Antidepressants: A Comprehensive Review of Molecular Mechanisms, US FDA Approvals Till 2025, Synthesis,...

Major depressive disorder (MDD) is a major global health concern characterized by complex etiology and multifactorial pathophysiology. This review brings together the current landscape of US FDA-approved drugs used for depressive disorders, spanning the early monoamine-based agents to recent approvals with distinct mechanisms. The manuscript summarizes the biological basis of depression and reviews the major pharmacological classes. To bridge medicinal chemistry with clinical performance, this review evaluates the structural diversity of 40 FDA-approved antidepressants and provides a harmonized QikProp-based in silico ADME data set. The results show that most agents converge within a physicochemical window compatible with oral dosing and CNS exposure, whereas a small subset deviates in patterns that reflect scaffold and mechanism differences. Representative synthetic schemes are included to illustrate practical access to key scaffolds, and selected SAR and lead-optimization examples are discussed where literature support is strongest (notably for TCAs, MAOIs, and neuroactive steroids). US prescription and patient trends are also integrated to place these drugs in a real-world utilization context. Emerging therapeutic targets, including glutamatergic and GABAergic systems, as well as novel rapid-acting agents like NMDA antagonists, are also discussed. By combining molecular pharmacology, synthetic chemistry, and real-world data, this review aims to provide a comprehensive and multidisciplinary resource that may support future research, drug development and clinical decision-making in the treatment of depression. It presents an integrated examination of FDA-approved antidepressant drugs across pharmacological, structural, metabolic and clinical dimensions.