significantly suppressed by cyproheptadine and subsequently increased.

Anorexia nervosa. Treatment efficacy of cyproheptadine and amitriptyline.

Patients with anorexia nervosa have concurrent problems of emaciation and depression. Therefore, treatment with medications affecting both weight gain and depression seemed reasonable. Seventy-two anorectic patients were randomly assigned in a double-blind study to receive cyproheptadine hydrochloride, a weight-inducing drug, amitriptyline hydrochloride, a tricyclic antidepressant, or placebo. Overall, cyproheptadine had a marginal effect on decreasing the number of days necessary to achieve a normal weight. There was a differential drug effect present in the bulimic subgroups of the anorectic patients: cyproheptadine significantly increased treatment efficiency for the nonbulimic patients and significantly impaired treatment efficiency for the bulimic patients when compared with the amitriptyline- and placebo-treated groups. The differential cyproheptadine effect on the anorectic bulimic subgroups is the first pharmacologic evidence of the validity of these subgroups. Cyproheptadine had an anti-depressant effect demonstrated by a significant decrease in the Hamilton depression ratings.

Catecholamine metabolism in anorexia nervosa.

Urinary catecholamine levels were measured in 25 anorexia nervosa patients at the time when they were acutely ill with secondary depressive symptoms and again after treatment and weight gain to see whether changes in weight, activity levels, and symptoms of depression occurring during treatment might be associated with changes in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations. The latter was significantly lower in the acutely ill anorectics than in the control group. An increase in urinary MHPG concentration after treatment was significantly correlated with a decrease in depressive symptomatology. The increase in urinary MHPG level during treatment did not correlate significantly with change in patient's activity level. There seems to be a relationship between MHPG and the symptom of depression in a group of patients who do not carry a primary diagnosis of depression.

Comorbidity of psychiatric diagnoses in anorexia nervosa.

The comorbidity of psychiatric diagnoses was examined with the Diagnostic Interview Schedule in 62 women who participated in a 10-year follow-up study of anorexia nervosa. Sixty-two age- and sex-matched controls, their parents, and parents of the anorectic probands were also interviewed with the Diagnostic Interview Schedule. There was a statistically significant comorbidity of the affective and anxiety disorders with anorexia nervosa. The first-degree relatives of the anorectic probands had significantly more alcoholism and total number of psychiatric diagnoses compared with the first-degree relatives of controls. There were two mothers with bulimia nervosa, two cases of anorexia nervosa and two of bulimia nervosa in other first-degree relatives of anorectic probands, and no cases of eating disorders in the first-degree relatives of controls.

Bulimia. Its incidence and clinical importance in patients with anorexia nervosa.

Among the various eating patterns encountered in anorexia nervosa, the occurrence of bulimia (rapid consumption of large amounts of food in a short period of time) is a perplexing phenomenon, because its presence contradicts the common belief that patients with anorexia nervosa are always firm in their abstinence from food. We studied the eating habits of 105 hospitalized female patients within the context of a prospective treatment study on anorexia nervosa: 53% had achieved weight loss by consistently fasting, whereas 47% periodically resorted to bulimia. The two groups were contrasted with regard to their developmental and psychosocial history, clinical characteristics, and psychiatric symptomatology. Fasting patients were more introverted, more often denied hunger, and displayed little overt psychic distress. In contrast, bulimic patients were more extroverted, admitted more frequently to a strong appetite and tended to be older. Vomiting was frequent, and kleptomania almost exclusively present in bulimic patients, who manifested greater anxiety, depression, guilt, interpersonal sensitivity, and had more somatic complaints. This association of bulimia with certain personality features and a distinct psychiatric symptomatology suggests that patients with bulimia form a subgroup among patients with anorexia nervosa.

LH and FSH response to gonadotropin-releasing hormone in anorexia nervosa: Effect of nutritional rehabilitation.

The LH and FSH responses to the administration of synthetic gonadotropin-releasing hormone (GnRH) were assessed in 14 patients with anorexia nervosa before, during and following weight gain. In 8 patients studied prior to therapy when they were at 53-64% of idal body weight, the LH response to GnRH was strikingly impaired while the FSH response was equal to that observed in normally menstruating women. After return to 79-88% of ideal body weight the LH response was improved but remained less than in the normal women. In a second group of 6 patients who were studied 4-11 months after hospital discharge when they were 90-94% of ideal body weight, the LH response was always equal to or greater than that found in the normal women. The serum estradiol concentration was low in all of the patients and remained less than 33 pg/ml even in those who returned to more than 90% of ideal body weight. Treatment with 25 mug of ethinyl estradiol for 3 days prior to repeat administration of GnRH did not result in a statistically significant increase of the LH or FSH responses above those before treatment. These data suggest changes occur in both hypothalamic and pituitary regulation of gonadotropin secretion in the course of nutritional rehabilitation of patients with anorexia nervosa and that synthesis and secretion of LH and FSH are modulated independently at the level of the pituitary gland.

Amenorrhea in anorexia nervosa: examination of the critical body weight hypothesis.

In order to examine the relevance of the critical body weight hypothesis to menstrual regulation in anorexia nervosa, extensive physical, dietary, and behavioral assessments were made in 40 anorexia nervosa patients immediately before and after treatment, and at 3-month intervals up to 1 year posttreatment. Fifteen patients recovered menses; the body weights of these patients agreed with weights predicted by the critical body weight hypothesis. However, 12 patients with continuing amenorrhea had also achieved similar body weights. Clinical assessment showed that patients with continuing amenorrhea, both of normal and low weights, had significantly more "anorectic" attitudes and behaviors than the menstruating patients.

Relationship of clinical factors to caloric requirements in subtypes of eating disorders.

Caloric requirements for weight gain in subgroups of anorectic patients (anorectic restrictors, anorectic binge-purgers) and weight maintenance in subgroups of anorectic and bulimic patients (bulimics with and without a prior history of anorexia nervosa) were studied in a total of 36 patients. No significant differences were found between subgroups of anorectic patients either in calories to gain weight or to maintain a normal weight. Bulimic patients, as a group, were found to require significantly fewer [corrected] calories than the group of anorectic patients to maintain a normal weight. Bulimic patients with a prior history of anorexia nervosa were found to require more calories for weight maintenance than bulimics with no such prior history. In the entire eating disorder population, there was a significant negative correlation between highest premorbid body mass index (BMI) and calories required to maintain weight. These findings suggest that differences in energy metabolism may be present in the eating disorder subgroups.

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.

Psychiatric diagnosis of morbidly obese gastric bypass patients.

Eighty morbidly obese patients who had had gastric bypass operations were interviewed for psychiatric diagnoses using DSM-III criteria. The lifetime prevalence of Axis I clinical psychiatric diagnoses was 47.5%, with depressive disorders occurring in 28.7% of the total sample. No other diagnosis exceeded a 2.5% prevalence. The authors believe there is no evidence of an increased prevalence of major psychiatric disorder in obese persons when strictly defined diagnostic criteria are used.

Perfectionism in anorexia nervosa: variation by clinical subtype, obsessionality, and pathological eating behavior.

OBJECTIVE: The purpose of this study was to examine the role of perfectionism as a phenotypic trait in anorexia nervosa and its relevance across clinical subtypes of this illness. METHOD: The Multidimensional Perfectionism Scale and the perfectionism subscale of the Eating Disorder Inventory were administered to 322 women with a history of anorexia nervosa who were participating in an international, multicenter genetic study of anorexia nervosa. All participants were additionally interviewed with the Yale-Brown Obsessive Compulsive Scale and the Yale-Brown-Cornell Eating Disorder Scale. Mean differences on dependent measures among women with anorexia nervosa and comparison subjects were examined by using generalized estimating equations. RESULTS: Persons who had had anorexia nervosa had significantly higher total scores on the Multidimensional Perfectionism Scale than did the healthy comparison subjects. In addition, scores of the anorexia subjects on the Eating Disorder Inventory-2 perfectionism subscale exceeded Eating Disorder Inventory-2 normative data. For the anorexia nervosa participants, the total score on the Multidimensional Perfectionism Scale and the Eating Disorder Inventory-2 perfectionism subscale score were highly correlated. Total score on the Multidimensional Perfectionism Scale was also significantly related to the total score and the motivation-for-change subscale score of the Yale-Brown-Cornell Eating Disorder Scale. CONCLUSIONS: These data show that perfectionism is a robust, discriminating characteristic of anorexia nervosa. Perfectionism is likely to be one of a cluster of phenotypic trait variables associated with a genetic diathesis for anorexia nervosa.

Outcome predictors for the cognitive behavior treatment of bulimia nervosa: data from a multisite study.

OBJECTIVE: The aim of this study was to discover clinically useful predictors of attrition and outcome in the treatment of bulimia nervosa with cognitive behavior therapy. METHOD: Pretreatment, course of treatment, and outcome data were gathered on 194 women meeting the DSM-III-R criteria for bulimia nervosa who were treated with 18 sessions of manual-based cognitive behavior therapy in a three-site study. Differences between dropouts and nondropouts and between recovered and nonrecovered participants were first examined descriptively, and signal detection analyses were then used to determine clinically significant cutoff points predicting attrition and abstinence. RESULTS: The dropouts were characterized by more severe bulimic cognitions and greater impulsivity, but it was not possible to identify clinically useful predictors. The participants with treatment failures were characterized by poor social adjustment and a lower body mass index, presumably indicating greater dietary restriction. However, early progress in therapy best predicted outcome. Signal detection analyses revealed that poor outcome was predicted by a reduction in purging of less than 70% by treatment session 6, allowing identification of a substantial proportion of prospective failures. CONCLUSIONS: A cutoff point based on reduction of purging by session 6 usefully differentiates patients who will and will not respond to cognitive behavior therapy for bulimia nervosa, potentially allowing early use of a second therapy.

Relationship of perceived macronutrient and caloric content to affective cognitions about food in eating-disordered, restrained, and unrestrained subjects.

Cognitive sets concerning food were examined in eating-disorder patients and in restrained and unrestrained control subjects. Subjects rated 38 common foods for preference, presence or absence of guilt and danger, preferred monthly frequency, and caloric, fat, and carbohydrate content. Cognitive ratings were examined based upon the individual's perceived amounts of calories and macronutrients. Hedonic ratings of foods perceived as high in fat or calories were different in patients with current or past anorexia and did not change with treatment. The fat-calorie aversions seen in these patients, therefore, appear to be stable trait characteristics of the disorder. Guilt and danger were perceived as separate constructs by unrestrained and restrained control subjects but not by patients. Perceived high amounts of calories or fat triggered stronger feelings of guilt and danger for restrained control subjects and patients (especially bulimic patients) as compared with unrestrained control subjects. The patients' expressions of guilt and danger improved with treatment.