Epigenetic Mechanisms of Depression and Antidepressant Action
Open accessAbstract
Epigenetic mechanisms, which control chromatin structure and function, mediate changes in gene expression that occur in response to diverse stimuli. Recent research has established that environmental events and behavioral experience induce epigenetic changes at particular gene loci and that these changes help shape neuronal plasticity and function and hence behavior. Some of these changes can be stable and can even persist for a lifetime. Increasing evidence supports the hypothesis that aberrations in chromatin remodeling and subsequent effects on gene expression within limbic brain regions contribute to the pathogenesis of depression and other stress-related disorders such as post-traumatic stress disorder and other anxiety syndromes. Likewise, the gradually developing but persistent therapeutic effects of antidepressant medications may be achieved in part via epigenetic mechanisms. This review discusses recent advances in our understanding of the epigenetic regulation of stress-related disorders and focuses on three distinct aspects of stress-induced epigenetic pathology: the effects of stress and antidepressant treatment during adulthood, the lifelong effects of early-life stress on subsequent stress vulnerability, and the possible transgenerational transmission of stress-induced abnormalities.
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In genetically susceptible models of treatment-resistant depression, SAHA inhibits HDAC2, restores histone acetylation and BDNF levels, and reverses antidepressant non-responsiveness.
“In genetically susceptible models of treatment-resistant depression, SAHA inhibits HDAC2, restores histone acetylation and BDNF levels, and reverses antidepressant non-responsiveness (Meylan et al., 2016; Vialou et al., 2013).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Vialou et al., 2013
The section on histone acetylation in adult responses to stress reports antidepressant-like effects from HDAC inhibition and, separately, links antidepressant treatment to increased acetylation at the Bdnf promoter. It does not report that SAHA inhibits HDAC2 or restores BDNF in genetically susceptible, treatment-resistant models, nor that it reverses antidepressant non-responsiveness. No page number is available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThis risk-averse approach increases cognitive sensitivity to sensory cues of social risk.
“This maintains that depressed mood reflects an adaptive, risk-averse approach to social interaction that reduces the likelihood of further aversive outcomes by: (1) increasing our cognitive sensitivity to (sensory) cues of social risk; (2) reducing our (behavioural) propensity for taking social risks; and (3) initiating signalling behaviours that elicit support and defuse conflict [32].”
From The depressed brain: an evolutionary systems theory (2017) · cites this paper as [32]
This risk-averse approach reduces behavioural propensity for taking social risks.
“This maintains that depressed mood reflects an adaptive, risk-averse approach to social interaction that reduces the likelihood of further aversive outcomes by: (1) increasing our cognitive sensitivity to (sensory) cues of social risk; (2) reducing our (behavioural) propensity for taking social risks; and (3) initiating signalling behaviours that elicit support and defuse conflict [32].”
From The depressed brain: an evolutionary systems theory (2017) · cites this paper as [32]
This risk-averse approach initiates signalling behaviours that elicit support and defuse conflict.
“This maintains that depressed mood reflects an adaptive, risk-averse approach to social interaction that reduces the likelihood of further aversive outcomes by: (1) increasing our cognitive sensitivity to (sensory) cues of social risk; (2) reducing our (behavioural) propensity for taking social risks; and (3) initiating signalling behaviours that elicit support and defuse conflict [32].”
From The depressed brain: an evolutionary systems theory (2017) · cites this paper as [32]
Depressed mood reflects an adaptive, risk-averse approach to social interaction that reduces the likelihood of further aversive outcomes.
“This maintains that depressed mood reflects an adaptive, risk-averse approach to social interaction that reduces the likelihood of further aversive outcomes by: (1) increasing our cognitive sensitivity to (sensory) cues of social risk; (2) reducing our (behavioural) propensity for taking social risks; and (3) initiating signalling behaviours that elicit support and defuse conflict [32].”
From The depressed brain: an evolutionary systems theory (2017) · cites this paper as [32]
The depressive response is adaptive when changes in mood state and behaviour reduce uncertainty in the face of socio-environmental change, and lead to re-engagement with that environment when volatility abates.
“The depressive response is adaptive when changes in mood state and behaviour reduce uncertainty in the face of socio-environmental change, and lead to re-engagement with that environment when volatility abates (which should, at least in part, be brought about by depressive behaviours; see [32]).”
From The depressed brain: an evolutionary systems theory (2017) · cites this paper as [32]
Exacerbation of normative depressed states into severe, dysfunctional forms is likely when depressive changes fail to alleviate social stress, creating a self-perpetuating cycle arising from heightened and prolonged arousal of ineffectual attempts to reduce socio-environmental volatility.
“Notably, the exacerbation of normative depressed states into severe, dysfunctional forms is also likely when depressive changes fail to alleviate social stress, creating a self-perpetuating cycle arising from heightened and prolonged arousal of ineffectual attempts to reduce socio-environmental volatility [32].”
From The depressed brain: an evolutionary systems theory (2017) · cites this paper as [32]
Cholinergic innervation regulates critical period plasticity.
“Cholinergic innervation has been known for a long time to regulate critical period plasticity209.”
From Neuronal plasticity and neurotrophic factors in drug responses (2017) · cites this paper as [209]
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- Authors
- Vialou, V., Feng, J., Robison, A. J., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Nestler, Eric J.
- Venue
- Annual Review of Pharmacology and Toxicology
- Publisher
- Annual Reviews
- Published
- 2013-01-06
- Volume
- 53
- Issue
- 1
- Pages
- 59-87
- ISSN
- 0362-1642 (ISSN-L)
- 1545-4304
- PMC
- PMC3711377
- OpenAlex
- W2130374405
- Cited by
- 277
- References
- 216
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 12 · 2023: 11 · 2022: 13 · 2021: 18 · 2020: 14 · 2019: 26 · 2018: 26 · 2017: 25 · 2016: 32 · 2015: 32 · 2014: 26 · 2013: 21 · 2012: 3
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Annual Review of Pharmacology and Toxicology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (P50MH096890, R01MH051399)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- epigenetics, depression, antidepressant mechanism, chromatin remodeling, neuroplasticity, limbic system, post-traumatic stress disorder, anxiety, early life stress, stress vulnerability, transgenerational transmission, gene expression regulation
- MeSH terms
- Animals, Antidepressive Agents, Depression, Humans, Gene Expression, DNA Methylation, Epigenesis, Genetic
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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