Case report: clinical improvements observed in first off-label metreleptin treatment of a patient with atypical anorexia nervosa

Hebebrand, Johannes; Antel, Jochen; Peters, Triinu

doi:10.1007/s00787-023-02315-4

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…The hypothesis that leptin plays a substantial role in entrapment has been supported by a Mendelian randomization study linking a low leptin level to an increased risk for development of AN (Peters, Antel, et al, 2021). Further, recent case reports of off-label treatment with recombinant human leptin (metreleptin) have entailed clinical improvements and the lessening of entrapment in patients with both AN (Antel et al, 2021;Gradl-Dietsch et al, 2023;Hebebrand, Antel, von Piechowski, et al, 2023;Milos et al, 2020) and atypical AN (Hebebrand, Antel, & Peters, 2023).…”

Section: Mechanisms Underlying Prediction Of Weight Loss By Premorbid...mentioning

confidence: 99%

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder

Hebebrand,

Seitz,

Föcker

et al. 2024

Intl J Eating Disorders

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ObjectiveFor adolescents, DSM‐5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI‐centile‐for‐age. We hypothesized that the diagnostic weight cut‐off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN.MethodBased on admission BMI‐centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t‐tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders.ResultsWeight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI‐standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN.DiscussionWhereas the weight cut‐off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight‐specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity.Public significanceBecause body weights of patients with AN must drop below the 5th BMI‐centile per DSM‐5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight.

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Section: Mechanisms Underlying Prediction Of Weight Loss By Premorbid...mentioning

confidence: 99%

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder

Hebebrand,

Seitz,

Föcker

et al. 2024

Intl J Eating Disorders

Self Cite

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“…Additionally, further studies will be necessary to identify the molecular mechanisms behind GABAergic alterations. Recent case reports showed that short term treatment of AN patients with leptin, improved their mood and reduced hyperactivity [44, 45]. As mood and hyperlocomotion involve dopamine transmission and leptin is known to modulate the VTA, including VTA GABA neurons [46, 47] and the drive for exercise [48–50], decreased leptin levels may be a causal factor in the reduced GABAergic signaling we found.…”

Section: Discussionmentioning

confidence: 55%

Reduced GABA transmission onto ventral tegmental area dopamine neurons underlies vulnerability for hyperactivity in a mouse model of Anorexia Nervosa

Ducrocq,

Brouwer,

Kooij

et al. 2024

Preprint

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Anorexia nervosa (AN) has the highest mortality among psychiatric diseases. Hyperactivity is a persistent symptom, which is difficult to control for patients and a major barrier to recovery as it interferes with weight gain. Alteration of mesolimbic dopamine transmission has been hypothesized as a critical factor for the development and maintenance of the disease and for hyperactivity. At what level the changes in dopamine occur in anorexic states and whether local mesolimbic neurocircuit plasticity is causally involved remains unclear. Especially the role of local GABA control over dopamine neurons, a powerful regulator of the dopamine system, in an AN context is unknown. We hypothesize that combining caloric restriction with exercise, such as in the activity-based anorexia (ABA) model, alters dopamine transmission via GABA disinhibition that, in turn, facilitates the expression of maladaptive behaviors such as hyperactivity.Therefore, we characterized the impact of the ABA model on plasticity of the dopamine reward system. In ex-vivo brain slices of mice exposed to this model, ventral tegmental area dopamine (VTADA) neurons displayed a higher firing frequency compared to control mice supporting that the midbrain dopamine system undergoes plasticity. This coincided with reduced GABAergic transmission on VTADAneurons. This reduction was at least in part attributable to local VTA GABA (VTAGABA) neurons. Indeed, VTAGABAneurons were less excitable, displayed a lower firing frequency and a lower probability of release onto VTADAneurons. Restoring the excitability of VTAGABAneurons via chemogenetic activation rescued mice from starvation, by decreasing running wheel activity.In summary, we found that the anorexic state leads to dysregulation of VTAGABAtransmission on VTADAneurons that reinforces maladaptive behaviors such as excessive exercise. We uncovered a new mechanism linked to the disturbed dopamine system in ABA-exposed animals, identifying a hitherto unknown role of decreased local GABAergic control over VTA dopamine neuron output.

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“…The delta of leptin concentrations between premorbid and acute stage may also be important. For instance, patients with premorbid overweight who develop AAN may well have higher mean leptin concentrations than patients with AN despite a psychopathology indistinguishable from acute AN (Hebebrand, Antel, & Peters, 2023). Entrapment in starvation was not observed in the Minnesota Starvation Experiment (Keys et al, 1950).…”

Section: How To Explain the Rapid Improvements Observed Upon Off-labe...mentioning

confidence: 94%

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

Hebebrand,

Plieger,

Milos

et al. 2024

Euro Eating Disorders Rev

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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.

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Case report: clinical improvements observed in first off-label metreleptin treatment of a patient with atypical anorexia nervosa

Cited by 5 publications

References 25 publications

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder

Reduced GABA transmission onto ventral tegmental area dopamine neurons underlies vulnerability for hyperactivity in a mouse model of Anorexia Nervosa

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

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