Prospective Two-Year Course and Predictors of Outcome in Avoidant/Restrictive Food Intake Disorder.

OBJECTIVE: To evaluate the 2-year course and outcomes of full and subthreshold avoidant/restrictive food intake disorder (ARFID) in youth ages 9-23 at baseline using a prospective longitudinal design to characterize the remission and persistence of ARFID, evaluate diagnostic crossover, and identify predictors of outcome. We hypothesized that greater severity in each ARFID profile - sensory sensitivity, fear of aversive consequences, and lack of interest - would predict greater likelihood of illness persistence, controlling for age, sex, BMI percentile, ARFID treatment status, and baseline diagnosis. METHOD: We followed participants (N = 100; ages 9-23 years; 49% female, 91% White) over two years. We used the Pica, ARFID, and Rumination Disorder Interview across three time points (Baseline, Year 1, Year 2) to measure the severity of each ARFID profile and evaluate illness persistence or remission, and the Eating Disorder Assessment for DSM-5 to evaluate diagnostic crossover. RESULTS: Across the 2-year follow-up period, half the sample persisted with their original diagnosis, and 3% of participants experienced diagnostic shift to anorexia nervosa. Greater severity in the sensory sensitivity and lack of interest profiles was associated with higher likelihood of ARFID persistence at Year 1 only; greater severity in the fear of aversive consequences profile was associated with higher likelihood of ARFID remission at Year 2 only. CONCLUSION: Findings underscore the distinctiveness of ARFID from other eating disorders and emphasize its persistence over 2 years. Results also highlight the predictive validity and prognostic value of ARFID profiles (i.e., sensory sensitivity, fear of aversive consequences, lack of interest).

Lower region-specific gray matter volume in females with atypical anorexia nervosa and anorexia nervosa.

OBJECTIVE: Few studies have focused on brain structure in atypical anorexia nervosa (atypical AN). This study investigates differences in gray matter volume (GMV) between females with anorexia nervosa (AN) and atypical AN, and healthy controls (HC). METHOD: Structural magnetic resonance imaging data were acquired for 37 AN, 23 atypical AN, and 41 HC female participants. Freesurfer was used to extract GMV, cortical thickness, and surface area for six brain lobes and associated cortical regions of interest (ROI). Primary analyses employed linear mixed-effects models to compare group differences in lobar GMV, followed by secondary analyses on ROIs within significant lobes. We also explored relationships between cortical gray matter and both body mass index (BMI) and symptom severity. RESULTS: Our primary analyses revealed significant lower GMV in frontal, temporal and parietal areas (FDR < .05) in AN and atypical AN when compared to HC. Lobar GMV comparisons were non-significant between atypical AN and AN. The parietal lobe exhibited the greatest proportion of affected cortical ROIs in both AN versus HC and atypical AN versus HC. BMI, but not symptom severity, was found to be associated with cortical GMV in the parietal, frontal, temporal, and cingulate lobes. No significant differences were observed in cortical thickness or surface area. DISCUSSION: We observed lower GMV in frontal, temporal, and parietal areas, when compared to HC, but no differences between AN and atypical AN. This indicates potentially overlapping structural phenotypes between these disorders and evidence of brain changes among those who are not below the clinical underweight threshold. PUBLIC SIGNIFICANCE: Despite individuals with atypical anorexia nervosa presenting above the clinical weight threshold, lower cortical gray matter volume was observed in partial, temporal, and frontal cortices, compared to healthy individuals. No significant differences were found in cortical gray matter volume between anorexia nervosa and atypical anorexia nervosa. This underscores the importance of continuing to assess and target weight gain in clinical care, even for those who are presenting above the low-weight clinical criteria.

Cognitive-behavioral therapy for avoidant/restrictive food intake disorder: A proof-of-concept for mechanisms of change and target engagement.

BACKGROUND: Cognitive-behavioral therapy for avoidant/restrictive food intake disorder (ARFID; CBT-AR) theoretically targets three prototypic motivations (sensory sensitivity, lack of interest/low appetite, fear of aversive consequences), aligned with three modularized interventions. As an exploratory investigation, we: (1) evaluated change in candidate mechanisms in relationship to change in ARFID severity, and (2) tested if assignment (vs. not) to a module resulted in larger improvements in the corresponding mechanism. METHOD: Males and females (N = 42; 10-55 years) participated in an open trial of CBT-AR. RESULTS: Decreases in scaled scores for each candidate mechanism had medium to large correlations with decreases in ARFID severity-sensory sensitivity: -0.7 decrease (r = .42, p = .01); lack of interest/low appetite: -0.3 decrease (r = .60, p < .0001); and fear of aversive consequences: -1.1 decrease (r = .33, p = .05). Linear mixed models revealed significant weekly improvements for each candidate mechanism across the full sample (ps < .0001). There were significant interactions for the sensory and fear of aversive consequences modules-for each, participants who received the corresponding module had significantly larger decreases in the candidate mechanism than those who did not receive the module. DISCUSSION: Sensory sensitivity and fear of aversive consequences improved more if the CBT-AR module was received, but lack of interest/low appetite may improve regardless of receipt of the corresponding module. Future research is needed to test target engagement in CBT-AR with adaptive treatment designs, and to identify valid and sensitive measures of candidate mechanisms. PUBLIC SIGNIFICANCE: The mechanisms through which components of CBT-AR work have yet to be elucidated. We conducted an exploratory investigation to test if assignment (vs. not) to a CBT-AR module resulted in larger improvements in the corresponding prototypic ARFID motivation that the module intended to target. Measures of the sensory sensitivity and the fear of aversive consequences motivations improved more in those who received the corresponding treatment module, whereas the lack of interest/low appetite measure improved regardless of if the corresponding module was received.

Avoidant/restrictive food intake disorder differs from anorexia nervosa in delay discounting.

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) and anorexia nervosa (AN) are the two primary restrictive eating disorders; however, they are driven by differing motives for inadequate dietary intake. Despite overlap in restrictive eating behaviors and subsequent malnutrition, it remains unknown if ARFID and AN also share commonalities in their cognitive profiles, with cognitive alterations being a key identifier of AN. Discounting the present value of future outcomes with increasing delay to their expected receipt represents a core cognitive process guiding human decision-making. A hallmark cognitive characteristic of individuals with AN (vs. healthy controls [HC]) is reduced discounting of future outcomes, resulting in reduced impulsivity and higher likelihood of favoring delayed gratification. Whether individuals with ARFID display a similar reduction in delay discounting as those with AN (vs. an opposing bias towards increased delay discounting or no bias) is important in informing transdiagnostic versus disorder-specific cognitive characteristics and optimizing future intervention strategies. METHOD: To address this research question, 104 participants (ARFID: n = 57, AN: n = 28, HC: n = 19) completed a computerized Delay Discounting Task. Groups were compared by their delay discounting parameter (ln)k. RESULTS: Individuals with ARFID displayed a larger delay discounting parameter than those with AN, indicating steeper delay discounting (M ± SD = -6.10 ± 2.00 vs. -7.26 ± 1.73, p = 0.026 [age-adjusted], Hedges' g = 0.59), with no difference from HC (p = 0.514, Hedges' g = -0.35). CONCLUSION: Our findings provide a first indication of distinct cognitive profiles among the two primary restrictive eating disorders. The present results, together with future research spanning additional cognitive domains and including larger and more diverse samples of individuals with ARFID (vs. AN), will contribute to identifying maintenance mechanisms that are unique to each disorder as well as contribute to the optimization and tailoring of treatment strategies across the spectrum of restrictive eating disorders.

Avoidant/restrictive food intake disorder (ARFID) and anorexia nervosa (AN) are both restrictive eating disorders. However, the reasons for restricting food intake differ between the two diagnoses. A key question in further understanding similarities and differences between ARFID and AN is to understand whether individuals with these disorders process information and make decisions in similar or distinct ways. When humans decide between two different outcomes (e.g., a smaller immediate or a larger delayed reward), outcomes decrease in their value the farther in the future we expect to receive them (delay discounting). Individuals with AN exhibit a reduced discounting of future outcomes, which makes them more likely to forego immediate gratification for later rewards. However, whether this holds true for individuals with ARFID too (or whether they show the opposite or no bias) is unknown. Our investigation is the first to compare delay discounting between individuals with ARFID, AN, and healthy controls (HC). Our results show that individuals with ARFID show more delay discounting than those with AN, with no difference from HC. Knowing how rewards are being chosen and decisions made (and knowing differences between diagnoses) will be helpful in further optimizing and tailoring treatments for restrictive eating disorders.

Anticipatory and consummatory pleasure in avoidant/restrictive food intake disorder.

BACKGROUND: Recent research suggests that individuals with eating disorders (EDs) report elevated anhedonia, or loss of pleasure. Although individuals with avoidant/restrictive food intake disorder (ARFID) often express that they do not look forward to eating, it is unclear whether they experience lower pleasure than those without EDs. Thus, identifying whether individuals with ARFID experience anhedonia may yield important insights that inform clinical conceptualization and treatment. METHODS: A sample of 71 participants ages 10-23 with full and subthreshold ARFID and 33 healthy controls (HCs) completed the Pica, ARFID, and Rumination Disorder Interview, a diagnostic interview to assess ARFID profile severity (lack of interest in food, sensory sensitivity, fear of aversive consequences) and the Temporal Experience of Pleasure Scale (TEPS), a self-report measure of consummatory and anticipatory pleasure. Statistical analyses were performed using the full TEPS and also the TEPS with food-related items removed. RESULTS: The ARFID group reported significantly lower anticipatory and consummatory pleasure compared to HCs, but these differences were no longer significant after controlling for depression, nor after removing food items from the TEPS. Within the ARFID sample, greater ARFID severity was associated with lower anticipatory pleasure across analyses, and greater endorsement of the lack of interest in food profile was related to lower anticipatory pleasure. ARFID severity was also associated with lower consummatory pleasure using the full TEPS, but this relationship was no longer significant with food items removed. CONCLUSIONS: These results provide initial evidence for lower pleasure before potentially pleasurable events in individuals with more severe ARFID, particularly those with the lack of interest phenotype. Our findings also suggest that depression is likely to contribute low pleasure in this population. Future research should seek to further characterize how dimensions of pleasure relate to the maintenance and treatment of ARFID symptoms.

Individuals with eating disorders often report elevated anhedonia, or an inability to experience pleasure. Past research on pleasure in eating disorders has focused primarily on individuals with anorexia nervosa and bulimia nervosa, and it is unclear whether people with other eating disorders also experience lower pleasure than healthy individuals. In the current study, we measured anticipatory pleasure (looking forward to something enjoyable) and consummatory pleasure (enjoying a pleasant stimulus) in a sample with avoidant/restrictive food intake disorder (ARFID) and healthy controls. We also repeated our analyses after removing food-related items from the scale assessing pleasure. The ARFID group scored lower on both dimensions of pleasure than controls, but this difference was primarily due to greater depression symptoms and the presence of food-related items in the pleasure questionnaire. Within the ARFID sample, individuals with more severe ARFID reported less anticipatory pleasure, even after removing questions about enjoyment of food. Lower anticipatory pleasure was especially characteristic of the lack of interest in eating phenotype of ARFID. These results suggest that ARFID severity, lack of interest in eating, and depression contribute to low pleasure in this population.

Dynamic Amygdala Nuclei Alterations in Relation to Weight Status in Anorexia Nervosa Are Mediated by Leptin.

OBJECTIVE: The amygdaloid complex is a subcortical limbic group of distinct nuclei. In a previous patient-control study, differential amygdala nuclei alterations were found in acute anorexia nervosa (AN); rostral-medial nuclei involved in fear and reward processing were substantially reduced in volume and associated with hypoleptinemia, a key neuroendocrine characteristic of AN. Here, longitudinal amygdala nuclei alterations in AN were investigated in relation to weight status and their associations with leptin levels. METHOD: T1-weighted structural magnetic resonance imaging scans were longitudinally processed with FreeSurfer. Amygdala nuclei volumes in young female patients with acute AN before and after short-term weight restoration (n = 110, >14% body mass index increase over 3 months) and female participants with a history of AN (n = 79, long-term [mean 5 years] weight recovered) were compared with female healthy control participants (n = 271) using linear mixed effects models. RESULTS: Rostral-medially clustered amygdala nuclei volumes, accessory basal, cortical, medial nuclei, and corticoamygdaloid transition, increased during short-term weight restoration (Cohen's d range 0.18-0.30). However, volumetric normalization across nuclei was heterogeneous. Right cortical, medial nuclei, bilateral corticoamygdaloid transitions, and anterior amygdaloid areas were only partially normalized following short-term weight restoration. Right anterior amygdaloid area remained reduced after long-term weight recovery compared with control participants (d = 0.36). Leptin increase, accompanying short-term weight restoration, mediated the effect of weight gain on volumetric increase in left corticoamygdaloid transition and bilateral medial nuclei. CONCLUSION: Rostral-medially clustered amygdala nuclei show pronounced volumetric increase but incomplete normalization in AN during and after short-term weight restoration. Leptin increase may be relevant for the recovery of specific amygdala nuclei in addition to nutritional rehabilitation, indicating links between amygdala substructure and leptin dynamics of potential pathophysiological and clinical relevance in AN. PLAIN LANGUAGE SUMMARY: The amygdala plays a critical role in processing fearful and rewarding stimuli, and alterations in the amygdala are associated with anorexia nervosa. In this study, the authors measured amygdala nuclei volumes in female patients with acute anorexia nervosa undergoing weight-restoration treatment (n = 110), long-term weight-recovered individuals with anorexia (n = 79), and healthy control participants (n = 271). Structural magnetic resonance imaging revealed that volumes of specific nuclei, clustered in the rostral-medial amygdala, were substantially reduced in acute anorexia nervosa and only partially normalized following weight restoration treatment. Residual reductions in volume persisted even after long-term weight-recovery, compared to healthy control participants. Short-term weight restoration was associated with increases in the neurohormone leptin, and increasing leptin levels were found to mediate the positive impact of weight gain on increased amygdala volume over the treatment course. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

The association of alcohol use and positive and negative urgency to same day objective binge eating in emerging adults.

Introduction: Objective binge eating and problematic alcohol use often co-occur and are common behaviors in emerging adults. Both behaviors are thought to be driven by affect regulation processes. Objective binge eating often occurs in the context of increasing or acute negative affect, and often occurs in solitude. Alcohol use in emerging adults can also be associated with negative affect regulation. However, in contrast to objective binge eating, a large body of research indicates that there are positively valenced pathways to alcohol use in this age group. Emerging adults often drink socially, to enhance enjoyment, and in the context of positive mood. We propose that one pathway to objective binge eating in this developmental period is through alcohol use itself, such that emerging adults who consume alcohol and who are more likely to act impulsively in the context of positive emotion (i.e., have high levels of positive urgency) may be more likely to binge eat following drinking. Methods: We collected data using ecological momentary assessment in 106 undergraduates on positive and negative affect, motives for drinking and eating, and alcohol use and objective binge eating, in addition to baseline questionnaires of impulsivity. Results: There were no significant changes in affect prior to drinking in this sample. Alcohol use at one time point significantly increased odds of objective binge eating at a later time point in the same day. Individual differences in positive urgency, the tendency to act rashly while experiencing positive affect, were also associated with increased odds of objective binge eating that occurred after alcohol use. Individual differences in negative urgency, the tendency to act rashly after experiencing negative affect, did not have a main effect on objective binge episodes, but did interact with alcohol use to increase the odds of objective binge eating following drinking. The vast majority of drinking episodes prior to objective binge eating were social drinking episodes, and participants most commonly endorsed "to have fun" as a reason for drinking. Discussion: Results suggest that alcohol consumption may increase risk for objective binge eating in emerging adults.

Oxytocin response to food intake in avoidant/restrictive food intake disorder.

OBJECTIVE: To investigate the response of anorexigenic oxytocin to food intake among adolescents and young adults with avoidant/restrictive food intake disorder (ARFID), a restrictive eating disorder characterized by lack of interest in food or eating, sensory sensitivity to food, and/or fear of aversive consequences of eating, compared with healthy controls (HC). DESIGN: Cross-sectional. METHODS: A total of 109 participants (54 with ARFID spectrum and 55 HC) were instructed to eat a ∼400-kcal standardized mixed meal. We sampled serum oxytocin at fasting and at 30-, 60-, and 120-min postmeal. We tested the hypothesis that ARFID would show higher mean oxytocin levels across time points compared with HC using a mixed model ANOVA. We then used multivariate regression analysis to identify the impact of clinical characteristics (sex, age, and body mass index [BMI] percentile) on oxytocin levels in individuals with ARFID. RESULTS: Participants with ARFID exhibited greater mean oxytocin levels at all time points compared with HC, and these differences remained significant even after controlling for sex and BMI percentile (P = .004). Clinical variables (sex, age, and BMI percentile) did not show any impact on fasting and postprandial oxytocin levels among individuals with ARFID. CONCLUSIONS: Consistently high oxytocin levels might be involved in low appetite and sensory aversions to food, contributing to food avoidance in individuals with ARFID.

Identification of State Markers in Anorexia Nervosa: Replication and Extension of Inflammation Associated Biomarkers Using Multiplex Profiling in Anorexia Nervosa and Atypical Anorexia Nervosa.

Proteomics provides an opportunity for detection and monitoring of anorexia nervosa (AN) and its related variant, atypical-AN (atyp-AN). However, research to date has been limited by the small number of proteins explored, exclusive focus on adults with AN, and lack of replication across studies. This study performed Olink Proseek Multiplex profiling of 92 proteins involved in inflammation among females with AN and atyp-AN (N = 64), all < 90% of expected body weight, and age-matched healthy controls (HC; N=44). After correction for multiple testing, nine proteins differed significantly in the AN/atyp-AN group relative to HC group ( lower levels: CXCL1, HGF, IL-18R1, TNFSF14, TRANCE; higher levels: CCL23, Flt3L, LIF-R, MMP-1). The expression levels of three proteins ( lower IL-18R1, TRANCE; higher LIF-R) were uniquely disrupted in females with AN. No unique expression levels emerged for atyp-AN. Across the whole sample, twenty-one proteins correlated positively with BMI (ADA, AXIN1, CD5, CD244, CD40, CD6, CXCL1, FGF-21, HGF, IL-10RB, IL-12B, IL18, IL-18R1, IL6, LAP TGF-beta-1, SIRT2, STAMBP, TNFRSF9, TNFSF14, TRAIL, TRANCE) and six (CCL11, CCL23, FGF-19, IL8, LIF-R, OPG) were negatively correlated with BMI. Overall, our results replicate the prior study demonstrating a dysregulated inflammatory status in AN, and extend these results to atyp-AN (AN/atyp-AN all < 90% of expected body weight). Of the 27 proteins correlated with BMI, 18 were replicated from a prior study using similar methods, highlighting the promise of inflammatory protein expression levels as biomarkers of disease monitoring. Additional studies of individuals across the entire weight spectrum are needed to understand the role of inflammation in atyp-AN.

Proposal for increasing diagnostic clarity in research and clinical practice by renaming and reframing atypical anorexia nervosa as "Restrictive Eating Disorder" (RED).

Atypical anorexia nervosa (AAN) in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), is characterized by meeting all criteria for anorexia nervosa (AN) except for weight being within or above the "normal" range despite significant weight loss. The current definition is plagued by several problems, resulting in widely heterogeneous operationalizations in research and clinical practice. As such, the poorly defined diagnosis of AAN negatively impacts affected individuals and frustrates research attempts to better understand the syndrome. We consider conceptual flaws in the AAN description and contend that the undefined weight range and nature of weight loss renders these two factors functionally inapplicable in research and practice. They also represent a departure from the originally intended use of the AAN category, i.e., arresting a negative weight trajectory likely to result in AN, making the target population, and the application of the label, unclear. We propose revised criteria and a new name, restrictive eating disorder (RED), intended to reduce stigma and encompass a wide but better-defined range of presentations. The RED criteria focus on clinically significant restrictive behavior that disrupts normal living (i.e., impairment), and cognitive symptoms of overevaluation, disturbed experience, and lack of recognition of illness seriousness. We believe that RED may enable more appropriate clinical application, but also inspire coordinated research toward a more valid psychiatric nosology in the eating disorders field.

Neural activation of regions involved in food reward and cognitive control in young females with anorexia nervosa and atypical anorexia nervosa versus healthy controls.

Anorexia nervosa (AN) and atypical AN (AtypAN) are complex neurobiological illnesses that typically onset in adolescence with an often treatment-refractory and chronic illness trajectory. Aberrant eating behaviors in this population have been linked to abnormalities in food reward and cognitive control, but prior studies have not examined respective contributions of clinical characteristics and metabolic state. Research is needed to identify specific disruptions and inform novel intervention targets to improve outcomes. Fifty-nine females with AN (n = 34) or AtypAN (n = 25), ages 10-22 years, all ≤90% expected body weight, and 34 age-matched healthy controls (HC) completed a well-established neuroimaging food cue paradigm fasting and after a standardized meal, and we used ANCOVA models to investigate main and interaction effects of Group and Appetitive State on blood oxygenation level-dependent (BOLD) activation for the contrast of exposure to high-calorie food images minus objects. We found main effects of Group with greater BOLD activation in the dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (DLPFC), hippocampus, caudate, and putamen for AN/AtypAN versus HC groups, and in the three-group model including AN, AtypAN, and HC (sub-)groups, where differences were primarily driven by greater activation in the AtypAN subgroup versus HC group. We found a main effect of Appetitive State with increased premeal BOLD activation in the hypothalamus, amygdala, nucleus accumbens, and caudate for models that included AN/AtypAN and HC groups, and in BOLD activation in the nucleus accumbens for the model that included AN, AtypAN, and HC (sub-)groups. There were no interaction effects of Group with Appetitive State for any of the models. Our findings demonstrate robust feeding-state independent group effects reflecting greater neural activation of specific regions typically associated with reward and cognitive control processing across AN and AtypAN relative to healthy individuals in this food cue paradigm. Differential activation of specific brain regions in response to the passive viewing of high-calorie food images may underlie restrictive eating behavior in this clinical population.

Atypical anorexia nervosa diagnosis should exclude those with lifetime anorexia nervosa: Commentary on Walsh, Hagan, and Lockwood (2022).

Atypical anorexia nervosa (AN) is not well-defined. Walsh, Hagan, and Lockwood (2022) review the data on atypical AN published in the last decade demonstrating overwhelming clinical similarities between atypical AN and AN. As written, atypical AN includes at least three clinical presentations that may not have the same underlying illness, and in turn, may have different prognoses and treatment needs: (1) higher-weight AN; (2) prodromal AN; and (3) partial remission from AN. While useful for the first two presentations, we suggest that the atypical AN diagnosis is not appropriate for those in partial remission from AN. Extant data document symptom fluctuation is part of illness course in AN rather than crossover to a distinct disorder. Further, lifetime AN carries the greatest risk for relapse to low-weight, premature death, and medical morbidities. Finally, emerging data support unique biobehavioral mechanisms in AN suggesting its combination with atypical AN is premature. Therefore, at this time, we recommend that the atypical AN diagnosis be reserved for those without lifetime AN. We encourage research to test and validate operational definitions of atypical AN and partial remission from AN, and further suggest documentation of lifetime AN across the eating disorders given its prognostic value.

Association Between Ghrelin and Body Weight Trajectory in Individuals With Anorexia Nervosa.

Importance: Individuals with anorexia nervosa maintain extremely low body weights despite elevations in the circulating orexigenic hormone ghrelin. Whether circulating levels of endogenous ghrelin are associated with weight gain in anorexia nervosa is unknown. Objective: To examine the association between baseline ghrelin and future weight change in individuals with anorexia nervosa. Design, Setting, and Participants: This prospective cohort study was conducted between April 1, 2014, and March 31, 2020, in the US. Girls and women aged 10 to 22 years were recruited from the greater Boston area from community and area treatment centers, enrolled, and followed up for 18 months. Statistical analyses were performed between January and August 2022. Exposures: Presence or absence of anorexia nervosa and elevations in endogenous ghrelin. Main Outcomes and Measures: Changes in age- and sex-standardized body mass index percentiles from baseline to 9- and 18-month follow-up were the main outcomes of interest. Results: A total of 68 girls and young women (11 [16%] Asian, 4 [6%] Hispanic or Latina, 51 [75%] White [non-Hispanic or Latina], and 2 [3%] other race or ethnicity), including 35 with anorexia nervosa and 33 healthy controls of similar Tanner stage, were included in this study. Anorexia nervosa and healthy control groups were not statistically different by race and ethnicity, Tanner stage, number completing follow-up visits, and the duration between baseline and follow-up visits. At baseline, individuals with anorexia nervosa were slightly older (median [IQR], 20.1 [18.5-21.0] vs 18.7 [14.7-19.4] years; P = .005), had lower body mass index percentiles (median [IQR], 2.4 [0.3-4.7] vs 52.9 [40.4-68.3]; P < .001), and had elevated circulating ghrelin area under the curve composite index (median [IQR], 1389.4 [1082.5-1646.4] vs 958.5 [743.0-1234.5] pg/mL; P = .003) compared with healthy individuals. In linear mixed-effects regression analyses, baseline ghrelin was associated with prospective weight gain after adjusting for diagnosis, age, race, and duration of follow-up (odds ratio, 2.35; 95% CI, 1.43-3.73; P = .004). Conclusions and Relevance: In this cohort study, endogenous ghrelin was associated with longitudinal weight gain in individuals with anorexia nervosa. Further studies are warranted to confirm this result and examine its potential clinical utility in treatment development.

Anorexia nervosa and muscle health: A systematic review of our current understanding and future recommendations for study.

OBJECTIVE: Conduct a systematic review on muscle size and strength in individuals with anorexia nervosa (AN). METHOD: In accordance with PRISMA guidelines, we searched Pubmed for articles published between 1995 and 2022 using a combination of search terms related to AN and muscle size, strength, or metabolism. After two authors screened articles and extracted data, 30 articles met inclusion criteria. Data were coded, and a risk bias was conducted for each study. RESULTS: The majority of studies focused on muscle size/lean mass (60%, n = 18) and energy expenditure (33%, n = 9), with few studies (17%, n = 5) investigating muscle function or possible mechanisms underlying muscle size (20%, n = 6). Studies supported that individuals with AN have smaller muscle size and reduced energy expenditure relative to controls. In some studies (33%, n = 10) recovery from AN was not sufficient to restore muscle mass or function. Mechanisms underlying short and long-term musculoskeletal alterations have not been thoroughly explored. DISCUSSION: Muscle mass and strength loss may be an unexplored component of physiological deterioration during and after AN. More research is necessary to understand intramuscular alterations during AN and interventions to facilitate muscle mass and functional gain following weight restoration in AN. PUBLIC SIGNIFICANCE: Muscle health is important for optimal health and is reduced in individuals with AN. However, we do not understand how muscle is altered at the cellular level throughout the course of AN. Here we review what is currently known regarding muscle health during AN and with weight restoration.

OBJETIVO: Realizar una revisión sistemática sobre el tamaño y la fuerza muscular en individuos que padecen anorexia nerviosa (AN). MÉTODO: De acuerdo con las guías PRISMA, se realizaron búsquedas en Pubmed de artículos publicados entre 1995 y 2022 mediante una combinación de términos de búsqueda relacionados con la anorexia nerviosa y el tamaño, la fuerza o el metabolismo muscular. Después de que dos autores examinaron los artículos y extrajeron los datos, 30 artículos cumplieron los criterios de inclusión. Se codificaron los datos y se realizó un sesgo de riesgo para cada estudio. RESULTADOS: La mayoría de los estudios se enfocaron en el tamaño muscular/masa magra (60%, n=18) y el gasto energético (33%, n=9), con pocos estudios (17%, n=5) investigando la función muscular o los posibles mecanismos subyacentes al tamaño muscular (20%, n=6). Los estudios apoyaron que los individuos que padecen anorexia nerviosa tienen un tamaño muscular más pequeño y un gasto de energía reducido en relación con los controles. En algunos estudios (33%, n = 10) la recuperación de la anorexia nerviosa no fue suficiente para restaurar la masa muscular o la función. Los mecanismos subyacentes a las alteraciones musculoesqueléticas a corto y largo plazo no se han explorado a fondo. DISCUSIÓN: La pérdida de masa muscular y fuerza puede ser un componente inexplorado del deterioro fisiológico durante y después de la AN. Se necesita más investigación para comprender las alteraciones intramusculares durante la anorexia nerviosa y las intervenciones para facilitar la masa muscular y la ganancia funcional después de la restauración del peso en la anorexia nerviosa.

Preliminary validation of the pica, ARFID and rumination disorder interview ARFID questionnaire (PARDI-AR-Q).

BACKGROUND: The Pica, ARFID, and Rumination Disorder Interview (PARDI) is a structured interview that can be used to determine diagnosis, presenting characteristics, and severity across three disorders, including avoidant/restrictive food intake disorder (ARFID). The purpose of this study was to evaluate the psychometric properties of a questionnaire focused specifically on ARFID (PARDI-AR-Q), which has the potential to provide related information with less participant burden. METHODS: Adolescents and adults (n = 71, ages 14-40 years) with ARFID (n = 42) and healthy control participants (HC, n = 29) completed the PARDI-AR-Q and other measures. A subset of the ARFID group (n = 27) also completed the PARDI interview. RESULTS: An exploratory factor analysis of proposed subscale items identified three factors corresponding to the ARFID phenotypes of avoidance based on the sensory characteristics of food, lack of interest in eating or food, and concern about aversive consequences of eating. Further analyses supported the internal consistency and convergent validity of the PARDI-AR-Q subscales, and subscale ratings on the questionnaire showed large and significant correlations (all p-values < 0.001; r's ranging from 0.48 to 0.77) with the corresponding subscales on the interview. The ARFID group scored significantly higher than HC on all subscales. Furthermore, 90% of the ARFID group scored positive on the PARDI-AR-Q diagnostic algorithm while 93% of the HC scored negative. CONCLUSIONS: Though replication in larger and more diverse samples is needed, findings provide early support for the validity of the PARDI-AR-Q as a self-report measure for possible ARFID in clinical or research settings.

Differential comorbidity profiles in avoidant/restrictive food intake disorder and anorexia nervosa: Does age play a role?

OBJECTIVE: Research comparing psychiatric comorbidities between individuals with avoidant/restrictive food intake disorder (ARFID) and anorexia nervosa (AN) is limited. ARFID often develops in childhood, whereas AN typically develops in adolescence or young adulthood. Understanding how age may impact differential psychological comorbidity profiles is important to inform etiological conceptualization, differential diagnosis, and treatment planning. We aimed to compare the lifetime frequency of psychiatric comorbidities and suicidality between females with ARFID (n = 51) and AN (n = 40), investigating the role of age as a covariate. METHOD: We used structured interviews to assess the comparative frequency of psychiatric comorbidities/suicidality. RESULTS: When age was omitted from analyses, females with ARFID had a lower frequency of depressive disorders and suicidality compared to AN. Adjusting for age, only suicidality differed between groups. DISCUSSION: This is the first study to compare comorbidities in a similar number of individuals with ARFID and AN, and a structured clinical interview to confer ARFID and comorbidities, covarying for age, and the first to compare suicidality. Although suicidality is at least three times less common in ARFID than AN, observed differences in other psychiatric comorbidities may reflect ARFID's relatively younger age of presentation compared to AN. PUBLIC SIGNIFICANCE: Our results highlight that, with the exception of suicidality, which was three times less common in ARFID than AN irrespective of age, observed differences in psychiatric comorbidities in clinical practice may reflect ARFID's younger age at clinical presentation compared to AN.

Food neophobia as a mechanism of change in video-delivered cognitive-behavioral therapy for avoidant/restrictive food intake disorder: A case study.

OBJECTIVE: The mechanisms through which cognitive-behavioral therapies (CBTs) for avoidant/restrictive food intake disorder (ARFID) may work have yet to be elucidated. To inform future treatment revisions to increase parsimony and potency of CBT for ARFID (CBT-AR), we evaluated change in food neophobia during CBT-AR treatment of a sensory sensitivity ARFID presentation via a single case study. METHOD: An adolescent male completed 21, twice-weekly sessions of CBT-AR via live video delivery. From pre- to mid- to post-treatment and at 2-month follow-up, we calculated percent change in food neophobia and ARFID symptom severity measures. Via visual inspection, we explored trajectories of week-by-week food neophobia in relation to clinical improvements (e.g., when the patient incorporated foods into daily life). RESULTS: By post-treatment, the patient achieved reductions across food neophobia (45%), and ARFID severity (53-57%) measures and no longer met criteria for ARFID, with sustained improvement at 2-month follow-up. Via visual inspection of week-by-week food neophobia trajectories, we identified that decreases occurred after mid-treatment and were associated with incorporation of a food directly tied to the patient's main treatment motivation. DISCUSSION: This study provides hypothesis-generating findings on candidate CBT-AR mechanisms, showing that changes in food neophobia were related to food exposures most connected to the patient's treatment motivations. PUBLIC SIGNIFICANCE: Cognitive-behavioral therapies (CBTs) can be effective for treating avoidant/restrictive food intake disorder (ARFID). However, we do not yet have evidence to show how they work. This report of a single patient shows that willingness to try new foods (i.e., food neophobia), changed the most when the patient experienced a clinical improvement most relevant to his motivation for seeking treatment.

Elevated Fasting Satiety-Promoting Cholecystokinin (CCK) in Avoidant/Restrictive Food Intake Disorder Compared to Healthy Controls.

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 (F1 = 25.0, P < .001, ηp2 = 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.

Genetics and neurobiology of eating disorders.

Eating disorders (anorexia nervosa, bulimia nervosa and binge-eating disorder) are a heterogeneous class of complex illnesses marked by weight and appetite dysregulation coupled with distinctive behavioral and psychological features. Our understanding of their genetics and neurobiology is evolving thanks to global cooperation on genome-wide association studies, neuroimaging, and animal models. Until now, however, these approaches have advanced the field in parallel, with inadequate cross-talk. This review covers overlapping advances in these key domains and encourages greater integration of hypotheses and findings to create a more unified science of eating disorders. We highlight ongoing and future work designed to identify implicated biological pathways that will inform staging models based on biology as well as targeted prevention and tailored intervention, and will galvanize interest in the development of pharmacologic agents that target the core biology of the illnesses, for which we currently have few effective pharmacotherapeutics.

Eighteen-month Course and Outcome of Adolescent Restrictive Eating Disorders: Persistence, Crossover, and Recovery.

OBJECTIVE: In adults, low-weight restrictive eating disorders, including anorexia nervosa (AN), are marked by chronicity and diagnostic crossover from restricting to binge-eating/purging. Less is known about the naturalistic course of these eating disorders in adolescents, particularly atypical AN (atyp-AN) and avoidant/restrictive food intake disorder (ARFID). To inform nosology of low-weight restrictive eating disorders in adolescents, we examined outcomes including persistence, crossover, and recovery in an 18-month observational study. METHOD: We assessed 82 women (ages 10-23 years) with low-weight eating disorders including AN (n = 40; 29 restricting, 11 binge-eating/purging), atyp-AN (n = 26; 19 restricting, seven binge-eating/purging), and ARFID (n = 16) at baseline, nine months (9 M; 75% retention), and 18 months (18 M; 73% retention) via semi-structured interviews. First-order Markov modeling was used to determine diagnostic persistence, crossover, and recovery occurring at 9 M or 18 M. RESULTS: Among all diagnoses, the likelihood of remaining stable within a given diagnosis was greater than that of transitioning, with the greatest probability among ARFID (0.84) and AN-R (0.62). Persistence of BP and atypical presentations at follow-up periods was less stable (AN-BP probability 0.40; atyp-AN-R probability 0.48; atyp-AN-BP probability, 0.50). Crossover from binge-eating/purging to restricting occurred 72% of the time; crossover from restricting to binge-eating/purging occurred 23% of the time. The likelihood of stable recovery (e.g., recovery at both 9 M and 18 M) was between 0.00 and 0.36. CONCLUSION: Across groups, intake diagnosis persisted in about two-thirds, and recovery was infrequent, underscoring the urgent need for innovative treatment approaches to these illnesses. Frequent crossover between AN and atyp-AN supports continuity between typical and atypical presentations, whereas no crossover to ARFID supports its distinction.