What are the causes and treatments of fatigue?

Causes and Management of Fatigue

Fatigue is a multifactorial symptom driven by biological, psychological, and social factors that requires systematic evaluation to identify treatable causes—most commonly sleep disorders, depression (18.5% of cases), and psychosocial stress—while organic causes like anemia and cancer are rare (4.3% and 0.6% respectively). 1

Primary Causes of Fatigue

Most Common Causes

• Sleep disorders and sleep-related breathing disorders are among the leading causes of persistent fatigue and should be evaluated first 1
• Depression accounts for 18.5% of fatigue cases and must be systematically screened using validated tools 1
• Excessive psychosocial stress is a predominant driver of fatigue in primary care populations 1
• Medications and their side effects frequently cause or worsen fatigue and require comprehensive review 2, 3

Less Common but Important Causes

• Anemia and other organic causes account for only 4.3% of cases [2.7-6.7% confidence interval], making extensive laboratory workup unnecessary in most patients 1
• Previously undiagnosed cancer is rare, representing only 0.6% of cases [0.3-1.3% confidence interval] 1
• Thyroid dysfunction, cardiac dysfunction, and pain commonly coexist with fatigue and require targeted evaluation 4, 5
• Inflammatory and autoimmune conditions (rheumatoid arthritis, lupus, multiple sclerosis) cause fatigue through immune system, central nervous system, and neuroendocrine dysregulation 2

Biological Mechanisms

• Inflammatory processes, HPA axis dysfunction, circadian rhythm disruption, and monoamine pathway disturbances (serotonin, dopamine, norepinephrine) contribute to fatigue pathophysiology 2
• Neuromuscular disorders show central activation deficits rather than peripheral causes, with over 60% of patients experiencing severe fatigue 6

Systematic Assessment Approach

Initial Screening

• Use a 0-10 numeric rating scale at every clinical encounter, with scores ≥4 indicating moderate-to-severe fatigue requiring focused evaluation 4
• Scores ≥7 correlate with marked decreases in physical functioning and require immediate intervention 4
• Single-item screening tools (BRAF-NRS, RAID-F) can be supplemented with multidimensional assessments when significant fatigue is identified 2

Focused History Components

• Evaluate onset, pattern, duration, change over time, and interference with daily function including work, social activities, and self-care 2, 4
• Assess whether fatigue is proportional to recent activity and whether rest provides relief 2, 7
• Review all prescription and over-the-counter medications for fatigue-inducing effects 2, 3
• Screen for clustering symptoms: pain, emotional distress (depression/anxiety), sleep disturbance, and nutritional deficits 2

Targeted Physical Examination

• Focus on cardiopulmonary, neurologic, and skin examinations rather than comprehensive systems review 7
• Evaluate for signs of thyroid dysfunction, cardiac disease, and anemia as these are treatable causes 4, 5

Laboratory Testing Strategy

• Laboratory studies affect management in only 5% of patients, so avoid extensive initial workup 3
• Initial testing should include: complete blood count, thyroid function, and basic metabolic panel only when history or examination suggests specific causes 3, 1
• If initial results are normal, repeat testing is generally not indicated unless new symptoms emerge 3

Evidence-Based Treatment Strategies

First-Line Non-Pharmacologic Interventions

• Tailored physical activity programs are the single most effective intervention with the strongest evidence base across all fatigue types 2
• Start with moderate-intensity aerobic exercise (walking) combined with stretching, even in deconditioned patients 2, 3
• Progressive exercise programs should be individually tailored to the patient's baseline capacity and gradually increased 5, 7

Critical caveat: Exercise can be harmful in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) because it triggers postexertional malaise—these patients require pacing strategies instead of exercise programs 7

Psychosocial Interventions

• Cognitive behavioral therapy (CBT) shows benefit during and after treatment for fatigue, particularly when delivered by trained providers 2
• Mindfulness-based programs yield positive effects especially in post-treatment settings for patients with persistent fatigue 2
• Web-based versions of effective in-person programs provide accessible and affordable alternatives 2
• Psychoeducational interventions providing information about fatigue and adaptive coping strategies in supportive environments are recommended 2

Integrative Therapies

• American ginseng may be recommended for patients undergoing active treatment based on rigorous trial evidence 2
• Acupressure may be recommended for patients with persistent post-treatment fatigue based on single rigorous trial 2

Pharmacologic Approaches

• Wakefulness agents, psychostimulants, and antidepressants are NOT effective for cancer-related fatigue and should not be routinely recommended 2
• Selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline) may improve energy specifically in patients with diagnosed depression 3
• Caffeine and modafinil may be useful for episodic situations requiring alertness but are not long-term solutions 3
• Corticosteroids may be considered only for managing fatigue in patients with advanced cancer 2

Treatment of Underlying Causes

• Treat identified sleep disorders with appropriate interventions including sleep hygiene education 1, 7
• Manage depression and anxiety with evidence-based psychotherapy and/or pharmacotherapy 3, 1
• Correct anemia, nutritional deficiencies (vitamin D, magnesium, iron), and electrolyte imbalances 4, 5
• Optimize management of chronic inflammatory conditions with appropriate immunomodulatory treatment 2

Management Algorithm

For All Patients with Fatigue

1. Screen with 0-10 numeric scale at every visit 4
2. If score ≥4: Conduct focused history evaluating onset, pattern, duration, and functional impact 2, 4
3. Assess for clustering symptoms: depression, anxiety, pain, sleep disturbance 2
4. Review medications for fatigue-inducing effects 2, 3
5. Perform targeted physical examination (cardiopulmonary, neurologic, thyroid) 7
6. Order selective laboratory testing only when history/exam suggests specific causes 3, 1

Treatment Prioritization

1. Address treatable medical causes first: anemia, thyroid dysfunction, sleep disorders, depression 5, 1
2. Implement tailored physical activity program for all patients except those with ME/CFS 2
3. Offer CBT or mindfulness-based interventions particularly for persistent fatigue 2
4. Consider psychoeducational support and symptom management strategies 2
5. Use shared decision-making to align interventions with patient preferences and circumstances 2

Follow-Up Strategy

• Schedule regular follow-up visits rather than sporadic urgent appointments for effective long-term management 3
• Reassess fatigue severity at each visit to determine treatment effectiveness 4
• If fatigue persists despite treatment of identified causes, consider referral to specialists (physiatry, rehabilitation, mental health) 4, 5
• Implement watchful waiting when diagnosis remains unclear to prevent overdiagnosis and excessive somatic focus 1

Critical Pitfalls to Avoid

• Do not pursue extensive laboratory workup without specific clinical indicators, as this leads to overdiagnosis and affects management in only 5% of cases 3, 1
• Do not assume fatigue is solely due to one cause (e.g., anemia)—multiple overlapping factors commonly coexist and require independent assessment 4, 5
• Do not prescribe exercise programs for patients with ME/CFS, as this can trigger postexertional malaise and worsen their condition 7
• Do not overlook medication review, as drug side effects are a frequent and reversible cause of fatigue 2, 3
• Do not fail to screen for depression, which accounts for nearly one-fifth of fatigue cases 1
• Do not dismiss persistent fatigue as "normal"—regular assessment and shared decision-making about management options should be part of routine clinical care 2