Carlos A. Zarate, M.D., 2011 Outstanding Achievement in Mood Disorders Research Prizewinner, has pioneered research on rapid-acting antidepressants and their mechanism of action. One such drug is ketamine, which has been shown to work within hours instead of the weeks it takes to see effects with current antidepressants.

New rapid-acting treatments could eliminate the disruption to daily life caused by the lag time of current antidepressants. Ketamine and the next generation treatments could also be used to target severe suicidal ideation such as occurs in E.R. settings.

Anyone who has taken an antidepressant is all too familiar with the up to six-week wait for the full effects of the drug to appear. For those suffering from the debilitating symptoms of depression to the point of suicidality, this treatment is unnecessarily slow. Dr. Zarate and his colleagues have for years been conducting trials of new compounds in an attempt to improve this response time for patients with major depressive disorder or bipolar disorder.

Applying techniques drawn from neuropsychopharmacology, electrophysiology, neuropsychology, and neuroimaging to identify antidepressant response and brain signatures of this response in patients, Dr. Zarate and colleagues pioneered the use of ketamine—which had been safely used for decades as an anesthetic—as a fast-acting antidepressant. Earlier studies had implicated the glutamatergic system—which involves the neurotransmitter glutamate—as being key to mood disorders. Extending this work, Dr. Zarate’s research convincingly demonstrated the rapid antidepressant effects of the glutamatergic modulator ketamine in patients with both treatment-resistant major depressive disorder and bipolar depression. Notably, ketamine acts within several hours, and its antidepressant effects after just a single infusion last approximately 7 days or more. In one of the studies that Dr. Zarate and colleagues conducted at the National Institute of Mental Health (NIMH), 9 of 16 (56 percent) patients receiving ketamine had at least a 50 percent reduction in symptoms within 40 minutes of receiving the drug. For most patients, response to the drug lasted approximately one week. Given that patients suffering from severe depression may be suicidal and require immediate, fast-acting treatment, this work may eventually lead to the saving of thousands of lives.  

As a result of his work, researchers across the country are investigating the antidepressant properties of novel antidepressants that affect the glutamatergic system. In addition, Dr. Zarate and his team are investigating another drug called scopolamine. While most currently available antidepressants affect signaling by serotonin (a neurotransmitter known to play a role in mood), scopolamine interacts with cell receptors for another neurotransmitter called acetylcholine. Response to this drug is also rapid. Further investigation of scopolamine may ultimately lead to greatly improved treatment options for depression.

Dr. Zarate’s work has also begun to identify biomarkers or brain signatures that are associated with rapid antidepressant response to ketamine, scopolamine, and other novel compounds. His lab is now testing a series of other compounds using multimodal imaging and other novel technologies to better understand the brain signatures involved in rapid onset of antidepressant effects.

Dr. Zarate has long been recognized for the quality of his pioneering research; for years, he and his colleagues have conducted innovative studies seeking to identify new therapeutic targets for mood disorders. He has been at the NIMH for over a decade and is currently Chief of the Experimental Therapeutics and Pathophysiology Branch at the Intramural Research Program of NIMH. Earlier in his career, he has served as Director of the Bipolar and Psychotic Disorders Outpatient Services at McLean Hospital of the consolidated Department of Psychiatry of Harvard Medical School and Director of the Bipolar and Psychotic Disorders Program at the University of Massachusetts.

Dr. Zarate’s research breakthroughs have earned him the 2011 Brain & Behavior Research Foundation Prize for Bipolar Mood Disorders Research. At the Brain & Behavior Research Symposium in New York City on October 26th, Dr. Zarate will speak in detail about his landmark studies on fast-acting antidepressants. To learn more about this event, or to hear Dr. Zarate speak about fast-acting antidepressants, please visit: bbrfoundation.org/events/symposium