Targeting glutamate to treat depression
In a new review, published in the journal Nature Reviews/Drug Discovery, researchers examined the progress made in treating major depressive disorder (MDD) using ketamine and other therapies that act on the glutamate system.
Researchers from the Icahn School of Medicine at Mount Sinai and other institutions found that glutamate-modulating agents including ketamine may represent the first major advancements in treating MDD in decades, but fundamental questions remain regarding safety, tolerability and efficacy.
Neurotransmitters, including glutamate, are substances that conduct signals from one nerve cell to another. Glutamate is the most abundant excitatory neurotransmitter that promotes the flow of signals between nerve cells.
Many mental disorders, such as depression and schizophrenia, involve an inability of the central nervous system to effectively use glutamate. Experimental drugs that block glutamate receptors in the central nervous system or lower glutamate brain levels may represent the next generation of antidepressant medications, and offer potential advantages over current drug treatments.
“The ongoing clinical trial research focusing on the glutamate system may lead to a completely new class of antidepressants that may significantly change the way patients with depression, and in particular, treatment-resistant depression are treated,” said the study’s first author, James Murrough, M.D., director of the Mood and Anxiety Disorders Program and Assistant Professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai.
“Targeting glutamate receptors could transform care for patients for this devastating disease.”
Researchers at Mount Sinai’s Mood and Anxiety Disorders Program (MAP) are conducting studies and clinical trials on agents, including ketamine, which modulate the glutamate system. No glutamate modulator has been approved for the treatment of depression worldwide.
The drug ketamine, a schedule III controlled substance drug with a potential for abuse, has been repurposed as a rapidly acting antidepressant. In low doses in a controlled environment, the drug has emerged as a promising medication to treat severe depression.
The review identifies key outstanding issues related to the development of ketamine and other glutamate modulators for use in depression. For example, most studies have selected patients who have failed to respond to one or more trials of conventional antidepressants and have not accounted for other factors, including trauma history or genetic predisposition for depression.
“Although substantial progress has been made over the past decade in identifying ketamine as a prototype rapid-acting antidepressant, there is a large gap in the literature, which represents a crucial unmet research need to examine its safety and efficacy beyond a single treatment administration,” said Murrough.
“An important unknown is the relationship between glutamate modulation and conventional therapeutic approaches for depression, which may shed light on the strengths and limitations of this approach.”