## Neurobiological Alterations in Major Depressive Disorder ### Established Findings **Key Point:** The monoamine hypothesis and HPA axis dysregulation are the two most robust neurobiological models of MDD. | Finding | Evidence | Clinical Relevance | |---------|----------|--------------------| | Reduced hippocampal volume | Consistent across meta-analyses; correlates with duration and severity | Memory/cognitive impairment | | ↓ Serotonin transporter (SERT) availability | PET/SPECT imaging; striatum, anterior cingulate, medial prefrontal cortex | Basis for SSRI efficacy | | HPA axis hyperactivity | Elevated cortisol, blunted ACTH response to CRH | Sleep, appetite, immune dysfunction | | ↓ BDNF (brain-derived neurotrophic factor) | Reduced in serum and CSF | Neuroplasticity impairment | ### Why Increased Dopamine Receptor Density is NOT Established **High-Yield:** The dopamine hypothesis in MDD focuses on **reduced dopamine transmission** (particularly in the nucleus accumbens and ventral tegmental area), not increased receptor density. Increased dopamine receptors would be a compensatory response to chronic hypoactivity, but this is NOT a primary finding in MDD neuroimaging. **Clinical Pearl:** Dopamine dysfunction in MDD manifests as: - Anhedonia (reward processing deficit) - Psychomotor retardation - Loss of motivation These are treated by dopamine-enhancing agents (bupropion, stimulants), but the underlying pathology is dopamine **hypofunction**, not receptor upregulation. ### Why the Other Options Are Correct 1. **Reduced hippocampal volume** — Well-replicated finding; stress-induced glucocorticoid toxicity damages CA3 pyramidal neurons. 2. **Decreased SERT availability** — Fundamental to monoamine hypothesis; explains SSRI mechanism. 3. **HPA axis hyperactivity** — Dexamethasone suppression test abnormalities; elevated 24-hour urinary cortisol in ~40% of depressed patients.
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