Targeting depression: Pharmacological mechanisms and therapeutic targets

Depression remains a leading cause of disability worldwide with a rapidly escalating disease burden, yet current pharmacotherapies are limited by delayed onset of action, insufficient efficacy in treatment-resistant depression, and troublesome adverse effects. This review provides a systematic and critical evaluation of pharmacological mechanisms in depression and related therapeutic targets. We examine established targets spanning the neurotransmitters corresponding to serotonergic, glutamatergic, GABAergic, and dopaminergic systems, alongside emerging glial gap junctions and inflammatory perspectives. For each target, we assess the quality of evidence from preclinical studies and clinical trials, discuss corresponding antidepressant drug classes, and identify knowledge gaps. Finally, we propose future directions for antidepressant drug development, including novel target discovery, rational multi-target design, and optimization of preclinical-to-clinical translation. By providing a pharmacology-driven roadmap of druggable targets and their therapeutic mechanisms, this review aims to inform both mechanistic understanding and drug discovery efforts in depression.