Epigenetic Signaling in Psychiatric Disorders
Open accessAbstract
Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function. While genetic factors are important in the etiology of disorders such as depression and addiction, relatively high rates of discordance among identical twins clearly indicate the importance of additional mechanisms. Environmental factors such as stress or prior drug exposure are known to play a role in the onset of these illnesses. Such exposure to environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental and adult exposures. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. Aspects of depression and addiction can be modeled in animals by inducing disease-like states through environmental manipulations (e.g., chronic stress, drug administration). Understanding how environmental factors recruit the epigenetic machinery in animal models reveals new insight into disease mechanisms in humans.
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HDAC2 and HDAC5 are associated with pro-depressant and antidepressant functions.
“Although medications targeting these epigenetic molecules are proving effective in preclinical animal studies, there is a lack of successful clinical trials of HDACi in neuropsychiatric disorders, perhaps because of the complexity of different HDAC isoforms (i.e., HDAC2 and HDAC5) that are associated with pro-depressant and antidepressant functions.408”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [408]
There is a lack of successful clinical trials of HDAC inhibitors in neuropsychiatric disorders.
“Although medications targeting these epigenetic molecules are proving effective in preclinical animal studies, there is a lack of successful clinical trials of HDACi in neuropsychiatric disorders, perhaps because of the complexity of different HDAC isoforms (i.e., HDAC2 and HDAC5) that are associated with pro-depressant and antidepressant functions.408”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [408]
The ‘Adult onset of depression’ section reports antidepressant-like effects of HDAC inhibition in rodents, and the concluding remarks call for translational studies. Neither passage addresses whether HDAC inhibitors have had successful clinical trials in neuropsychiatric disorders; searches for clinical trials and human HDAC-inhibitor treatment found no passage that does. (LLM, conf=0.72)
Experimental — accuracy not yet measuredDisruptions in transcription occur in various brain areas in preclinical models of depression and in patients with major depressive disorder.
“Indeed, disruptions in transcription occur in various brain areas in preclinical models of depression and in MDD patients.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [25]
The pathophysiology of major depressive disorder and the response to antidepressants are suggested to be controlled by epigenetic modulation of transcription.
“The pathophysiology of MDD and response to antidepressants are suggested to be controlled by epigenetic modulation of transcription.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [25]
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References 192 · Cited by 163
- Authors
- Peña, C. J., Bagot, R. C., Labonté, B., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Nestler, Eric J.
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 426
- Issue
- 20
- Pages
- 3389-3412
- ISSN
- 0022-2836 (ISSN-L)
- PMC
- PMC4177298
- OpenAlex
- W2043153024
- Cited by
- 163
- References
- 192
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 4 · 2023: 9 · 2022: 9 · 2021: 11 · 2020: 9 · 2019: 16 · 2018: 15 · 2017: 25 · 2016: 15 · 2015: 25 · 2014: 7
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (P50MH096890)
- National Institute on Drug Abuse (R37DA007359, P01DA008227)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- epigenetic regulation, mental illness, depression, addiction, chronic stress, environmental factors, gene expression, neural circuit function, transcriptional dysregulation, animal models
- MeSH terms
- Animals, Depressive Disorder, Humans, Hypothalamo-Hypophyseal System, Models, Genetic, Pituitary-Adrenal System, Signal Transduction, Behavior, Addictive, Epigenesis, Genetic
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