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.