The NP must understand the evolving neurobiological models of depression to make informed pharmacotherapy decisions. While the monoamine hypothesis remains foundational, modern understanding integrates multiple interconnected systems. The Monoamine Hypothesis: Depression involves deficient serotonergic, noradrenergic, and dopaminergic neurotransmission. Serotonin (5-HT) from dorsal raphe nuclei modulates mood, anxiety, sleep, and appetite. Norepinephrine (NE) from the locus coeruleus mediates alertness, energy, and concentration. Dopamine (DA) in mesolimbic pathways drives motivation and reward. SSRIs, SNRIs, and NDRIs increase these neurotransmitters — but the 4-6 week delay in clinical response indicates the mechanism is more complex than simply increasing monoamine levels. The Neuroplasticity Model: Chronic stress and depression reduce brain-derived neurotrophic factor (BDNF), leading to hippocampal neuronal atrophy, dendritic spine loss, and impaired neurogenesis. Antidepressants gradually restore BDNF levels and promote synaptogenesis over weeks — this explains the treatment delay. Ketamine and its derivative esketamine produce rapid antidepressant effects (within hours) by directly stimulating BDNF release through NMDA receptor antagonism and subsequent AMPA receptor activation, triggering rapid synaptogenesis. The HPA Axis Model: Chronic stress hyperactivates the hypothalamic-pituitary-adrenal axis, causing sustained cortisol elevation. Hypercortisolism damages...