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Objective: Avoidant/restrictive food intake disorder (ARFID) is associated with increased risk for anxiety, which may adversely affect prognosis. The appetite-stimulating hormone, ghrelin, increases in response to stress, and exogenous ghrelin decreases anxiety-like behaviors in animal models. The aim of this study was to evaluate the relationship between ghrelin levels and measures of anxiety in youth with ARFID. We hypothesized that lower ghrelin levels would be associated with increased anxiety symptoms., Methods: We studied a cross-sectional sample of 80 subjects with full and subthreshold ARFID diagnosed by DSM-5 criteria, aged 10-23 years (female, n = 39; male, n = 41). Subjects were enrolled in a study of the neurobiology of avoidant/restrictive eating conducted from August 2016 to January 2021. We assessed fasting ghrelin levels and anxiety symptoms (State-Trait Anxiety Inventory [STAI] and STAI for Children [STAI-C] measuring general trait anxiety; Beck Anxiety Inventory [BAI] and BAI for youth [BAI-Y] assessing cognitive, emotional, and somatic symptoms of anxiety; and Liebowitz Social Anxiety Scale [LSAS] assessing symptoms of social anxiety)., Results: Consistent with our hypothesis, ghrelin levels were inversely associated with anxiety symptoms as assessed by STAI/STAI-C T scores ( r  = -0.28, P  = .012), BAI/BAI-Y T scores ( r  = -0.28, P  = .010), and LSAS scores ( r  = -0.3, P  = .027), all with medium effect sizes. Findings held in the full threshold ARFID group when adjusting for body mass index z scores (STAI/STAI-C T scores, β = -0.27, P  = .024; BAI/BAI-Y T scores, β = -0.26, P  = .034; LSAS, β = -0.34, P  = .024)., Conclusions: These findings demonstrate that lower levels of ghrelin are associated with more severe anxiety symptoms in youth with ARFID and raise the question of whether ghrelin pathways could be targeted in the treatment of ARFID., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Objective: Avoidant/restrictive food intake disorder (ARFID) is characterized by food avoidance or dietary restriction not primarily motivated by body weight/shape concerns. Individuals with ARFID can report early satiation, post-prandial fullness, and high intermeal satiety, but whether these symptoms are related to differences in the biology underlying appetite regulation is unknown. In male and female children and adolescents, we hypothesized that fasting levels of cholecystokinin (CCK), a satiety hormone, would be elevated in participants with ARFID (full or subthreshold) versus healthy controls (HCs). Within the ARFID group, we also explored the relations of CCK with weight status, subjective appetite ratings, and ARFID severity and phenotypes., Methods: A total of 125 participants (83 with full/subthreshold ARFID (per DSM-5 ) and 42 HCs, aged 10.2-23.7 years; 61% female; July 2014-December 2019) underwent fasting blood draws for CCK, completed self-report measures assessing subjective state and trait appetite ratings, and completed a semistructured interview assessing ARFID severity., Results: Fasting CCK was higher in those with full/subthreshold ARFID versus HCs with a large effect ( F 1  = 25.0, P  < .001, η p 2  = 0.17), controlling for age, sex, and body mass index (BMI) percentile. Within the ARFID group, CCK was not significantly related to BMI percentile, subjective appetite ratings, or ARFID characteristic measures., Conclusions: CCK may contribute to etiology and/or maintenance of ARFID, as children and adolescents with heterogeneous presentations of avoidant/restrictive eating appear to show elevated fasting levels compared to healthy youth. Further research is needed to understand relations between CCK and appetite, weight, and eating behavior in ARFID., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Objective: The DSM-5 criteria for avoidant/restrictive food intake disorder (ARFID) include ambiguities. Diagnostic criteria that allow for clinical judgment are essential for clinical practice. However, ambiguities can have major implications for treatment access and comparability and generalizability of research studies. The purpose of this study was to determine the degree to which distinct operationalizations of the diagnostic criteria for ARFID contribute to differences in the frequency of individuals who are eligible for the ARFID diagnosis., Methods: Because criteria B, C, and D are rule-outs, we focused on criterion A, identified 19 potential operational definitions, and determined the extent to which these different methods impacted the proportion of individuals who met criteria for ARFID in a sample of children, adolescents, and young adults (n = 80; September 2016-February 2020) enrolled in an avoidant/restrictive eating study., Results: Within each criterion, the proportion of individuals meeting diagnostic criteria differed significantly across the methodologies (all P values < .008). Using the strictest definition of each criterion, 50.0% (n = 40) of participants met criteria for ARFID. In contrast, under the most lenient definition of each criterion, the number nearly doubled, resulting in 97.5% (n = 78) meeting ARFID criteria., Conclusions: Comparison of diagnostic definitions for ARFID among children, adolescents, and young adults confirmed a broad range of statistically distinct proportions within a single sample. Our findings support the need for additional contextual support and consensus among disciplines on operationalization in both research and clinical settings., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Objective: To assess the effects of relamorelin-an agonist of the appetite-stimulating hormone ghrelin, which has effects on gastric emptying-on (1) weight gain and (2) gastric emptying in women with anorexia nervosa., Methods: In a randomized, double-blind, placebo-controlled design, the effects of the ghrelin agonist relamorelin were studied in 22 outpatient women with anorexia nervosa, diagnosed using DSM-5 criteria. The study was conducted at the Massachusetts General Hospital Clinical Research Center between March 11, 2013, and February 26, 2015. Ten participants were randomly assigned to relamorelin 100 μg subcutaneously daily (mean ± SEM age: 28.9 ± 2.4 y), and 12 were randomly assigned to placebo (28.9 ± 1.9 y). We measured changes in weight and gastric emptying time using a gastric emptying breath test (GEBT) for relamorelin versus placebo after 4 weeks of treatment., Results: At baseline, subjects did not differ in weight, plasma ghrelin levels, or gastric emptying time. Three subjects randomized to relamorelin stopped use of the study medication due to reported feelings of increased hunger. After 4 weeks, there was a trend toward an increase in weight in participants randomized to relamorelin (mean ± SEM change: 0.86 ± 0.40 kg) compared to placebo (0.04 ± 0.28 kg; P = .07), and gastric emptying time was significantly shorter in patients taking relamorelin (median [interquartile range]: 58.0 [51.0, 78.0] minutes) compared to placebo (85.0 [75.8,100.5] minutes; P = .03)., Conclusions: Treatment with a ghrelin agonist in women with anorexia nervosa significantly decreases gastric emptying time, leads to a trend in weight gain after only 4 weeks, and is well-tolerated. Further study is necessary to determine the long-term safety and efficacy of a ghrelin agonist in the treatment of anorexia nervosa., Trial Registration: ClinicalTrials.gov identifier: NCT01642550., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Objective: The course of eating disorders is often protracted, with fewer than half of adults achieving recovery from anorexia nervosa or bulimia nervosa. Some argue for palliative management when duration exceeds a decade, yet outcomes beyond 20 years are rarely described. This study investigates early and long-term recovery in the Massachusetts General Hospital Longitudinal Study of Anorexia and Bulimia Nervosa., Methods: Females with DSM-III-R/DSM-IV anorexia nervosa or bulimia nervosa were assessed at 9 and at 20 to 25 years of follow-up (mean [SD] = 22.10 [1.10] years; study initiated in 1987, last follow-up conducted in 2013) via structured clinical interview (Longitudinal Interval Follow-Up Evaluation of Eating Disorders [LIFE-EAT-II]). Seventy-seven percent of the original cohort was re-interviewed, and multiple imputation was used to include all surviving participants from the original cohort (N = 228). Kaplan-Meier curves estimated recovery by 9-year follow-up, and McNemar test examined concordance between recovery at 9-year and 22-year follow-up., Results: At 22-year follow-up, 62.8% of participants with anorexia nervosa and 68.2% of participants with bulimia nervosa recovered, compared to 31.4% of participants with anorexia nervosa and 68.2% of participants with bulimia nervosa by 9-year follow-up. Approximately half of those with anorexia nervosa who had not recovered by 9 years progressed to recovery at 22 years. Early recovery was associated with increased likelihood of long-term recovery in anorexia nervosa (odds ratio [OR] = 10.5; 95% CI, 3.77-29.28; McNemar χ²₁ = 31.39; P < .01) but not in bulimia nervosa (OR = 1.0; 95% CI, 0.49-2.05; McNemar χ²₁ = 0; P = 1.0)., Conclusion: At 22 years, approximately two-thirds of females with anorexia nervosa and bulimia nervosa were recovered. Recovery from bulimia nervosa happened earlier, but recovery from anorexia nervosa continued over the long term, arguing against the implementation of palliative care for most individuals with eating disorders., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Objective: Anorexia nervosa (AN), a psychiatric disorder characterized by restriction of food intake despite severe weight loss, is associated with increased comorbid anxiety and depression. Secretion of oxytocin, an appetite-regulating neurohormone with anxiolytic and antidepressant properties, is abnormal in AN. The link between oxytocin levels and psychopathology in AN has not been well explored., Methods: We performed a cross-sectional study of 79 women aged 18-45 years (19 AN, 26 AN in partial recovery [ANPR], and 34 healthy controls [HC]) investigating the relationship between basal oxytocin levels and disordered eating psychopathology, anxiety, and depressive symptoms. AN diagnoses were based on DSM-5 criteria. Data acquisition took place between December 2008 and March 2014. Fasting serum oxytocin levels were obtained, and the following self-report measures were used to assess psychopathology: Eating Disorder Examination Questionnaire, State-Trait Anxiety Inventory, and Beck Depression Inventory-II., Results: Fasting oxytocin levels were low in ANPR compared to HC (P = .0004). In ANPR but not AN, oxytocin was negatively associated with disordered eating psychopathology (r = -0.39, P = .0496) and anxiety symptoms (state anxiety: r = -0.53, P = .006; trait anxiety: r = -0.49, P = .01). Furthermore, ANPR with significant disordered eating psychopathology, anxiety symptoms, or depressive symptoms had lower oxytocin levels compared to those with minimal or no symptoms (P = .04, .02, and .007, respectively)., Conclusions: We speculate that a dysregulation of oxytocin pathways may contribute to persistent psychopathology after partial weight recovery from anorexia nervosa., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Objective: Anorexia nervosa is a psychiatric illness characterized by low weight, disordered eating, and hallmark neuroendocrine dysfunction. Behavioral phenotypes are defined by predominant restriction or bingeing/purging; binge-eating/purging type anorexia nervosa is associated with poorer outcome. The pathophysiology underlying anorexia nervosa types is unknown, but altered hormones, known to be involved in eating behaviors, may play a role., Method: To examine the role of anorexigenic hormones in anorexia nervosa subtypes, we examined serum levels of peptide YY (PYY; total and active [3-36] forms), brain-derived neurotrophic factor (BDNF), and leptin as primary outcomes in women with DSM-5 restricting type anorexia nervosa (n = 50), binge-eating/purging type anorexia nervosa (n = 25), and healthy controls (n = 22). In addition, women completed validated secondary outcome measures of eating disorder psychopathology (Eating Disorder Examination-Questionnaire) and depression and anxiety symptoms (Hamilton Rating Scales for Depression [HDRS] and Anxiety [HARS]). The study samples were collected from May 22, 2004, to February 7, 2012., Results: Mean PYY 3-36 and leptin levels were lower and BDNF levels higher in binge-eating/purging type anorexia nervosa than in restricting type anorexia nervosa (all P values < .05). After controlling for body mass index, differences in PYY and PYY 3-36 between anorexia nervosa types were significant (P < .05) and differences in BDNF were at the trend level (P < .10). PYY 3-36 was positively (r = 0.27, P = .02) and leptin was negatively (r = -0.51, P < .0001) associated with dietary restraint; BDNF was positively associated with frequency of purging (r = 0.21, P = .04); and leptin was negatively associated with frequency of bingeing (r = -0.29, P = .007) and purging (r = -0.31, P = .004)., Conclusions: Among women with anorexia nervosa, the anorexigenic hormones PYY, BDNF, and leptin are differentially regulated between the restricting and binge/purge types. Whether these hormone pathways play etiologic roles with regard to anorexia nervosa behavioral types or are compensatory merits further study., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Objective: Anorexia nervosa is characterized by low weight, aberrant eating attitudes, body image distortion, and hypogonadism. Anxiety is a common comorbid condition. Estrogen replacement reduces anxiety in animal models, and reported variations in food intake across the menstrual cycle may be related to gonadal steroid levels. The impact of estrogen replacement on anxiety, eating attitudes, and body image has not been reported in anorexia nervosa. We hypothesized that physiologic estrogen replacement would ameliorate anxiety and improve eating attitudes without affecting body image in anorexia nervosa., Method: Girls 13-18 years old with anorexia nervosa (DSM-IV) were randomized to transdermal estradiol (100 μg twice weekly) with cyclic progesterone or placebo patches and pills for 18-months, between 2002 and 2010. The State-Trait Anxiety Inventory for Children (STAIC), the Eating Disorders Inventory-2 (EDI-2), and the Body Shape Questionnaire (BSQ-34) were administered. 72 girls completed these measures at baseline (n=38 [girls receiving estrogen] and n=34 [girls receiving placebo]) and 37 at 18 months (n=20 [girls receiving estrogen] and n=17 [girls receiving placebo]). The primary outcome measure was the change in these scores over 18 months., Results: Estrogen replacement caused a decrease in STAIC-trait scores (-3.05 [1.22] vs. 2.07 [1.73], P=.02), without impacting STAIC-state scores (-1.11 [2.17] vs. 0.20 [1.42], P=.64). There was no effect of estrogen replacement on EDI-2 or BSQ-34 scores. Body mass index (BMI) changes did not differ between groups, and effects of estrogen replacement on STAIC-trait scores persisted after controlling for BMI changes (P=.03). Increases in serum estradiol were significantly associated with decreases in STAIC-trait scores (Spearman ρ = -0.45, P=.03)., Conclusions: Estrogen replacement improved trait anxiety (the tendency to experience anxiety) but did not impact eating attitudes or body shape perception., Trial Registration: ClinicalTrials.gov identifier: NCT00088153., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Objective: Anorexia nervosa, a psychiatric disorder characterized by self-induced starvation, is associated with endocrine dysfunction and comorbid anxiety and depression. Animal data suggest that oxytocin may have anxiolytic and antidepressant effects. We have reported increased postprandial oxytocin levels in women with active anorexia nervosa and decreased levels in weight-recovered women with anorexia nervosa compared to healthy controls. A meal may represent a significant source of stress in patients with disordered eating. We therefore investigated the association between postprandial oxytocin secretion and symptoms of anxiety and depression in anorexia nervosa., Method: We performed a cross-sectional study of 35 women (13 women with active anorexia nervosa, 9 with weight-recovered anorexia nervosa, and 13 healthy controls). Anorexia nervosa was diagnosed according to DSM-IV-TR criteria. Serum oxytocin and cortisol and plasma leptin levels were measured fasting and 30, 60, and 120 minutes after a standardized mixed meal. The area under the curve (AUC) and, for oxytocin, postprandial nadir and peak levels were determined. Anxiety and depressive symptoms were assessed using the Spielberger State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory II (BDI-II). The study was conducted from January 2009 to March 2011., Results: In women with anorexia nervosa, oxytocin AUC and postprandial nadir and peak levels were positively associated with STAI trait and STAI premeal and postmeal state scores. Oxytocin AUC and nadir levels were positively associated with BDI-II scores. After controlling for cortisol AUC, all of the relationships remained significant. After controlling for leptin AUC, most of the relationships remained significant. Oxytocin secretion explained up to 51% of the variance in STAI trait and 24% of the variance in BDI-II scores., Conclusions: Abnormal postprandial oxytocin secretion in women with anorexia nervosa is associated with increased symptoms of anxiety and depression. This link may represent an adaptive response of oxytocin secretion to food-related symptoms of anxiety and depression., (© Copyright 2013 Physicians Postgraduate Press, Inc.)