A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.

Anorexia nervosa (AN) is a psychiatric illness with the highest mortality. Current treatment options have been limited to psychotherapy and nutritional support, with low efficacy and high relapse rates. Hypothalamic AgRP (agouti-related peptide) neurons that coexpress AGRP and neuropeptide Y (NPY) play a critical role in driving feeding while also modulating other complex behaviors. We have previously reported that genetic ablation of Tet3, which encodes a member of the TET family dioxygenases, specifically in AgRP neurons in mice, activates these neurons and increases the expression of AGRP, NPY, and the vesicular GABA transporter (VGAT), leading to hyperphagia and anxiolytic effects. Bobcat339 is a synthetic small molecule predicted to bind to the catalytic pockets of TET proteins. Here, we report that Bobcat339 is effective in mitigating AN and anxiety/depressive-like behaviors using a well-established mouse model of activity-based anorexia (ABA). We show that treating mice with Bobcat339 decreases TET3 expression in AgRP neurons and activates these neurons leading to increased feeding, decreased compulsive running, and diminished lethality in the ABA model. Mechanistically, Bobcat339 induces TET3 protein degradation while simultaneously stimulating the expression of AGRP, NPY, and VGAT in a TET3-dependent manner both in mouse and human neuronal cells, demonstrating a conserved, previously unsuspected mode of action of Bobcat339. Our findings suggest that Bobcat339 may potentially be a therapeutic for anorexia nervosa and stress-related disorders.

The impact of anorexia nervosa and BMI polygenic risk on childhood growth: A 20-year longitudinal population-based study.

Growth deviating from the norm during childhood has been associated with anorexia nervosa (AN) and obesity later in life. In this study, we examined whether polygenic scores (PGSs) for AN and BMI are associated with growth trajectories spanning the first two decades of life. AN PGSs and BMI PGSs were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 8,654). Using generalized (mixed) linear models, we associated PGSs with trajectories of weight, height, body mass index (BMI), fat mass index (FMI), lean mass index (LMI), and bone mineral density (BMD). Female participants with AN PGSs one standard deviation (SD) higher had, on average, 0.004% slower growth in BMI between the ages 6.5 and 24 years and a 0.4% slower gain in BMD between the ages 10 and 24 years. Higher BMI PGSs were associated with faster growth for BMI, FMI, LMI, BMD, and weight trajectories in both sexes throughout childhood. Female participants with both a high AN PGS and a low BMI PGS showed slower growth compared to those with both a low AN PGS and a low BMI PGS. We conclude that AN PGSs and BMI PGSs have detectable sex-specific effects on growth trajectories. Female participants with a high AN PGS and low BMI PGS likely constitute a high-risk group for AN, as their growth was slower compared to their peers with high PGSs on both traits. Further research is needed to better understand how the AN PGS and the BMI PGS co-influence growth during childhood and whether a high BMI PGS can mitigate the effects of a high AN PGS.

Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study.

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, we conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HC). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 ANBP) and 92 HC using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000019303 .

Influence of the gut microbiome on appetite-regulating neuropeptides in the hypothalamus: Insight from conventional, antibiotic-treated, and germ-free mouse models of anorexia nervosa.

Recent research highlights the profound impact of the gut microbiome on neuropsychiatric disorders, shedding light on its potential role in shaping human behavior. In this study, we investigate the role of the gut microbiome in appetite regulation using activity-based anorexia (ABA) mouse model of anorexia nervosa (AN) - a severe eating disorder with significant health consequences. ABA was induced in conventional, antibiotic-treated, and germ-free mice. Our results show the clear influence of the gut microbiome on the expression of four orexigenic (neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, and orexin) and four anorexigenic peptides (cocaine- and amphetamine-regulated transcript, corticotropin-releasing hormone, thyrotropin-releasing hormone, and pro-opiomelanocortin) in the hypothalamus. Additionally, we assessed alterations in gut barrier permeability. While variations were noted in germ-free mice based on feeding and activity, they were not directly attributable to the gut microbiome. This research emphasizes that the gut microbiome is a pivotal factor in AN's appetite regulation beyond just dietary habits or physical activity.

New perspectives on the role of biological factors in anorexia nervosa: Brain volume reduction or oxidative stress, which came first?

Anorexia nervosa (AN) is an eating disorder (ED) that has seen an increase in its incidence in the last thirty years. Compared to other psychosomatic disorders, ED can be responsible for many major medical complications, moreover, in addition to the various systemic impairments, patients with AN undergo morphological and physiological changes affecting the cerebral cortex. Through immunohistochemical studies on portions of postmortem human brain of people affected by AN and healthy individuals, and western blot studies on leucocytes of young patients and healthy controls, this study investigated the role in the afore-mentioned processes of altered redox state. The results showed that the brain volume reduction in AN could be due to an increase in the rate of cell death, mainly by apoptosis, in which mitochondria, main cellular organelles affected by a decreased dietary intake, and a highly compromised intracellular redox balance, may play a pivotal role.

Positive thinking about negative studies.

The non-reporting of negative studies results in a scientific record that is incomplete, one-sided and misleading. The consequences of this range from inappropriate initiation of further studies that might put participants at unnecessary risk to treatment guidelines that may be in error, thus compromising day-to-day clinical practice.

From awareness to action: an urgent call to reduce mortality and improve outcomes in eating disorders.

High mortality rates and poor outcomes from eating disorders, especially anorexia nervosa, are largely preventable and require urgent action. A national strategy to address this should include prevention; early detection; timely access to integrated physical and psychological treatments; safe management of emergencies; suicide prevention; and investment in training, services and research.

Not niche: eating disorders as an example in the dangers of overspecialisation.

Labelling specific psychiatric concerns as 'niche' topics relegated to specialty journals obstructs high-quality research and clinical care for these issues. Despite their severity, eating disorders are under-represented in high-impact journals, underfunded, and under-addressed in psychiatric training. We provide recommendations to stimulate broad knowledge dissemination for under-acknowledged, yet severe, psychiatric disorders.

Change in food choice during acute treatment and the effect on longer-term outcome in patients with anorexia nervosa.

BACKGROUND: Restriction of food intake is a central pathological feature of anorexia nervosa (AN). Maladaptive eating behavior and, specifically, limited intake of calorie-dense foods are resistant to change and contribute to poor long-term outcomes. This study is a preliminary examination of whether change in food choices during inpatient treatment is related to longer-term clinical course. METHODS: Individuals with AN completed a computerized Food Choice Task at the beginning and end of inpatient treatment to determine changes in high-fat and self-controlled food choices. Linear regression and longitudinal analyses tested whether change in task behavior predicted short-term outcome (body mass index [BMI] at discharge) and longer-term outcome (BMI and eating disorder psychopathology). RESULTS: Among 88 patients with AN, BMI improved significantly with hospital treatment (p < 0.001), but Food Choice Task outcomes did not change significantly. Change in high-fat and self-controlled choices was not associated with BMI at discharge (r = 0.13, p = 0.22 and r = 0.10, p = 0.39, respectively). An increase in the proportion of high-fat foods selected (ß = 0.91, p = 0.02) and a decrease in the use of self-control (ß = -1.50, p = 0.001) predicted less decline in BMI over 3 years after discharge. CONCLUSIONS: Short-term treatment is associated with improvement in BMI but with no significant change, on average, in choices made in a task known to predict actual eating. However, the degree to which individuals increased high-fat choices during treatment and decreased the use of self-control over food choice were associated with reduced weight loss over the following 3 years, underscoring the need to focus on changing eating behavior in treatment of AN.

Shared genetic influences between eating disorders and gastrointestinal disease in a large, population-based sample of adult women and men.

BACKGROUND: Some preliminary research suggests higher rates of gastrointestinal disease in individuals with eating disorders (EDs). However, research is limited, and it remains unknown what etiologic factors account for observed associations. This was the first study to examine how EDs and dimensional ED symptoms (e.g. body dissatisfaction, binge eating) are phenotypically and etiologically associated with gastrointestinal disease in a large, population-based twin sample. METHODS: Adult female (N = 2980) and male (N = 2903) twins from the Michigan State University Twin Registry reported whether they had a lifetime ED (anorexia nervosa, bulimia nervosa, or binge-eating disorder) and completed a measure of dimensional ED symptoms. We coded the presence/absence of lifetime gastrointestinal disease (e.g. inflammatory bowel disease) based on responses to questions regarding chronic illnesses and medications. We first examined whether twins with gastrointestinal disease had higher rates of EDs and ED symptoms, then used correlated factors twin models to investigate genetic and environmental contributions to the overlap between disorders. RESULTS: Twins with gastrointestinal disease had significantly greater dimensional ED symptoms (ß = 0.21, p < 0.001) and odds of a lifetime ED (OR 2.90, p = 0.001), regardless of sex. Shared genetic factors fully accounted for the overlap between disorders, with no significant sex differences in etiologic associations. CONCLUSIONS: Comorbidity between EDs and gastrointestinal disease may be explained by overlap in genetic influences, potentially including inflammatory genes implicated in both types of disorders. Screening for gastrointestinal disease in people with EDs, and EDs in those with gastrointestinal disease, is warranted.

Brain-based gene expression of putative risk genes for anorexia nervosa.

The etiology of anorexia nervosa (AN) remains elusive. Recent genome-wide association studies identified the first genes liked to AN which reached genome-wide significance, although our understanding of how these genes confer risk remains preliminary. Here, we leverage the Allen Human Brain Atlas to characterize the spatially distributed gene expression patterns of genes linked to AN in the non-disordered human brain, developing whole-brain maps of AN gene expression. We found that genes associated with AN are most expressed in the brain, relative to all other body tissue types, and demonstrate gene-specific expression patterns which extend to cerebellar, temporal and basal ganglia structures in particular. fMRI meta-analyses reveal that AN gene expression maps correspond with functional brain activity involved in processing and anticipating appetitive and aversive cues. Findings offer novel insights around putative mechanisms through which genes associated with AN may confer risk.

Exploring the influence of circulating endocannabinoids and nucleus accumbens functional connectivity on anorexia nervosa severity.

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by a harmful persistence of self-imposed starvation resulting in significant weight loss. Research suggests that alterations in the nucleus accumbens (NAcc) and circulating endocannabinoids (eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), may contribute to increased severity and maladaptive behaviors in AN, warranting an examination of the interplay between central reward circuitry and eCBs. For this purpose, we assessed NAcc functional connectivity and circulating AEA and 2-AG concentrations in 18 individuals with AN and 18 healthy controls (HC) to test associations between circulating eCBs, NAcc functional connectivity, and AN severity, as defined by body mass index (BMI). Decreased connectivity was observed between the NAcc and the right insula (NAcc-insula; pFWE < 0.001) and the left supplementary motor area (NAcc-SMA; pFWE < 0.001) in the AN group compared to HC. Reduced NAcc-insula functional connectivity mediated the association between AEA concentrations and BMI in the AN group. However, in HC, NAcc-SMA functional connectivity had a mediating role between AEA concentrations and BMI. Although no significant differences in eCBs concentrations were observed between the groups, our findings provide insights into how the interaction between eCBs and NAcc functional connectivity influences AN severity. Altered NAcc-insula and NAcc-SMA connectivity in AN may impair the integration of interoceptive, somatosensory, and motor planning information related to reward stimuli. Furthermore, the distinct associations between eCBs concentrations and NAcc functional connectivity in AN and HC could have clinical implications for weight maintenance, with eCBs being a potential target for AN treatment.

AgRP neurons coordinate the mitigation of activity-based anorexia.

Anorexia nervosa (AN) is a debilitating and deadly disease characterized by low body mass index due to diminished food intake, and oftentimes concurrent hyperactivity. A high percentage of AN behavioral and metabolic phenotypes can be replicated in rodents given access to a voluntary running wheel and subject to food restriction, termed activity-based anorexia (ABA). Despite the well-documented bodyweight loss observed in AN human patients and ABA rodents, much less is understood regarding the neurobiological underpinnings of these maladaptive behaviors. Hunger-promoting hypothalamic agouti-related peptide (AgRP) neurons have been well characterized in their ability to regulate appetite, yet much less is known regarding their activity and function in the mediation of food intake during ABA. Here, feeding microstructure analysis revealed ABA mice decreased food intake due to increased interpellet interval retrieval and diminished meal number. Longitudinal activity recordings of AgRP neurons in ABA animals exhibited a maladaptive inhibitory response to food, independent of basal activity changes. We then demonstrated that ABA development or progression can be mitigated by chemogenetic AgRP activation through the reprioritization of food intake (increased meal number) over hyperactivity, but only during periods of food availability. These results elucidate a potential neural target for the amelioration of behavioral maladaptations present in AN patients.

Inpatient admissions and mortality of anorexia nervosa patients according to their preceding psychiatric and somatic diagnoses.

OBJECTIVE: Anorexia nervosa (AN) is associated with increased risk of mortality, but little is known about the risk of inpatient admissions and mortality outcomes in individuals with diagnoses of both AN and other psychiatric and somatic conditions. We aimed to investigate the inpatient admissions and mortality among people with AN and other diagnosed conditions using Danish national registers. METHOD: This retrospective cohort study included individuals diagnosed with AN in Denmark, born 1977-2010. We identified other mental and somatic conditions in this population. We used Cox proportional hazards regression to estimate the risk of inpatient admission and mortality, focusing on (i) the number of other diagnosed conditions, and (ii) specific combinations of conditions diagnosed prior to the AN diagnosis. Categories of inpatient admissions considered were due to: (i) AN, (ii) any psychiatric disorder, and (iii) any somatic disorder. Additionally, competing risks survival analysis was used to calculate the cumulative incidence of inpatient admission and all-cause mortality over the follow-up period. RESULTS: The study population included 11,489 individuals. The most common conditions individuals had prior to their AN diagnosis were other eating disorders (34.5%) and anxiety disorders (32.7%). During the follow-up, 3184 (27.7%), 4604 (40.1%), and 6636 (57.8%) individuals were admitted for AN, any psychiatric disorder, and any somatic disorder, respectively; and in total 106 (0.9%) died. The risk of all outcomes was highest among those who had received a higher number of other diagnoses. For most combinations, the risks of admission and mortality were increased. DISCUSSION: Our study presents the prevalence of other conditions in patients with AN in Denmark and elucidates their association with higher rates of inpatient admission and mortality. Our findings highlight the need for comprehensive, multidisciplinary care of patients with AN considering the spectrum of other diagnosed conditions to improve health outcomes.

EEG Spatial-temporal Dynamics of Resting-state Activity in Young Women with Anorexia Nervosa: Preliminary Evidence.

The aim of this study was to provide preliminary evidence on temporal dynamics of resting-state brain networks in youth with anorexia nervosa (AN) using electroencephalography (EEG). Resting-state EEG data were collected in 18 young women with AN and 18 healthy controls (HC). Between-group differences in brain networks were assessed using microstates analyses. Five microstates were identified across all subjects (A, B, C, D, E). Using a single set of maps representative of the whole dataset, group differences were identified for microstates A, C, and E. A common-for-all template revealed a relatively high degree of consistency in results for reduced time coverage of microstate C, but also an increased presence of microstate class E. AN and HC had different microstate transition probabilities, largely involving microstate A. Using LORETA, for microstate D, we found that those with AN had augmented activations in the left frontal inferior operculum, left insula, and bilateral paracentral lobule, compared with HC. For microstate E, AN had augmented activations in the para-hippocampal gyrus, caudate, pallidum, cerebellum, and cerebellar vermis. Our findings suggest altered microstates in young women with AN associated with integration of sensory and bodily signals, monitoring of internal/external mental states, and self-referential processes. Future research should examine how EEG-derived microstates could be applied to develop diagnostic and prognostic models of AN.

Cross-sectional and longitudinal changes in body composition, anxiety, and depression in a clinical sample of adolescents with anorexia nervosa.

OBJECTIVE: Eating disorders among children and adolescents have increased in prevalence, and mortality rates for anorexia nervosa are among the highest for any psychiatric disorder. Our current study aimed to (a) examine the cross-sectional relationship between body composition and anxiety/depressive symptoms among 97 adolescents and young adults who have been diagnosed with anorexia nervosa, (b) examine the longitudinal changes in body composition and anxiety/depressive symptoms over three months (from baseline to follow-up visit), and (c) examine the longitudinal relationship between change in body composition and change in anxiety/depression over three months. METHOD: A retrospective chart review was conducted within an interdisciplinary eating disorder clinic between August 2019 and December 2021. In total, 97 adolescents aged 11-20 years old with diagnoses of anorexia nervosa were included in the analyses. Body composition data were collected at each visit along with parent- and youth-report measures of symptoms of anxiety/depression symptoms. RESULTS: Findings indicated adolescents demonstrated some improvement in body composition, as well as parent-reported reductions in anxiety/depression symptoms. Based on parent reports, increased BMI percentile was associated with improvements in anxiety/depression symptoms. On the other hand, youth did not report significant changes in anxiety/depressive symptoms. Additionally, there were no associated improvements with body composition measures, which may be associated with continued body dissatisfaction or symptoms of anxiety and depression predating the eating disorder. CONCLUSIONS: These results suggest the importance of including interventions addressing depression, anxiety, and body image as part of treatment.

A new conceptual model for anorexia nervosa: A role for connective tissue?

The etiology of anorexia nervosa (AN) remains to be fully elucidated, and current theories also fail to account for the direct effect of starvation on the health of the organs and tissues, specifically the connective tissue present in most organs of the body. Individuals with hereditary disorders of connective tissue manifest with clinical symptoms that overlap with AN, as the abnormal connective tissue also contributes to many of the other extra-articular manifestations of these hereditary disorders. This article hypothesizes that a similar pathophysiology may also contribute to the clinical presentation of AN. Therefore, a better understanding is needed to elucidate: (1) the relationship between abnormal connective tissue and AN, (2) the impact of starvation toward the development of abnormal connective tissue and how this manifests clinically, (3) the etiology of autonomic nervous system changes contributing to the dysautonomia in AN, and (4) how the sensory signals sent from potentially abnormal connective tissue to the central nervous system impact interoception in AN. A conceptual model incorporating abnormal connective tissue is provided. PUBLIC SIGNIFICANCE: The etiology of AN remains poorly understood and current theories fail to account for the direct impact of starvation on the health of the organs and tissues of the body. There is significant clinical overlap between AN and hereditary connective tissue disorders. This paper attempts to provide a new conceptual model for AN in which abnormal connective tissue contributes to the underlying pathogenesis.

Testing the role of associative learning in evidence-based treatments for anorexia nervosa.

Treatments for anorexia nervosa (AN) remain ineffective for many patients. Processes that can account for differential treatment outcomes remain mostly unknown. We propose that the field test the role of associative learning in current psychological treatments. We hold that this line of research could yield actionable information for understanding non-response and improving long-term outcomes. To make this argument, we define associative learning and outline its proposed role in understanding psychiatric disorders and their treatment. We then briefly review data exploring associative learning in AN. We argue that associative learning processes are implicitly implicated in existing treatments; by this rationale, baseline differences in learning may interfere with treatment response. Finally, we outline future research to test our hypotheses. Altogether, future research aimed at better understanding how associative learning may contribute to AN symptom persistence has the potential to inform novel directions in intervention research. PUBLIC SIGNIFICANCE: There is a pressing need to improve outcomes in treatments for anorexia nervosa (AN). We propose that individual differences in associative learning-the ability to form and update associations between cues, contexts, behaviors, and outcomes-may account for differential response to existing treatments. Undertaking this research could provide an understanding of how current treatments work and inform new approaches for those who may be at risk of poor outcomes.

Time to revisit the definition of atypical anorexia nervosa.

In this special issue, international researchers investigate how atypical anorexia nervosa (atypical AN) differs from anorexia nervosa (AN) and other eating disorders with respect to demographics, psychological and physiological morbidity, as well as treatment course and outcome. Manuscripts in this special issue report that atypical AN is associated with substantial medical and psychological morbidity, and the majority of studies find few differences between atypical AN and AN. While much remains to be learned about the long-term course and treatment response of individuals with atypical AN to psychological and pharmacological interventions, the evidence supports conceptualization of atypical AN as part of a spectrum-based restrictive eating disorder. These findings together with the potentially stigmatizing use of the term "atypical" suggest it may be time to revise the existing definition of atypical AN.

An overview and investigation of relapse predictors in anorexia nervosa: A systematic review and meta-analysis.

OBJECTIVE: An extensive number of predictors has been examined across the literature to improve knowledge of relapse in anorexia nervosa (AN). These studies provide various recovery and relapse definitions, follow-up durations and relapse rates. The current study summarizes these values and predictors of relapse in AN in a review and meta-analysis. METHOD: The study was executed according to PRISMA guidelines. Different databases were searched and studies in which participants did not receive an official clinical diagnosis were excluded. A quality analysis was performed using the National Institute of Health's Study Quality Assessment Tool. Random-effects meta-analyses were conducted to summarize data. RESULTS: Definitions of relapse and recovery were diverse. During an average follow-up period of 31 months an average relapse rate of 37% was found. Predictive variables from 28 studies were grouped in six categories: age and sex, symptoms and behaviors, AN subtype and duration, weight or weight change, comorbidity, and personality. The studies were characterized by non-significant and contradictory results. Meta-analyses were performed for the predictors age, AN duration, pre-treatment BMI, post-treatment BMI and depression. These yielded significant effects for post-treatment BMI and depression: higher pre-treatment depression (SMD = .40 CI [.21-.59] and lower post-treatment BMI (SMD = -.35 CI [-.63 to -.07]) increased relapse chances in AN. DISCUSSION: Our results emphasized a lack of sufficiently powered studies, consistent results, and robust findings. Solely post-treatment BMI and pre-treatment depression predicted relapse. Future research should use uniform definitions, larger samples and better designs, to improve our understanding of relapse in AN. PUBLIC SIGNIFICANCE: Knowledge about predictors is important to understand high relapse rates. Our study performed a review and meta-analysis of relapse predictors in AN. Related to the heterogeneity in studies examining predictors, an overview of relapse and recovery definitions, follow-up durations and relapse rates for AN was provided. Significant effects were found for post-treatment BMI and pre-treatment depression. More studies with uniform definitions are needed to improve clinical implications.

OBJETIVO: En la literatura se ha examinado un amplio número de predictores para mejorar el conocimiento de la recaída en la anorexia nerviosa (AN). Estos estudios proporcionan diversas definiciones de recuperación y recaída, duraciones del seguimiento y tasas de recaída. El presente estudio resume estos valores y predictores de recaída en AN en una revisión y metaanálisis. MÉTODO: El estudio se realizó siguiendo las directrices PRISMA. Se realizaron búsquedas en diferentes bases de datos y se excluyeron los estudios en los que los participantes no recibieron un diagnóstico clínico oficial. Se realizó un análisis de calidad mediante la herramienta de evaluación de la calidad de los estudios del Instituto Nacional de Salud. Se realizaron metaanálisis de efectos aleatorios para resumir los datos. RESULTADOS: Las definiciones de recaída y recuperación fueron diversas. Durante un período de seguimiento promedio de 31 meses se encontró una tasa media de recaída del 37%. Las variables predictivas de 28 estudios se agruparon en seis categorías: edad y sexo, síntomas y conductas, subtipo y duración de la AN, peso o cambio de peso, comorbilidad y personalidad. Los estudios se caracterizaron por resultados no significativos y contradictorios. Se realizaron metaanálisis para los predictores edad, duración de la AN, IMC pretratamiento, IMC postratamiento y depresión. Éstos arrojaron efectos significativos para el IMC postratamiento y la depresión: una mayor depresión pretratamiento (DME = −,40; IC: [21 a, 59] y un menor IMC postratamiento (DME = −,35; IC: [−,63 a −,07]) aumentaron las probabilidades de recaída en la AN. DISCUSIÓN: Nuestros resultados enfatizaron la falta de estudios con suficiente potencia, resultados consistentes y hallazgos robustos. Sólo el IMC postratamiento y la depresión pretratamiento predijeron la recaída. Las investigaciones futuras deberían utilizar definiciones uniformes, muestras más grandes y mejores diseños, para mejorar nuestra comprensión de la recaída en la AN.