The two main challenges in the treatment of depression are firstly, almost 50 percent of patients do not respond well to existing antidepressants and secondly conventional medications take almost three to five weeks to have the desired effect. To tackle the second problem, the researchers used epigenetic modulators to try to "erase" the consequences of stress.
Epigenetic mechanisms are a part of the complex system, controlling how genes are switched on or off.
The study conducted by a group of researchers affiliated with the University of São Paulo (USP) in Brazil is published in the journal Molecular Neurobiology.
Stress is a key trigger of depression that alters certain epigenetic markers in the brain associated with neuroplasticity, the brain's ability to change in response to experience. In these genes, stress increases DNA methylation in which there is chromatin remodeling process regulating gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factors to DNA.
Most of the current antidepressants are designed to reduce this process.
An in-depth investigation into the action of BDNF (brain-derived neurotrophic factor), that is a nervous system protein with well-documented effects on the regulation of neuronal plasticity was led by Sâmia Joca a professor at USP and the University of Aarhus in Denmark.
During stress, the expression of BDNF was reduced and antidepressants have no effect if BDNF signaling is blocked. Hence the researchers focused on BDNF. They tested the hypothesis that stress increases methylation of the gene for BDNF, reducing its expression and that this reduction is linked to depressive behavior.
Joca said, "Our starting point was this: if we administered a genetic modulator that inhibited DNA methylation, the process wouldn't happen, BDNF levels would be normal, and there would be an antidepressant effect. If the antidepressant effect is indeed linked to normalization of the methylation profile, so that conventional drugs take time to work because it takes time to eliminate stress-induced alterations, we imagined that direct modulation of these epigenetic mechanisms would produce the effect rapidly. We found this was indeed the case."
She added, "We tested two drugs, one of which is used to treat cancer (gliomas). The other is completely experimental. It's important to note that these drugs can't be used to treat depression because if they reduce DNA methylation unrestrictedly they'll increase the expression of several genes rather than just the gene that interests us. So there will be adverse effects. The findings point not to prospects for novel antidepressants but to an interesting angle from which to develop novel treatments."
To the test the hypothesis whether the direct modulation of epigenetic mechanisms would work faster, it was necessary to use (and validate) a model that distinguished very clearly between acute and chronic treatment. The scientists first used a stress-induced depression model in rats treated with well-known conventional drugs. In this model, the rats were exposed to inescapable stress followed seven days later by a situation in which it was possible to avoid stress by moving to the other side of the chamber they were in.
The result of the study showed a higher number of failures to learn this avoidance behavior among stressed than non-stressed animals. This was reduced by chronic treatment with conventional antidepressants and acute treatment with epigenetic modulators.
Joca said, "What we call learned helplessness in this model is similar to depression in humans, to the feeling that there's nothing the person can do to make the situation better. The model was validated and showed that when continuously treated with antidepressants, the animals returned to normal and resembled non-stressed animals in behavioral terms. However, this only happened if they were treated repeatedly. The same applies to depressed people, who have to take the drug continuously. There is no acute effect from a single dose."
Two different drugs were tested as modulators, 5-AzaD and RG108 that inhibit the enzyme responsible for DNA methylation. These drugs are not chemically related but show rapid antidepressant effect.
A molecular analysis of 5-AzaD was performed in order to produce a methylation profile of the gene of interest. It was found that stress increased methylation of BDNF as well as TrkB, another nervous system protein. Joca said, "In 2010, we published an article showing that these drugs had an antidepressant effect. Not long after that, we published another article showing that antidepressant treatment modulated DNA methylation. The interesting point in this latest study was the production of the antidepressant effect by means of an acute intervention. This is the first time epigenetic modulators have been shown to have a rapid antidepressant effect.