Clinical meaning
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 MDD, impairing synaptic plasticity and neuronal resilience; antidepressant treatment restores BDNF levels over weeks, explaining the 2-4 week therapeutic latency. The DSM-5 diagnostic criteria require five or more of nine specified symptoms present during the same two-week period, representing a change from previous functioning, with at least one symptom being either depressed mood or anhedonia (loss of interest or pleasure). The nine criteria are captured by the SIG-E-CAPS mnemonic: Sleep disturbance (insomnia or hypersomnia), Interest loss (anhedonia), Guilt or worthlessness (excessive or inappropriate), Energy loss (fatigue), Concentration impairment (difficulty thinking or deciding), Appetite change (increase or decrease with corresponding weight change), Psychomotor agitation or retardation (observable by others), and Suicidality (recurrent thoughts of death, suicidal ideation, or attempt). Symptoms must cause clinically significant distress or functional impairment and cannot be attributable to substance effects or another medical condition. Specifiers include severity (mild, moderate, severe), psychotic features, catatonia, anxious distress, mixed features, melancholic features, atypical features, peripartum onset, and seasonal pattern.