Pathophysiology
Clinical meaning
Major depressive disorder (MDD) is a complex neuropsychiatric illness involving dysregulation of multiple neurotransmitter systems and neural circuits. The monoamine hypothesis proposes that depression results from deficient serotonergic, noradrenergic, and/or dopaminergic neurotransmission. Serotonin (5-HT) modulates mood, appetite, sleep, and impulse control via raphe nuclei projections to the prefrontal cortex, limbic system, and hypothalamus. Norepinephrine from the locus coeruleus mediates arousal, attention, and energy. Dopamine from the ventral tegmental area drives motivation and reward (anhedonia reflects mesolimbic dopamine hypofunction). Beyond monoamines, the HPA axis is hyperactive in MDD: chronic stress elevates CRH and cortisol, causing hippocampal neuronal atrophy and reduced neurogenesis through BDNF (brain-derived neurotrophic factor) downregulation. Neuroinflammatory mechanisms (elevated IL-6, TNF-alpha, CRP) contribute to treatment-resistant depression and explain the bidirectional relationship between depression and medical illness. Glutamatergic NMDA receptor dysfunction underlies the rapid antidepressant effect of ketamine/esketamine. The NP integrates these mechanisms when selecting antidepressants: SSRIs for serotonin-predominant symptoms (anxiety, rumination), SNRIs for pain and fatigue comorbidities, bupropion (norepinephrine-dopamine) for fatigue and anhedonia, mirtazapine for insomnia and appetite loss. Treatment-resistant depression (failure of ≥ 2 adequate antidepressant trials) may warrant...