What is the best course of action for a 37-year-old woman with persistent anxiety, significant unintentional weight loss, paresthesias, and cognitive impairment, who has undergone extensive negative workup, including normal thyroid studies, vitamin B12 (385 pg/mL), pheochromocytoma and celiac screens, complete blood count (CBC), metabolic panel, antinuclear antibody (ANA) test, and computed tomography (CT) of the abdomen and pelvis, with mild inflammatory markers, elevated morning cortisol (29 mcg/dL) and normal adrenocorticotropic hormone (ACTH) levels, and a history of treatment with fluoxetine (Prozac), escitalopram (Lexapro), divalproex (Depakote), buspirone (Buspar), and dextroamphetamine-amphetamine (Adderall), and recently lybalvi?

Immediate Workup for ACTH-Dependent Cushing Syndrome

This patient requires immediate 24-hour urinary free cortisol collection to confirm true hypercortisolism, followed by pituitary MRI and likely bilateral inferior petrosal sinus sampling (BIPSS), as the combination of elevated cortisol (29 mcg/dL) with normal (detectable) ACTH definitively indicates ACTH-dependent Cushing syndrome—not a primary psychiatric disorder. 1, 2

Why This Is ACTH-Dependent Cushing Syndrome

The biochemical pattern is diagnostic:

• Elevated morning cortisol with detectable/normal ACTH rules out primary adrenal causes (which would suppress ACTH to undetectable levels) and confirms ACTH-dependent disease 1, 2
• The clinical presentation—anxiety, significant weight loss (30 lbs over 6 months), paresthesias from possible hypercortisolism-induced myopathy, cognitive impairment, mild inflammatory markers, and impaired fasting glucose—all align with hypercortisolism 1
• Cushing syndrome causes significant unintentional weight loss in 20% of patients despite classic teaching of weight gain 1

Critical Diagnostic Algorithm

Step 1: Confirm True Hypercortisolism

• Obtain 24-hour urinary free cortisol immediately to distinguish true hypercortisolism from stress-related elevation 1
• This is the mandatory first confirmatory test before proceeding with localization studies 1, 2

Step 2: Localize the ACTH Source

Once hypercortisolism is confirmed, the two possible sources are pituitary adenoma (Cushing disease) or ectopic ACTH-secreting tumor:

• Order pituitary MRI with sellar cuts protocol as the first imaging study (sensitivity 63% for detecting pituitary adenomas) 1, 2
• If pituitary MRI is negative or equivocal, proceed directly to BIPSS, which is the gold standard with 95% diagnostic accuracy 1, 2
• A central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin and ≥3:1 after stimulation confirms pituitary source 1, 2
• If BIPSS suggests ectopic ACTH production, obtain chest/abdominal/pelvic CT or whole-body PET/CT to locate tumors in lung, thyroid, pancreas, or bowel (detection rate 80%) 1, 2

Step 3: Concurrent Screening for Complications

While awaiting localization studies:

• Screen for hypertension, hypokalemia, and hyperglycemia (prevalence 50% in hypercortisolism) 1
• The patient's impaired fasting glucose (116 mg/dL) and mild inflammatory markers (ESR 29, CRP 15) are consistent with hypercortisolism-induced metabolic dysfunction 1
• Consider supplementing B12 to >400 pg/mL (current level 385 pg/mL) to address potential contribution to paresthesias, though hypercortisolism-induced myopathy is the more likely primary cause 1

Treatment Based on Source

If Pituitary Adenoma (Most Likely)

• Transsphenoidal surgical resection is first-line treatment (80% success rate) 1, 2
• Postoperative corticosteroid supplementation is mandatory until HPA axis recovery 1, 2
• Ketoconazole 400-1200 mg/day is the preferred medical therapy if surgery is delayed or unsuccessful (70% response rate, relatively tolerable side effects) 1, 2

If Ectopic ACTH Source

• Surgical removal of the ectopic tumor if resectable 2
• If unresectable, options include bilateral laparoscopic adrenalectomy or medical management with adrenostatic agents 2

Critical Pitfalls to Avoid

• Do not attribute symptoms to primary psychiatric disease when objective evidence of hypercortisolism exists—this causes a 6-month delay in diagnosis on average 1
• Do not rely solely on pituitary MRI, as 37% of pituitary adenomas are not visible on imaging, requiring BIPSS for diagnosis 1
• Do not delay workup for "psychiatric stabilization"—untreated Cushing syndrome causes progressive morbidity with 10% mortality 1
• Monitor for adrenal crisis risk during BIPSS procedure (10% risk) 1

Monitoring During Workup

• Follow-up imaging and biomarkers every 3-6 months if treatment is delayed 1, 2
• Monitor for worsening hypertension, hyperglycemia, hypokalemia, and muscle atrophy 1, 2

Regarding the Anxiety Treatment

The patient's persistent anxiety despite multiple SSRI trials (Prozac, Lexapro) and adjunctive agents (Buspar) is likely secondary to untreated hypercortisolism rather than primary psychiatric disease 1. Benzodiazepines may reduce CRF neuron activity but are not recommended for routine long-term use 3, 4. The anxiety will likely improve with definitive treatment of the underlying Cushing syndrome 1.