Neuronal plasticity and antidepressant actions
Open accessAbstract
Antidepressant treatments enhance plasticity and increase neurogenesis in the adult brain, but it has been unclear how these effects influence mood. We propose that, like environmental enrichment and exercise, antidepressant treatments enhance adaptability by increasing structural variability within the nervous system at many levels, from proliferating precursors to immature synaptic contacts. Conversely, sensory deprivation and chronic stress reduce this structural variability. Activity-dependent competition within the mood-related circuits, guided by rehabilitation, then selects for the survival and stabilization of those structures that best represent the internal or external milieu. Increased variability together with competition-mediated selection facilitates normal function, such as pattern separation within the dentate gyrus and other mood-related circuits, thereby enhancing adaptability toward novel experiences.
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When neuroplasticity is enhanced (e.g., by treatment), synaptic contacts increase, enhancing adaptability by allowing activity-dependent competition to stabilize the neural structures that best represent internal and external conditions.
“Conversely, when neuroplasticity is enhanced (e.g., by treatment), synaptic contacts increase, enhancing adaptability by allowing activity-dependent competition to stabilize the neural structures that best represent internal and external conditions 24-26 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [25]
The Synaptic connections section says increased spine formation and retraction can provide more trial contacts for activity-dependent selection, supporting the proposed adaptability mechanism. But it distinguishes increased turnover from a net increase in synapses and reports only a minor effect of antidepressants on net spine number in the hippocampal CA1 area. The claim’s unqualified statement that synaptic contacts increase with enhanced plasticity overstates that evidence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredNeuronal plasticity is a central mechanism in the action of antidepressant drugs.
“They further imply that neuronal plasticity is a central mechanism in the action of antidepressant drugs.”
From Neuronal plasticity and neurotrophic factors in drug responses (2017) · cites this paper as [3]
Experience and activity-dependent plasticity fine-tune neuronal connectivity by stabilizing active neurons and connections and weakening or eliminating inactive contacts.
“Although gross connectivity develops through genetically governed guidance, fine-tuning takes place through experience and activity-dependent plasticity, where neurons and connections that actively participate in network function are selected for stabilization and strengthened, whereas inactive contacts are weakened or eliminated1–3.”
From Neuronal plasticity and neurotrophic factors in drug responses (2017) · cites this paper as [3]
Both BDNF and mTOR complex appear to be key effectors for rapidly enhancing synaptic connectivity and increasing dendritic spines and are proposed to underlie the persistent antidepressant effects of ketamine.
“Both BDNF and mTOR complex appear to be the key effectors for rapidly enhancing synaptic connectivity and increasing dendritic spines (Castren & Hen, 2013;Fortress, Smith, & Pang, 2018) and are proposed to underlie the persistent antidepressant effects of ketamine.”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Castren & Hen, 2013
Chronic administration of typical antidepressants that block the reuptake and breakdown of monoamines increase synaptic plasticity at several levels including increased birth of new neurons in the adult hippocampus, increased neurotrophic factor expression, and regulation of synapse formation.
“Chronic administration of typical antidepressants that block the reuptake and breakdown of monoamines increase synaptic plasticity at several levels including increased birth of new neurons in the adult hippocampus, increased neurotrophic factor expression, and regulation of synapse formation10,132,133.”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [132]
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- [74]Thoenen H 1995 Neurotrophins and Neuronal Plasticity Science 270 593 598 7570017
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Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants
Duman, R. S., Aghajanian, G. K., Sanacora, G., & Krystal, J. H. (2016) · Nature Medicine · doi:10.1038/nm.4050 · Cited by 1,750 · see citing works
Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model
Price, R. B., & Duman, R. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0615-x · Cited by 721 · see citing works
Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation
Moda-Sava, R. N., Murdock, M. H., Parekh, P. K., Fetcho, R. N., Huang, B. S., Huynh, T. N., Witztum, J., Shaver, D. C., Rosenthal, D. L., Alway, E. J., et al. (2019) · Science · doi:10.1126/science.aat8078 · Cited by 643 · see citing works
The Role of BDNF on Neural Plasticity in Depression
Yang, T., Nie, Z., Shu, H., Kuang, Y., Chen, X., Cheng, J., Yu, S., & Liu, H. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00082 · Cited by 435 · see citing works
Brain-derived neurotrophic factor in mood disorders and antidepressant treatments
Castrén, E., & Kojima, M. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.07.010 · Cited by 337 · see citing works
Self-citationNeurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression
Levy, M. J. F., Boulle, F., Steinbusch, H. W., van den Hove, D. L. A., Kenis, G., & Lanfumey, L. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4950-4 · Cited by 308 · see citing works
Neuronal plasticity and neurotrophic factors in drug responses
Castrén, E., & Antila, H. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.61 · Cited by 284 · see citing works
Self-citationSartori, S. B., & Singewald, N. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107402 · Cited by 236 · see citing works
Page, C. E., & Coutellier, L. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.07.024 · Cited by 213 · see citing works
What is mood? A computational perspective
Clark, J. E., Watson, S., & Friston, K. J. (2018) · Psychological Medicine · doi:10.1017/s0033291718000430 · Cited by 204 · see citing works
Su, K.-P., Lai, H.-C., Yang, H.-T., Su, W.-P., Peng, C.-Y., Chang, J. P.-C., Chang, H.-C., & Pariante, C. M. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.01.008 · Cited by 205 · see citing works
GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response
Gunn, B. G., Cunningham, L., Mitchell, S. G., Swinny, J. D., Lambert, J. J., & Belelli, D. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.06.001 · Cited by 149 · see citing works
Role of brain imaging in disorders of brain–gut interaction: a Rome Working Team Report
Mayer, E. A., Labus, J., Aziz, Q., Tracey, I., Kilpatrick, L., Elsenbruch, S., Schweinhardt, P., Van Oudenhove, L., & Borsook, D. (2019) · Gut · doi:10.1136/gutjnl-2019-318308 · Cited by 138 · see citing works
Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression
Ling, S., Ceban, F., Lui, L. M. W., Lee, Y., Teopiz, K. M., Rodrigues, N. B., Lipsitz, O., Gill, H., Subramaniapillai, M., Mansur, R. B., et al. (2022) · CNS Drugs · doi:10.1007/s40263-021-00877-y · Cited by 127 · see citing works
Synaptic Mechanisms Regulating Mood State Transitions in Depression
Parekh, P. K., Johnson, S. B., & Liston, C. (2022) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-110920-040422 · Cited by 101 · see citing works
Lima da Cruz, R. V., Moulin, T. C., Petiz, L. L., & Leão, R. N. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00312 · Cited by 84 · see citing works
Kuipers, S. D., Trentani, A., Tiron, A., Mao, X., Kuhl, D., & Bramham, C. R. (2016) · Scientific Reports · doi:10.1038/srep21222 · Cited by 83 · see citing works
iPlasticity: Induced juvenile‐like plasticity in the adult brain as a mechanism of antidepressants
Umemori, J., Winkel, F., Didio, G., Llach Pou, M., & Castrén, E. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12683 · Cited by 80 · see citing works
Self-citationNew Treatment Strategies of Depression: Based on Mechanisms Related to Neuroplasticity
Huang, Y.-J., Lane, H.-Y., & Lin, C.-H. (2017) · Neural Plasticity · doi:10.1155/2017/4605971 · Cited by 74 · see citing works
Fenton, E. Y., Fournier, N. M., Lussier, A. L., Romay-Tallon, R., Caruncho, H. J., & Kalynchuk, L. E. (2015) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2015.02.001 · Cited by 69 · see citing works
Page, C. E., Epperson, C. N., Novick, A. M., Duffy, K. A., & Thompson, S. M. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02625-2 · Cited by 80 · see citing works
Pringle, A., & Harmer, C. J. (2015) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2015.17.4/apringle · Cited by 61 · see citing works
HCN Channel Targets for Novel Antidepressant Treatment
Ku, S. M., & Han, M.-H. (2017) · Neurotherapeutics · doi:10.1007/s13311-017-0538-7 · Cited by 54 · see citing works
Antidepressant drug action--From rapid changes on network function to network rewiring
Rantamäki, T., & Yalcin, I. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2015.06.001 · Cited by 50 · see citing works
TrkB neurotrophin receptor at the core of antidepressant effects, but how?
Rantamäki, T. (2019) · Cell and Tissue Research · doi:10.1007/s00441-018-02985-6 · Cited by 45 · see citing works
Jha, M. K., Minhajuddin, A., Chin-Fatt, C., Greer, T. L., Carmody, T. J., & Trivedi, M. H. (2019) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2019.03.013 · Cited by 40 · see citing works
“Response to antidepressant treatment is associated with changes in neural circuits (Castren and Hen, 2013).”
BackgroundMcAvoy, K., Russo, C., Kim, S., Rankin, G., & Sahay, A. (2015) · Hippocampus · doi:10.1002/hipo.22464 · Cited by 36 · see citing works
Rethinking the role of TRKB in the action of antidepressants and psychedelics
Brunello, C. A., Cannarozzo, C., & Castrén, E. (2024) · Trends in Neurosciences · doi:10.1016/j.tins.2024.08.011 · Cited by 31 · see citing works
“Furthermore, neuroplastic modi fi cations produced by antidepressants, including maturation and consolidation of synapses, arborization of axons and dendrites, and hippocampal neurogenesis [51 – 53], take time.”
BackgroundThe molecular basis of depression: implications of sex-related differences in epigenetic regulation
Kawatake-Kuno, A., Murai, T., & Uchida, S. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.708004 · Cited by 23 · see citing works
The role of Neurotrophin 3 (NT-3) on neural plasticity in depression: A literature review
Shatri, H., Pranandi, M., Ardani, Y., Firmansyah, I., Faisal, E., & Putranto, R. (2023) · Intisari Sains Medis · doi:10.15562/ism.v14i3.1830 · Cited by 2 · see citing works
- Authors
- Castrén, E., & Hen, R.
- Affiliations
- Columbia University (US)
- Corresponding author
- Hen, René
- ORCID
- Hen, René
- Venue
- Trends in Neurosciences
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 36
- Issue
- 5
- Pages
- 259-267
- ISSN
- 0166-2236 (ISSN-L)
- PMC
- PMC3648595
- OpenAlex
- W2022555874
- Cited by
- 243
- References
- 93
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 18 · 2023: 14 · 2022: 24 · 2021: 30 · 2020: 21 · 2019: 21 · 2018: 16 · 2017: 14 · 2016: 13 · 2015: 19 · 2014: 14 · 2013: 6
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Trends in Neurosciences (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- Hope for Depression Research Foundation
- Sigrid Juséliuksen Säätiö
- H. Lundbeck A/S
- National Institute on Aging (R01AG043688)
- National Institute of Mental Health (R37MH068542)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- neuroplasticity, antidepressants, adult neurogenesis, environmental enrichment, physical activity, sensory deprivation, chronic stress, rehabilitation, pattern separation, dentate gyrus, mood, synaptic plasticity
- MeSH terms
- Affect, Animals, Antidepressive Agents, Humans, Nerve Net, Neuronal Plasticity, Neurons, Neurogenesis
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