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Is there a future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders
Abstract
In recent years, it has become widely recognized that a comprehensive understanding of chromatin biology is necessary to better appreciate its role in a wide range of diseases. The histone code has developed as a new layer of our appreciation of transcription factor-based mechanisms of gene expression. Although epigenetic regulation refers to a host of chromatin modifications that occur at the level of DNA, histones, and histone-associated proteins, how this regulation is orchestrated is still incompletely understood. Of those processes that comprise the epigenetic regulatory machinery, DNA methylation and histone acetylation/deacetylation have been the most thoroughly studied. Compounds that act as inhibitors of DNA methyltransferases or histone deacetylases (HDACs) activate a variety of intracellular signaling pathways that ultimately affect the coordinated expression of multiple genes. The altered patterns of mRNA and protein expression collectively converge on pathways linked to apoptosis and cell cycle arrest, among others. This has prompted a widespread search for epigenetic inhibitors that could be used as chemotherapeutic agents, and several are undergoing clinical evaluation. More recently, there has been interest in the use of HDAC inhibitors to activate the expression of mRNAs that are down-regulated in various neurological and psychiatric conditions. Considerably less is known regarding the effect these drugs have on postmitotic cells such as neurons. Before we consider the clinical use of additional HDAC inhibitors to treat schizophrenia or unipolar depression, there are a number of key issues that need to be resolved.
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“An example of an epigenetic-based therapy is HDAC inhibition, which increase histone acetylation thereby relaxing the chromatic and increasing gene expression (27).”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [27]
In the citing paper
“abnormal histone modifications have been linked to multiple psychiatric disorders”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [27]
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“Fortunately, there are a number of drugs that target epigenetic enzymes; although originally developed for the treatment of specific cancers, application of these agents to psychiatric disorders, including alcohol and substance use disorders, may be possible (Grayson et al. 2010).”
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“A large majority of hydroxamate HDAC inhibitors act as pan-HDAC inhibitors, and do not show selectivity within the zinc dependent classes of HDAC enzymes [53]; however due to the large variation in chemical structure among peptides, peptide HDAC inhibitors can elicit inhibition of different HDAC isoforms, including mo…”
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Repurposing Vorinostat for the Treatment of Disorders Affecting Brain
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“A number of HDAC inhibitors have been developed belonging to various classes (Table 1) (Didonna & Opal, 2015; Grayson et al., 2010; Souza, 2015; Wash et al., 2008).”
BackgroundHistone deacetylase inhibitors as potential treatment for spinal muscular atrophy
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“In this regard, HDACs are actually “lysinedeacetylases” (Grayson et al., 2010; Xu et al., 2007).”
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“Accordingly, local administration of HDACi in such brain regions has been observed to have antidepressant-like actions in several behavioral assays (Schroeder et al., 2007; Bredy and Barad, 2008; Grayson et al., 2010).”
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“Histone acetylation plays a significant role in regulating gene transcription [15,16].”
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“Importantly, the use of drugs that can manipulate the levels of these modifying enzymes are already being explored for the treatment of mental illnesses [18].”
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Calabrese, F., Molteni, R., & Riva, M. A. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.05.007 · Cited by 42
Stertz, L., Fries, G. R., de Aguiar, B. W., Pfaffenseller, B., Valvassori, S. S., Gubert, C., Ferreira, C. L., Moretti, M., Ceresér, K. M. M., Kauer‐Sant’Anna, M., et al. (2013) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2013-1094 · Cited by 41
Renani, P. G., Taheri, F., Rostami, D., Farahani, N., Abdolkarimi, H., Abdollahi, E., Taghizadeh, E., & Hayat, S. M. G. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28622 · Cited by 43
Qin, L., Ma, K., & Yan, Z. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01212-1 · Cited by 43
“Increased HDAC expression and ensuring transcriptional dysfunction involved in synaptic transmission have been implicated in psychiatric disorders [5, 6].”
BackgroundEpigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia
Moos, W. H., Maneta, E., Pinkert, C. A., Irwin, M. H., Hoffman, M. E., Faller, D. V., & Steliou, K. (2016) · Drug Development Research · doi:10.1002/ddr.21295 · Cited by 41
“With respect to epigenetic mechanisms, including HDACs and their inhibition, SCFAs like butyrate have a profound influence on microglial homeostasis [Erny et al., 2015].”
BackgroundInfluentialThe possibility of evidence-based psychiatry: depression as a case
Stojanov, D., Korf, J., de Jonge, P., & Popov, G. (2010) · Clinical Epigenetics · doi:10.1007/s13148-010-0014-2 · Cited by 35
“Most recently, there are experimental data reported (Grayson et al. 2010) which suggest the application of inhibitors of DNA methyl transferase and histone deacetylase (HDAC) as potential therapeutic agents in the causal treatments of psychiatric disorders.”
BackgroundClass I HDAC Inhibitors: Potential New Epigenetic Therapeutics for Alcohol Use Disorder (AUD)
Bourguet, E., Ozdarska, K., Moroy, G., Jeanblanc, J., & Naassila, M. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00115 · Cited by 36
Chakravarty, S., Maitra, S., Reddy, R. G., Das, T., Jhelum, P., Kootar, S., Rajan, W. D., Samanta, A., Samineni, R., Pabbaraja, S., et al. (2015) · Scientific Reports · doi:10.1038/srep14134 · Cited by 32
Bi, M., Feng, L., He, J., Liu, C., Wang, Y., Jiang, H., & Liu, S. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101759 · Cited by 32
The Epigenetic Code in Depression: Implications for Treatment
Schroeder, M., Hillemacher, T., Bleich, S., & Frieling, H. (2011) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.282 · Cited by 32
Class I HDAC imaging using [3H]CI-994 autoradiography
Wang, Y., Zhang, Y., Hennig, K. M., Gale, J. P., Hong, Y., Cha, A., Riley, M. M., Wagner, F. F., Haggarty, S. J., Holson, E. B., et al. (2013) · Epigenetics · doi:10.4161/epi.25202 · Cited by 30
Balasubramanian, D., Deng, A. X., Doudney, K., Hampton, M. B., & Kennedy, M. A. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.06.018 · Cited by 31
Zhang, F., Rein, B. A., Zhong, P., Shwani, T., Conrow‐Graham, M., Wang, Z., & Yan, Z. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01233-w · Cited by 32
Epigenetic Regulatory Mechanisms in Stress-Induced Behavior
Chakravarty, S., Pathak, S. S., Maitra, S., Khandelwal, N., Karisetty, B. C., & Kumar, A. (2014) · International review of neurobiology · doi:10.1016/b978-0-12-801311-3.00004-4 · Cited by 32
Plazas-Mayorca, M. D., & Vrana, K. E. (2010) · Journal of Proteome Research · doi:10.1021/pr100463y · Cited by 27
Inflammation as a Mechanism of Bipolar Disorder Neuroprogression
Barichello, T., Giridharan, V. V., Bhatti, G. S., Sayana, P., Doifode, T., Macêdo, D. S., & Quevedo, J. (2020) · Current topics in behavioral neurosciences · doi:10.1007/7854_2020_173 · Cited by 28
Pharmacogenomic Implications of Variants of Monoaminergic-Related Genes in Geriatric Psychiatry
Shiroma, P. R., Geda, Y. E., & Mrazek, D. A. (2010) · Pharmacogenomics · doi:10.2217/pgs.10.118 · Cited by 26
Is there any therapeutic value for the use of histone deacetylase inhibitors for chronic pain?
Wang, W., Cui, S.-S., Lu, R., & Zhang, H. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.04.010 · Cited by 26
Epigenetic approaches for bipolar disorder drug discovery
Peedicayil, J. (2014) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2014.922537 · Cited by 25
“It appears that those HDACis that facilitate DNA demethylation have greater efficacy than those that do not [19,20].”
BackgroundLi, Y.-C., Panikker, P., Xing, B., Yang, S.-S., Alexandropoulos, C., McEachern, E., Akumuo, R. C., Zhao, E. E., Gulchina, Y., Pletnikov, M. V., et al. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.10.025 · Cited by 24
Epigenetic management of major psychosis
Peedicayil, J. (2011) · Clinical Epigenetics · doi:10.1007/s13148-011-0038-2 · Cited by 24
“Epigenetic drugs that are being investigated for such a purpose include SAHA (vorinostat), MS275, and phenylbutyrate (Best and Carey 2010; Grayson et al. 2010).”
BackgroundSchizophrenia and the Epigenetic Hypothesis
Grayson, D. R. (2010) · Epigenomics · doi:10.2217/epi.10.22 · Cited by 22
Histone deacetylases and inhibitors in diabetes mellitus and its complications
Wang, L., Bai, Y., Cao, Z., Guo, Z., Lian, Y., Liu, P., Zeng, Y., Lyu, W., & Chen, Q. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117010 · Cited by 24
Histone Deacetylase Inhibitors as Cognitive Enhancers and Modifiers of Mood and Behavior
Pal, D., Sahu, P., Mishra, A. K., Hagelgans, A., & Sukocheva, O. A. (2022) · Current Drug Targets · doi:10.2174/1389450124666221207090108 · Cited by 19
Comparison of Different Histone Deacetylase Inhibitors in Attenuating Inflammatory Pain in Rats
Mao, Y., Zhou, J., Liu, X., Gu, E., Zhang, Z., & Tao, W. (2019) · Pain Research and Management · doi:10.1155/2019/1648919 · Cited by 20
“Although Table 1 lists the sensitivities of tested drugs to the isoforms of HDAC classes [63, 65], our results provided di erent HDACI e¢cacies in rat models of persistent inammatory pain.”
ResultZhou, Q., Dalgard, C. L., Wynder, C., & Doughty, M. L. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.06.037 · Cited by 19
“Furthermore, at high doses VPA inhibits histone deacetylase (HDAC) activity [11] and HDACmediated responses are proposed to contribute to the differential neurogenic effects of VPA in the normal and epileptic adult rodent brain [14,15,23].”
Auta, J., Gatta, E., Davis, J. M., Pandey, S. C., & Guidotti, A. (2018) · Pharmacology Research & Perspectives · doi:10.1002/prp2.416 · Cited by 19
“17 Conversely, DNA promoter methylation which involves the covalent coupling of a methyl group to the C5 position of cytosine residues of CpG dinucleotide upstream of the transcription start site, is catalyzed by DNA methyltransferases [DNA methyltransferase 1 (Dnmt1), DNA methyltransferase 3a (Dnmt13a) DNA methyltran…”
BackgroundGenome-Wide Screening for Genes Associated with Valproic Acid Sensitivity in Fission Yeast
Zhang, L., Ma, N., Liu, Q., & Ma, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068738 · Cited by 20
“HDAC inhibitors could benefit diseases such as neurological and psychiatric disorders [11].”
BackgroundGavin, D. P., & Floreani, C. V. (2014) · International review of neurobiology · doi:10.1016/b978-0-12-801311-3.00005-6 · Cited by 17
Histone deacetylase inhibition is cytotoxic to oligodendrocyte precursor cells in vitro and in vivo
Dincman, T. A., Beare, J. E., Ohri, S. S., Gallo, V., Hetman, M., & Whittemore, S. R. (2016) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2016.08.006 · Cited by 19
Lopez, Y. P., Kenis, G., Stettinger, W., Neumeier, K., de Jonge, S., Steinbusch, H. W. M., Zill, P., van den Hove, D., & Myint, A.-M. (2016) · Molecular Biology Reports · doi:10.1007/s11033-016-4006-y · Cited by 18
“Vice versa, HDAC inhibitors have also been shown to possess antidepressant properties [32, 33].”
Mechanism of methylation and acetylation of high GDNF transcription in glioma cells: A review
Zhang, L., Wang, D., Han, X., Tang, F., & Gao, D. (2019) · Heliyon · doi:10.1016/j.heliyon.2019.e01951 · Cited by 17
Preventing epigenetic traces of caregiver maltreatment: A role for HDAC inhibition
Doherty, T. S., Chajes, J. R., Reich, L. N., Duffy, H. B. D., & Roth, T. L. (2019) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2019.05.002 · Cited by 20
“drugs were first used in cancer therapy, they may be effective in treating various psychopathologies (Grayson et al., 2010; Shepard et al., 2018; Szyf, 2009; Varela et al., 2015) and physical health problems following early adversity (Moloney et al.”
BackgroundMethod
Metadata
- Authors
- Grayson, D. R., Kundakovic, M., & Sharma, R. P.
- Affiliations
- University of Illinois Chicago (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 77
- Issue
- 2
- Pages
- 126-135
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2099118364
- Cited by
- 171
- References
- 85
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 12 · 2018: 7 · 2017: 9 · 2016: 14 · 2015: 14 · 2014: 22 · 2013: 16 · 2012: 16
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Food and Drug Administration
- University of Illinois at Chicago
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- histone deacetylase inhibitors, epigenetic regulation, chromatin biology, histone code, histone acetylation, DNA methylation, mental illness, schizophrenia, major depressive disorder, gene expression, neurons, epigenetic drugs
- MeSH terms
- Animals, Mental Disorders, Forecasting, Gene Expression Regulation, Histone Deacetylases, Humans, Histone Deacetylase Inhibitors
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