A 52-year-old man with a 6-month history of depressed mood, anhedonia, and significant weight loss (8 kg) is evaluated for Major Depressive Disorder. Routine blood work (CBC, electrolytes, renal function, liver function) and TSH are normal. Which investigation is most appropriate as the next step to evaluate for medical comorbidity?

## Screening for Medical Comorbidity in Major Depressive Disorder ### Why Glucose and HbA1c? **High-Yield:** Depression and diabetes mellitus have a bidirectional relationship. Patients with depression have a 60% increased risk of developing type 2 diabetes; conversely, diabetic patients have 2–3 times higher rates of depression. Screening for glucose dysregulation is part of the standard metabolic workup in MDD, especially with constitutional symptoms like weight loss. **Key Point:** Weight loss in depression can mask underlying metabolic disease. Undiagnosed diabetes is common in depressed patients and may perpetuate mood symptoms through metabolic derangement, inflammation, and microvascular complications. **Clinical Pearl:** The combination of depression + weight loss + age >50 years raises suspicion for occult diabetes or malignancy. Fasting glucose and HbA1c are non-invasive, cost-effective first-line screening tools. ### Rationale for Glucose Screening 1. **Prevalence**: Type 2 diabetes occurs in 10–15% of patients with MDD 2. **Shared pathophysiology**: Both conditions involve HPA axis dysregulation, inflammation, and insulin resistance 3. **Symptom overlap**: Fatigue, weight changes, and cognitive dysfunction occur in both 4. **Treatment implications**: Some antidepressants (tricyclics, atypical antipsychotics) worsen glucose control; screening guides drug selection 5. **Guideline-recommended**: Metabolic screening is standard in depression workup ### Comparison of Investigations in Depression Workup | Investigation | Indication | Yield in MDD | |---|---|---| | **Fasting glucose + HbA1c** | Screen for diabetes; assess glycemic control | High—common comorbidity, treatable | | **Chest X-ray** | Respiratory symptoms, smoking history, malignancy suspicion | Low—not routine unless clinical indication | | **Abdominal ultrasound** | Abdominal pain, hepatomegaly, weight loss with GI symptoms | Low—not routine; indicated only with specific GI signs | | **Lumbar puncture + CSF** | Meningitis, encephalitis, neurosyphilis | Very low—only if fever, meningeal signs, or serology positive | **Mnemonic: METABOLIC SCREENING IN DEPRESSION — THIEF-D** - **T**hyroid (TSH, free T4) - **H**yponatremia, **H**ypercalcemia - **I**nfections (serology: RPR, HIV, TB) - **E**ndocrine (**Fasting glucose, HbA1c**, cortisol if Cushing's suspected) - **F**olate, **B**12, iron - **D**rug screening (toxicology if substance use suspected) **Warning:** Do not order imaging (CXR, ultrasound) or invasive tests (LP) without clinical indication. Routine screening in uncomplicated MDD wastes resources and may lead to incidental findings requiring further workup. [cite:Harrison 21e Ch 470; American Psychiatric Association Practice Guidelines]