Does hypoleptinemia trigger entrapment in anorexia nervosa? Etiological and clinical considerations.

Based on the recent observation that human recombinant leptin (r-Met-hu-leptin; metreleptin) may induce a profound alleviation of the complex symptomatology of patients with anorexia nervosa (AN), we examine the implications for our conceptualisation of this eating disorder. Hypoleptinemia as a core endocrine feature of AN serves as a central and peripheral trigger of tissue-specific adaptations to starvation. In this narrative review, we argue that leptin deficiency may explain many of the puzzling features of this eating disorder. Weight loss can be viewed as a two-step process, with only the second step entailing hypoleptinemia and thereby the entrapment characteristic of AN. We discuss the central and peripheral distribution of leptin receptors and consider possible functional implications of hypoleptinemia. We contrast the slow psychological recovery of patients with AN and of people who experienced starvation upon weight recovery with the rapid onset of improvements upon off-label metreleptin treatment. Characteristics of the sex and age dependent secretion of leptin may contribute to the elevated vulnerability of young females to develop AN.

Eating disorder treatment in routine clinical care: A descriptive study examining treatment characteristics and short-term treatment outcomes among patients with anorexia nervosa and bulimia nervosa in Germany and Switzerland.

This descriptive study examined patient characteristics, treatment characteristics, and short-term outcomes among patients with Anorexia Nervosa (AN) and Bulimia Nervosa (BN) in routine clinical care. Results for patients receiving full-time treatment were contrasted with results for patients receiving ambulatory treatment. Data of a clinical trial including 116 female patients (18-35 years) diagnosed with AN or BN were subjected to secondary analyses. Patients were voluntarily admitted to one of nine treatment facilities in Germany and Switzerland. Patients received cognitive-behavioral interventions in accordance with the national clinical practice guidelines for the treatment of EDs under routine clinical care conditions, either as full-time treatment or ambulatory treatment. Assessments were conducted after admission and three months later. Assessments included a clinician-administered diagnostic interview (DIPS), body-mass-index (BMI), ED pathology (EDE-Q), depressive symptoms (BDI-II), symptoms of anxiety (BAI), and somatic symptoms (SOMS). Findings showed that treatment intensity differed largely by setting and site, partly due to national health insurance policies. Patients with AN in full-time treatment received on average 65 psychotherapeutic sessions and patients with BN in full-time treatment received on average 38 sessions within three months. In comparison, patients with AN or BN in ambulatory treatment received 8-9 sessions within the same time. Full-time treatment was associated with substantial improvements on all measured variables for both women with AN (d = .48-.83) and BN (d = .48-.81). Despite the relatively small amount of psychotherapeutic sessions, ambulatory treatment was associated with small increases in BMI (d = .37) among women with AN and small improvements on all measured variables among women with BN (d = .27-.43). For women with AN, reduction in ED pathology were positively related to the number of psychotherapeutic sessions received. Regardless of diagnosis and treatment setting, full recovery of symptoms was rarely achieved within three months (recovery rates ranged between 0 and 4.4%). The present study shows that a considerable amount of patients with EDs improved after CBT-based ED treatment in routine clinical care within three months after admission. Intensive full-time treatment may be particularly effective in quickly improving ED-related pathology, although full remission of symptoms is typically not achieved. A small amount of ambulatory sessions may already produce considerable improvements in BN pathology and weight gain among women with AN. As patient characteristics and treatment intensity differed largely between settings, results should not be interpreted as superiority of one treatment setting over another. Furthermore, this study shows that treatment intensity is quite heterogeneous, indicating the possibility for increasing effectiveness in the treatment of EDs in routine clinical care.

Plasma concentrations of SSRI/SNRI after bariatric surgery and the effects on depressive symptoms.

Background: Depression and treatment with antidepressants SSRI/SNRI are common in people with morbid obesity who are candidates for bariatric surgery. There is few and inconsistent data about the postoperative plasma concentrations of SSRI/SNRI. The aims of our study were to provide comprehensive data about the postoperative bioavailability of SSRI/SNRI, and the clinical effects on depressive symptoms. Methods: Prospective multicenter study including 63 patients with morbid obesity and therapy with fixed doses of SSRI/SNRI: participants filled the Beck Depression Inventory (BDI) questionnaire, and plasma levels of SSRI/SNRI were measured by HPLC, preoperatively (T0), and 4 weeks (T1) and 6 months (T2) postoperatively. Results: The plasma concentrations of SSRI/SNRI dropped significantly in the bariatric surgery group from T0 to T2 by 24.7% (95% confidence interval [CI], -36.8 to -16.6, p = 0.0027): from T0 to T1 by 10.5% (95% 17 CI, -22.7 to -2.3; p = 0.016), and from T1 to T2 by 12.8% (95% CI, -29.3 to 3.5, p = 0.123), respectively.There was no significant change in the BDI score during follow-up (-2.9, 95% CI, -7.4 to 1.0; p = 0.13).The clinical outcome with respect to SSRI/SNRI plasma concentrations, weight change, and change of BDI score were similar in the subgroups undergoing gastric bypass surgery and sleeve gastrectomy, respectively. In the conservative group the plasma concentrations of SSRI/SNRI remained unchanged throughout the 6 months follow-up (-14.7, 95% CI, -32.6 to 1.7; p = 0.076). Conclusion: In patients undergoing bariatric surgery plasma concentrations of SSRI/SNRI decrease significantly by about 25% mainly during the first 4 weeks postoperatively with wide individual variation, but without correlation to the severity of depression or weight loss.

Disrupted longitudinal restoration of brain connectivity during weight normalization in severe anorexia nervosa.

Altered intrinsic brain connectivity of patients with anorexia nervosa has been observed in the acute phase of the disorder, but it remains unclear to what extent these alterations recover during weight normalization. In this study, we used functional imaging data from three time points to probe longitudinal changes in intrinsic connectivity patterns in patients with severe anorexia nervosa (BMI ≤ 15.5 kg/m2) over the course of weight normalization. At three distinct stages of inpatient treatment, we examined resting-state functional connectivity in 27 women with severe anorexia nervosa and 40 closely matched healthy controls. Using network-based statistics and graph-theoretic measures, we examined differences in global network strength, subnetworks with altered intrinsic connectivity, and global network topology. Patients with severe anorexia nervosa showed weakened intrinsic connectivity and altered network topology which did not recover during treatment. The persistent disruption of brain networks suggests sustained alterations of information processing in weight-recovered severe anorexia nervosa.

Rapid Emergence of Appetite and Hunger Resulting in Weight Gain and Improvement of Eating Disorder Symptomatology during and after Short-Term Off-Label Metreleptin Treatment of a Patient with Anorexia Nervosa.

Off-label treatment of a 15-year-old female patient with anorexia nervosa (AN) with human recombinant leptin (metreleptin) for nine days was associated with self-reported increments of appetite and hunger resulting in rapid weight gain and substantial improvement of eating disorder cognitions and of depression. The results further substantiate the effects of metreleptin on both AN and depression. We contrast these results with the widespread view that leptin is an anorexigenic hormone. Randomized controlled trials are warranted to confirm the described effects.

Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa: A Coordinated Analysis by the ENIGMA Eating Disorders Working Group.

BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251). RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients. CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.

Estimation of meal portions in bulimia nervosa compared to anorexia nervosa and healthy controls.

PURPOSE: Bulimia nervosa (BN) and anorexia nervosa (AN) are potentially life-threatening eating disorders (ED) that primarily affect young people, mostly women. The central common pathology is linked to the relationship with food and with abnormalities in food intake. A previous study indicated that individuals with AN tend to overestimate food portion sizes compared to healthy controls (HC), but no study has investigated these patterns in BN, which was the objective of this study. METHODS: Women with BN (27), AN (28), and HC (27) were asked to rate different meal portion sizes in two conditions: as if they were supposed to eat them (intent-to-eat condition) or in general (general condition). BN results were compared to HC and AN using mixed model analyses. RESULTS: BN showed larger estimations compared to HC, while smaller estimations compared to AN. These differences were found mostly for intermediate portion sizes. No difference for conditions (intent-to-eat; general) was found between groups. CONCLUSION: When estimating food portion sizes, individuals with BN seem to fall intermediately between HC and AN. ED symptoms in BN were most strongly associated with higher portion estimation. This might therefore reflect one aspect of the cognitive distortions typically seen also in AN. A therapeutic option could include the frequent visual exposure to increasing portions of food, what may serve to recalibrate visual perceptions of what a "normal-sized" portion of food looks like. LEVEL OF EVIDENCE: Level II: Evidence obtained from well-designed controlled trials without randomization.

Rapid amelioration of anorexia nervosa in a male adolescent during metreleptin treatment including recovery from hypogonadotropic hypogonadism.

With this case report we support our medical hypothesis that metreleptin treatment ameliorates starvation related emotional, cognitive and behavioral symptomatology of anorexia nervosa (AN) and show for the first time strong effects in a male patient with AN. A 15.9 year old adolescent with severe AN of eight-month duration was treated off-label with metreleptin. Hyperactivity was assessed with accelerometry. Visual analogue scales (VAS), validated self- and clinician rating scales and lab results tracked changes from baseline to end of the 24-day dosing period and a five-month follow-up. Substantial improvements of mood and eating disorder related cognitions and hyperactivity set in after two days of treatment. During dosing, sub-physiological testosterone and TT3 levels normalized; clinically libido reemerged. Weight did not increase substantially during the dosing period. During follow-up target weight was attained; mood did not deteriorate; hyperactivity ceased. The results substantiate the strong effects seen in female cases and underscore the need for a double-blind placebo-controlled trial to confirm the observed strong, multiple and rapid onset beneficial effects of metreleptin in AN.

Consequences of exposure to the thin ideal in mass media depend on moderators in young women: An experimental study.

This study examined the consequences of media exposure to thin ideals compared to pictures of landscapes in healthy young women and women with eating and mixed mental disorders and investigated whether appearance-related cognitive factors and cognitive distortions moderate the effects. Two hundred seventy-five women in a multisite laboratory trial (174 in- or outpatients and 101 healthy women; Mage 22.87 years, SD = 3.94) were exposed to either thin ideals or to landscape pictures and guided through a vivid imagery of these pictures thereafter. Changes in body image dissatisfaction, mood, eating behavior, and physiological markers were assessed. After thin ideal exposure and even more after guided imagery, women's body image dissatisfaction increased and mood declined. The effect on mood was most pronounced in women with eating disorders, less in women with mixed disorders, and smallest in healthy controls. No effects were found on physiological measures. Higher values of appearance-related cognitive factors moderated the effect of thin ideal exposure and guided imagery on all psychological outcomes. Cognitive distortions moderated the effect of thin ideal exposure and guided imagery on mood. Findings indicate an overall susceptibility to viewing thin ideal pictures in magazines in young and especially in women with eating disorders. Though exposure in the laboratory resulted in psychological effects, it did not lead to a physiological stress response. The impact of thin ideal exposure on mood is in line with affect-regulation models in eating disorders, with appearance-related cognitive factors and cognitive distortions potentially accelerating such effects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Lifetime Weight Characteristics of Adult Inpatients With Severe Anorexia Nervosa: Maximal Lifetime BMI Predicts Treatment Outcome.

Background: The body mass index is a key predictor of treatment outcome in patients with anorexia nervosa. In adolescents, higher premorbid BMI is a strong predictor of a favorable treatment outcome. It is unclear whether this relationship holds true for adults with anorexia nervosa. Here, we examine adult patients with AN and investigate the lowest and highest lifetime BMI and weight suppression as predisposing factors for treatment outcome. Methods: We included 107 patients aged 17-56 with anorexia nervosa and tracked their BMI from admission to inpatient treatment, through discharge, to follow-up at 1-6 years. Illness history, including lowest and highest lifetime BMI were assessed prior to admission. We used multiple linear regression models with minimal or maximal lifetime BMI or weight suppression at admission as independent variables to predict BMI at admission, discharge and follow-up, while controlling for patients' age, sex, and duration of illness. Results: Low minimal BMI had a negative influence on the weight at admission, which in turn resulted in a lower BMI at discharge. Higher maximal BMI had a substantial positive influence on BMI at discharge and follow-up. Weight suppression was highly correlated with maximal BMI and showed similar effects to maximal BMI. Conclusion: Our findings strongly support a relationship between low minimal lifetime BMI and lower BMI at admission, and between higher maximal lifetime BMI or weight suppression and a positive treatment outcome, even years after discharge. Overall, maximal BMI emerged as the most important factor in predicting the weight course in adults with AN.

Does local cerebellar volume predict treatment success in anorexia nervosa?

Anorexia nervosa (AN) is difficult to treat with up to half of patients failing to gain weight during treatment. Neurobiological factors predicting treatment response in AN are poorly understood. In this longitudinal study, we aimed to identify morphological characteristics in the grey matter which predict treatment success in patients with AN. Fifty patients with severe AN participated in an eating disorder-specific inpatient treatment. On admission, T1-weighted magnetic resonance images were acquired from all patients. Half of the patients successfully gained weight, reaching a body-mass index ≥ 17.5 kg/m2. Using voxel-based morphometry, local grey matter volumes were compared between the two groups of patients who gained weight and those who did not. This approach allowed us to identify anatomical characteristics which predict treatment success in terms of post-treatment weight status. Patients who did not reach the weight threshold at discharge had a smaller volume in the right cerebellar crus I at the time of admission. In this group, smaller volume was associated with a greater alexithymia score. The findings suggest that a trophic state within the cerebellum before treatment might be prognostic for treatment success. Consistent with previous reports, this result further substantiates the possible role of the cerebellum in the psychopathology of AN.

Positive Effect of Teriparatide on Areal Bone Mineral Density in Young Women with Anorexia Nervosa: A Pilot Study.

The present pilot study investigated the effect of Teriparatide 1-34 rh-PTH (TPT) in young women diagnosed with anorexia nervosa (AN), and markedly compromised Bone Mineral Density (BMD). Patients were included who had (i) very low BMD (defined as Z-Score < - 2.5 or T-Score < - 2.5 if available) in at least one of the assessed localizations (lumbar spine L1-L4, total hip, femoral neck) without any previous fragility fracture; or (ii) low bone mineral density (defined as Z-Score < - 1.5 or T-Score < - 1.5 if available) in at least one of the assessed localizations (lumbar spine L1-L4, total hip, femoral neck) and at least one previous fragility fracture. Ten patients with an age range of 21-33 were recruited and their bone outcome was assessed after 12, 18, and 24 months. After 24 months of TPT treatment, BMD improved by 13.5% in the spine, 5.0% in the femoral neck, and 4.0% in the hip. Radius cortical bone density (- 2.6%) and radius cortical thickness (- 6.4%) decreased significantly, while in tibia there was no significant decrease. Neither in radius nor in tibia a significant change in trabecular bone parameters occurred. During the treatment, the patients' body weight did not increase significantly. Patients did not experience severe adverse events; only mild side effects were observed. Although these results emerged from a single-arm prospective study, it seems that AN patients with a severely compromised bone situation can benefit from TPT. Larger studies are needed to ascertain the effect of this promising substance.

Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects.

To examine the hypothesis that normalization of low circulating leptin levels in patients with anorexia nervosa ameliorates hyperactivity, three seriously ill females with hyperactivity were treated off-label with metreleptin (recombinant human leptin) for up to 14 days. Drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased in two patients. Surprisingly, depression improved rapidly in all patients. No serious adverse events occurred. Due to obvious limitations of uncontrolled case series, placebo-controlled clinical trials are mandatory to confirm the observed rapid onset of beneficial effects. Our findings suggest an important role of hypoleptinemia in the mental and behavioral phenotype of anorexia nervosa.

Age influences structural brain restoration during weight gain therapy in anorexia nervosa.

Neuroimaging studies on anorexia nervosa (AN) have consistently reported globally reduced gray matter in patients with acute AN. While first studies on adolescent AN patients provide evidence for the reversibility of these impairments after weight gain, longitudinal studies with detailed regional analysis for adult AN patients are lacking and factors associated with brain restitution are poorly understood. We investigated structural changes in anorexia nervosa using T1-weighted magnetic resonance images with surface-based morphometry. The sample consisted of 26 adult women with severe AN and 30 healthy controls. The longitudinal design comprised three time points, capturing the course of weight-restoration therapy in AN patients at distinct stages of weight gain (BMI ≤ 15.5 kg/m2; 15.5 < BMI < 17.5 kg/m2; BMI ≥ 17.5 kg/m2). Compared to controls, AN patients showed globally decreased cortical thickness and subcortical volumes at baseline. Linear mixed effect models revealed the reversibility of these alterations, with brain restoration being most pronounced during the first half of treatment. The restoration of cortical thickness of AN patients negatively correlated with age, but not duration of illness. After weight restoration, residual group differences of cortical thickness remained in the superior frontal cortex. These findings indicate that structural brain alterations of adult patients with severe AN recuperate independently of the duration of illness during weight-restoration therapy. The temporal pattern of brain restoration suggests a decrease in restoration rate over the course of treatment, with patients' age as a strong predictor of brain restitution, possibly reflecting decreases of brain plasticity as patients grow older.

Effects of hunger on mood and affect reactivity to monetary reward in women with obesity - A pilot study.

Worldwide, nearly 3 million people die every year because of being overweight or obese. Although obesity is a metabolic disease, behavioral aspects are important in its etiology. Hunger changes the rewarding potential of food in normal-weight controls. In obesity, impairments related to reward processing are present, but it is not clear whether these are due to mental disorders more common among this population. Therefore, in this pilot study, we aimed at investigating whether fasting influence mood reactivity to reward in people with obesity. Women with obesity (n = 11, all mentally healthy) and normal weight controls (n = 17) were compared on a computerized monetary reward task (the wheel of fortune), using self-reports of mood and affect (e.g., PANAS and mood evaluation during the task) as dependent variables. This task was done in 2 satiety conditions, during fasting and after eating. Partially, in line with our expectation of a reduced affect and mood reactivity to monetary reward in participants with obesity accentuated by fasting, our results indicated a significant within-group difference across time (before and after the task), with monetary gains significantly improving positive affect in healthy controls (p>0.001), but not in individuals with obesity (p = 0.32). There were no significant between-group differences in positive affect before (p = 0.328) and after (p = 0.70) the task. In addition, women with obesity, compared to controls, reported more negative affect in general (p < 0.05) and less mood reactivity during the task in response to risky gains (p < 0.001) than healthy controls. The latter was independent of the level of satiety. These preliminary results suggest an impairment in mood reactivity to monetary reward in women with obesity which is not connected to the fasting state. Increasing the reinforcing potential of rewards other than food in obesity may be one target of intervention in order to verify if that could reduce overeating.

Metabotropic glutamate receptor 5 in bulimia nervosa.

Bulimia nervosa (BN) shares central features with substance-related and addictive disorders. The metabotropic glutamate receptor subtype 5 (mGlu5) plays an important role in addiction. Based on similarities between binge eating and substance-related and addictive disorders, we investigated mGlu5 in vivo in 15 female subjects with BN and 15 matched controls. We measured mGlu5 distribution volume ratio (DVR) with positron emission tomography (PET) using [11 C]ABP688. In BN mGlu5 DVR was higher in the anterior cingulate cortex (ACC), subgenual prefrontal cortex, and straight gyrus (p < 0.05). In BN, higher mGlu5 DVR in various brain regions, including ACC, pallidum, putamen, and caudate, positively correlated with "maturity fears" as assessed using the Eating Disorder Inventory-2 (p < 0.05). In BN and controls, smokers had globally decreased mGlu5 DVR. We present the first evidence for increased mGlu5 DVR in BN. Our findings suggest that pharmacological agents inhibiting mGlu5 might have a therapeutic potential in BN.

Altered circulating endocannabinoids in anorexia nervosa during acute and weight-restored phases: A pilot study.

Anorexia nervosa (AN) is an eating disorder characterized by a low food intake and often exceeding exercise, leading to a particularly low body × weight proportion. Patients with AN usually report less hunger than healthy controls. Endogenous endocannabinoids (eCBs), specifically the anandamide, have been associated to hunger, as a meal initiator, but research regarding AN and eCB and inconclusive. In this pilot study, we investigated plasma levels of eCB in inpatients with AN during fasting and after eating, both during the acute AN phase and after weight recovery. After an 8-hr fasting period, blood sample was collected from all participants. After that, participants were given a muffin test meal. Blood samples for the investigation of endogenous eCBs anandamide (N-arachidonoylethanolamide [AEA]) and 2-arachidonoylglycerol (2-AG) were then collected after 120 and 240 min. Participants were only allowed to eat and drink what was offered them during the research. AN reported less hunger than controls during fasting and at the end of the experiment. Also, plasma levels of AEA were significantly smaller in AN in comparison with controls in all time points. No significant difference was found for 2-AG plasma levels. After recovery, no significant difference was found for eCB levels. These findings could be interpreted as an AEA deregulation in AN before and after food intake, which persists after weight recovery. These findings may have implications to the pharmacological treatment of AN and to relapse occurring in the disorder.

Behavioral Responses to Uncertainty in Weight-Restored Anorexia Nervosa - Preliminary Results.

Impaired decision-making under conditions of uncertainty seems to contribute to the expression and maintenance of anorexia nervosa (AN), but it is not clear whether this impairment is a disease state that would remit with treatment, or a persisting trait in patients with AN. To examine this question, a longitudinal study was conducted in 12 female inpatients with AN (age M = 22.2, SE = 1.36), before (Time-1) and after reaching a body mass index of >17.5 kg/m2 (Time-2). Intolerance of uncertainty (IU) was assessed via a decision-making task, the wheel of fortune (WOF). Weight gain at Time-2 was accompanied with significant changes in uncertainty-related performance compared to Time-1 [(Time × Uncertainty), p < 0.05]. At Time-1, reaction times (RTs) varied in function of uncertainty, while at Time-2, uncertainty did not modulate RTs. These findings support a change in decision-making under uncertainty with successful weight-rehabilitation in AN. While IU was present in underweight patients, it became non-significant after weight restoration.