Advancing translational neuroscience research for eating disorders

Targeting food craving with orexin-based compounds

The increasingly popular notion that some foods have ‘addictive’ properties raises the interesting possibility that treatments designed to manage substance use disorders may have some utility in managing problematic eating (Mehr et al., 2021). Pharmacological management of substance use disorders has conventionally involved the prescription of substitution therapies that act on similar/identical targets to the drug of abuse. However, currently there is significant interest in the development of a new class of medications that target a more ‘global’ craving system in the brain: the orexin neuropeptide system. Orexins do not mediate the rewarding properties of drugs of abuse per se, but rather play a critical role in translating drug craving (particularly that evoked by exposure to drug-associated stimuli) into drug seeking and taking behaviours. Studies in laboratory rodents indicate that the orexins play a similarly important role in food behaviors; orexin neurons are activated by energy-dense foods, and compounds that block orexin receptor signalling are effective at reducing palatable food intake at doses that do not interfere with normal homeostatic feeding. These and other findings have given impetus to explorations into the potential utility of orexin compounds for the management of overeating. Notably however, Idorsia Pharma ceuticals recently announced that a Phase II clinical trial of their selective orexin-1 receptor antagonist ACT-539313 failed to find any improvement in the number of binge-eating days per week in adult patients with moderate to severe binge eating disorder (BED). Although details of this trial are limited at this time, clearly further work is required to explore and optimize such compounds for clinical use. Moreover, this outcome points to a need for a better mechanistic understanding of the orexin system in overeating, which can only be achieved through the use of preclinical models that recapitulate the human condition as closely as possible.

A novel model of ‘emotional’ stress-induced binge eating will assist our understanding of the neural circuits driving stress-induced binge eating in women

BED is the most common eating disorder affecting 3.5% of women and is chronic in nature typically leading to obesity, which is accompanied by numerous deleterious health consequences. The chronic and relapsing nature of binge eating underscores the urgent need to understand its underlying biological factors in order to derive successful treatments. It is well established that stress and negative affect (e.g. sadness, anger, loneliness) trigger overeating and that the brains of men and women respond to stress in different ways (for review see Anversa et al., 2021). As such, it is not surprising that stress-related eating disproportionately affects females. The precise biological mechanisms underpinning this sex-specific behaviour remain underexplored. This has, in part, been due to the lack of robust animal models that faithfully recapitulate the human condition and a historical focus on male subjects in neuroscientific research. Indeed, neuroscience research has historically overlooked the relevance of biological sex in preclinical research. Common practice is to generalise findings in one sex (usually males) to the other sex (usually females). This scenario has not only led to pharmacotherapies that are more efficacious in males, but put women at risk of adverse side effects, including a higher incidence of adverse drug events and poorer health outcomes compared with men.

We recently established a highly reproducible model of ‘emotional’ stress-induced bingeing that is independent of caloric restriction. Importantly, in our model, only female (not male) mice display binge-like behaviour in response to an acute emotional stressor, thus providing for the first time, an animal model which faithfully recapitulates human conditions. Cyclic caloric restriction is commonly applied in animal models of binge eating but is suboptimal for examining reward-based eating and binge eating driven by hedonic processes independent of the metabolic memory of negative energy balance. Crucially, stress-induced bingeing in our model still occurs in ovariectomised mice, indicating that factors other than ovarian hormones must be involved and that centrally mediated processes instigate this behaviour. Accordingly, our animal model provides an ideal tool to dissect the brain networks underlying the stress-induced drive to eat in females. Understanding the cellular correlates and neural pathways that drive stress-related eating is a critical first step for deriving successful approaches to address this behaviour and towards developing new therapeutic options.

GLP-1 receptor agonists: a potential avenue in the treatment of binge eating disorder or bulimia nervosa?

Glucagon-like peptide 1 (GLP-1) agonists have been firmly established in the treatment algorithm of Type 2 diabetes, as well as obesity. Working through a variety of mechanisms, GLP-1 agonists help improve insulin sensitivity and insulin secretion, as well as delay gastric emptying, all of which help improve glycaemic control in Type 2 diabetes mellitus (T2DM), while also aiding weight loss. In addition to this peripheral effect, GLP-1 agonists are known to act on the central nervous system, where they have a role in energy homeostasis influencing food intake and cravings, appetite, satiety, as well as the reward centres in the brain (Drucker, 2018).

Therefore, it stands to reason that GLP-1 agonists may have a potential role in the treatment of BED and bulimia nervosa (BN). While the only current approved pharmacological treatment for BED is lisdexamphetamine and fluoxetine for BN, GLP-1 agonists could become another tool in the treatment of BED and BN. There are a few small studies that suggest Liraglutide (Saxenda) and Dulaglutide (Trulicity) may help reduce binge eating, but no large randomised controlled trials have been carried out to confirm this. Significantly greater weight loss has been demonstrated in people without T2DM with the once weekly GLP-1 agonist Semaglutide at a higher dose (Wegovy), which has been approved by the Food and Drug Administration (FDA) for use in the United States. More recently, Tirzepatide (Mounjaro), a dual GLP-1 receptor and glucose-dependent insulinotropic peptide (GIP) receptor agonist, has been approved by the FDA for use in T2DM management, and both medications result in significantly greater weight loss (over 15% body weight loss) and appetite suppression compared to previously marketed GLP-1 receptor agonists.

We know from previous studies that anti-obesity agents have not been successful in treating BED or BN, and nausea and vomiting are common side effects of these drugs, conveying increased risk in using these in people with BN. There is also potential for misuse of these medications in people with AN. While the management of BED/BN and achieving weight loss are two very different outcomes, and, although we know that weight loss does not necessarily help treat the eating disorder symptomatology, the potential for these newer agents to help reduce binge eating behaviours warrants investigation.

Using animal models to scrutinise the effects of psilocybin on feeding behaviour

In recent years, there has been a resurgence of interest in the therapeutic use of psychedelics, including psilocybin, the psychoactive compound produced by ‘magic’ mushrooms for a range of psychiatric conditions. A growing base of evidence supports the potential efficacy of psilocybin in alleviating symptoms of depression, addiction and end-of-life anxiety (Carhart-Harris et al., 2018) and in improving outcomes in patient populations by increasing cognitive and neural flexibility (Doss et al., 2021). There are presently three active clinical trials investigating the safety and tolerability of psilocybin in patients with AN, and the preliminary results from the COMP360 study (UCSD School of Medicine) show significant reductions in eating disorder pathologies in a subpopulation of patients.

While it is appreciated that animal models in general only partially capture the behavioural, emotional and phenomenological aspects of the human conditions they aim to model, this may be particularly true for psychedelics (considering the subjective perceptual experience elicited by psychedelics, as well as the interpretation of this experience in the context of enduring effects). However, the range of responses identified already within patient populations suggests that there are underlying biological differences in some patients – but not others – implying subsets of patients may be particularly well-suited to psychedelic treatment. This is the major benefit of using animal models to probe the neurochemical, neural circuit-based and biochemical signalling drivers of the effects of psilocybin on feeding behaviour and pathological weight loss. A multidisciplinary, interactive approach to eating disorder drug discovery, where animal models generate neurobiological hypotheses to be tested in the clinic and vice versa, could prove to be beneficial and should be cultivated. In this context, the most well-established animal model of AN, known as activity-based anorexia (ABA), can be used to reveal behavioural and neurobiological biomarkers that can be used to predict whether an individual animal will respond to psilocybin with positive body weight outcomes which can, in turn, direct the clinical application of psychedelics to subgroups of patients that are most likely to respond.

Conclusion

Effective brain-based interventions, especially when combined with evidence-based psychological treatments, have the potential to radically reduce the burden of eating disorders. Translational research is key to expanding the knowledge base for the development of novel pharmacological interventions and precision medicine tools. As such, greater strategic investment in neuroscience eating disorders research is required to support every phase of the translational pipeline and to ultimately improve outcomes for eating disorder patients receive.