Network pharmacology of cellular targets in major depressive disorder and differential mechanisms of fluoxetine, ketamine and esketamine
Computational and Structural Biotechnology Journal December 29, 2025 Silvia Tapia-Gonzalez, Josue G. Yagüe, George E. Barreto
Major depressive disorder involves genetic, environmental, and neurobiological factors. Conventional antidepressants like fluoxetine take weeks to work, while ketamine and esketamine act rapidly by modulating glutamate and possibly inhibiting GSK3B, which increases BDNF and neuroplasticity. Ketamine's effects also partly depend on opioid receptor activation. A network pharmacology meta-analysis identified OPRM1, EGFR, and GSK3B as key druggable targets and suggests NFKB may regulate all three, linking inflammation, synaptic plasticity, and metabolism. Targeted modulation of these genes could optimize treatment, and NFKB may serve as a biomarker for guiding therapy.