Pharmacology, biochemistry, and behaviorMay 26, 2026

Disrupted stress response, brain growth signals, and chemical communication networks in depression

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated May 27, 2026

Abstract

The review highlights the Brain-Derived Neurotrophic Factor/cAMP-responsive Element Binding Protein (BDNF/CREB) signaling pathway as a central hub in the dysfunction of multiple systems related to depression.

Depression is associated with disruptions in emotional-cognitive circuits, the HPA axis, neurotransmitter systems, and neuroplasticity.
Current research tends to examine these systems in isolation, lacking an integrated framework for understanding their interactions.
The BDNF/CREB signaling pathway may mediate these multisystem dysfunctions through genetic changes, stress-related epigenetic alterations, and microRNA regulation.
This pathway shows bidirectional effects on the plasticity of emotional-cognitive circuits, neurotoxic influences of the HPA axis, and neurotransmitter system imbalances.
Antidepressant treatments, such as ketamine and SSRIs, may target this pathway, suggesting its potential as a biomarker and therapeutic target.
Future research may benefit from integrating multiomics and neuroimaging to redefine depression as a network disorder centered on BDNF/CREB signaling.

Simplified

Depression is a complex mental disorder threatening global public health. Its pathophysiological mechanisms involve multidimensional dysfunctions including the emotional-cognitive circuit, Hypothalamic-Pituitary-Adrenal (HPA) axis, neurotransmitter systems and neuroplasticity. Current studies mostly analyze each system in isolation, lacking a unified integrated framework. This review proposes that the Brain-Derived Neurotrophic Factor/cAMP-responsive Element Binding Protein (BDNF/CREB) signaling pathway serves as the core hub mediating multisystem network dysfunction in depression. It systematically elucidates the multilevel molecular mechanisms of this pathway, such as genetic polymorphisms, stress-induced epigenetic modifications, and post-transcriptional regulation by microRNAs (miRNAs); clarifies its bidirectional regulatory effects on the plasticity of the prefrontolimbic emotional-cognitive circuit, neurotoxic effects of the HPA axis, and imbalance of monoaminergic/amino acid neurotransmitter systems; summarizes the targeted activation mechanisms of antidepressant interventions (e.g., ketamine, repetitive Transcranial Magnetic Stimulation (rTMS), Selective Serotonin Reuptake Inhibitors (SSRIs)) on this pathway, and verifies its value as a disease biomarker and therapeutic target combined with clinical evidence. This review points out the limitations of current research and prospects the precision research direction integrating multiomics and neuroimaging, reconceptualizing depression as a network disorder centered on the abnormality of the BDNF/CREB signaling hub, so as to provide theoretical support for elucidating the pathological mechanism of depression and developing precision diagnosis and treatment strategies.

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Competing interests

Declaration of competing interest The authors declare no conflict of interest.

PubMed

Disrupted stress response, brain growth signals, and chemical communication networks in depression

Abstract

Full Text

Funding

Competing interests

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