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Ketamine works as an antidepressant at least in part by activating the brain’s opioid system, new research reports.

The finding overturns previously held beliefs that the drug’s antidepressant effects stemmed solely from its impact on the glutamate system. These beliefs led to the widespread use of ketamine to treat depression and spurred the development of glutamate-blocking drugs for use as antidepressants.

The new finding also highlights the interaction between depression, pain, and opioid addiction and presents an opportunity for clinicians to reframe treatment approaches for these three public health crises.

The researchers believe their work is the first to address how ketamine works in the human brain to provide relief from depression. A paper describing the work appears in the American Journal of Psychiatry.

“Before we did the study, I wasn’t sure that ketamine really worked to treat depression. Now I know the drug works, but it doesn’t work like everyone thought it was working,” says Alan Schatzberg, a professor of psychiatry and behavioral sciences at Stanford University School of Medicine, who shares senior authorship of the paper with Carolyn Rodriguez, an assistant professor of psychiatry and behavioral sciences.

The rise of ketamine

Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It can cause dissociative side effects, including hallucinations, and has been used as a recreational drug. If used regularly, it can lead to dependence.

Although the Food and Drug Administration has not approved the drug’s use for depression, some doctors have prescribed it “off-label” in recent years as a rapid but short-acting antidepressant. Traditional antidepressants, such as selective serotonin reuptake inhibitors, take four to six weeks to have an effect but don’t work in two-thirds of patients who try them.

Stand-alone ketamine clinics have popped up all over the country to administer expensive intravenous infusions of ketamine to patients, even though some scientists caution that not enough is known about the drug to warrant its widespread use for depression.

“The results were so clear that we ended the study early to avoid exposing additional patients to the ineffective combination treatment.”

Ketamine infusions are also used to treat chronic pain, which is a common condition in depressed patients. Exactly how ketamine blunts pain is not fully understood, but scientists know it works at least in part on the opioid system.

The researchers wanted to see if the antidepressive effects of ketamine were also generated by its activation of the opioid system. To answer that question, they conducted a small clinical trial in which people with depression were given an opioid-receptor blocker prior to taking ketamine.

The researchers recruited adults with treatment-resistant depression, meaning their condition had not improved after multiple treatment efforts. Twelve participants received infusions of ketamine twice—once preceded by naltrexone, an opioid-receptor blocker, and once with placebo. Neither the study participants nor the researchers knew whether active drug or placebo was administered during each test.

The findings showed that ketamine reduced depressive symptoms by about 90 percent for three days in more than half of the participants when administered with a placebo, but had virtually no effect on depressive symptoms when it was preceded by naltrexone.

“This was purely a mechanistic study, not a treatment trial,” says Nolan Williams, a clinical assistant professor of psychiatry and behavioral science. “And the results were so clear that we ended the study early to avoid exposing additional patients to the ineffective combination treatment.”

Because the field of anesthesia has long regarded ketamine specifically as a nonopioid drug, co-lead author Boris Heifets, a clinical assistant professor of anesthesiology, perioperative, and pain medicine, was skeptical when Williams approached him about joining the research effort.

“Everything that I was taught, and everything that I’ve always taught my students—all of the evidence supports the fact that ketamine is not an opioid,” Heifets says. “I was really surprised at the results.”

How does it work?

Although some small studies have shown that ketamine has rapid, although transient, antidepressant effects, Schatzberg says the researchers wanted to understand how ketamine works. He says he came to suspect that ketamine’s effects might be linked to the brain’s opioid system when Rodriguez published a report on ketamine’s ability to reduce symptoms of obsessive compulsive disorder, which was similar to previous research using the opioid morphine.

The prevailing hypothesis for ketamine’s antidepressant effect was that the drug blocked a receptor for glutamate, an excitatory neurotransmitter in the brain that is implicated in memory and learning.

“But ketamine’s mechanism is complicated, as it acts on many different receptor types beyond glutamate receptors, and it acts in three distinct phases—rapid effects, sustained effects, and return to baseline,” Rodriguez says.

Schatzberg notes that no other glutamate-receptor blocker has an antidepressant effect like ketamine and that attempts to develop similar drugs have largely failed.

The researchers say the findings from the new study may explain why ketamine works so quickly as an antidepressant: It activates the brain’s opioid receptors during its first phase of activity. The glutamate system may be responsible for the sustaining effects after ketamine is metabolized, they say.

Revealing the role of the opioid system in the antidepressant effects of ketamine is critical in the effort to develop new antidepressants, the researchers say. For instance, glutamate receptor blockers may not have rapid antidepressant effects unless they also involve the opioid system, Williams says.

“There is truly a link between depression, pain, and opioid use. You can’t go after one without addressing the others.”

“Psychiatry used opioids, barbiturates, and high doses of stimulants to treat depression 50 or 60 years ago,” Schatzberg says. “We have to properly examine the risks associated with using drugs of abuse—even in low doses—to treat depression. It’s not limited to ketamine; other antidepressant drugs that target the opioid system are in development now, too.”

While a standard opioid like morphine initially has an antidepressant effect, it promotes depression after repeated use, Williams says. People who are depressed take as much as 2.4 times as many opioids immediately after painful surgeries than those who aren’t depressed, he says. “There is truly a link between depression, pain, and opioid use,” Heifets says. “You can’t go after one without addressing the others.”

Rodriguez has consulted for Allergan, BlackThorn Therapeutics, and Rugen Therapeutics. Schatzberg has consulted for Alkermes and Avanir, has equity in Corcept and Merck, and received a grant from Janssen Pharmaceuticals.

The National Institutes of Health, the Brain and Behavior Research Foundation, the Avy L. and Roberta L. Miller Foundation, and the Pritzker Family Fund funded the study. Stanford’s psychiatry and behavioral sciences department also supported the work.

Source: Kimber Price for Stanford University