What initial diagnostic tests are recommended for a patient with anhedonia and no anemia, specifically regarding cortisol and vitamin D 25-OH levels?

Diagnostic Testing for Anhedonia Without Anemia

Check cortisol levels first—specifically morning cortisol with ACTH—as anhedonia with elevated cortisol is a documented biomarker pattern in depression and other conditions, while vitamin D 25-OH testing is reasonable but less directly linked to anhedonia pathophysiology. 1, 2

Priority Testing: Cortisol Assessment

Morning cortisol with ACTH should be your first-line test for a patient presenting with anhedonia, as this directly evaluates hypothalamic-pituitary-adrenal (HPA) axis dysfunction, which is mechanistically linked to anhedonic symptoms. 1, 2

Why Cortisol Testing Matters for Anhedonia

• Elevated plasma cortisol levels serve as a potential biomarker for anhedonia in patients with treatment-resistant depression, with baseline cortisol levels showing direct correlation with anhedonia severity. 2

• Post-stroke anhedonia patients demonstrate significantly higher morning cortisol levels (1,671.9±604.0 ng/dL versus 1,103.9±821.9 ng/dL) and larger diurnal cortisol variation compared to non-anhedonic patients, indicating HPA axis dysfunction. 3

• Anhedonia is associated with dysfunction of the hypothalamic-pituitary-adrenal axis, making cortisol assessment diagnostically relevant beyond just screening for adrenal insufficiency. 3

Specific Testing Protocol

Obtain paired early morning (8 AM) serum cortisol and plasma ACTH measurements as your initial diagnostic approach. 1

• If morning cortisol is <250 nmol/L (<9 μg/dL) with elevated ACTH, this is diagnostic of primary adrenal insufficiency. 1

• If cortisol is <400 nmol/L with elevated ACTH in the context of acute illness, this raises strong suspicion for adrenal insufficiency. 1

• Adrenal insufficiency presents with anhedonia-like symptoms and must be excluded, as hyponatremia occurs in 90% of newly diagnosed cases and the clinical picture can mimic primary psychiatric conditions. 1

Secondary Testing: Vitamin D 25-OH

Vitamin D 25-OH testing is reasonable but represents a lower priority compared to cortisol assessment for anhedonia evaluation.

Evidence for Vitamin D Testing

• Vitamin D treatment (1,25-(OH)2 vitamin-D3) enhanced sucrose preference and improved anhedonia-like symptoms in chronic mild stress rat models by regulating dopamine transporter levels in the nucleus accumbens. 4

• The mechanism involves vitamin D's protective and regulatory effects on the brain dopamine system, particularly in reward circuits and mesolimbic dopamine transmission. 4

• However, this evidence comes from animal models rather than human clinical trials, making it less directly applicable to clinical decision-making. 4

When to Check Vitamin D

If you decide to assess vitamin D metabolism in a patient with anhedonia, measure both 25-OH vitamin D and 1,25-OH vitamin D levels before any vitamin D replacement. 5

• This dual measurement approach is recommended when determining if vitamin D replacement is indicated, though this guideline comes from sarcoidosis literature rather than psychiatric contexts. 5

• Standard vitamin D deficiency is defined as plasma 25-OH vitamin D <50 nmol/L, with severe deficiency at <30 nmol/L. 5

Clinical Algorithm

1. Start with morning cortisol and ACTH to evaluate HPA axis function and exclude adrenal insufficiency. 1, 2

2. If cortisol results are indeterminate (neither clearly normal nor clearly low), proceed with ACTH stimulation testing using 0.25 mg cosyntropin with cortisol measurements at 30 minutes, where peak cortisol <500 nmol/L is diagnostic of adrenal insufficiency. 1

3. Add vitamin D 25-OH testing as a secondary measure, particularly if considering vitamin D supplementation as an adjunctive treatment strategy. 4

4. Consider basic metabolic panel to assess for hyponatremia, which occurs in 90% of adrenal insufficiency cases and can present with anhedonia. 1

Critical Pitfalls to Avoid

• Do not assume normal electrolytes exclude adrenal insufficiency—hyperkalemia is present in only ~50% of cases, and some patients have completely normal electrolytes at presentation. 1

• Never delay treatment of suspected acute adrenal insufficiency for diagnostic testing if the patient is clinically unstable. 1

• Recognize that exogenous steroids (including inhaled fluticasone or oral prednisolone) can suppress the HPA axis and confound cortisol testing results. 1