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Ketamine study changed how researchers looked at depression. Could nitrous oxide be next?

Laughing gas has been used to dull pain in dental offices and maternity units for more than a century, and researchers now think the gas, called nitrous oxide, may effectively treat depression when other therapies have failed.

That’s according to the results of a small phase 2 clinical trial, published Wednesday in the journal Science Translational Medicine.

Up to 30 percent of people diagnosed with major depressive disorder don’t respond to typical treatments, leaving a significant proportion of patients in need of new treatment options.

The landscape for those patients began shifting in 2019, when the Food and Drug Administration approved a therapy for treatment-resistant depression based on the anesthetic ketamine. It works by blocking N-methyl-D-aspartate receptors in the brain, which have been linked to major depressive disorder. Traditional antidepressants act on serotonin receptors in the brain.

“The ketamine discovery is considered one of the biggest breakthroughs in depression research in 50 years,” said a co-lead author of the new study, Dr. Peter Nagele, a professor of psychiatry and behavioral neuroscience and chair of anesthesia and critical care at the University of Chicago.

Nitrous oxide is thought to work in the same way as ketamine, Nagele said.

The new study expanded on an earlier proof-of-concept trial, which showed that inhaling 50 percent nitrous oxide — the amount typically used for pain management during medical procedures — reduced depressive symptoms in people who were resistant to other treatments. Nagele and the other co-authors wanted to know whether those effects were long-lasting, as well as whether a lower dose could produce the same results with fewer side effects.

The trial included 24 participants. More than 70 percent were women, 96 percent were white, and all experienced treatment-resistant depression. Twenty participants completed the full trial, which involved receiving two doses — at 25 percent and 50 percent concentrations — of nitrous oxide and a placebo in a random order over three months. Each session took one hour.

Feb. 15, 202101:40

According to one of the three metrics of depression used to measure progress, the lower dose of nitrous oxide appeared to have a similar effect as the higher dose but with fewer side effects, which commonly included headache, nausea and tingling. The effects also appeared to last up to two weeks in some patients.

However, the study is far from definitive.

“The key limitation is that it’s a very small study,” said Ravi Das, a researching psychopharmacologist at University College London.

Every participant received all three treatments, unlike in a randomized controlled clinical trial, in which one group receives the treatment and the other is given a placebo. While the design allowed the researchers to compare people to themselves, rather than to other people, it also may have muddied the results, because a lasting effect of one treatment may have boosted the outcome of another, Das said.

Das said that despite its shortcomings, the new trial adds to a promising body of research.

“What I would like to see is the comparison of this with ketamine. If they sourced similar effects, I would use the nitrous oxide every time,” he said, noting that both drugs are cheap and easily administered but that nitrous oxide typically has milder side effects.

Dr. Madhukar Trivedi, director of the Center for Depression Research and Clinical Care at UT Southwestern Medical Center in Dallas, said, “One thing has become clear, especially after the success of ketamine: It is necessary to find different mechanisms of changing brain function in patients with depression.

“What has been developed by drugmakers in the past 25 years is not sufficient,” said Trivedi, who wasn’t involved in the trial.

Nagele said the next step is to perform a larger trial that includes hundreds of patients. “We need to be sure that it works and also understand why it might not work in some patients,” Nagele said.

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