Antidepressant Exerts Epigenetic Changes

Molecular markers could aid researchers’ assessment of patient response to the drug.
 

By | November 25, 2015

WIKIMEDIA, RYAN

A commonly prescribed antidepressant exerts epigenetic effects that may provide a useful biomarker of whether the drug works in patients. A team led by researchers at the Max Planck Institute of Psychiatry in Germany identified a molecular pathway that results in altered DNA methylation in the presence of the selective serotonin reuptake inhibitor paroxetine. In an in vitro study published this week (November 24) in Science Signaling, the team presented a link between molecular stress signals and epigenetic activity, both of which have been previously implicated in depressive disorders.

“The authors identified one interesting mechanism of the effects of an antidepressant and really defined this pathway biochemically in an impressive way,” said Ted Abel, director of the Training Program in Behavioral and Cognitive Neuroscience at the University of Pennsylvania who was not involved in the new study.

“Depression is considered a stress-related disease and it has been known for a while that stress can change long-term behavior, probably by reprogramming gene activity,” said study coauthor Theo Rein of Max Planck. Several groups previously demonstrated that environmental factors could influence epigenetic changes associated with psychiatric disorders, including depression. Different classes of antidepressant drugs have also been found to induce epigenetic changes in both animal brain cells and in clinical studies. “In depression, we’ve seen alterations in gene expression that coincide with DNA methylation and other epigenetic changes,” explained Rein.

The present study builds on previous work suggesting that the activity of a protein chaperone called FKBP51—which is known to regulate the glucocorticoid receptor implicated in stress responses—is necessary for the efficacy of the antidepressant paroxetine. The researchers have now provided evidence that this drug can reduce the activity of DNMT1, a DNA methyltransferase that globally adds methyl groups throughout the genome.

Studying animal and human cells in culture, Rein and his colleagues found that FKBP1 interacts with DNMT1, inhibiting the enzyme’s activity and dampening DNA methylation throughout the genome. The observation brings together two adaptive systems—epigenetic activity and stress pathways—that had not previously been shown to interact in models of depressive disorders.

“This work suggests that FKBP51 is an important gene in stress and depression,” said Yogesh Dwivedi, director of translational research at the University of Alabama at Birmingham’s Mood Disorder Program who was not involved with the work.

Adding paroxetine to mouse fibroblasts and primary astrocytes, the researchers observed decreased activity of DNMT1 that was FKBP51 dependent and increased expression of a gene, BDNF, that plays a role in the brain’s ability to cope with stress. (See “Stress Fractures,” The Scientist, January 2015.)

“This paper increases our knowledge about the integrated actions of steroid hormones, neurotrophic factors such as BDNF, and epigenetic mechanisms with an important example of a specific target for drug action,” Carla Nasca, a neuroendocrinology postdoc at Rockefeller University in New York City, wrote in an email to The Scientist.

Blood samples from healthy volunteers and people with major depressive disorder (MDD) also showed FKBP51 inhibiting the DNA methylation activity of DNMT1. Treating blood cells derived from 40 MDD patients with paroxetine, the researchers observed that those whose cells responded to the drug with a reduction in DMNT1 activity and higher BDNF expression showed better clinical responses to the antidepressant.

“[This study] shows there is a potential to predict patients’ responses to this class of antidepressants,” said Dwivedi, adding that further studies are needed.

For Rein, using DNMT1 activity or BDNF expression as a biomarker for treatment efficacy is just the first step. “I think we are on the way, but I don't think a single readout will be reliable as a test,” he said.

Patients taking antidepressants often only experience relief after several weeks of treatment, if ever at all. “What is most promising about this study,” said Abel, “is the potential biomarker to follow the biochemical response before waiting to see if the patients improve clinically.”

The authors are now probing whether other classes of antidepressants have a similar effect on DNMT1 activity. “It’s not clear whether what we observed here is a global phenomenon of all antidepressants,” said Rein. “If all antidepressants acted the same, then the potential biomarker would just predict responsiveness or not, but could not guide the clinician towards a particular medication,” he added.

Abel would like to know what effects, if any, these epigenetic alterations may have on behavior. What happens in the brain regions crucial for depression and the action of mood-altering drugs also remains to be explored. In an email to The Scientist, Joanne Ryan, a research fellow at the Murdoch Childrens Research Institute who studies psychiatric epigenetics, wrote: “The findings here are using human peripheral blood cells which are unlikely to reflect epigenetic mechanisms occurring in different brain regions.”

N.C. Gassen et al., “Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1, and mediates epigenetic effects of the antidepressant paroxetine,” Science Signaling, doi:10.1126/scisignal.aac7695, 2015.

Add a Comment

Avatar of: You

You

Processing...
Processing...

Sign In with your LabX Media Group Passport to leave a comment

Not a member? Register Now!

LabX Media Group Passport Logo

Comments

Avatar of: Aviel

Aviel

Posts: 1

November 26, 2015

I appreciate the posting of this synopsis, which has introduced me to a fascinating and thought-provoking study. The first question that it raises in my mind is whether the dampening of DNA methylation throughout the genome that results from FKBP51's inhibition of DNMT1 affects other neurobiological (or biological) processes in addition to modulation of the stress response through its activity at the glucocorticoid receptor. Thank you.. 

Avatar of: James V. Kohl

James V. Kohl

Posts: 444

November 28, 2015

Excerpt:

The observation brings together two adaptive systems—epigenetic activity and stress pathways—that had not previously been shown to interact in models of depressive disorders.

The fact that nutrient stress and social stress act via the same RNA-mediated pathway in all vertebrates has been known for at least a decade.

Feedback loops link odor and pheromone signaling with reproduction

The link to depressive disorders was reported in the context of a single nutrient-denpendent RNA-mediated amino acid substitution.

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

 

Avatar of: Ferez

Ferez

Posts: 12

November 30, 2015

It is gratifying to find the numbers of ways in which our observations in epigenetics first made in 1984 with Y chromosome linked sequences, is now being reinforced: https://lnkd.in/BEdavh

Avatar of: James V. Kohl

James V. Kohl

Posts: 444

Replied to a comment from Ferez made on November 30, 2015

December 1, 2015

It is frrustrating to see our section on the molecular epigenetics of RNA-mediated cell type differentiation continue to be ignored

From Fertilization to Adult Sexual Behavior

Molecular epigenetics. It is now understood that certain genes undergo a process called “genomic or parental imprinting.” Early in embryonic development attached methyl groups become removed from most genes. Several days later, methyl groups are reattached in appropriate sites. Fascinatingly, some such genes reestablish methylation patterns based upon whether the chromosomal segment carrying the gene came from maternal or paternal chromosomes. These sexually dimorphic patterns are labeled genomic or parental imprinting, and these imprintings are inheritable but non-genetic modifications of specific genes (Razin and Shemer, 1995; Reik, 1989; Surani, 1991; Zuccotti and Monk, 1995).

There are at least 16 known genomic-imprintings in the human genome and each particular imprint depends upon whether the chromosome is of maternal or paternal origin (Hurst, McVean, and Moore, 1996).

Popular Now

  1. Major German Universities Cancel Elsevier Contracts
  2. Grass Routes
    Features Grass Routes

    Researchers are discovering a suite of new locations and functions of endocannabinoid receptors that play roles in sickness and in health.

  3. Studies Retracted After UCLA Investigation
  4. Trump Nominates Sam Clovis to Lead USDA Research
AAAS