Review An integrative review on the orexin system and hypothalamic dysfunction in [ME/CFS]: implications for precision medicine, 2025, López-Amador

[forestglip]

An integrative review on the orexin system and hypothalamic dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: implications for precision medicine

Noé López-Amador

[Line breaks added]

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder affecting an estimated 0.4% to 2.5% of community populations.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and marked metabolic heterogeneity underscore its complex pathophysiology. The hypothalamic peptides hypocretin-1 and -2 (also known as orexin-A and orexin-B), synthesized by neurons in the lateral hypothalamus, regulate sleep-wake cycles, arousal, autonomic function, and energy homeostasis.

This integrative review aimed to synthesize current evidence on hypothalamic orexinergic dysfunction in ME/CFS and assess its potential as a biomarker framework for stratification in precision medicine. The review followed Whittemore and Knafl’s five-stage methodology.

Comprehensive searches were conducted across PubMed, Scopus, Web of Science, and OpenAlex up to April 2025, supplemented by manual screening of reference lists. Data extraction and synthesis were performed using constant comparison techniques to integrate quantitative outcomes with theoretical insights.

Twenty-seven studies met the inclusion criteria, consistently reporting reduced orexin-A levels in individuals with ME/CFS and variable orexin-B responses indicative of biomarker potential.

Neuroendocrine findings, including alterations in cortisol and adrenocorticotropic hormone levels, along with inflammatory profiles, confirmed the involvement of neuroimmune interactions.

Multi-omics analyses further delineated distinct patient subtypes characterized by unique molecular signatures.

Hypothalamic orexinergic dysfunction emerges as a central feature of ME/CFS, with orexin-B representing a promising candidate biomarker. The integration of orexin profiling with multi-omics data and machine learning strategies provides a viable pathway towards precision-medicine interventions for this heterogeneous condition.

Web | PDF | Exploration of Neuroprotective Therapy | Open Access

 

[forestglip]

Previously on Qeios with two comments:

Orexinergic and Hypothalamic Dysfunction in CFS/ME: An Integrative Review with a Focus on Precision Medicine

 

[Utsikt]

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder affecting an estimated 0.4% to 2.5% of community populations.

That’s not a very good start. If you can’t properly assess the prevalence studies and presumably don’t have a very good understanding of how to define the concept you’re trying to study, I don’t trust your judgement on other matters.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and marked metabolic heterogeneity underscore its complex pathophysiology.

This is presumably their opinion, but it’s presented like a fact.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) encompasses a range of case definitions, from the Centers for Disease Control and Prevention (CDC)-1994 Fukuda criteria to the Canadian Consensus Criteria, that are clinically and pathophysiologically equivalent, assuming the next acronym ME/CFS [1].

As expected, the into shows that they don’t understand the difference of experiencing PEM and not experiencing PEM.

Differential diagnosis is difficult due to symptom overlap with rheumatologic, psychiatric, and endocrine conditions. Although genetic, infectious, and immune contributions are implicated, their interplay remains unclear, limiting diagnostic precision [16, 17].

No, it’s not difficult if you know what you’re doing. There’s always going to be uncertainties, but not more than for any other condition where you have to consider if any given symptom is best explained by X or Y.

Therapeutically, graded exercise therapy (GET) and cognitive behavioral therapy (CBT) are currently recommended but demonstrate limited efficacy. Anti-inflammatory diets show potential; pharmacologic agents, including selective serotonin reuptake inhibitors (SSRIs) and stimulants like modafinil or caffeine, yield variable results [18].

GET/CBT is no longer recommended in many places, and it demonstrates no efficacy, not limited efficacy. Diet has not shown any potential. Why you’d single out SSRIs or stimulants like that is beyond me. Regardless, the evidence for them is far from sufficient.

ME/CFS affects roughly 0.4% to 2.5% of community populations [25, 26], yet its underlying mechanisms remain elusive due to marked clinical and biological heterogeneity [27].

That is really not the issue here. The issue is that we’ve been subjected to decades of research that at best, has been terrible, and at worst has been outright harmful and deceptive.

Metabolomic and phenotypic studies have uncovered distinct patient subtypes characterized by alterations in energy, immune, and neuroendocrine pathways [28, 29].

Continues to go beyond the evidence.

I can’t say I’m very motivated to read the rest of this. The intro makes it seem like they don’t know what they are doing.