In a new study, researchers have found that epigenetic effects can result from taking a popular antidepressant drug, which may help indicate whether or not a patient will respond positively to the drug. The research team, led by scientists in Germany from the Max Planck Institute of Psychiatry, found a molecular pathway that changes global DNA methylation while in the presence of paroxetine, also referred to as Paxil, a selective serotonin reuptake inhibitor (SSRI). SSRIs are the most commonly prescribed antidepressants and they work by blocking the reabsorption of serotonin in the brain, ultimately boosting mood. Unfortunately, the medications prescribed for depression are effective for only one third of patients. A greater knowledge of how antidepressants work could help improve the success of these medications.
The study was an in vitro investigation published in Science Signaling. The researchers found a connection between epigenetic activity and molecular stress signals, which are both thought to be involved in depressive disorders.
Theo Rein, the study’s coauthor from Max Planck, said that, “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.” Numerous research has previously shown that the environment can epigenetically impact gene expression changes linked to psychiatric disorders and various diseases, including depression. Researchers have also demonstrated, in the brain cells of animals as well as in clinical studies, that various classes of antidepressant medications can cause epigenetic alterations. “In depression, we’ve seen alterations in gene expression that coincide with DNA methylation and other epigenetic changes,” he added.
The team of researchers built upon previous evidence that suggested that FKBP51, a protein chaperone that plays a role in regulating the glucocorticoid receptor involved in stress responses, is crucial for the antidepressant paroxetine to work properly. The current study now builds off of this information and shows that this antidepressant medication can lessen DNA methyltransferase activity. The specific DNA methyltransferase that was reduced is known as DNMT1. DNA methyltransferases (DNMTs) are enzymes that catalyze the process of DNA methylation, defined as the addition of a methyl group to parts of the genome, which impacts gene expression.
Rein and his team members focused on human and animal cells and found that FKBP51 interacts with DNMT1 by reducing the DNA methyltransferase’s activity and thereby reducing total DNA methylation across the genome. Their study is the first to bring to light the interaction between epigenetic activity and stress pathways, a connection that had not been previously demonstrated in models of depression and related disorders.
The researchers uncovered that a decrease in DNMT1 was dependent on FKBP51 and an increase in gene expression of BDNF, which is highly implicated in how the brain copes with stress. The study’s lead author, Nils Gassen, said, “what was really interesting is that the antidepressant paroxetine only decreased DNMT1 when in the presence of FKBP51.”
Carla Nasca, a neuroendocrinology postdoc at Rockefeller University in New York City, commented that the paper adds to the scientific body of knowledge we have on “the integrated actions of steroid hormones, neurotrophic factors such as BDNF, and epigenetic mechanisms” and offers “an important example of a specific target for drug action.”
The researchers also found that FKBP51 inhibited the DNA methylation activity of DNMT1 in blood samples of people who are healthy and those diagnosed with major depressive disorder (MDD). After blood cells from 40 patients with MDD were treated with paroxetine, the researchers found that cells had reduced DNMT1 activity and those with higher BDNF expression displayed better clinical responses to the drug.
The director of translational research, Yogesh Dwivedi, from the University of Alabama at Birmingham’s Mood Disorder Program who was not a part of the study, said that it demonstrates “a potential to predict patients’ responses to this class of antidepressants” and indicated that additional studies should be conducted.
Using the activity level of DNMT1 and BDNF expression as potential biomarkers to assess how successful the antidepressant treatment may be is just the beginning, according to Rein. A single readout, he thinks, won’t be reliable as a test.
Relief from depression is often felt only after a patient has undergone several weeks of treatment. Often times, antidepressants may not even work for many patients. Ted Abel, director of the Training Program in Behavioral and Cognitive Neuroscience at the University of Pennsylvania who did not conduct the study, indicated that the most promising aspect of the study “is the potential biomarker to follow the biochemical response before waiting to see if the patients improve clinically.”
The next step researchers are curious about is whether all classes of antidepressants have an effect on DNMT1 activity or if these results are specific to this particular class. The effects observed may or may not be seen in all antidepressants, explained Rein. If this phenomenon does apply to all classes of antidepressants, then the potential biomarker would just be able to predict whether or not the patient might respond positively to the treatment, but could not help the clinician decide what medication specifically would be best suited.
Abel is also interested in what behavioral effects may be caused by these epigenetic changes. The impact on certain brain regions linked to depression and mood-altering drugs still need to be investigated. Further investigation may be useful; however, as another research fellow at the Murdoch Childrens Research Institute who studies psychiatric epigenetics noted, the current findings use human peripheral blood cells, which “are unlikely to reflect epigenetic mechanisms occurring in different brain regions.”
Source: Gassen NC, Fries GR, Zannas AS, Hartmann J, Zschocke J, Hafner K, Carrillo-Roa T, Steinbacher J, Preißinger SN, Hoeijmakers L, Knop M, Weber F, Kloiber S, Lucae S, Chrousos GP, Carell T, Ising M, Binder EB, Schmidt MV, Rüegg J and Rein T. (2015). Chaperoning epigenetics: FKBProtein51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine. Science Signaling, 8(404): ra119.
References: Max Planck Institute of Psychiatry. Understanding a missing link in how antidepressants work. Research News. 24 Nov 2015. Web.
Azvolinsky, A. Antidepressant Exerts Epigenetic Changes. The Scientist. 25 Nov 2015. Web.
