Keywords
Neuroplasticity
Neuroinflammation
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Abstract
Objective: To analyze the main mechanisms involved in neuroplasticity associated with the pathophysiology of Major Depressive Disorder (MDD) and their therapeutic implications. Literature review: Neuroplasticity plays a central role in the pathophysiology of MDD, involving structural, functional, and synaptic alterations, as well as mechanisms related to neuroinflammation, chronic stress, and neurotrophic signaling. Reduced activity of the BDNF-TrkB and mTORC1 pathways, loss of dendritic spines, decreased neuronal connectivity, and alterations in brain network activity contribute to the persistence of clinical manifestations of the disorder. Conversely, different therapeutic interventions, including conventional antidepressants, ketamine, and non-pharmacological strategies, may promote the reorganization of neural circuits, synaptogenesis, and the recovery of brain plasticity. Final considerations: Understanding neuroplasticity in Major Depressive Disorder highlights new therapeutic targets, supporting strategies capable of restoring neural connectivity and improving the effectiveness of depression treatment.
References
AMERICAN PSYCHIATRIC ASSOCIATION. DSM-5-TR: neurocognitive disorders supplement – updated excerpts for delirium codes, major and mild neurocognitive disorders. Washington, DC: American Psychiatric Association Publishing, 2022.
CASTRÉN E, MONTEGGIA LM. Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biological Psychiatry, 2021; 90(2): 128–136.
DUMAN RS, et al. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nature Medicine, 2016; 22(3): 238–249.
FAISAL H, et al. Effect of ketamine on reward processing in depressive disorders: a systematic review of neuroimaging studies. CNS Spectrums, 2026; 31(1): e9.
FOGAÇA MV, DUMAN RS. Cortical GABAergic dysfunction in stress and depression: new insights for therapeutic interventions. Frontiers in Cellular Neuroscience, 2019; 13: 87.
HUANG YJ, et al. New treatment strategies of depression: based on mechanisms related to neuroplasticity. Neural Plasticity, 2017; 2017: 4605971.
LIAO C, et al. Structural neural plasticity evoked by rapid-acting antidepressant interventions. Nature Reviews Neuroscience, 2025; 26(2): 101–114.
LIU W, et al. The role of neural plasticity in depression: from hippocampus to prefrontal cortex. Neural Plasticity, 2017; 2017: 6871089.
LIU Y, et al. Emotional roles of mono-aminergic neurotransmitters in major depressive disorder and anxiety disorders. Frontiers in Psychology, 2018; 9: 2201.
LOVRENČIĆ MV, et al. Improvement in depressive symptoms is associated with reduced oxidative damage and inflammatory response in type 2 diabetic patients with subsyndromal depression: the results of a randomized controlled trial comparing psychoeducation, physical exercise, and enhanced treatment as usual. International Journal of Endocrinology, 2015; 2015: 210406.
MA K, et al. The molecular mechanism underlying GABAergic dysfunction in nucleus accumbens of depression-like behaviours in mice. Journal of Cellular and Molecular Medicine, 2019; 23: 7397–7409.
MAGARAGGIA I, et al. Improving cognitive function in major depressive disorder with psychedelics: a dimensional approach. Neurobiology of Learning and Memory, 2021; 183: 107467.
PAGE CE, et al. Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder. Molecular Psychiatry, 2024; 29(12): 3802–3813.
PAREKH PK, et al. Synaptic mechanisms regulating mood state transitions in depression. Annual Review of Neuroscience, 2022; 45: 581–601.
PISANU C, et al. Effect of ketamine and esketamine on RNA expression and its relevance for depression: a systematic review. Pharmacological Research, 2025; 219: 107894.
PRICE RB e DUMAN R. Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Molecular Psychiatry, 2020; 25: 530–543.
RĂDULESCU I, et al. Neuroplasticity and depression: rewiring the brain’s networks through pharmacological therapy (review). Experimental and Therapeutic Medicine, 2021; 22(4): 1131.
SACCARO L, et al. Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: a systematic review and meta-analysis. Journal of Affective Disorders, 2024; 355: 265–282.
TAYYAB M, et al. Sonic hedgehog, Wnt, and brain-derived neurotrophic factor cell signaling pathway crosstalk: potential therapy for depression. Journal of Neuroscience Research, 2018; 96(1): 53–62.
UMEMORI J, et al. iPlasticity: induced juvenile-like plasticity in the adult brain as a mechanism of antidepressants: antidepressant-induced plasticity. Psychiatry and Clinical Neurosciences, 2018; 72(9): 633–653.
VAISHNAVI S, et al. Changes in neural activities and neuroplasticity related to nonpharmacological interventions for major depressive disorder: a systematic literature review. Biological Psychiatry Global Open Science, 2025; 5(6): 100572.
VOSE LR, STANTON PK. Synaptic plasticity, metaplasticity and depression. Current Neuropharmacology, 2017; 15(1): 71–86.
WILKINSON ST, et al. Leveraging neuroplasticity to enhance adaptive learning: the potential for synergistic somatic-behavioral treatment combinations to improve clinical outcomes in depression. Biological Psychiatry, 2019; 85(6): 454–465.
WU A, ZHANG J. Neuroinflammation, memory, and depression: new approaches to hippocampal neurogenesis. Journal of Neuroinflammation, 2023; 20: 283.
YUKSEL D, et al. Longitudinal brain volume changes in major depressive disorder. Journal of Neural Transmission, 2018; 125: 1433–1447.
ZARZA-REBOLLO JA, et al. The relationship between BDNF and physical activity on depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2024; 134: 111033.