Psychiatrists could be on the way to developing a test that predicts which patients with depression will benefit from which antidepressant. The in vitro test represents a relatively safe way of predicting success, since the patient will not have to take the drug.
The research, led by Theo Rein at the Max Planck Institute of Psychiatry in Munich, Germany, and published in Science Signaling
on 24 November 2015, has shown that the antidepressant paroxetine triggers epigenetic processes that alter the levels of certain proteins in the blood. Epigenetic processes are the non-genetic processes that control what genes do; a patient might have a particular gene, but it might not work without the relevant epigenetic process.
With this information in mind, the researchers suggest that a blood test could one day be developed that would show whether or not an antidepressant is effective in a particular patient. The presence of a protein in the blood would show whether an antidepressant was having the desired effect. The test could be carried out in a lab, using a sample of the patient’s blood, without having to give the drug to the patient.
While DNA sequences are generally responsible for controlling gene activity, there are many examples where activity is controlled by epigenetic processes.
Depression is known to trigger epigenetic changes, including a process called DNA methylation, which in turn controls gene expression. One gene controlled in this way encodes a protein called brain-derived neurotrophic factor (BDNF), which regulates brain circuits involved in learning, memory, and coping with stress.
Some antidepressants reverse epigenetic changes by blocking an enzyme called DNMT1 that is responsible for methylation.
To better understand how antidepressants work, Rein’s team studied the effects of paroxetine in mice and in patients. When paroxetine was added to mouse brain cells, there was an increase in the binding of a protein called FKBP51 to an enzyme that would otherwise have activated DNMT1. The decreased DNMT1 activity reduced overall DNA methylation, increasing expression of the BDNF gene.
When the researchers treated patient cells with the antidepressant, they found that patients with cells that reduced DNMT1 activity and had higher levels of BDNF also showed better clinical responses to the antidepressant. In theory, such a method could one day be developed to produce a blood test that predicts a patient’s response to a particular antidepressant.
“It is a nice contribution to our understanding of the molecular mechanisms of antidepressant action,” says Vincent Vialou, a neuroscientist at the Institut de Biologie Paris-Seine, France.
While the epigenetic mechanism underlying the effects of FKBP51 is novel, “the implication of FKBP51 and its interactants in antidepressant mode of action were expected”, says Vialou.
“The bottom line of [the research team’s] findings is that FKBP51 regulates in fine BDNF levels. BDNF has been implicated in monoaminergic-based antidepressant activity for at least a decade,” he adds.
Rein says the most immediate impact of the study is in understanding depression and the mode of action of antidepressants, “but a blood test would be more exciting in the end”.
“What is needed is the analysis of more antidepressants to know whether the blood test would indicate simply responsiveness or not… or whether it might also guide in the choice of treatment,” he explains.
Rein finds the range of actions of FKBP51 “remarkable”, and next wants to obtain a better understanding of what FKBP51 is doing and how it is acting. “Where the epigenetic changes precipitate on the genome, and whether the convergence with antidepressants is general or specific for a subgroup,” he says.
But Vialou warns that FKBP proteins as drug targets might have many side effects due to their multiple roles in the body.
 Gassen N, Fries G, Zannas A et al. Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1, and mediates epigenetic effects of the antidepressant paroxetine. Science Signaling 2015. doi:10.1126/scisignal.aac7695