Trends in Psychopharmacology

Epigenetics As a Therapeutic Target for Psychiatric Illnesses

Adjunct Professor of Psychiatry, University of California, San Diego

First published in Psychiatry Weekly, Volume 5, Issue 15, on June 21, 2010

The strategy of targeting epigenetic mechanisms as a route to new therapeutics in psychiatry may be more feasible than modifying human genes, a complex, ethically troublesome, and potentially dangerous undertaking. That is, good or bad, the sequence of your genes is faithful throughout your lifetime. However, the developmentally programmed silencing and activation of some of your genes may be open to change if enticed by seductive epigenetic molecular mechanisms. This approach is based upon the idea that if mental illnesses are caused by the expression of risk genes that make altered proteins, or by the expression of normal genes that turn them into risk genes by making normal proteins but at the wrong time, then maybe silencing risk genes or activating compensatory genes would treat or even prevent mental illnesses.^1-3

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In order to turn your genes on or off, epigenetic mechanisms must be employed. Epigenetic molecular switches turn genes on and off by modifying the structure of chromatin in the cell nucleus.^1-4 Chromatin is an octet of proteins called histones, around which your DNA is wrapped (Figure).^1-4 DNA contains genes and also promoters that tell genes when to make RNA, which can then go on to make proteins. To silence genes, histones can be methylated or gene promoter DNA sequences can be methylated. Methylation is often followed by another chemical process called de-acetylation, which occurs at histones, and which also inactivates nearby genes. To activate genes, the reverse is done: histones and genes are demethylated and histones are acetylated. All of these processes are regulated by numerous enzymes, and methylation is regulated by the availability of methyl donors, as well.^1-4

Therapeutic epigenetics seeks to silence undesirable genes without silencing desirable genes, and to activate desirable genes without activating undesirable ones. This is a complex process, because there are over 20,000 genes and it is not yet proven which genes conspire to cause which mental disorders, let alone how to target the right genes selectively without also going off target and silencing or activating the wrong genes, as well. Furthermore, psychiatric illnesses are likely to be caused by a conspiracy of many genes and many epigenetic mechanisms that act simultaneously, so therapeutics may ultimately require multiple simultaneous genes to be silenced while others are activated.⁴ This can appear to be a formidable task, but some progress is already being made in epigenetic therapeutics in psychiatry by taking three main approaches to this: silencing genes by promoting methylation, activating genes by blocking de-acetylation, and stopping genes from being translated into proteins by interfering with their RNA.

Click here to view the unabridged version of Dr. Stahl's article at CNS Spectrums.

References:

1. Nestler EJ. Epigenetic mechanisms in psychiatry. Biol Psychiatry. 2009;65:189-90.

2. Stahl SM. Epigenetics and methylomics in psychiatry. J Clin Psychiatry. 2009;70:1204-1205.

3. Sweatt JD. Experience-dependent epigenetic modifications in the central nervous system. Biol Psychiatry. 2009;65:191-197.

4. Stahl SM. Methylated Spirits: Epigenetic Hypotheses of Psychiatric Disorders. CNS Spectr. 2010;15:220-230.

Disclosure: Dr. Stahl has served as a consultant to Allergan, AstraZeneca, BioMarin, BioVail, Boehringer Ingelheim, Bristol-Myers Squibb, Cenerex, Covance, Cypress Bioscience, Dianippon, Eisai, Eli Lilly, Forest pharmaceuticals, GlaxoSmithKline, Labopharm, Lundbeck, Marinus, Meda Corp, Meiji, Merck, Novartis, Pfizer, Pfizer Canada, Pierre Fabre, Pamlab, Prexa, Propagate Pharma, Royalty Pharma, sanofi-aventis, Schering Plough, Shire, SK Corporation, Soffinova, Solvay, Vanda, and Wyeth; has served on speaker’s bureaus of Pfizer, Schering Plough, and Wyeth; and has received grant support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, Dainippon, Eli Lilly, Forest pharmaceuticals, Lundbeck, Novartis, Pamlab, Pfizer, Pfizer Canada, Pharmasquire, sanofi-aventis, Schering Plough, Shire, and Wyeth.