A team of researchers funded by the National Institutes of Health (NIH) recently discovered why the drug ketamine may act as a rapid antidepressant.
Ketamine is best known as an illicit, psychedelic club drug. Often referred to as “Special K” or a “horse tranquilizer” by the media, it has been around since the 1960s and is a staple anesthetic in emergency rooms and burn centers. In the last 10 years, studies have shown that it can reverse — sometimes within hours or even minutes — the kind of severe, suicidal depression that traditional antidepressants can’t treat.
Researchers writing in the August 2010 issue of Archives of General Psychiatry reported that people in a small study who had treatment-resistant bipolar disorder experienced relief from depression symptoms in as little as 40 minutes after getting an intravenous dose of ketamine. Eighteen of these people had previously been unsuccessfully treated with at least one antidepressant medication and a mood stabilizer; the average number of medications they had tried unsuccessfully was seven. Within 40 minutes, 9 of 16 (56 percent) of the participants receiving ketamine had at least a 50 percent reduction in symptoms, and 2 of 16 (13 percent) had full remission and became symptom-free. The response lasted an average of about a week.
In a small 2006 NIMH study, one of the first to look at ketamine for depression, 18 treatment-resistant, depressed (unipolar) patients were randomly selected to receive either a single intravenous dose of ketamine or a placebo. Depression symptoms improved within one day in 71 percent of those who were given ketamine, and 29 percent of the patients became nearly symptom-free in a day. Thirty-five percent of patients who received ketamine still showed benefits seven days later.
In the most recent study published online in the journal Nature in May 2016, researchers discovered that a chemical byproduct, or metabolite, is created as the body breaks down ketamine. The metabolite reversed depression-like behaviors in mice without triggering any of the anesthetic, dissociative, or addictive side effects associated with ketamine.
As put by Carlos Zarate, MD, of the National Institute of Mental Health (NIMH), and a study coauthor and pioneer of research using ketamine to treat depression:
This discovery fundamentally changes our understanding of how this rapid antidepressant mechanism works, and holds promise for development of more robust and safer treatments. By using a team approach, researchers were able to reverse-engineer ketamine’s workings from the clinic to the lab to pinpoint what makes it so unique.”
In response to the Nature report, Sara Solovitch of The Washington Post wrote that:
experts are calling [ketamine] the most significant advance in mental health in more than half a century.
She reported that many academic medical centers, including Yale University, the University of California in San Diego, the Mayo Clinic, and the Cleveland Clinic, have all begun offering ketamine treatments off-label for severe depression.
It all sounds too good to be true, right?
The Drawbacks of Ketamine
The predominant drawback of ketamine is the lack of data.
There haven’t been enough clinical trials on the drug to assure its safety, and there’s a lack of information on the long-term effects of its use.
Ketamine’s effects are also short-lived. To be used as an effective antidepressant, it would need to be administered regularly, which leads to concerns about addiction, tolerance, and, again, long-term effects. The data that we do have on long-term use comes from people who have taken ketamine recreationally, as well as those who have used it to treat chronic pain.
One 2014 study published in the British Journal of Clinical Pharmacology included among possible side effects, psychedelic symptoms (hallucinations and panic attacks), nausea, cardiovascular stimulation, memory defects, and bladder and renal complications.
Still, the drug holds promise for uncovering new ways of treating depression and offers hope for the most severe and complicated mood disorders that baffle psychiatrists today.
Richard J. Hodes, MD, director of the National Institute on Aging, commented on the most recent NIH study and the importance of furthering the research:
Unraveling the mechanism mediating ketamine’s antidepressant activity is an important step in the process of drug development. New approaches are critical for the treatment of depression, especially for older adults and for patients who do not respond to current medications.
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Diazgranados, N., Ibrahim, L., Brutsche, N., Newberg, A., Kronstein, P., & Khalife, S. et al. (2010). A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression. Archives Of General Psychiatry, 67(8), 793. DOI: archgenpsychiatry.2010.90.
Zanos, P., Moaddel, R., Morris, P., Georgiou, P., Fischell, J., & Elmer, G. et al. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533(7604), 481-486. DOI: 10.1038/nature17998.
Zarate, C., Singh, J., Carlson, P., Brutsche, N., Ameli, R., & Luckenbaugh, D. et al. (2006). A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression. Archives Of General Psychiatry, 63(8), 856. DOI: 10.1001/archpsyc.63.8.856.
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