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Pathophysiology
Clinical meaning
Major depressive disorder (MDD) involves dysregulation of monoamine neurotransmitters (serotonin, norepinephrine, dopamine) in prefrontal cortex, hippocampus, and limbic structures. The monoamine hypothesis posits that depression results from deficient serotonergic and noradrenergic transmission, though current understanding encompasses neuroplasticity deficits, hypothalamic-pituitary-adrenal (HPA) axis hyperactivity with chronic cortisol elevation, neuroinflammation, and reduced brain-derived neurotrophic factor (BDNF). Chronic stress-induced cortisol elevation causes hippocampal atrophy and prefrontal cortex hypofunction. Generalized anxiety disorder (GAD) involves excessive activation of the amygdala fear circuits with insufficient prefrontal cortical inhibition. GABA (inhibitory) and glutamate (excitatory) imbalance contributes to the hyperarousal state. SSRIs increase serotonin availability by blocking presynaptic reuptake, but clinical effect takes 4-6 weeks due to required downstream neuroplastic changes including BDNF upregulation and hippocampal neurogenesis.
Diagnostics & workup:
- PHQ-9 screening (score >= 10 suggests moderate depression; >= 20 severe)
- GAD-7 screening (score >= 10 suggests moderate anxiety; >= 15 severe)
- DSM-5 criteria for MDD: >= 5 symptoms for >= 2 weeks including depressed mood or anhedonia
- Columbia Suicide Severity Rating Scale (C-SSRS) for suicidality assessment
- TSH to rule out thyroid disorder mimicking depression or anxiety
- CBC, electrolytes, B12, folate to exclude medical causes
Risk factors:
- Family history of mood or anxiety disorders (heritability 40-50% for MDD)
- History of adverse childhood experiences or trauma
- Chronic medical illness (diabetes, cardiovascular disease, cancer, chronic pain)
- Substance use disorder (alcohol, cannabis, stimulants)
- Social isolation, unemployment, relationship breakdown
- Female sex (2x risk of MDD compared to males)
- Previous depressive episodes (50% recurrence after first episode, 90% after third)
Management
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Prescribing & monitoring
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Takeaways
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