Intriguingly, it’s not actually the drug itself.
The striking antidepressant powers of Ketamine have been taking the scientific community by storm in the recent months — some experts have even claimed that the drug has led to the “most significant advance in mental health” in more than half a century.
However, researchers have been unsure of how exactly the drug elicits its therapeutic effects, but a breakthrough discovery in a new study likely holds the secret to ketamine’s rapid antidepressant action.
Interestingly, as the body breaks down ketamine, metabolites are created, which are chemical byproducts of the breakdown process. The scientists at the National Institutes of Health (NIH) observed that a specific metabolite reversed the depression-like behaviors in mice, and it did so without triggering any of the dissociative, anesthetic, or addictive side-effects associated with ketamine.
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"This is potentially a major breakthrough," senior author Todd Gould, a researcher in the Department of Psychiatry at the University of Maryland School of Medicine, said in a press statement. "It could allow depressed patients to get the rapid benefits of ketamine, while at the same time avoiding the risks."
The most commonly used antidepressants are selective serotonin reuptake inhibitors (SSRIs), and they work by increasing levels of serotonin or norepinephrine in the brain. However, SSRIs only work in about half of patients with depression, and even when they do work, they typically take between three and eight weeks to start relieving symptoms.
Ketamine, on the other hand, doesn’t work via serotonin or norepinephrine, and research has shown that it can lift depression within mere hours after administration.
"For years, we have been searching for ways to treat depression faster and more effectively," said co-author UM SOM researcher Scott Thompson, who has spent more than a decade studying depression. "These results open up exciting new vistas for the first new generation of antidepressant compounds in the last 30 years."
In the study, the researchers used mice to test the effects of several different metabolites, and they eventually focused on a specific one called hydroxynorketamine, which is thought to have no psychoactive effects.
The researchers demonstrated the effectiveness of the metabolite by blocking the breakdown of ketamine to hydroxynorketamine in mice, which effectively blocked ketamine’s antidepressant effects. Further, treatment with the metabolite alone reduced depression with none of ketamine’s side effects.
"This discovery fundamentally changes our understanding of how this rapid antidepressant mechanism works, and holds promise for development of more robust and safer treatments," said co-author Carlos Zarate, of NIMH and a pioneer of research using ketamine to treat depression. "By using a team approach, researchers were able to reverse-engineer ketamine from the clinic to the lab to pinpoint what makes it so unique."
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The researchers had previously thought that the antidepressant mechanisms of ketamine worked the same way as the drug’s anesthetic and dissociative actions — by blocking a particular receptor, the NMDA glutamate receptor. Now they know this isn’t true.
Instead, they found that the hydroxynorketamine metabolite appears to activate another type of glutamate receptor, called the AMPA receptor, which mediates fast synaptic transmission in the central nervous system. According to Gould, hydroxynorketamine likely works on depression via AMPA receptors, either directly or indirectly.
"Now that we know that ketamine's antidepressant actions in mice are due to a metabolite, not ketamine itself, the next steps are to confirm that it works similarly in humans, and determine if it can lead to improved therapeutics for patients," explained Gould in another press release.
By pinpointing the exact mechanism by which ketamine relieves depression, the research team can now focus on developing a more practical treatment for humans.
The scientists plan to follow up this discovery with safety and toxicity studies of the metabolite as part of a drug development plan, and Gould points out that “the compound has, in effect, already been in humans in years as a metabolite following ketamine administration,” the press release notes.
He concludes, “This gives us confidence that it will be safe.”
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