Overview
Clinical Meaning
Major depressive disorder (MDD) is a neurobiological illness with a complex, multifactorial pathophysiology involving dysregulation of monoamine neurotransmitter systems, hypoth...
Major depressive disorder (MDD) is a neurobiological illness with a complex, multifactorial pathophysiology involving dysregulation of monoamine neurotransmitter systems, hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, neuroinflammation, impaired neuroplasticity, and altered neural circuit function. The monoamine hypothesis, while incomplete, remains foundational: deficient synaptic availability of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) in limbic and prefrontal circuits contributes to depressed mood, cognitive dysfunction, and psychomotor changes. Serotonergic neurons projecting from the dorsal raphe nuclei to the prefrontal cortex, amygdala, and hippocampus modulate mood, anxiety, and impulse control. Noradrenergic projections from the locus coeruleus influence attention, energy, and motivation. Dopaminergic pathways in the mesolimbic reward circuit (ventral tegmental area to nucleus accumbens) mediate anhedonia, the hallmark feature of MDD. HPA axis dysregulation produces sustained cortisol elevation through impaired negative feedback at hippocampal glucocorticoid receptors, leading to hippocampal volume reduction (documented on neuroimaging), impaired neurogenesis in the dentate gyrus, and dendritic atrophy in prefrontal neurons. Chronic neuroinflammation involves elevated pro-inflammatory cytokines (IL-1-beta, IL-6, TNF-alpha) that reduce tryptophan availability by shunting metabolism toward the kynurenine pathway, depleting serotonin precursors. Brain-derived neurotrophic factor (BDNF) is reduced in...