Understanding Epigenetics May Offer Insights for Treatment of Mental Illness

Life is more than DNA, said Moshe Szyf, Ph.D., a professor of pharmacology and therapeutics at McGill University in Montreal.

“The genome is the book of life, but it is a static book and life is dynamic,” said Szyf at APA’s 2015 annual meeting in Toronto in May.

Part of that dynamism is attributable to epigenetics, the pattern of methylation found on the gene. Call it coding—the organism’s basic DNA—and coating—the attachment of a methyl group onto the surface of DNA that shuts down the expression of the gene.

“Genes come with a sequence and a methylation pattern defined by evolution,” he said. “Methylation defines which gene works, in which cell, at what time.”

In the brain, a constantly changing combination of chemical, biological, and social inputs interactively affects signaling pathways that influence methylation and demethylation and thus can influence behavior, mental health, and mental illness.

Animal studies, including those by Michael Meaney, Ph.D., a professor of psychiatry, neurology, and neurosuregery at McGill University, have shown that high and low levels of maternal care by mother rats are associated with different methylation patterns in their pups. The offspring of mothers who spent more time licking and grooming their pups grew up to exhibit less anxiety and a more resilient stress response as adults. Cross-fostering experiments show that care counts more than heritability, and those positive effects are carried by the pups to their own offspring.

The biochemical train of events that connects the social environment around the organism to its genome begins once the senses perceive an event and the brain appraises it, said Szyf. The response may trigger production of glucocorticoids or other hormones, which are then carried throughout the body.

The glucocorticoids usually act indirectly, through intermediary genes that Szyf calls “master regulators.” Those are methylated or demethylated and then produce proteins that change methylation states in other genes downstream.

Epigenetic therapies may not be ready for the clinic yet, but it is important that psychiatrists know about the field, said Szyf.

For one thing, epigenetics can provide a way to understand how early life events relate to mental health later on.

“Epigenetics is a form of genomic memory,” he said. “It memorizes and interprets events and embeds them in the genome.”

Also, experts may one day be able to use these objective genetic markers to assess a patient’s vulnerability and resiliency instead of relying solely on methods currently used by psychiatrists to assess patients, he said.

Finally, once epigenetic processes and patterns are better understood, researchers may begin to design drugs to turn methylation events on and off.

“The problem now is specificity,” he said. “If you change methylases, it’s not just one gene that is affected. How do we get the methylation that we want?”

But that’s the wrong question, he said. “Who says we need a magic bullet? There are thousands of genes all over the system, and one gene can have thousands of methylation consequences. So we need to change the system as a whole from a pathological state to a less pathological state. We want to manipulate states systemwide, knowing full well that it will not be perfect.”

Such interventions might take several forms. Medications that promote or block methylation could be tried. DNA methylation inhibitors are already known from cancer research, for example.

Behavioral approaches are also possible, Szyf said. “If experience caused these effects, experience should be able to change them.” ■

An abstract of “Prospects for the Development of Epigenetic Drugs for CNS Conditions” can be accessed here.