UT Southwestern Medical Center researchers have generated fresh insights that could aid in the development of rapid-acting antidepressants for treatment-resistent depression.
The researchers found that by blocking NMDA receptors with the drug ketamine, they could elicit rapid antidepressant effects in patients with treatment-resistant depression. Ketamine was developed as an anesthetic, but is better known publicly for its abuse as the party drug Special K. Researchers are now seeking alternatives because ketamine can produce side effects that include hallucinations and the potential for abuse — limiting its utility as an antidepressant.
Therefore, researchers had been investigating a drug called memantine, currently FDA-approved for treating moderate to severe Alzheimer’s disease, as a potentially promising therapy for treatment-resistant depression. Memantine acts on the same receptors in the brain as fast-acting ketamine, said Dr. Lisa Monteggia, Professor of Neuroscience. However, recent clinical data suggest that memantine does not exert rapid antidepressant action for reasons that are poorly understood.
“Although, both ketamine and memantine have similar actions when nerve cells are active, under resting conditions, memantine is less effective in blocking nerve cell communication compared to ketamine, This fundamental difference in their action could explain why memantine has not been effective as a rapid antidepressant” said Dr. Monteggia, who holds the Ginny and John Eulich Professorship in Autism Spectrum Disorders.
The different effects of ketamine and memantine alter signals emanating from NMDA receptors, in particular those that determine antidepressant efficacy. Dr. Monteggia noted that the new findings point a way to blocking NMDA receptors to control depression with fewer side effects.
Dr. Monteggia’s lab focuses on the molecular and cellular bases of neural plasticity, the fundamental property of nerve cells to alter their communication, as they pertains to neuropsychiatric disorders, as well as understanding the mechanisms underlying antidepressant efficacy.
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