Network dysregulation in depression: A synthesis of HPA Axis, BDNF signaling, and neurotransmitter interactions across multidimensional systems.
Mengyang He, Zhifei Shi, Ruijie Zhan, Zhidong Zhuang, Xinyue Li, Wenrui Xue
Pharmacology, Biochemistry, and Behavior August 1, 2026 DOI: 10.1016/j.pbb.2026.174215 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | Review of depression pathophysiology |
| Interventions | ketamine repetitive Transcranial Magnetic Stimulation (rTMS) Selective Serotonin Reuptake Inhibitors (SSRIs) |
| Topics | Depression Neuroplasticity |
| Keywords | Bdnf/creb signaling pathway Emotional–cognitive circuit Epigenetic regulation Hpa axis Neurotransmitter systems |
| Key findings | The BDNF/CREB signaling pathway serves as a core hub mediating multisystem network dysfunction in depression, integrating emotional-cognitive circuits, HPA axis activity, neurotransmitter systems, and neuroplasticity. |
Abstract
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.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cites 3
- Rethinking the role of TRKB in the action of antidepressants and psychedelics. Trends in Neurosciences November 1, 2024
- Microglial BDNF modulates arketamine's antidepressant-like effects through cortico-accumbal pathways. Science Advances July 11, 2025
- The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring. Neuropsychopharmacology February 1, 2026