A 38-year-old woman presents with persistent depressed mood, anhedonia, and sleep disturbance for the past 3 months. She denies any significant psychosocial stressor in the recent past. Which of the following is the most common neurobiological abnormality implicated in the pathogenesis of Major Depressive Disorder?

## Neurobiological Basis of Major Depressive Disorder **Key Point:** The monoamine hypothesis, particularly serotonin dysregulation, remains the most widely supported neurobiological model of MDD, though modern understanding recognizes a multifactorial etiology. ### The Monoamine Hypothesis Serotonin dysfunction is the cornerstone of MDD pathophysiology: - Decreased serotonin availability in synaptic cleft - Reduced serotonin transporter (SERT) function - Altered 5-HT receptor sensitivity and expression - This forms the basis for SSRI efficacy — the most commonly prescribed antidepressants **High-Yield:** SSRIs work by blocking serotonin reuptake, increasing synaptic serotonin concentration. Their clinical efficacy validates the serotonin hypothesis as the primary mechanism. ### Other Monoamine Systems (Secondary Roles) | System | Role in MDD | Evidence | |--------|------------|----------| | **Serotonin** | Primary dysregulation | Strongest; SSRI response | | **Norepinephrine** | Mood, motivation, attention | SNRIs effective; secondary role | | **Dopamine** | Anhedonia, motivation | Relevant but less primary | | **Glutamate** | Emerging evidence | Newer theories; not primary | | **GABA** | Anxiety component | Supportive, not primary | **Clinical Pearl:** While dopamine dysfunction is important in anhedonia and negative symptoms, serotonin dysregulation is the most consistent finding across depressed populations and the most therapeutically validated target. ### Why Serotonin Is "Most Common" Epidemiological and pharmacological evidence: 1. ~70% of MDD patients respond to serotonergic agents (SSRIs) 2. Serotonin transporter polymorphisms (5-HTTLPR) associated with depression vulnerability 3. Post-mortem studies show altered serotonin receptor binding in depressed brains 4. Tryptophan depletion (serotonin precursor) can precipitate depressive relapse **Mnemonic:** **SERT** = **S**erotonin **E**fficacy **R**ecognized **T**herapeutically — remember serotonin as the primary target. [cite:Harrison 21e Ch 470]