What is the most likely diagnosis and initial work‑up for a 22‑year‑old woman with extreme fatigue, insomnia, recurrent headaches, and brain fog?

Differential Diagnosis for a 22-Year-Old Woman with Extreme Fatigue, Sleep Issues, Headaches, and Brain Fog

The most likely diagnosis is Major Depressive Disorder, which requires immediate systematic evaluation to distinguish from primary sleep disorders and other medical conditions that can present with identical symptoms.

Critical Diagnostic Distinction: Fatigue vs. Sleepiness

The first and most important step is determining whether this patient experiences true fatigue (low energy, tiredness, weariness) or pathological sleepiness (involuntary tendency to fall asleep) 1, 2:

• Fatigue is the expected consequence of insomnia and depression, not true sleepiness 1, 2
• Involuntary daytime sleep episodes or falling asleep while driving mandates urgent polysomnography to rule out obstructive sleep apnea, narcolepsy, or periodic limb movement disorder 1, 2
• Ask specifically about voluntary versus involuntary napping episodes 1

Primary Differential Diagnosis

1. Major Depressive Disorder (Most Likely)

This patient meets diagnostic criteria for Major Depressive Disorder based on the constellation of extreme fatigue, insomnia, and cognitive impairment ("brain fog") 3:

• Requires at least 5 symptoms present for ≥2 weeks, with at least one being depressed mood or loss of interest/pleasure 3
• Neurovegetative symptoms (insomnia, fatigue, cognitive impairment) are the physical manifestations of depression reflecting disruption of basic biological functions 3
• Brain fog represents the cognitive component including difficulty concentrating, impaired memory, and mental inefficiency 1, 3

Essential next steps for confirming depression:

• Screen for suicidal ideation immediately - this is imperative for patient safety 3
• Assess for additional diagnostic criteria: significant weight/appetite changes, psychomotor agitation/retardation, feelings of worthlessness or excessive guilt, diminished ability to concentrate, recurrent thoughts of death 3
• Evaluate for quality of life deterioration including social withdrawal, work avoidance, or loss of interest in activities 1

2. Primary Insomnia Disorder

If depression screening is negative, consider primary chronic insomnia 1, 2:

• Obtain 7-14 days of detailed sleep diary before any intervention to establish baseline patterns 2
• Assess sleep behaviors: bedtime routine, time in bed vs. actual sleep time, nighttime awakenings 2
• Cognitive Behavioral Therapy for Insomnia (CBT-I) is mandatory first-line treatment, superior to medications for long-term efficacy 2

3. Medication-Induced Sleep Disruption

Review all current medications systematically 1:

• Stimulants: caffeine, methylphenidate, amphetamines 1
• Antidepressants: SSRIs, SNRIs, MAO inhibitors 1
• Cardiovascular agents: β-blockers, α-receptor agents, diuretics 1
• Pulmonary medications: theophylline, albuterol 1
• Assess alcohol use or withdrawal 1

4. Migraine (Consider if Headaches are Prominent)

Evaluate headache characteristics against migraine criteria 4:

• Migraine without aura: ≥5 attacks lasting 4-72 hours with unilateral location, pulsating quality, moderate-severe intensity, aggravated by routine activity, plus nausea/vomiting or photophobia/phonophobia 4
• Chronic migraine: headaches on ≥15 days/month for >3 months 4
• Family history of migraine strengthens suspicion 4
• Note: Migraine can cause fatigue and cognitive impairment but typically does not cause chronic insomnia as the primary complaint 4

5. Secondary Medical Conditions (Lower Priority in Young Patient)

Consider if above diagnoses are excluded 4:

• Thyroid dysfunction: hypothyroidism can cause fatigue, cognitive impairment, and depression-like symptoms 4
• Obstructive sleep apnea: only if true sleepiness (not fatigue) is present 1, 2
• Narcolepsy or hypersomnia: extremely unlikely given age and symptom pattern; requires excessive daytime sleepiness, not fatigue 4

Initial Workup Algorithm

Step 1: Immediate Assessment

• Suicidal ideation screening 3
• Distinguish fatigue from pathological sleepiness 1, 2
• Medication review for sleep-disrupting agents 1

Step 2: Structured Diagnostic Interview

• Complete Major Depressive Disorder criteria assessment (9 symptoms over 2 weeks) 3
• Detailed headache characterization using migraine diagnostic criteria 4
• 7-14 day sleep diary to document sleep patterns 2

Step 3: Targeted Laboratory Testing

• Thyroid function tests (TSH, free T4) to exclude hypothyroidism 4
• Complete blood count to exclude anemia
• Basic metabolic panel

Step 4: Polysomnography (Only if Indicated)

• Only order if true sleepiness with involuntary sleep episodes 1, 2
• Not indicated for insomnia with fatigue alone 1, 2

Critical Pitfalls to Avoid

• Do not confuse fatigue with sleepiness - this distinction determines whether sleep study is needed 1, 2
• Do not order polysomnography for chronic insomnia without sleepiness - this is inappropriate and wastes resources 1, 2
• Do not start pharmacological treatment for insomnia before obtaining sleep diary and attempting CBT-I 2
• Do not miss depression - psychiatric disorders have 50-75% insomnia rates, requiring bidirectional evaluation 1
• Do not attribute all symptoms to stress or "adjustment disorder" without meeting duration criteria (adjustment disorder is short-lived and resolves when stressor disappears) 3

Most Likely Clinical Scenario

Given the constellation of extreme fatigue (not sleepiness), insomnia, headaches, and brain fog in a 22-year-old woman, Major Depressive Disorder is the most probable diagnosis 3. The neurovegetative symptoms (insomnia, fatigue) combined with cognitive impairment (brain fog) form the classic triad of depression 3. Headaches may represent comorbid tension-type headaches or migraine, which have high comorbidity with depression 4, 1.