The monoamine hypothesis of depression proposes that MDD results from deficiencies in monoamine neurotransmitters — serotonin (5-HT), norepinephrine (NE), and dopamine (DA) — in key neural circuits. Serotonin, synthesized from tryptophan by tryptophan hydroxylase in the raphe nuclei, projects widely to the prefrontal cortex, amygdala, hypothalamus, and hippocampus, modulating mood, anxiety, appetite, sleep, and impulse control. Serotonin is removed from the synapse by the serotonin transporter (SERT) and metabolized by monoamine oxidase (MAO) to 5-HIAA. Norepinephrine, synthesized from tyrosine via dopamine beta-hydroxylase in the locus coeruleus, modulates arousal, attention, energy, and the stress response. Dopamine from the ventral tegmental area (VTA) mediates reward, motivation, and pleasure through the mesolimbic pathway; hypofunction manifests as anhedonia. Beyond monoamines, the HPA axis is hyperactivated in depression: elevated CRH from the hypothalamus drives ACTH release from the anterior pituitary, increasing cortisol from the adrenal cortex. Chronic hypercortisolism causes hippocampal neuronal atrophy, reduced BDNF expression, impaired neuroplasticity, and dysregulated negative feedback (dexamethasone non-suppression). The glutamate hypothesis explains ketamine's rapid antidepressant effect: NMDA receptor blockade on GABAergic interneurons disinhibits glutamate signaling, activating AMPA receptors and triggering...