Genome-wide mapping of epigenetic modifications in the brain suggest an important role for epigenetic processes in neurodevelopment (Lister et al, 2013). It is hypothesized that epigenetic alterations mediate neurodevelopmental diseases such as schizophrenia or autism, as well as other mental health conditions such as addiction and dementia.
The main appeal of this hypothesis is that, since epigenetic modifications are catalyzed by reversible enzymatic reactions they could be modulated by pharmacological agents, potentially reprogramming pathological states. There is strong preclinical evidence that learning and memory involve changes in DNA methylation and histone acetylation (Heyward and Sweatt, 2015). The involvement of DNA methylation and histone acetylation/deacetylation enzymes in learning and memory raises the possibility that they might be targeted to attenuate remote memories for treatment of PTSD(Graff et al, 2014). HDAC inhibition enhances cognitive performance in a mouse model of impaired cognition, and CREB pathway-specific selected HDAC inhibitor crebinostat was shown to significantly improve memory (Fass et al, 2013). It is unclear, however, whether this approach works in humans. If indeed the clinical data replicates animal studies, isotype-specific HDAC inhibitors should have a large impact on the treatment of cognitive decline and dementia, and perhaps PTSD.
Evidence suggests that addiction is mediated by epigenetic reprogramming in response to drug exposure (Massart et al, 2015). Epigenetic therapy might potentially ‘reprogram’ the addicted state and revert the phenotype to a non-addictive phenotype. Treatment of rats that crave cocaine with the DNA methylation inhibitor RG108 inhibited cocaine craving. Importantly, although the treatment was acute, the effects on blocking addiction persisted up to 60 days, suggesting stable epigenetic reprogramming by the treatment (Massart et al, 2015). Epigenetic therapy could potentially erase the epigenetic marks of exposure and exert a long-lasting effect that should persist unless a similar exposure is encountered, in difference from symptomatic therapy, which provides a transient relief.
However, there are critical caveats that need to be addressed. First, epigenetic drugs target general epigenetic processes, how could we guarantee specificity to particular genes? Nevertheless, since epigenetic reprogramming probably involves gene networks (for example, see (Massart et al, 2015), perhaps multi-targeted epigenetic drugs might be more potent than other approaches. Second, neurodevelopmental programs involve an organized sequence of epigenetic alterations, how could they be reversed once the neurodevelopmental processes have taken shape? There is genetic evidence that this might be possible; a RETT syndrome phenotype caused by transgenic mecp2 mutation in mice could be rescued by restoring MeCP2 gene expression in adult mutant animals (Guy et al, 2007). Animal studies have shown that general HDAC inhibitors could reverse learning deficiencies in a neurodegenerative mouse model (Fischer et al, 2007), but clinical studies have been limited, used nonspecific HDAC inhibitors, and examined a small number of patients (Sajatovic et al, 2008). The main epigenetic drug that is currently in use in psychiatry is valproic acid, a nonspecific HDAC inhibitor. A recent meta-analysis suggests that Valproic acid augmentation might improve treatment of schizophrenia patients (Tseng et al, 2016). The question remains, however, whether HDAC inhibitors could reverse behavioral and neuropsychiatric disorders, whether isotype-specific inhibitors would exhibit a more potent reprogramming activity, or whether multi-targeted drugs acting on gene networks rather than single selective agents would exert a more potent clinical benefit, and whether other epigenetic modulators such as DNA methylation inhibitors might elicit stronger responses?
The preclinical evidence for a potential paradigm shift in treatment of mental health conditions using epigenetic modulators has been surprisingly slow in translation to the clinical arena. The clinical studies are sparse, and the selection of epigenetic modulators that cross the blood–brain barrier that are appropriate for clinical studies is limited. Though more work needs to be done, there is vast potential for epigenetic approaches to change the way mental health disorders are treated.
Funding and Disclosure
The author declares no conflict of interest.
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Szyf, M. Prospects for Medications to Reverse Causative Epigenetic Processes in Neuropsychiatry Disorders. Neuropsychopharmacol 42, 367–368 (2017). https://doi.org/10.1038/npp.2016.219