Fatigue is far more than just feeling tired—it can be a multidimensional syndrome that affects both physical and mental well-being.
The causes behind fatigue are complex and multifactorial, and they demand an individualized approach to diagnosis and treatment.
For clinicians in 2025, fatigue is recognized as both a symptom and a disease process in its own right.
According to recent insights from Dr. Olivia Schmidt, a neurologist at the University of California, San Francisco, "Fatigue isn't just about lack of sleep or stress. It's frequently the underlying consequence of a metabolic, immunologic, or neurological disorder."
Recent research underscores the importance of understanding fatigue's neurophysiological roots, moving beyond traditional assumptions. No longer confined to being a "catch-all" diagnosis, fatigue is now seen as a symptom with clear and identifiable biological underpinnings, especially in chronic conditions.
Medical Causes of Fatigue: A Complex Web
1. Chronic Infections and Post-Viral Fatigue
The ongoing post-viral fatigue seen in patients recovering from COVID-19, Epstein-Barr virus, and other infectious agents is increasingly well-documented. Chronic post-viral fatigue syndrome (PVFS) now represents a major area of research.
Experts such as Dr. Sarah Thompson, an infectious disease specialist at Harvard Medical School, point to elevated inflammatory cytokines and disrupted neural signaling as core contributors to persistent exhaustion after viral infections.
A 2024 study published in The Lancet Infectious Diseases revealed that microglial activation—an immune response in the brain—was highly correlated with fatigue severity in patients recovering from COVID-19. Notably, the study found that persistent neuroinflammation is likely to play a central role in long COVID fatigue, even when other symptoms have resolved.
2. Endocrine Imbalance: Thyroid and Adrenal Contributions
Hypothyroidism is a well-known culprit behind fatigue. However, adrenal insufficiency, caused by conditions such as Addison's disease or chronic stress, also disrupts metabolic balance and energy production. The adrenal gland regulates cortisol, a key hormone that plays a role in wakefulness, and chronic low levels can lead to unrelenting tiredness.
3. Mitochondrial Dysfunction: The Cellular Energy Crisis
Fatigue can be rooted at the cellular level. Mitochondria, the powerhouse of the cell, are responsible for generating the energy we need for day-to-day functioning. In conditions like fibromyalgia, chronic fatigue syndrome (CFS), and multiple sclerosis (MS), mitochondrial dysfunction is thought to contribute to energy depletion.
A groundbreaking study in 2025 from Dr. Marcus Jensen, a mitochondrial specialist at Stanford University, introduced the concept of "mitochondrial reserve depletion". This condition occurs when mitochondrial energy production pathways become overwhelmed or damaged, leading to a cumulative loss of energy over time.
4. Sleep Apnea: The Hidden Fatigue Factor
Sleep disturbances, especially obstructive sleep apnea (OSA), are notorious for contributing to unexplained fatigue. OSA leads to disrupted sleep cycles, often preventing patients from reaching the restorative deep sleep phases. What's more concerning, however, is its silent progression, often overlooked in the absence of obvious symptoms like snoring or choking at night.
Current estimates suggest that 80% of people with OSA remain undiagnosed, leading to severe daytime fatigue. As Dr. Matthew Ford, a sleep medicine expert at Cleveland Clinic, points out, "Fatigue caused by sleep apnea is not just about poor sleep—it's about chronic oxygen desaturation that can result in brain fog and decreased cognitive performance."
5. Psychiatric and Neurological Contributions
Psychiatric conditions like depression, anxiety disorders, and post-traumatic stress disorder (PTSD) are common causes of fatigue, but the pathophysiology is often debated. Dr. Rachel Diaz, a psychiatrist at Columbia University, explains that "Fatigue in psychiatric disorders is related to altered neurotransmitter signaling, particularly involving serotonin and dopamine pathways, which are critical to energy levels and motivation."
Fatigue in conditions such as Parkinson's disease and multiple sclerosis (MS) has also been linked to neurological degradation of energy-regulating brain regions. In MS, demyelination disrupts nerve impulse conduction, leading to the depletion of energy stores and muscle fatigue.
Innovative Treatments for Fatigue: From Pharmacology to Lifestyle
1. Targeted Pharmaceutical Approaches
Pharmacologic treatments for fatigue are highly individualized. For example, modafinil, a wakefulness-promoting agent, has found success in treating fatigue in multiple sclerosis and CFS patients, particularly those resistant to standard treatments.
Dr. Elias Wong, a clinical pharmacologist at Massachusetts General Hospital, notes that modafinil improves wakefulness without the addictive properties of traditional stimulants. In hypothyroid fatigue, clinicians now focus on the refined use of T3 (liothyronine) alongside T4. Evidence shows that this combined therapy better addresses fatigue symptoms compared to traditional T4-only treatments.
2. Cognitive Behavioral Therapy for Fatigue (CBT-F)
In the management of chronic fatigue, Cognitive Behavioral Therapy (CBT) has proven highly effective. Research from the American Psychological Association (2024) indicates that CBT for fatigue can reframe maladaptive beliefs around energy limitations, fostering active coping mechanisms and gradual physical activity. For those suffering from CFS or long COVID, graded exercise therapy (GET) remains a gold-standard intervention when paired with CBT.
3. Nutraceuticals: From CoQ10 to L-Carnitine
Over the past few years, nutraceuticals have garnered attention for their role in managing mitochondrial-related fatigue. Coenzyme Q10 (CoQ10) has been extensively studied for its role in energy production. A 2025 study published in JAMA Internal Medicine found that daily supplementation with CoQ10 improved fatigue in patients with fibromyalgia.
Similarly, L-carnitine, an amino acid derivative, is increasingly used to help with fatigue in chronic diseases, such as cancer-related fatigue. As Dr. Mark Harris, a leading researcher in cancer rehabilitation, explains, "L-carnitine aids in fatty acid metabolism, providing essential energy for patients undergoing chemotherapy or radiation therapy."
Fatigue, far from being a straightforward symptom, represents a complex and multi-factorial issue that requires a thorough and holistic evaluation. From addressing mitochondrial dysfunction to improving sleep quality, effective management must be individualized. As our understanding of the mechanisms behind fatigue evolves, treatments continue to improve, offering hope to millions of people around the world suffering from this debilitating condition.
In 2025, the landscape of fatigue treatment is brighter than ever, thanks to both biological insights and innovative clinical practices. However, early diagnosis and personalized care remain key in providing relief to patients.
