Pharmacotherapy in Psychiatry and Neurology

Farmakoterapia w Psychiatrii i Neurologii
Farmakoter Psychiatr Neurol.
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Pharmacotherapy in Psychiatry and Neurology

2026, vol. 42, nr 1, January-June, p. 23–36

doi: 10.17219/fpn/218458

Publication type: review

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Shedding new light on anorexia nervosa: The therapeutic promise of the orexin system

Nadzieje związane z układem oreksynowym w terapii jadłowstrętu psychicznego

Karolina Kasprzak1,A,B,C,D,E,F, Julia Sadlak1,A,B,C,D,E,F, Wojciech Ziemichód1,A,E,F, Hanna Karakuła-Juchnowicz1,A,E,F

1 I Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Poland

Abstract

Anorexia nervosa (AN) is a severe psychiatric disorder associated with high morbidity and mortality. Despite decades of research, pharmacological treatments remain largely ineffective. Increasing evidence suggests that the orexin (hypocretin) system, which regulates arousal, motivation, feeding behavior, and stress responses, may play an important role in the pathophysiology of AN.

The present review aims to summarize current evidence regarding the involvement of the orexin system in AN, including its neurobiological mechanisms, interactions with dopaminergic and serotonergic pathways, and the therapeutic potential of orexin receptor modulators.

A literature review was conducted using the PubMed®, Scopus and Web of Science databases. Studies using animal models (activity-based anorexia (ABA)) and clinical investigations were included to assess orexin expression, signaling and modulation in AN. Preclinical findings indicate that orexin contributes to hyperactivity, disrupted reward processing and altered feeding behavior in anorexia models. Both orexin receptor type 1 (OX1R) and type 2 (OX2R) appear to play distinct but complementary roles. Pharmacological modulation, particularly via antagonists such as suvorexant and tebideutorexant (JNJ-61393215), shows promise for reducing hyperarousal and maladaptive motivation. However, clinical evidence remains limited and inconclusive. Human studies have reported inconsistent concentrations of orexin A (OXA) in AN, possibly due to methodological heterogeneity.

The orexin system represents a promising but underexplored target in AN. Further clinical trials are urgently needed to clarify its therapeutic potential and safety profile in malnourished populations. Incorporating orexin modulators into multimodal treatment strategies may provide novel approaches to addressing the biological complexity of AN.

Keywords: anorexia nervosa, orexin system, orexin receptors, reward processing, neuropharmacology

Streszczenie

Przegląd ma na celu podsumowanie wiedzy o roli układu oreksynowego w jadłowstręcie psychicznym (grec. anorexia nervosa - AN), w tym w mechanizmach neurobiologicznych, interakcjach z układami dopaminergicznym i serotoninergicznym oraz potencjale terapeutycznym modulatorów receptorów oreksynowych. Jadłowstręt psychiczny jest ciężkim zaburzeniem psychicznym o wysokiej śmiertelności. Pomimo licznych badań leczenie farmakologiczne pozostaje w dużej mierze nieskuteczne. Coraz więcej dowodów wskazuje na to, że układ oreksynowy (hipokretynowy), regulujący pobudzenie, motywację, zachowania żywieniowe i reakcje na stres, może odgrywać rolę w patofizjologii AN.

Przeprowadzono przegląd literatury w bazach PubMed® i Scopus obejmujący badania przedkliniczne (np. activity-based anorexia) oraz badania kliniczne analizujące ekspresję, sygnalizację i modulację oreksyny w AN. Wyniki badań przedklinicznych wskazują, że oreksyna przyczynia się do nadpobudliwości, zaburzeń układu nagrody i zmian w zachowaniach żywieniowych w modelach jadłowstrętu psychicznego. Receptory oreksynowe 1 (OX1R) i 2 (OX2R) mają odrębne, ale wzajemnie uzupełniające się funkcje. Farmakologiczna modulacja układu oreksynowego, szczególnie za pomocą antagonistów, takich jak suworeksant i JNJ-61393215 (tebideutorexant), wykazuje potencjał w redukcji nadmiernego pobudzenia i nieadaptacyjnych stanów motywacyjnych. Jednak dane kliniczne pozostają ograniczone i niejednoznaczne. Wyniki badań poziomu oreksyny A przeprowadzone u osób cierpiących na AN są niespójne, co prawdopodobnie jest spowodowane heterogennością metodologiczną oraz różnicami w stadium choroby i stanie odżywienia pacjentów.

Układ oreksynowy stanowi obiecujący, lecz wciąż słabo zbadany cel terapeutyczny w jadłowstręcie psychicznym. Niezbędne są dobrze zaprojektowane badania kliniczne, które pozwolą określić skuteczność i bezpieczeństwo interwencji ukierunkowanych na oreksynę, szczególnie w populacjach osób niedożywionych. Włączenie modulatorów oreksynowych do wielomodalnych strategii terapeutycznych może zaoferować nowe podejście do leczenia AN, które będzie uwzględniać jej złożoną neurobiologię.

Słowa kluczowe: anorexia nervosa, jadłowstręt psychiczny, układ nagrody, układ oreksynowy, receptory oreksyny, leczenie jadłowstrętu psychicznego

Introduction

Anorexia nervosa (AN), which is characterized by restrictive food intake, is considered one of the most severe and complex psychiatric disorders. Individuals with AN commonly experience an intense fear of weight gain and a distorted perception of their body image (Resmark et al., 2019). The highest incidence of AN is observed among adolescents aged 15–19 years. Recent studies from European countries have reported an increasing incidence of AN among girls aged 10–14 years and even younger children (Holland et al., 2016; Reas and Rø, 2018; Udo and Grilo, 2022; van Eeden et al., 2023). Research published in 2022 estimated that eating disorders affect approx. 0.91% of the population over a lifetime, whereas AN occurred in 0.16% of the population (Qian et al., 2022). More recently, a study published in 2024 reported a marked increase in the incidence of AN among children and adolescents following the coronavirus disease 2019 (COVID-19) pandemic (Datta et al., 2024).

The development of AN is associated with numerous mental and physical health issues, including depression, anxiety, hormonal problems, and obsessive-compulsive disorder (Resmark et al., 2019). Despite advances in the treatment of AN, no pharmacological therapy has yet demonstrated clinical efficacy (Datta et al., 2024). Furthermore, the neurobiological mechanisms underlying the characteristic features of AN, such as reduced appetite, anxiety, and sleep disturbances associated with excessive arousal and physical activity, remain incompletely understood (Charrat et al., 2023; Datta et al., 2024). These observations suggest the involvement of neurobiological systems regulating feeding behavior, stress, arousal, and reward processing. The orexin system regulates mechanisms of reward, motivation, arousal, eating behavior, and the stress response (Sakurai et al., 2021).

Although behavioral and physiological abnormalities in AN have been well documented, the mechanisms underlying these alterations remain incompletely understood due to limitations and inconsistencies in the available evidence.

The role of orexin receptor agonists and antagonists has not been fully established in the context of AN. Current evidence regarding the role of the orexin system is inconsistent and inconclusive, highlighting the need for further clinical research.

The orexin system serves as a critical interface between metabolic information and reward processing, motivational responses, and arousal regulation within the central nervous system (Katzman and Katzman, 2022).

The disruption of orexin signaling pathways, which are linked to dopaminergic and serotonergic systems, may result in appetite problems and reward system abnormalities, as well as hyperactivity and increased anxiety in AN (Mavanji et al., 2022; Sakurai et al., 2021; Schéle et al., 2023).

Despite growing interest in these mechanisms, research supporting pharmacological interventions targeting the orexin system remains limited (Miskovic-Wheatley et al., 2023). The evidence supporting the involvement of the orexin system in AN is scarce as only preclinical models have been used and no consistent results have been found in clinical studies (Schéle et al., 2023). Consequently, a comprehensive review of the current literature is necessary to clarify the potential role of orexin system regulation as a therapeutic approach in AN (Datta et al., 2024).

The present review summarizes current evidence regarding the involvement of the orexin system in the pathogenesis of AN by integrating findings from both animal and human studies. In addition, it proposes novel therapeutic strategies for psychiatric conditions, including AN.

Material and methods

This narrative review was conducted following the SANRA (Scale for the Assessment of Narrative Review Articles) scale to ensure methodological rigor, transparency, and coherence. Although not a systematic review, a structured and reproducible approach was employed, including predefined search terms, the inclusion of multiple databases, clear selection criteria, and critical evaluation of study quality.

A literature search was conducted in the PubMed®, Scopus and Web of Science databases, covering the period from 2000 to 2025. Additional databases such as ClinicalTrials.gov were searched for registered trials on orexin modulators. The following keywords and their combinations were used: “orexin”; “hypocretin”; “anorexia nervosa”; “eating disorders”; “OX1R”; “OX2R”; “orexin receptor antagonists”; “orexin receptor agonists”; “activity-based anorexia”; “suvorexant”; “JNJ-61393215”; “orexin signaling”; “dopaminergic system”; and “serotonergic system”.

The inclusion criteria were as follows: (1) preclinical or clinical studies involving orexin receptor modulators in the context of AN, feeding behavior, motivation, stress, or hyperarousal; (2) research presenting neurobiological, molecular, behavioral, or clinical endpoints related to orexin signaling; (3) clinical trials or animal model studies including activity-based anorexia (ABA) models.

The exclusion criteria encompassed the following: (1) studies with low methodological quality or unclear outcomes; (2) non-original publications, e.g., opinion pieces, commentaries, editorials, or duplicate reports; (3) studies focused exclusively on sleep disorders, addiction, or metabolic conditions not relevant to eating disorders, anorexia or the orexin system; (4) studies for which the full text was unavailable or conference abstracts without peer-reviewed data.

A total of 121 peer-reviewed English-language articles (original research and reviews) were initially identified. Duplicates were removed, and full texts were reviewed for eligibility by 2 independent reviewers. The quality of the studies was assessed by 2 investigators on a scale from 0 to 2, where: 2 – fully addressing at least one of the 3 aims of the article; 1 – partially addressing the aims; 0 – not addressing the aims. Discrepancies were resolved through discussion and consensus.

The obtained data were extracted into standardized fields:

• study type (preclinical/clinical);

• model (human, animal, etc.);

• intervention (compound target/receptor target);

• endpoints assessed (e.g., orexin expression, brain-derived neurotrophic factor (BDNF) levels, anxiety behaviors, hyperactivity, feeding regulation, reward processing);

• key findings and author conclusions.

All included studies were grouped thematically into 4 major domains: (1) feeding regulation and energy homeostasis; (2) hyperactivity and arousal; (3) anxiety, stress and affective processes; and (4) reward processing and motivational mechanisms.

Additionally, the discussion addressed methodological limitations, translational gaps, and clinical implications based on the extracted evidence.

Neurobiological foundations of the orexin system

The orexin system was first described in 1998 by 2 independent research groups (de Lecea et al., 1998; Sakurai et al., 1998). Sakurai et al. (1998), using chromatography, identified an appetite-enhancing neuropeptide. In parallel, another research team used molecular techniques to discover the same hypothalamic peptide, which they named hypocretin (de Lecea et al., 1998). Orexin (also known as hypocretin) was originally thought to play a key role in the regulation of sleep and wakefulness, reward processing, motivation, and appetite (Xia et al., 2023). Recent studies have demonstrated that orexin influences additional functions, including physi­ological processes such as circadian rhythms. Furthermore, environmental factors, such as food restriction, have been shown to influence the activity of the orexin system (Zink et al., 2014).

The system consists of 2 peptides secreted by hypothalamic neurons: orexin A (OXA), which is highly conserved among mammals, suggesting a crucial role in physiological regulation; and orexin B (OXB), which exhibits greater interspecies variability and may have more diverse functions (Grady et al., 2022; Wong et al., 2011). Both peptides are formed through the enzymatic cleavage of a common precursor protein, prepro-orexin (Chieffi et al., 2017).

Orexin A is composed of 33 amino acids and contains 2 disulfide bridges, while OXB consists of 28 amino acids (Ten-Blanco et al., 2023). Studies have shown that orexin-producing neurons are located primarily in the lateral hypothalamus (LH) and adjacent brain regions, including the periventricular area, dorsal hypothalamus, and posterior hypothalamus. From these regions, orexin neurons regulate feeding behavior, energy expenditure, reward processing, sleep, and stress responses (Chatterjee et al., 2023; Xiao et al., 2025). More recent studies have emphasized the role of orexin in the regulation of circadian rhythms and its potential utility as a therapeutic target in sleep and metabolic disorders (Mohammadkhani et al., 2024).

Two G protein-coupled orexin receptors have been identified: orexin receptor type 1 (OX1R), which is found only in mammals and exhibits a higher affinity for OXA; and orexin receptor type 2 (OX2R), which is present in all vertebrates and displays similar affinity for both OXA and OXB (Soya and Sakurai, 2020). OX1R is predominantly expressed within the midbrain dopaminergic system, including the ventral tegmental area (VTA) and substantia nigra (SN), whereas OX2R plays a major role in the obligatory regulation of sleep and wakefulness and is highly expressed in the tuberomammillary nucleus, posterior subthalamic nuclei, and selected thalamic nuclei (Soya and Sakurai, 2020).

Once stimulated, these receptors initiate multiple intracellular signaling pathways, including Gq-phospholipase C signaling, Ca2+ signaling, and mitogen-activated protein kinase (MAPK) signaling (Couvineau et al., 2022). These pathways influence neurotransmitter excitability and gene expression, thereby contributing to the broad physiological effects of orexin (Chatterjee et al., 2023).

Interplay between the orexin, dopaminergic and serotonergic systems

Orexin activates and modulates both dopaminergic and serotonergic pathways, enabling the organism to respond effectively to rewarding stimuli (Katzman and Katzman, 2022).

The dopaminergic and orexin systems are interconnected, particularly in the regulation of motivation, reward processing and arousal (Calipari and España, 2012). Moreover, both systems contribute to the regulation of food intake and energy expenditure. Orexins have been shown to influence the axonal network of the VTA and SN, which together contain the majority of dopaminergic neurons in both humans and rodents (Fadel and Deutch, 2002; Hrabovszky et al., 2013). Stimulation of the orexin system within the VTA and nucleus accumbens leads to dopamine release, thereby reinforcing behaviors associated with the introduced stimuli or rewards (Kukkonen et al., 2024). Furthermore, activation of OX1R receptors on dopaminergic neurons modulates neuronal activity, influencing learning processes and the development of addictive behaviors (Aston-Jones et al., 2009). The orexin system also suppresses GABAergic neurotransmission, resulting in enhanced dopaminergic activity (Baimel et al., 2015; Tung et al., 2016). The interaction between these systems is bidirectional, as dopamine can influence the activity of the orexin system through D1 and D2 receptors (Bubser et al., 2005; Li et al., 2025). These systems maintain a two-way relationship because dopamine activates orexin system neurons through its binding to D1 and D2 receptors (Bubser et al., 2005; Li et al., 2025). Coordinated signaling between the orexin and dopaminergic systems is essential for the regulation of reward-based behaviors, motivational responses, and arousal levels, while dysregulation of these pathways has been implicated in eating disorders, sleep disorders, and addictive behaviors (Tsujino and Sakurai, 2009). Excessive activation of the orexin system may lead to heightened motivation but has also been associated with addiction, eating disorders, and mood disturbances. Conversely, reduced orexin activity may contribute to diminished motivation and depressive symptoms (Mohammadkhani et al., 2024).

The serotonergic and orexin systems interact closely in the regulation of sleep–wake cycles, physical movement, and feeding behavior (Narayanan et al., 2010). In addition to their role in appetite regulation, both systems influence glucose processing, body thermoregulation and autonomic nervous system function (Xiao et al., 2021). Their coordinated activity contributes to the maintenance of normal sleep architecture and helps prevent excessive daytime sleepiness and disrupted sleep patterns (Hasegawa et al., 2014; Tabuchi et al., 2013). The orexin and serotonergic systems also participate in the regulation of mood and stress responses and may therefore prevent the development of depressive disorders (Staton et al., 2018; Zhang et al., 2022). The serotonergic system in the dorsal raphe nucleus receives stimulation from orexin neurons, which may result in increased dopaminergic activity (Brown et al., 2001; Hasegawa et al., 2014). The orexin system receives inhibitory signals from serotonergic neurons through activation of 5-HT1A receptors, forming a negative feedback mechanism that contributes to sleep stabilization (Sakurai et al., 2005; Tabuchi et al., 2013).

Orexins and anorexia: Evidence from animal studies

Research investigating the role of the orexin system and its receptors, OX1R and OX2R, in AN is ongoing, with some studies suggesting their therapeutic potential while highlighting the complexity of orexin-mediated mechanisms (Xia et al., 2023).

The OX1R is primarily associated with motivation- and reward-related aspects of feeding behavior, whereas OX2R is more closely involved in the regulation of activity levels, energy expenditure and, according to animal studies, meat production (Kukkonen et al., 2024; Mohammadkhani et al., 2024).

Animal studies have demonstrated that selective OX2R agonists, such as YNT-18, attenuated chemotherapy-induced anorexia in mice (Xia et al., 2023). However, the use of OX1R receptor agonists has shown limited efficacy, suggesting that simultaneous activation of both orexin receptors may be more effective in the treatment of AN (Xia et al., 2023).

Activity-based anorexia is a well-established animal model that replicates core features of AN (Foldi, 2023; Gutierrez, 2013; Spadini et al., 2021). In this model, rodents are provided with free access to a running wheel while food availability is restricted, resulting in a paradoxical combination of excessive physical activity and reduced food intake that ultimately leads to rapid and severe weight loss (Gutierrez, 2013; Schalla and Stengel, 2019; Skowron et al., 2021; Spadini et al., 2021). Originally developed in the late 1960s, the ABA model remains the most valid and extensively used preclinical paradigm for investigating the neurobiological, hormonal, and behavioral mechanisms underlying AN (Beeler and Burghardt, 2021; Gutierrez, 2013; Schalla and Stengel, 2019).

The ABA model reliably induces alterations in homeostatic systems, including changes in neuropeptide expression, neural circuitry, hormonal profiles, and immune function, thereby reproducing many of the physiological and behavioral abnormalities observed in patients with AN (Chowdhury et al., 2015; Gutierrez, 2013; Schalla and Stengel, 2019; Spadini et al., 2021).

Importantly, the severity and progression of ABA are influenced by factors such as age, sex, genetic background, and specific protocol details (e.g., duration and timing of food access, wheel adaptation). These variables must be carefully controlled to ensure reproducibility and translational relevance of the model (Gutierrez, 2013; Miletta and Horvath, 2023; Schalla and Stengel, 2019; Spadini et al., 2021).

Despite certain limitations, including its acute rather than chronic nature and its inability to fully capture the complexity of human AN, the ABA model remains a valuable tool for investigating vulnerability, resilience, and potential therapeutic interventions for eating disorders (Beeler et al., 2020; Foldi, 2023; Gutierrez, 2013; Schalla and Stengel, 2019; Spadini et al., 2021).

Given its established role in the regulation of arousal, feeding behavior, and energy expenditure, the orexin system has emerged as a promising candidate for involvement in ABA (Jászberényi et al., 2024; Pinos et al., 2022; Schéle et al., 2023; Xia et al., 2023). Recent studies have investigated changes in the expression of orexin in ABA and examined how pharmacological or genetic manipulation of the orexin system influences the ABA phenotype (Pinos et al., 2022; Schéle et al., 2023; Xia et al., 2023). Furthermore, evidence from ABA models suggests that pharmacological antagonism of orexin receptors can reduce hyperactivity, supporting the hypothesis that the orexin system may represent a promising therapeutic target for the treatment of hyperactivity and energy dysregulation associated with AN (Jászberényi et al., 2024; Pinos et al., 2022; Schéle et al., 2023; Xia et al., 2023).

Recent studies using the ABA mouse model have demonstrated that a large population of hypothalamic orexin neurons becomes highly activated during the severe anorectic state. This activation was visualized using the Fos-TRAP2 technique, which captures active neurons, and was subsequently confirmed by immunohistochemistry. The increased activity of orexin neurons was associated with enhanced food anticipatory activity and hyperactivity. According to the researchers, pharmacological antagonism of orexin receptors (e.g., with suvorexant) reduces hyperactivity, supporting a functional role of orexin in driving excessive activity during ABA (Schéle et al., 2023).

In rats, the capacity to upregulate orexin expression in response to ABA depends on stress-coping style and prenatal stress exposure. Vulnerable animals, characterized by passive coping behavior and prenatal stress exposure, did not exhibit an increase in orexin expression in the LH during ABA. This impaired response was associated with greater weight loss and reduced food intake. In contrast, resilient animals exhibited increased orexin expression, suggesting that orexin upregulation is an adaptive response to starvation and stress (Boersma et al., 2016)

Moreover, in male rats, the number of OXA-immunoreactive cells in the LH decreases significantly at the end of the ABA protocol, particularly when food restriction is combined with increased physical activity. This reduction is more pronounced than that observed following either food restriction or increased activity, suggesting that the combination of severe energy deficit and hyperactivity suppresses orexin expression in the LH (Pinos et al., 2022; Pinos et al., 2023). This decline may represent an adaptive response to prolonged energy deficiency, similar to changes observed during long-term fasting (Pinos et al., 2023).

Some studies report no significant changes in prepro-orexin mRNA expression in the LH during the development of ABA, even as other neuropeptides (e.g., agouti-related peptide (AgRP) and neuropeptide Y (NPY)) are robustly regulated. These findings suggest that orexin expression may not always be directly responsive to negative energy balance or may be regulated by additional factors (de Rijke et al., 2005; Hillebrand et al., 2007).

Human studies investigating anorexia nervosa and orexin signaling

The role of the orexin system in patients with AN remains insufficiently understood, and further studies are required to clarify the specific roles of orexin receptors in the complex pathogenesis of this disorder.

Preliminary studies investigating the role of OXA in AN and its association with cognitive function, sleep, and appetite regulation have yielded inconclusive results (Mogavero et al., 2023; Xia et al., 2023). In a study by Steward et al. (2019), involving 51 adult women with AN and 51 age- and education-matched controls, plasma OXA concentrations were significantly lower in patients with AN than in the control group. Participants completed neuropsychological tests for the assessment of cognitive functions, including the Wisconsin Card Sorting Test (WCST) and the Iowa Gambling Task (IGT). Patients with AN demonstrated poorer performance on both tests than the control group. The authors suggested that reduced OXA concentrations may be associated with cognitive impairment in AN, indicating a possible relationship between orexin signaling and cognitive dysfunction in this disorder (Steward et al., 2019).

The study by Sauchelli et al. (2016) investigated the relationship between OXA concentration, sleep quality, and treatment outcomes in 48 patients with AN and 98 healthy women who served as controls. Although the mean concentration of OXA did not differ between the 2 groups, in patients with AN, higher concentrations of OXA were correlated with reduced sleep quality, which, in turn, was associated with a poorer therapeutic response to treatment (Sauchelli et al., 2016).

Janas-Kozik et al. (2011) examined plasma levels of leptin, a hormone involved in satiety regulation, and OXA, a neuropeptide associated with appetite regulation, in patients with the restrictive subtype of AN. The research focused on analyzing the hormonal disturbances accompanying this disorder. Because both leptin and OXA play important roles in the regulation of appetite and feeding behavior, alterations in their circulating concentrations may contribute to the development or progression of AN. The researchers reported decreased levels of periodin A and leptin in patients with restrictive type of AN compared to the control group. With increasing body weight in AN patients, the concentration of OXA decreased whereas leptin concentration increased, leading the authors to conclude that the regulation of the orexin system in restrictive AN is independent of body weight (Janas-Kozik et al., 2011).

Recent publications from 2020 to 2025 highlight the limited clinical evidence regarding the role of the orexin system in patients with AN (Mohammadkhani et al., 2024; Toor et al., 2021). Further analysis of human orexin studies is needed, particularly to clarify the role of the orexin system in the pathogenesis of AN (Nigro et al., 2025; Toor et al., 2021).

Mechanisms of OX2R agonism and OX1R antagonism in the regulation of body weight and motivation

Increased OX2R expression has been shown to protect against high-fat diet-induced obesity by enhancing the metabolic rate and improving leptin sensitivity, rather than by directly suppressing appetite (Funato et al., 2009).

Long-term administration of a selective OX2R agonist to mice fed a high-fat diet inhibited weight gain and protected against the development of obesity. While short-term orexin activity may stimulate appetite, chronic stimulation of OX2R receptors, particularly in the context of a high-fat diet, has been shown to increase the metabolic rate and prevent obesity (Funato et al., 2009). OX2R may therefore represent a promising target for regulating energy balance and body weight. However, there is no clear evidence that OX2R activation leads to weight gain, particularly in humans. On the contrary, numerous studies indicate that OX2R may be involved in mechanisms that protect against the development of obesity (Chieffi et al., 2017; Funato et al., 2009; Perez-Leighton et al., 2013).

Orexin receptors influence glutamatergic neurotransmission and may affect motivational mechanisms related to food intake and reward processing (Borgland et al., 2008). OX2R is more closely associated with the regulation of wakefulness and arousal, whereas OX1R has a greater impact on reward-related motivation. However, both receptors appear to play complementary roles in these processes (Gozzi et al., 2011; Hopf, 2020; Mohammadkhani et al., 2024).

The orexin system is intricately connected with multiple aspects of metabolism, including hunger, energy status, and stress. Through its actions on hypothalamic–mesolimbic structures, the orexin system influences behaviors such as increased activity, heightened vigilance, and social interactions (Mohammadkhani et al., 2024).

Reduced activity of this system may lead to decreased motivation to eat, diminished interest in pleasurable activities, and indifference, which are symptoms commonly observed in AN and depression (Mohammadkhani et al., 2024; Wang et al., 2018). However, in AN, increased orexin activity may lead to heightened arousal, hyperactivity, and anxiety. Rather than promoting food intake, this elevated activity may unexpectedly reinforce restrictive eating behaviors (Mohammadkhani et al., 2024). Conversely, the overactivation of the orexin system can lead to excessive motivation to seek rewards, which plays a significant role in addictions and compulsive overeating (Mehr et al., 2021).

As discussed above, modulation of the orexin system appears to be a promising therapeutic approach; nevertheless, its clinical application requires careful consideration due to the multifunctional nature of this system and the potential adverse effects associated with its manipulation.

Steiner et al. (2024) described the first selective OX1R antagonist, SB-334867, which demonstrated markedly greater affinity for ORX1R than for OX2R. This discovery represented an important advance in defining the specific role of OX1R antagonism.

OX1R antagonists are the subject of active investigation as promising pharmacological agents for the treatment of various mental conditions. They are being extensively studied as a potential strategy for reducing hyperactivity, anxiety, stress, and impulsive behavior (Fagan et al., 2023; Williams et al., 2024).

Previous studies indicate that pharmacological blockade of OX1R receptors reduces arousal and anxiety in both animal models and humans (Salvadore et al., 2020).

In studies evaluating the selective OX1R antagonist tebideutorexant (JNJ-61393215), researchers observed a reduction in lactam- and CO2-induced panic attacks in rodents, confirming the important role of OX1R in regulating anxiety and memory responses. Notably, the antagonist did not affect motor activity or sleep (Salvadore et al., 2020).

In a clinical study involving patients with anxiety disorders, researchers demonstrated that this compound reduced both the subjective and somatic symptoms of panic. OX1R blockade decreased excessive neuronal activity without inducing sedation, distinguishing it from traditional sedative medications. Additionally, OX1R stimulated the serotonergic, dopaminergic, and noradrenergic systems, leading to increased wakefulness, heightened arousal, faster responses, and difficulty returning to a calm physiological state (Salvadore et al., 2020).

High OX1R activity intensifies the stress response by increasing the secretion of corticotropin-releasing hormone (CRH), stimulating the amygdala, and elevating autonomic arousal. This heightened activity results in excessive sensitivity to stimuli, leading to a stronger stress response and somatic manifestations such as tachycardia and hyperactivity (Salvadore et al., 2020).

In contrast, blockade of OX1R exerts anxiolytic effects by reducing excessive stimulation and normalizing behavior (Merlo Pich and Melotto, 2014; Salvadore et al., 2020).

In stress-free and anxiety-free conditions, OX1R blockade did not produce any changes in motor activity. Similarly, studies evaluating tebideutorexant in healthy individuals demonstrated no significant alterations in motor function (Brooks et al., 2023).

The publication by Williams et al. (2024) describes the development of nivasorexant (ACT-539313), the first selective OX1R antagonist to advance into later-stage clinical trials. The researchers provide a detailed account of the compound discovery process, including the identification of an OX1R-selective compound and the assessment of its pharmacokinetic properties and safety profile. Selective blockade of OX1R inhibited responses associated with stress, emotional arousal, and reward-seeking behavior (Williams et al., 2024).

Nivasorexant is considered a promising therapeutic option due to its favorable pharmacological profile and lack of sedative effects, supporting its potential use in the treatment of disorders characterized by excessive stress responses and compulsive behaviors (Williams et al., 2024).

OX1R antagonists may represent a promising therapeutic option, particularly under conditions of heightened stress and motivation rather than during periods of rest (Bonaventure et al., 2015).

Importance of further research

The integration of orexin modulators into multimodal treatment strategies for AN represents a promising but still emerging field. Preclinical and early clinical evidence supports the role of orexin in the regulation of appetite, reward processing, and sleep, all of which are disrupted in patients with AN (Beckenstrom et al., 2023; Kukkonen and Leonard, 2014; Mehr et al., 2021; Reichelt et al., 2015). However, direct clinical trials in AN are lacking, and most evidence is extrapolated from related disorders or animal models (Beckenstrom et al., 2023; McElroy et al., 2019; Mehr et al., 2021; Reichelt et al., 2015). The combination of pharmacotherapy targeting the orexin, dopamine, or glutamate systems with psychotherapy (enhanced cognitive behavioral therapy (CBT-E)) is theoretically well justified, given the complex neurobiology of AN. Nevertheless, robust clinical data are needed (Frank and Shott, 2016; Lewis et al., 2024; Mitchell et al., 2023).

The quality of the available evidence varies considerably. While mechanistic studies and animal models provide substantial support for the involvement of the orexin system, clinical trials remain limited, and no orexin-targeted pharmacological agents have been approved for the treatment of AN (Beckenstrom et al., 2023; Muratore and Attia, 2022). Progress in this field is further hindered by the heterogeneity of AN, small sample sizes, and the challenges associated with translating neurobiological insights into effective therapeutic interventions (Frank and Shott, 2016; Lewis et al., 2024).

Orexin receptor antagonists and agonists: Risks and safety profile

Both orexin receptor antagonists and agonists have been investigated as therapeutic agents for the treatment of sleep disorders, including insomnia and narcolepsy (Hartman et al., 2025; Na et al., 2024; Xue et al., 2021).

A well-characterized representative of selective orexin receptor antagonists (SORAs) is seltorexant, a selective orexin 2 receptor antagonist (2-SORA) (Ziemichód et al., 2023), under investigation for insomnia disorder and major depressive disorder (MDD) (Mesens et al., 2025; Savitz and Saoud, 2020; Recourt et al., 2019). It has demonstrated efficacy in the treatment of insomnia and MDD, with a favorable safety and tolerability profile in clinical trials; however, it has not yet been approved for clinical use. The most frequently reported adverse effects included somnolence, fatigue, headache, dizziness, abdominal discomfort, and nightmares (Recourt et al., 2019).

Among orexin receptor antagonists, dual orexin receptor antagonists (DORAs), including lemborexant, suvorexant, and daridorexant, have been extensively studied and approved for the treatment for insomnia (Kukkonen et al., 2024; Xue et al., 2021; Ziemichód et al., 2022). These DORAs have been reported to consistently improve sleep onset and sleep maintenance in adults with insomnia, with benefits sustained for up to 12 months (Kunz et al., 2023; Michelson et al., 2014; Yardley et al., 2021). Nonetheless, they have also been associated with a greater incidence of adverse effects compared to placebo (Na et al., 2024). Despite their effectiveness, DORAs may cause excessive daytime sleepiness, sleep paralysis (Na et al., 2024), as well as somnolence, abnormal dreams, fatigue, and xerostomia (Xue et al., 2021). No significant differences in safety have been reported between suvorexant, lemborexant, and daridorexant (Xue et al., 2021). However, among these DORAs, suvorexant has been reported to be associated with the highest relative risk of excessive daytime sleepiness compared with placebo (Na et al., 2024).

Furthermore, several compounds with orexin receptor agonistic activity have also been studied for their potential to promote wakefulness, particularly in patients with narcolepsy. These include oveporexton (TAK-861) (Dauvilliers et al., 2025) and firazorexton (TAK-994) (Dauvilliers et al., 2023). Novel OX2R agonists, such as ORX750, investigated in phase 1 study for the treatment of narcolepsy and idiopathic hypersomnia, have shown a favorable safety profile, with only transient and mild adverse events reported in healthy volunteers (Hartman et al., 2025). In contrast, the OX2R agonist TAK-994 was evaluated in a phase 2, randomized, placebo-controlled trial in patients with narcolepsy type 1. Although the drug demonstrated robust improvements in sleep latency, daytime sleepiness, and cataplexy compared with placebo, its safety profile raised significant concerns. TAK-994 was associated with a high rate of adverse events, most notably serious liver toxicity, which led to the premature termination of the clinical trial (Dauvilliers et al., 2023).

Overall, while sedation and sleep disturbances are the most commonly reported risks, serious metabolic effects and drug interactions are rare or have not yet been reported, especially for OX2R agonists. Additional longitudinal and real-world studies are needed to provide a more comprehensive characterization of their safety profile (Hartman et al., 2025; Na et al., 2024; Ufer et al., 2021; Xue et al., 2021).

Orexin modulators: Registered studies and evidence transfer to anorexia nervosa

Current research on orexin receptor modulators (agonists and antagonists) is most advanced in sleep disorders, particularly narcolepsy, with emerging studies on depression and addiction. However, to date, there are no active or registered interventional studies directly targeting orexin pathways in AN or other eating disorders. Table 1 summarizes key registered studies investigating orexin modulators in narcolepsy, depression, and related conditions, together with their current status and key findings.

Preclinical studies have linked orexin signaling to food-seeking behavior and binge-like eating, and altered orexin levels have been observed during caloric deprivation and in animal models of eating disorders (Beckenstrom et al., 2023; Carpi et al., 2024; Kukkonen et al., 2024). Orexin modulators are being actively investigated for narcolepsy, insomnia, depression, and addiction, but no clinical trials have evaluated these agents in patients with AN (Carpi et al., 2024). Moreover, pathophysiological differences between narcolepsy, depression, addiction, and AN limit the direct evidence transfer. Consequently, the safety and efficacy of orexin modulators in malnourished patients with AN remain unknown (Beckenstrom et al., 2023; Carpi et al., 2024). Although preclinical and mechanistic studies suggest considerable translational potential, dedicated clinical trials are needed. At present, evidence transfer to AN is speculative and highlights a significant research gap.

Knowledge gaps and recommendations for the future

The following section outlines the current state of knowledge regarding the role of the orexin system in AN, identifies key research gaps, and proposes priorities for future investigation.

What we know

Clinical studies examining OXA levels in patients with AN have yielded relevant but inconsistent findings. Steward et al. (2019) reported reduced OXA levels in individuals with AN, a finding supported by Janas-Kozik et al. (2011). Furthermore, Steward et al. stated that reduced orexin levels were associated with cognitive impairment. In contrast, Bronsky et al. (2011) documented both increases and decreases in OXA concentrations during an eight-week refeeding period. Moreover, Sauchelli et al. (2016) found no significant differences in OXA concentrations between patients with AN and healthy controls, although higher orexin levels within the AN group were associated with poorer sleep quality. Collectively, these discrepancies highlight the limited nature of the current evidence and the considerable heterogeneity of study populations and methodologies.

In summary, the presence of orexin in the brain, together with findings from behavioral and animal studies, suggests that the orexin system may represent a potential therapeutic target in AN. However, the evidence remains mixed, and further studies are needed to elucidate the underlying mechanisms and assess the translational potential of orexin-modulated interventions.

What we do not know

To advance the field, future studies should be rigorously designed to assess both OXA and OXB across different stages of the disorder while distinguishing between the restrictive and binge–purge subtypes of anorexia. Given the complex physiological roles of orexins, it is essential to control for key confounding variables, including age, sleep quality, comorbid psychiatric conditions, and substance use. In addition, the interplay between the orexin system and other systems that may affect the patient’s condition should be carefully considered.

Although the ABA model has been instrumental in elucidating orexin-related mechanisms, it exhibits critical translational limitations. Activity-based anorexia reflects an acute, short-term state of malnutrition, whereas human AN is a chronic, relapsing disorder driven by psychological and sociocultural factors. Moreover, interspecies differences limit the applicability of pharmacological findings from rodent models to clinical settings. Consequently, findings derived from the ABA model should be interpreted with appropriate caution when extrapolated to human disease. There is therefore a need for refined or alternative preclinical models that more accurately reproduce the chronic course and psychosocial complexity of AN, for example through protocols incorporating prolonged food restriction, stress exposure, or repeated relapse cycles.

Another important research gap is the absence of clinical trials directly evaluating orexin modulators in individuals with AN. Although preclinical and mechanistic studies provide a rationale for their potential use, differences in pathophysiology and the particular vulnerability of malnourished patients necessitate dedicated investigations of the pharmacodynamics, pharmacokinetics, and safety profiles of these compounds in this population. Therefore, the extrapolation of evidence from other disorders to AN remains speculative and highlights a significant research gap.

Additionally, inconsistencies in the current literature may reflect methodological differences across studies, including the assessment of mRNA vs. protein expression, differences in the timing of tissue collection, and variation in the hypothalamic subregions analyzed. For instance, some studies focus solely on the LH, whereas others include broader hypothalamic areas, contributing to variability in the reported changes in orexin expression (Boersma et al., 2016; de Rijke et al., 2005; Hillebrand et al., 2007; Mavanji et al., 2024; Schéle et al., 2023).

What should be investigated

Multimodal treatment approaches integrating pharmacotherapy (e.g., orexin modulators, dopamine agents, or NMDA antagonists) with psychotherapy, such as CBT-E, represent a promising but still underexplored direction in the treatment of AN (Beckenstrom et al., 2023; Frank and Shott, 2016; Lewis et al., 2024; Mitchell et al., 2023). Ketamine and zinc have been proposed as agents targeting the dysregulation of excitatory and inhibitory neurotransmission, potentially enhancing the effects of psychotherapy (Lewis et al., 2024; Mitchell et al., 2023), while dopamine modulation may facilitate fear extinction and reduce eating-related distress (Baik, 2020; Frank and Shott, 2016).

Sleep dysregulation is common in eating disorders and may exacerbate compulsive eating through hyperactivity of the orexin system (Beckenstrom et al., 2023; Mehr et al., 2021). Therefore, pharmacological interventions that normalize orexin signaling could improve both sleep quality and eating behaviors. Dual orexin receptor antagonists, which are already being investigated for sleep disorders and substance use, may also have therapeutic potential in eating disorders such as binge eating disorder (BED) (Mehr et al., 2021). Animal studies suggest that chronic binge eating may induce plasticity and hyperactivity within the orexin system, contributing to both compulsive eating and sleep disturbances. Furthermore, stress and chronic undernutrition can disrupt dopamine-mediated reward processing, further contributing to the pathophysiology of AN (Baik, 2020; Frank and Shott, 2016; Kukkonen and Leonard, 2014).

The integration of orexin modulators into multimodal treatment strategies for AN remains a promising but emerging field. Although mechanistic studies and animal models provide valuable insights, clinical trials remain limited, and no orexin-targeted drugs have been approved for the treatment of AN (Beckenstrom et al., 2023; Muratore and Attia, 2022). Progress in this area is further limited by the clinical heterogeneity of AN, small sample sizes, and the difficulty of translating neurobiological findings into effective therapeutic interventions.

In conclusion, although preclinical evidence provides a compelling rationale for targeting orexin pathways in AN, well-designed clinical trials are urgently needed to evaluate the safety, efficacy, and potential integration of orexin-targeted therapies into individualized treatment frameworks.

Conclusions

Although the number of published studies investigating the role of the orexin system in the behavioral and physiological abnormalities associated with AN is increasing, the available evidence remains inconsistent, and the underlying mechanisms have not yet been fully elucidated. The orexin system represents a promising but underexplored therapeutic target in AN. Since the role of orexin receptor agonists and antagonists has not been fully evaluated in patients with AN or other eating disorders, further clinical trials are urgently needed to clarify their therapeutic potential and safety profile in malnourished populations.

Although evidence from experimental animal studies indicates that the orexin system plays an important role in hyperactivity and energy dysregulation in model ABA, its contribution appears to be context-dependent rather than exclusive. The variability observed across experimental models highlights the influence of genetic and environmental factors, while the complexity of orexin system regulation warrants further investigation. Additional studies are required to clarify the precise roles of orexin and its therapeutic potential in AN. Moreover, translational research bridging findings from animal models to human AN remains limited. Despite significant advances, important knowledge gaps persist, including the need to investigate sex-specific differences, the long-term effects of orexin manipulation, and the translation of animal findings into clinical practice.

Based on the available sources, there are no active or registered clinical trials directly targeting orexin pathways in AN or other restrictive eating disorders, making this a promising yet unvalidated therapeutic approach. Evidence from clinical trials in other neuropsychiatric disorders suggest that orexin modulation may influence appetite regulation and reward processing; however, its clinical translation to AN remains untested and speculative.

Orexin modulators represent a novel and biologically plausible therapeutic strategy for AN, particularly when incorporated into multimodal treatment approaches that combine pharmacotherapy targeting reward, sleep, and neurohormonal pathways with psychotherapy to address the complex neurobiology of the disorder. Such integrated approaches may provide novel opportunities to improve treatment outcomes, particularly in patients with severe, chronic, or comorbid forms of AN. However, clinical evidence remains preliminary, and further research is essential to establish the efficacy and safety of orexin-targeted therapies in this patient population.

Modulation of sleep and reward systems is central to both the pathophysiology and potential treatment of AN. Interventions targeting these systems, including orexin modulators and dopaminergic agents, are under active investigation and may offer new therapeutic options for patients who do not respond adequately to standard treatment. Ultimately, personalized, multimodal treatment strategies tailored to an individual’s neurobiology and clinical presentation are likely to play an important role in the management of AN. Future studies should therefore focus on establishing the efficacy and safety of these integrated strategies.

Ethics approval and consent to participate

Not applicable.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Consent for publication

Not applicable.

Use of AI and AI-assisted technologies

Not applicable.

Tables


Table 1. Summary of key registered and completed clinical studies evaluating orexin receptor modulators

Topic

Study

Indication

Drug (NCT/Ref)

Summary

Status

Narcolepsy and sleep disorders

Dauvilliers et al., 2025

narcolepsy type 1

oveporexton (TAK-861, NCT05687903)

Phase 2 RCT in patients with narcolepsy type 1; oral OX2R agonist significantly improved wakefulness and reduced daytime sleepiness and cataplexy over 8 weeks. The most common side effects were insomnia and urinary symptoms, and no hepatotoxicity was observed.

completed

Dauvilliers et al., 2023

narcolepsy type 1

firazorexton (TAK-994, NCT04096560, NCT04820842)

Phase 2 RCT in patients with narcolepsy type 1; oral OX2R agonist improved sleep latency and reduced cataplexy but was associated with liver toxicity, leading to early termination of the trial.

terminated

Hartman et al., 2025

narcolepsy, hypersomnia

cleminorexton (ORX750)

Phase 1 in healthy volunteers; oral OX2R agonist demonstrated dose-dependent wake-promoting effects and was well tolerated, with only mild, transient side effects.

ongoing

Grunstein et al., 2025

narcolepsy, hypersomnia

alixorexton (ALKS 2680)

Phase 1b study in patients with narcolepsy and idiopathic hypersomnia; OX2R agonist improved wakefulness in a dose-dependent manner and demonstrated a favorable safety profile, with only mild side effects and no serious safety concerns.

completed

Na et al., 2024; Mieda and Sakurai, 2013

insomnia

DORAs (suvorexant, lemborexant, daridorexant)

Multiple RCTs and meta-analyses in patients with insomnia; DORAs improved sleep onset and sleep maintenance but increased the risk of mild narcolepsy-like adverse events, including sleep paralysis and daytime sleepiness.

approved/completed

Depression

Meshkat et al., 2025

MDD

seltorexant

Several RCTs in patients with MDD; OX2R antagonist (20 mg) reduced depressive symptoms in some studies, especially when used as adjunctive therapy, although findings remain inconsistent.

completed

Fagan et al., 2022; Meshkat et al., 2025

MDD

filorexant

RCT in patients with MDD; filorexant did not demonstrate significant improvement in depressive symptoms compared with placebo.

completed

Schmidt et al., 2025

MDD with anxious distress

tebideutorexant (JNJ-61393215, NCT04080752)

Phase 2a in patients with MDD with anxious distress; OX1R antagonist did not significantly improve depression or anxiety scores compared to placebo but demonstrated an acceptable safety profile.

completed
DORAs – dual orexin receptor antagonists; MDD – major depressive disorder; NCT – National Clinical Trial number; RCT – randomized controlled trial; OX2R – orexin receptor type 2.

References (120)

  1. Aston-Jones G, Smith RJ, Moorman DE, Richardson KA. Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology 2009; 56 Suppl 1(Suppl 1): 112–121. doi:10.1016/j.neuropharm.2008.06.060
  2. Baik JH. Stress and the dopaminergic reward system. Exp Mol Med 2020; 52(12): 1879–1890. doi:10.1038/s12276-020-00532-4
  3. Baimel C, Bartlett SE, Chiou LC, Lawrence AJ, Muschamp JW, Patkar O, et al. Orexin/hypocretin role in reward: Implications for opioid and other addictions. Br J Pharmacol 2015; 172(2): 334–348. doi:10.1111/bph.12639
  4. Bandarabadi M, Li S, Aeschlimann L, Colombo G, Tzanoulinou S, Tafti M, et al. Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control. Mol Psychiatry 2024; 29(2): 327–341. doi:10.1038/s41380-023-02329-z
  5. Beckenstrom AC, Coloma PM, Dawson GR, Finlayson AK, Malik A, Post A, et al. Use of experimental medicine approaches for the development of novel psychiatric treatments based on orexin receptor modulation. Neurosci Biobehav Rev 2023; 147: 105107. doi:10.1016/j.neubiorev.2023.105107
  6. Beeler JA, Burghardt NS. Activity-based anorexia for modeling vulnerability and resilience in mice. Bio Protoc 2021; 11(9): e4009. doi:10.21769/bioprotoc.4009
  7. Beeler JA, Mourra D, Zanca RM, Kalmbach A, Gellman C, Klein BY, et al. Vulnerable and resilient phenotypes in a mouse model of anorexia nervosa. Biol Psychiatry 2020; 90(12): 829–842. doi:10.1016/j.biopsych.2020.06.030
  8. Boersma GJ, Liang NC, Lee RS, Albertz JD, Kastelein A, Moody LA, et al. Failure to upregulate Agrp and Orexin in response to activity based anorexia in weight loss vulnerable rats characterized by passive stress coping and prenatal stress experience. Psychoneuroendocrinology 2016; 67: 171–181. doi:10.1016/j.psyneuen.2016.02.002
  9. Bonaventure P, Yun S, Johnson PL, Shekhar A, Fitz SD, Shireman BT, et al. A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. J Pharmacol Exp Ther 2015; 352(3): 590–601. doi:10.1124/jpet.114.220392
  10. Borgland SL, Storm E, Bonci A. Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur J Neurosci 2008; 28(8): 1545–1556. doi:10.1111/j.1460-9568.2008.06397.x
  11. Bronsky J, Nedvidkova J, Krasnicanova H, Vesela M, Schmidtova J, Koutek J, et al. Changes of orexin A plasma levels in girls with anorexia nervosa during eight weeks of realimentation. Int J Eat Disord 2011; 44(6): 547–552. doi:10.1002/eat.20857
  12. Brooks S, Zuiker R, Bleys C, Ziagkos D, Moyer JA, van Nueten L, et al. Pharmacological characterization of the selective orexin-1 receptor antagonist JNJ-61393215 in healthy volunteers. J Psychopharmacol 2023; 37(6): 577–589. doi:10.1177/02698811231167989
  13. Brown RE, Sergeeva O, Eriksson KS, Haas HL. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 2001; 40(3): 457–459. doi:10.1016/S0028-3908(00)00178-7
  14. Bubser M, Fadel JR, Jackson LL, Meador-Woodruff JH, Jing D, Deutch AY. Dopaminergic regulation of orexin neurons. Eur J Neurosci 2005; 21(11): 2993–3001. doi:10.1111/j.1460-9568.2005.04121.x
  15. Calipari ES, España RA. Hypocretin/orexin regulation of dopamine signaling: Implications for reward and reinforcement mechanisms. Front Behav Neurosci 2012; 6: 54. doi:10.3389/fnbeh.2012.00054
  16. Carpi M, Palagini L, Fernandes M, Calvello C, Geoffroy PA, Miniati M, et al. Clinical usefulness of dual orexin receptor antagonism beyond insomnia: Neurological and psychiatric comorbidities. Neuropharmacology 2024; 245: 109815. doi:10.1016/j.neuropharm.2023.109815
  17. Charrat JP, Massoubre C, Germain N, Gay A, Galusca B. Systematic review of prospective studies assessing risk factors to predict anorexia nervosa onset. J Eat Disord 2023; 11(1): 163. doi:10.1186/s40337-023-00882-0
  18. Chatterjee O, Gopalakrishnan L, Pullimamidi D, Raj C, Yelamanchi S, Gangadharappa BS, et al. A molecular network map of orexin–orexin receptor signaling system. J Cell Commun Signal 2023; 17(1): 217–227. doi:10.1007/s12079-022-00700-3
  19. Chieffi S, Carotenuto M, Monda V, Valenzano A, Villano I, Precenzano F, et al. Orexin system: The key for a healthy life. Front Physiol 2017; 8: 357. doi:10.3389/fphys.2017.00357
  20. Chowdhury TG, Chen YW, Aoki C. Using the activity-based anorexia rodent model to study the neurobiological basis of anorexia nervosa. J Vis Exp 2015; (105): e52927. doi:10.3791/52927
  21. Couvineau A, Nicole P, Gratio V, Voisin T. The orexin receptors: Structural and anti-tumoral properties. Front Endocrinol (Lausanne) 2022; 13: 931970. doi:10.3389/fendo.2022.931970
  22. Dalle Grave R, El Ghoch M, Sartirana M, Calugi S. Cognitive behavioral therapy for anorexia nervosa: An update. Curr Psychiatry Rep 2016; 18(1): 2. doi:10.1007/s11920-015-0643-4
  23. Datta N, Hossepian K, Xie I, Gurcan HY, Behr S, Pouliadi M, et al. Anorexia nervosa across the lifespan: A review of recent literature. Focus (Am Psychiatr Publ) 2024; 22(3): 269–277. doi:10.1176/appi.focus.20230037
  24. Dauvilliers Y, Mignot E, Del Río Villegas R, Du Y, Hanson E, Inoue Y, et al. Oral orexin receptor 2 agonist in narcolepsy type 1. N Engl J Med 2023; 389(4): 309–321. doi:10.1056/nejmoa2301940
  25. Dauvilliers Y, Plazzi G, Mignot E, Lammers GJ, Del Río Villegas R, Khatami R, et al. Oveporexton, an oral orexin receptor 2-selective agonist, in narcolepsy type 1. N Engl J Med 2025; 392(19): 1905–1916. doi:10.1056/nejmoa2405847
  26. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998; 95(1): 322–327. doi:10.1073/pnas.95.1.322
  27. de Rijke CE, Hillebrand JJG, Verhagen LAW, Roeling TAP, Adan RAH. Hypothalamic neuropeptide expression following chronic food restriction in sedentary and wheel-running rats. J Mol Endocrinol 2005; 35(2): 381–390. doi:10.1677/jme.1.01808
  28. Fadel J, Deutch AY. Anatomical substrates of orexin–dopamine interactions: Lateral hypothalamic projections to the ventral tegmental area. Neuroscience 2002; 111(2): 379–387. doi:10.1016/S0306-4522(02)00017-9
  29. Fagan HA, Huneke NTM, Domschke K, Baldwin DS. The role of the orexin system in the neurobiology of anxiety disorders: Potential for a novel treatment target. Neurosci Appl 2023; 3: 103922. doi:10.1016/j.nsa.2023.103922
  30. Fagan H, Jones E, Baldwin DS. Orexin receptor antagonists in the treatment of depression: A leading article summarising pre-clinical and clinical studies. CNS Drugs 2022; 37(1): 1–12. doi:10.1007/s40263-022-00974-6
  31. Foldi CJ. Taking better advantage of the activity-based anorexia model. Trends Mol Med 2023; 30(4): 330–338. doi:10.1016/j.molmed.2023.11.011
  32. Frank GKW, Shott ME. The role of psychotropic medications in the management of anorexia nervosa: Rationale, evidence and future prospects. CNS Drugs 2016; 30(5): 419–442. doi:10.1007/s40263-016-0335-6
  33. Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, et al. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metabolism 2009; 9(1): 64–76. doi:10.1016/j.cmet.2008.10.010
  34. Gozzi A, Turrini G, Piccoli L, Massagrande M, Amantini D, Antolini M, et al. Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists. PLoS One 2011; 6(1): e16406. doi:10.1371/journal.pone.0016406
  35. Grady FS, Boes AD, Geerling JC. A century searching for the neurons necessary for wakefulness. Front Neurosci 2022; 16: 930514. doi:10.3389/fnins.2022.930514
  36. Grunstein R, Yee B, Chapman J, Tai J, Sivam S, Hopkinson C, et al. 0838 The orexin 2 receptor agonist ALKS 2680 in patients with narcolepsy or idiopathic hypersomnia: A phase 1b study. Sleep 2025; 48(1): A363–A364. doi:10.1093/sleep/zsaf090.0838
  37. Gutierrez E. A rat in the labyrinth of anorexia nervosa: Contributions of the activity-based anorexia rodent model to the understanding of anorexia nervosa. Int J Eat Disord 2013; 46(4): 289–301. doi:10.1002/eat.22095
  38. Hartman D, Sterkel A, Kong J, Ratti E, Accardi M, Saha S, et al. 0863 phase 1 clinical data with orexin receptor 2 (OX2R) agonist, ORX750, in acutely sleep-deprived healthy volunteers. Sleep 2025; 48(1): A374–A375. doi:10.1093/sleep/zsaf090.0863
  39. Hasegawa E, Yanagisawa M, Sakurai T, Mieda M. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J Clin Invest 2014; 124(2): 604–616. doi:10.1172/JCI71017
  40. Hillebrand JJG, de Rijke CE, Verhagen LAW, de Krom M, Van Elburg AA, Hoek HW, et al. Neurobiological parameters and anorexia nervosa: Findings from animal studies. Appetite 2007; 49(1): 298. doi:10.1016/j.appet.2007.03.090
  41. Holland J, Hall N, Yeates DGR, Goldacre M. Trends in hospital admission rates for anorexia nervosa in Oxford (1968–2011) and England (1990–2011): Database studies. J R Soc Med 2016; 109(2): 59–66. doi:10.1177/0141076815617651
  42. Hopf FW. Recent perspectives on orexin/hypocretin promotion of addiction-related behaviors. Neuropharmacology 2020; 168: 108013. doi:10.1016/j.neuropharm.2020.108013
  43. Howe MW, Dombeck DA. Rapid signalling in distinct dopaminergic axons during locomotion and reward. Nature 2016; 535(7613): 505–510. doi:10.1038/nature18942
  44. Hrabovszky E, Molnár CS, Borsay BÁ, Gergely P, Herczeg L, Liposits Z. Orexinergic input to dopaminergic neurons of the human ventral tegmental area. PLoS One 2013; 8(12): e83029. doi:10.1371/journal.pone.0083029
  45. Inutsuka A, Yamanaka A. The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Front Endocrinol (Lausanne) 2013; 4: 18. doi:10.3389/fendo.2013.00018
  46. Janas-Kozik M, Krupka-Matuszczyk I, Stachowicz M, Mazurek U. Jadłowstręt psychiczny w aspekcie mikromacierzy oligonukleotydowych – badania własne. Psychiatr Pol 2007; 41(3): 377–386. https://www.psychiatriapolska.pl/pdf-154120-78674?filename=78674.pdf (last accessed on 21.12.2025).
  47. Janas-Kozik M, Stachowicz M, Krupka-Matuszczyk I, Szymszal J, Krysta K, Janas A, et al. Plasma levels of leptin and orexin A in the restrictive type of anorexia nervosa. Regul Pept 2011; 168(1–3): 5–9. doi:10.1016/j.regpep.2011.02.005
  48. Jászberényi M, Thurzó B, Bagosi Z, Vécsei L, Tanaka M. The orexin/hypocretin system, the peptidergic regulator of vigilance, orchestrates adaptation to stress. Biomedicines 2024; 12(2): 448. doi:10.3390/biomedicines12020448
  49. Katzman MA, Katzman MP. Neurobiology of the orexin system and its potential role in the regulation of hedonic tone. Brain Sci 2022; 12(2): 150. doi:10.3390/brainsci12020150
  50. Koreshe E, Paxton S, Miskovic-Wheatley J, Bryant E, Le A, Maloney D, et al. Prevention and early intervention in eating disorders: Findings from a rapid review. J Eat Disord 2023; 11(1): 38. doi:10.1186/s40337-023-00758-3
  51. Kukkonen JP, Jacobson LH, Hoyer D, Rinne MK, Borgland SL. International Union of Basic and Clinical Pharmacology CXIV: Orexin receptor function, nomenclature and pharmacology. Pharmacol Rev 2024; 76(5): 625–688. doi:10.1124/pharmrev.123.000953
  52. Kukkonen JP, Leonard CS. Orexin/hypocretin receptor signalling cascades. Br J Pharmacol 2014; 171(2): 314–331. doi:10.1111/bph.12324
  53. Kunz D, Dauvilliers Y, Benes H, García-Borreguero D, Plazzi G, Kinter SD, et al. Long-term safety and tolerability of daridorexant in patients with insomnia disorder. CNS Drugs 2023; 37(1): 93–106. doi:10.1007/s40263-022-00980-8
  54. Lewis YD, Bergner L, Steinberg H, Bentley J, Himmerich H. Pharmacological studies in eating disorders: A historical review. Nutrients 2024; 16(5): 594. doi:10.3390/nu16050594
  55. Li H, Wang S, Wang D, Li J, Song G, Guo Y, et al. Dopamine drives feedforward inhibition to orexin feeding system, mediating weight loss induced by morphine addiction. Adv Sci (Weinh) 2025; 12(10): e2411858. doi:10.1002/advs.202411858
  56. Liu RJ, van den Pol AN, Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 2002; 22(21): 9453–9464. doi:10.1523/JNEUROSCI.22-21-09453.2002
  57. Mavanji V, Pomonis B, Kotz CM. Orexin, serotonin, and energy balance. WIREs Mech Dis 2022; 14(1): e1536. doi:10.1002/wsbm.1536
  58. Mavanji V, Pomonis BL, Shekels L, Kotz CM. Interactions between lateral hypothalamic orexin and dorsal raphe circuitry in energy balance. Brain Sci 2024; 14(5): 464. doi:10.3390/brainsci14050464
  59. McElroy SL, Guerdjikova AI, Mori N, Romo-Nava F. Progress in developing pharmacologic agents to treat bulimia nervosa. CNS Drugs 2019; 33(1): 31–46. doi:10.1007/s40263-018-0594-5
  60. Mehr JB, Bilotti MM, James MH. Orexin (hypocretin) and addiction. Trends Neurosci 2021; 44(11): 852–855. doi:10.1016/j.tins.2021.09.002
  61. Mehr JB, Mitchison D, Bowrey HE, James MH. Sleep dysregulation in binge eating disorder and “food addiction”: The orexin (hypocretin) system as a potential neurobiological link. Neuropsychopharmacology 2021; 46(12): 2051–2061. doi:10.1038/s41386-021-01052-z
  62. Merlo Pich E, Melotto S. Orexin 1 receptor antagonists in compulsive behavior and anxiety: Possible therapeutic use. Front Neurosci 2014; 8: 26. doi:10.3389/fnins.2014.00026
  63. Mesens S, Krystal AD, Melkote R, Xu H, Pandina G, Saoud JB, et al. Efficacy and safety of seltorexant in insomnia disorder: A randomized clinical trial. JAMA Psychiatry 2025; 82(10): 967–976. doi:10.1001/jamapsychiatry.2025.1999
  64. Meshkat S, Kwan ATH, Le GH, Wong S, Teopiz KM, Wang L, et al. Efficacy of orexin antagonists for the management of major depressive disorder: A systematic review of randomized clinical trials. J Affect Disord 2025; 327: 409–419. doi:10.1016/j.jad.2024.12.008
  65. Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: A phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; 13(5): 461–471. doi:10.1016/s1474-4422(14)70053-5
  66. Mieda M, Sakurai T. Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status. CNS Drugs 2013; 27(2): 83–90. doi:10.1007/s40263-012-0036-8
  67. Mieda M, Tsujino N, Sakurai T. Differential roles of orexin receptors in the regulation of sleep/wakefulness. Front Endocrinol (Lausanne) 2013; 4: 57. doi:10.3389/fendo.2013.00057
  68. Miletta MC, Horvath TL. Construction of activity-based anorexia mouse models. Bio Protoc 2023; 13(15): e4730. doi:10.21769/bioprotoc.4730
  69. Miskovic-Wheatley J, Bryant E, Ong SH, Vatter S, Le A, Touyz S, et al. Eating disorder outcomes: Findings from a rapid review of over a decade of research. J Eat Disord 2023; 11(1): 85. doi:10.1186/s40337-023-00801-3
  70. Mitchell JS, Hermens DF, Bennett MR, Can AT, Lagopoulos J. Ketamine and zinc: Treatment of anorexia nervosa via dual NMDA receptor modulation. CNS Drugs 2023; 37(2): 159–180. doi:10.1007/s40263-022-00984-4
  71. Mogavero MP, Godos J, Grosso G, Caraci F, Ferri R. Rethinking the role of orexin in the regulation of REM sleep and appetite. Nutrients 2023; 15(17): 3679. doi:10.3390/nu15173679
  72. Mohammadkhani A, Mitchell C, James MH, Borgland SL, Dayas CV. Contribution of hypothalamic orexin (hypocretin) circuits to pathologies of motivation. Br J Pharmacol 2024; 181(22): 4430–4449. doi:10.1111/bph.17325
  73. Muratore AF, Attia E. Psychopharmacologic management of eating disorders. Curr Psychiatry Rep 2022; 24(7): 345–351. doi:10.1007/s11920-022-01340-5
  74. Na HJ, Jeon N, Staatz CE, Han N, Baek IH. Clinical safety and narcolepsy-like symptoms of dual orexin receptor antagonists in patients with insomnia: A systematic review and meta-analysis. Sleep 2024; 47(2): zsad293. doi:10.1093/sleep/zsad293
  75. Narayanan NS, Guarnieri DJ, DiLeone RJ. Metabolic hormones, dopamine circuits, and feeding. Front Neuroendocrinol 2010; 31(1): 104–112. doi:10.1016/j.yfrne.2009.10.004
  76. Nigro E, Argentino F, Musumeci G, Daniele A. Orexin and lifestyle habits: A meaningful connection among nutrition, physical activity, and sleep pattern in health and diseases. Int J Mol Sci 2025; 26(18): 8980. doi:10.3390/ijms26188980
  77. Perez-Leighton CE, Butterick-Peterson TA, Billington CJ, Kotz CM. Role of orexin receptors in obesity: From cellular to behavioral evidence. Int J Obes (Lond) 2013; 37(2): 167–174. doi:10.1038/ijo.2012.30
  78. Pinos H, Sánchez-Serrano R, Carrillo B, Fernández-García JM, García-Úbeda R, de Paz A, et al. Activity-based anorexia alters hypothalamic POMC and orexin populations in male rats. Behav Brain Res 2023; 436: 114055. doi:10.1016/j.bbr.2022.114055
  79. Qian J, Wu Y, Liu F, Zhu Y, Jin H, Zhang H, et al. An update on the prevalence of eating disorders in the general population: A systematic review and meta-analysis. Eat Weight Disord 2022; 27(2): 415–428. doi:10.1007/s40519-021-01162-z
  80. Reas DL, Rø Ø. Time trends in healthcare-detected incidence of anorexia nervosa and bulimia nervosa in the Norwegian National Patient Register (2010–2016). Int J Eat Disord 2018; 51(10): 1144–1152. doi:10.1002/eat.22949
  81. Recourt K, de Boer P, Zuiker R, Luthringer R, Kent J, van der Ark P, et al. The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder. Transl Psychiatry 2019; 9(1): 216. doi:10.1038/s41398-019-0553-z
  82. Reichelt AC, Westbrook RF, Morris MJ. Integration of reward signalling and appetite regulating peptide systems in the control of food-cue responses. Br J Pharmacol 2015; 172(22): 5225–5238. doi:10.1111/bph.13321
  83. Resmark G, Herpertz S, Herpertz-Dahlmann B, Zeeck A. Treatment of anorexia nervosa – New evidence-based guidelines. J Clin Med 2019; 8(2): 153. doi:10.3390/jcm8020153
  84. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92(4): 573–585. doi:10.1016/s0092-8674(00)80949-6
  85. Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, et al. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 2005; 46(2): 297–308. doi:10.1016/j.neuron.2005.03.010
  86. Sakurai T, Saito YC, Yanagisawa M. Interaction between orexin neurons and monoaminergic systems. Front Neurol Neurosci 2021; 45: 11–21. doi:10.1159/000514955
  87. Salvadore G, Bonaventure P, Shekhar A, Johnson PL, Lord B, Shireman BT, et al. Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans. Transl Psychiatry. 2020; 10(1): 308. doi:10.1038/s41398-020-00937-9
  88. Sauchelli S, Jiménez-Murcia S, Sánchez I, Riesco N, Custal N, Fernández-García JC, et al. Orexin and sleep quality in anorexia nervosa: Clinical relevance and influence on treatment outcome. Psychoneuroendocrinology 2016; 65: 102–108. doi:10.1016/j.psyneuen.2015.12.014
  89. Savitz A, Saoud JB. 0504 efficacy and safety of seltorexant in insomnia disorder. Sleep 2020; 43(1): A193. doi:10.1093/sleep/zsaa056.501
  90. Schalla MA, Stengel A. Activity based anorexia as an animal model for anorexia nervosa – a systematic review. Front Nutr 2019; 6: 69. doi:10.3389/fnut.2019.00069
  91. Schéle E, Stoltenborg I, Xie A, Peris-Sampedro F, Adan RAH, Dickson SL. Engagement of the brain orexin system in activity-based anorexia behaviour in mice. Eur Neuropsychopharmacol 2023; 70: 63–71. doi:10.1016/j.euroneuro.2023.02.014
  92. Schmidt ME, Moyer JA, Kezic I, Zhou X, Samtani MN, Bleys C, et al. Efficacy, safety, and tolerability of JNJ-61393215 (tebideutorexant), a selective orexin-1 receptor antagonist, as adjunctive treatment for major depressive disorder with anxious distress: A double-blind, placebo-controlled, randomized phase 2a study. Eur Neuropsychopharmacol 2025; 95: 14–23. doi:10.1016/j.euroneuro.2025.03.007
  93. Skowron K, Kurnik-Łucka M, Jurczyk M, Aleksandrovych V, Stach P, Dadański E, et al. Is the activity-based anorexia model a reliable method of presenting peripheral clinical features of anorexia nervosa? Nutrients 2021; 13(8): 2876. doi:10.3390/nu13082876
  94. Soya S, Sakurai T. Evolution of orexin neuropeptide system: Structure and function. Front Neurosci 2020; 14: 691. doi:10.3389/fnins.2020.00691
  95. Spadini S, Ferro M, Lamanna J, Malgaroli A. Activity-based anorexia animal model: A review of the main neurobiological findings. J Eat Disord 2021; 9(1): 123. doi:10.1186/s40337-021-00481-x
  96. Staton CD, Yaeger JDW, Khalid D, Haroun F, Fernandez BS, Fernandez JS, et al. Orexin 2 receptor stimulation enhances resilience, while orexin 2 inhibition promotes susceptibility, to social stress, anxiety and depression. Neuropharmacology 2018; 143: 79–94. doi:10.1016/j.neuropharm.2018.09.016
  97. Steiner MA, Botticelli L, Bergamini G, Micioni Di Bonaventura E, Gatfield J, Williams JT, et al. Evaluating the efficacy of the selective orexin 1 receptor antagonist nivasorexant in an animal model of binge-eating disorder. Int J Eat Disord 2024; 57(7): 1418–1432. doi:10.1002/eat.24181
  98. Steward T, Mestre-Bach G, Granero R, Sánchez I, Riesco N, Vintró-Alcaraz C, et al. Reduced plasma orexin-A concentrations are associated with cognitive deficits in anorexia nervosa. Sci Rep 2019; 9(1): 7910. doi:10.1038/s41598-019-44450-6
  99. Tabuchi S, Tsunematsu T, Kilduff TS, Sugio S, Xu M, Tanaka KF, et al. Influence of inhibitory serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and wakefulness. Sleep 2013; 36(9): 1391–1404. doi:10.5665/sleep.2972
  100. Ten-Blanco M, Flores Á, Cristino L, Pereda-Pérez I, Berrendero F. Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: From animal to clinical studies. Front Neuroendocrinol 2023; 69: 101066. doi:10.1016/j.yfrne.2023.101066
  101. Thomas CS, Mohammadkhani A, Rana M, Qiao M, Baimel C, Borgland SL. Optogenetic stimulation of lateral hypothalamic orexin/dynorphin inputs in the ventral tegmental area potentiates mesolimbic dopamine neurotransmission and promotes reward-seeking behaviours. Neuropsychopharmacology 2022; 47(3): 728–740. doi:10.1038/s41386-021-01196-y
  102. Toor B, Ray LB, Pozzobon A, Fogel SM. Sleep, orexin and cognition. Front Neurol Neurosci 2021; 45: 38–51. doi:10.1159/000514960
  103. Tsujino N, Sakurai T. Orexin/hypocretin: A neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 2009; 61(2): 162–176. doi:10.1124/pr.109.001321
  104. Tsujino N, Sakurai T. Role of orexin in modulating arousal, feeding, and motivation. Front Behav Neurosci 2013; 7: 28. doi:10.3389/fnbeh.2013.00028
  105. Tung LW, Lu GL, Lee YH, Yu L, Lee HJ, Leishman E, et al. Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. Nat Commun 2016; 7: 12199. doi:10.1038/ncomms12199
  106. Udo T, Grilo CM. Epidemiology of eating disorders among US adults. Curr Opin Psychiatry 2022; 35(6): 372–378. doi:10.1097/YCO.0000000000000814
  107. Ufer M, Kelsh D, Schoedel KA, Dingemanse J. Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem. Sleep 2021; 45(3): zsab224. doi:10.1093/sleep/zsab224
  108. van Eeden AE, van Hoeken D, Hendriksen JMT, Hoek HW. Increase in incidence of anorexia nervosa among 10- to 14-year-old girls: A nationwide study in the Netherlands over four decades. Int J Eat Disord 2023; 56(12): 2295–2303. doi:10.1002/eat.24064
  109. Wang C, Wang Q, Ji B, Pan Y, Xu C, Cheng B, et al. The orexin/receptor system: Molecular mechanism and therapeutic potential for neurological diseases. Front Mol Neurosci 2018; 11: 220. doi:10.3389/fnmol.2018.00220
  110. Williams JT, Bolli MH, Brotschi C, Sifferlen T, Steiner MA, Treiber A, et al. Discovery of nivasorexant (ACT-539313): The first selective orexin-1 receptor antagonist (SO1RA) investigated in clinical trials. J Med Chem 2024; 67(4): 2337–2348. doi:10.1021/acs.jmedchem.3c01894
  111. Wong KKY, Ng SYL, Lee LTO, Ng HKH, Chow BKC. Orexins and their receptors from fish to mammals: A comparative approach. Gen Comp Endocrinol 2011; 171(2): 124–130. doi:10.1016/j.ygcen.2011.01.001
  112. Xia L, Liu HY, Wang BY, Lin HN, Wang MC, Ren JX. A review of physiological functions of orexin: From instinctive responses to subjective cognition. Medicine (Baltimore) 2023; 102(26): e34206. doi:10.1097/MD.0000000000034206
  113. Xiao X, Yeghiazaryan G, Eggersmann F, Cremer AL, Backes H, Kloppenburg P, et al. Deficiency of orexin receptor type 1 in dopaminergic neurons increases novelty-induced locomotion and exploration. eLife 2025; 12: RP91716. doi:10.7554/eLife.91716
  114. Xiao X, Yeghiazaryan G, Hess S, Klemm P, Sieben A, Kleinridders A, et al. Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity. Nat Commun 2021; 12(1): 5249. doi:10.1038/s41467-021-25380-2
  115. Xue T, Wu X, Chen S, Yang Y, Yan Z, Song Z, et al. The efficacy and safety of dual orexin receptor antagonists in primary insomnia: A systematic review and network meta-analysis. Sleep Med Rev 2021; 61: 101573. doi:10.1016/j.smrv.2021.101573
  116. Yardley J, Kärppä M, Inoue Y, Pinner K, Perdomo C, Ishikawa K, et al. Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: Results from a phase 3 randomized clinical trial. Sleep Med 2021; 80: 333–342. doi:10.1016/j.sleep.2021.01.048
  117. Zhang R, Li D, Mao H, Wei X, Xu MD, Zhang S, et al. Disruption of 5-hydroxytryptamine 1A receptor and orexin receptor 1 heterodimer formation affects novel G protein-dependent signaling pathways and has antidepressant effects in vivo. Transl Psychiatry 2022; 12(1): 122. doi:10.1038/s41398-022-01886-1
  118. Ziemichód W, Grabowska K, Kurowska A, Biała G. A comprehensive review of daridorexant, a dual-orexin receptor antagonist as new approach for the treatment of insomnia. Molecules 2022; 27(18): 6041. doi:10.3390/molecules27186041
  119. Ziemichód W, Kurowska A, Grabowska K, Kurowska M, Biała G. Characteristics of seltorexant-innovative agent targeting orexin system for the treatment of depression and anxiety. Molecules 2023; 28(8): 3575. doi:10.3390/molecules28083575
  120. Zink AN, Perez-Leighton CE, Kotz CM. The orexin neuropeptide system: Physical activity and hypothalamic function throughout the aging process. Front Syst Neurosci 2014; 8: 211. doi:10.3389/fnsys.2014.00211
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