Researchers have identified a new mechanism involved in depression, as well as an effective means of targeting it. The team consisted of researchers from McGill University in Canada, in collaboration with France's Institut National de la Santé et de la Recherche Médicale (INSERM).
Led by McGill’s professor of psychiatry Bruno Giros and INSERM director of research Eléni Tzavara, the team examined the biological and molecular activity within neurons during standard-of-care antidepressant treatment.
The study was conducted simultaneously in human and mice models and was intended to show the effect of antidepressants on serotonin and norepinephrine, two neurotransmitters known to influence mood. When these neurotransmitters come into contact with neuron receptors, they stimulate a chain of molecule signalling, which causes the nucleus to activate or inactivate the gene expressions involved in various biological functions. As the neurotransmitters affected by antidepressants perform a range of functions, the drugs often come with a number of unwanted side effects.
The team found that the molecule Elk-1, which is part of the signalling chain, could be isolated and targeted.
Elk-1 is a transcription factor of the extracellular signal–regulated kinase (ERK) pathway. This pathway itself proves an elusive drug target due to its pleiotropic functions; however Elk-1 could be targeted independently of ERK. High levels of Elk-1 mRNA were found in post-mortem hippocampal tissues from depressed suicides and in blood samples from depressed individuals, indicating its direct impact on depressive disorders.
Findings have also indicated that it could be a therapeutic biomarker for determining the patients who are more likely to respond to treatments.
"What's interesting and rather new is that we have shown the advantage of targeting signalling modules (a runner) rather than the entire pathway," Giros said.
"This surgical approach should enable us to avoid the adverse effects of classical antidepressants.
"The drug we've tested could also constitute a treatment with fewer failures. Classic antidepressants take up to three weeks to have an effect and this new approach could give quicker response times."
Depression is a leading cause of disability worldwide, affecting 350 million people or 5% of the global population. Each individual case is unique, and as current medications target specific symptoms, each patient requires a different dose and type of medication. These are found through trial and error, making the treatment process long and difficult for many. Around a third of patients find existing treatments ineffective. As such, new treatment options that target signal transduction pathways are in high demand.
The potential new Elk-1-based drug is protected by a patent and was developed by Melkin Pharmaceuticals, a biotech co-founded by Giros. Findings were published in Nature Medicine.