This article examines the pharmacodynamic mechanisms of classical antidepressants and contrasts them with the emerging generation of rapid-acting agents, particularly ketamine and esketamine. Traditional antidepressants, including SSRIs, SNRIs, TCAs, and MAO inhibitors, primarily target monoaminergic neurotransmission and require several weeks before clinical benefits appear. Their limitations, combined with high rates of treatment resistance, have driven interest in novel approaches. Ketamine and esketamine represent a major shift in antidepressant development due to their rapid onset of action and unique effects on glutamatergic signaling, synaptic plasticity, and neurotrophic pathways. This article explores the cellular and molecular principles underlying their therapeutic properties, reviews clinical evidence, considers safety concerns, and outlines future research directions in neurobiologically informed treatments for major depressive disorder.

antidepressants, pharmacodynamics, ketamine, esketamine, NMDA receptor, monoamines, neuroplasticity, treatment-resistant depression, glutamate modulation, synaptic connectivity

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