Major depressive disorder (MDD) occurs in up to 17% of the population, is associated with profound dysfunction and, according to the WHO Global Burden of Disease Study, is estimated to become the second leading cause of disability worldwide by 2020. While traditional antidepressants have proven efficacy, they usually take weeks to work and
For the last 40 years, researchers have focused on antidepressants that modulate serotonergic and noradrenergic neurotransmitters. While studies have shown that approximately 50-60% of individuals with major depressive disorder respond positively to the first antidepressant prescribed, many with depression do not respond to these traditional antidepressants or cannot tolerate side effects. In addition, individuals with bipolar depression may be at risk for switching when treated with conventional serotonergic and noradrenergic reuptake inhibitors.
Glutamate Neurotransmission as a Target for Newer Antidepressants
Recent advances in our understanding of the pathophysiology of depression have led to a growing interest in glutamate neurotransmission. Glutamate is the most abundant excitatory neurotransmitter in the brain and plays a pivotal role in synaptic plasticity, learning, and memory. There is accumulating evidence indicating that dysregulation of glutamatergic neurotransmission, particularly via N-methyl-d-aspartate (NMDA) receptors, plays an important role in the pathophysiology of major depressive disorder.
Thus, recent research has focused on novel treatment approaches targeting the glutamatergic system, including ketamine, an NMDA receptor antagonist. In contrast to traditional antidepressants, ketamine has demonstrated rapid antidepressant effects, suggesting that agents modulating glutamate transmission may relieve depression but may use a pathway different from serotonerigc and noradrenergic reuptake inhibitors. Our evolving understanding of glutamate’s role in the pathogenesis of depression underscores the intricate nature of depression and the need for ongoing exploration of innovative treatments beyond traditional serotonin-focused approaches.
Xenon: A Novel Modulator of Glutamate Neurotransmission
Xenon is an inert gas, and like ketamine, is an anesthetic agent that has been safely used as an anesthetic for many years. Xenon has potent anti-glutaminergic effects similar to those of ketamine. Xenon also has neuroprotective effects consistent with the effects of other antidepressants, and therefore has the potential to be a novel antidepressant drug. Current research indicates that xenon would be well tolerated in patients with MDD and bipolar depression and possibly helpful in alleviating depressive symptoms with a mechanism of action similar to ketamine.
Andrew Nierenberg, MD, Director of the Dauten Family Center for Bipolar Treatment Innovation, and Cristina Cusin, MD, Director of the MGH Ketamine Clinic, are currently recruiting patients for a study exploring the antidepressant effects of inhaled xenon for the treatment of major depressive disorder and bipolar depression.
You can also read more about this study HERE and at ClinicalTrials.gov.
Andrew Nierenberg, MD holds the Thomas P. Hackett, MD, Endowed Chair in Psychiatry at Massachusetts General and is the Director of the Dauten Family Center for Bipolar Treatment Innovation, Associate Director of the Depression Clinical and Research Program, and Co-Director of Center for Clinical Research Education, Division of Clinical Research at the Mass General Research Institute. Dr. Nierenberg is a professor of psychiatry at Harvard Medical School.
Cristina Cusin, MD is the Founder and Director of the MGH Ketamine Clinic, a psychiatrist in the Depression Clinical and Research Program, and an Associate Professor in Psychiatry at Harvard Medical School. Her research and clinical work has focused on the treatment of treatment-refractory mood disorders, using innovative strategies including ketamine and deep brain stimulation.
