Network dysregulation in depression: A synthesis of HPA Axis, BDNF signaling, and neurotransmitter interactions across multidimensional systems.
Pharmacology, biochemistry, and behavior August 1, 2026 Mengyang He, Zhifei Shi, Ruijie Zhan et al.
Depression involves multiple dysfunctions across brain systems, including emotional-cognitive circuits, stress hormone regulation, neurotransmitter systems, and neuroplasticity. This review argues that the BDNF/CREB signaling pathway acts as a central hub connecting these systems. It explains how genetic variations, stress-related epigenetic changes, and microRNA regulation affect this pathway, which in turn influences brain plasticity, stress toxicity, and neurotransmitter balance. The review also describes how antidepressants like ketamine, rTMS, and SSRIs work by activating this pathway, supporting its potential as a biomarker and treatment target. Limitations and future directions integrating multiomics and neuroimaging are discussed, reconceptualizing depression as a network disorder centered on BDNF/CREB signaling.