According to new research from Washington University School of Medicine in St. Louis and the University of Chicago, a single one-hour treatment that involves breathing in a mixture of oxygen and nitrous oxide – also known as laughing gas – significantly improved symptoms in people with treatment-resistant depression.
The researchers demonstrated in the phase 2 clinical trial that symptoms of depression improve rapidly after treatment with inhaled nitrous oxide. They also stated that the benefits can last for several weeks.
The findings are published in the journal Science Translational Medicine.
“A large percentage of patients do not respond to standard antidepressant therapies; the patients in this study had failed an average of 4.5 antidepressant trials,” said Charles R. Conway, MD, a professor of psychiatry at Washington University and one of the study’s senior investigators. “The fact that we saw rapid improvements in many of these patients in the study suggests that nitrous oxide may help people with extremely severe, resistant depression.”
For the past decade, Conway and the study’s other co-senior investigator, Peter Nagele, MD, professor, and chair of the Department of Anesthesia & Critical Care at the University of Chicago, and who previously held an appointment in the Department of Anesthesiology at Washington University School of Medicine, have been investigating the potential of nitrous oxide as an antidepressant.
Researchers have found that a single, one-hour treatment that involves breathing in a mixture of oxygen and the anesthetic drug nitrous oxide, otherwise known as laughing gas can significantly improve symptoms in people with treatment-resistant depression.
Standard antidepressant medications act on norepinephrine and serotonin receptors in the brain, but it can take weeks for symptoms to improve. Nitrous oxide, on the other hand, interacts with different receptors on brain cells — NMDA glutamate receptors — and, when effective, tends to improve symptoms within hours.
“Our primary goals in this study were twofold: to determine whether a lower dose of nitrous oxide might be just as effective as doses we’d tested previously and it was for the majority of patients and to see how long the relief lasted,” Nagele explained. “We assessed patients for 24 hours in a proof-of-concept study several years ago. We continued to assess them for two weeks in this study, and the majority of them continued to feel better.”
There were 24 patients in the study. Each received three treatments spaced about a month apart. In one session, patients breathed a gas that was half nitrous oxide and half oxygen for an hour. In a subsequent treatment, the same patients inhaled a 25% nitrous oxide solution. A third treatment, the placebo, consisted of only breathing oxygen and no nitrous oxide.
“There isn’t a better comparison group than comparing a person to himself or herself,” Nagele said. “It is ideal to serve as your own control. The alternative is to study the effects of a drug in two similar groups of people, each of whom receives one of two treatments. But the problem with that is that you need a much larger sample size before you can draw any meaningful conclusions.”
The primary findings of this study were that nitrous oxide, both at 25% and in a 50-50 mixture with oxygen, improved depression in 17 of the study participants. The main difference between a 25% mix and a 50% mix was how long the antidepressant effects lasted. Whereas the 50% dose resulted in greater antidepressant effects two weeks after treatment, the 25% dose resulted in fewer adverse events, the most common of which was nausea.
“Some patients experience side effects — it’s a small subset, but it’s very real — and the most common one is nausea,” Conway explained. “However, only when people received the 50% dose did they experience nausea in our study. No one became nauseous when they were given 25% nitrous oxide. And the lower dose was nearly as effective as the higher dose in alleviating depression.”
After breathing a nitrous oxide solution for one hour, 55 percent (11 of 20) of the 20 people who completed all of the study’s treatments and follow-up exams experienced a significant improvement in at least half of their depressive symptoms, and 40 percent (eight of 20) were considered to be in remission – meaning they were no longer clinically depressed.
Over the course of the study, 85 percent (17 of 20) of the study participants experienced a significant enough improvement to move their clinical classification from severe to moderate depression, after receiving both dose levels of nitrous oxide and the placebo treatment.
Many of those in the study also took antidepressant medications, which had failed to relieve their depression in the majority of cases, but they were allowed to continue taking those medications while taking part in the study.
One-third of people who take antidepressants do not improve. Nitrous oxide and ketamine, another anesthetic that interacts with NMDA glutamate receptors, have recently shown promise in the treatment of treatment-resistant depression. Conway and Nagele believe that both drugs could be game-changers for people suffering from treatment-resistant depression, but that nitrous oxide may have some practical advantages.
“One potential advantage of nitrous oxide over ketamine is that, because it’s a volatile gas, its anesthetic effects fade quickly,” Conway said. “It’s similar to what happens in a dentist’s office when patients drive themselves home after having a tooth extracted. Patients must be observed for two hours after ketamine treatment to ensure they are okay, and then they must arrange for someone else to drive them home.”
According to Nagele and Conway, it is critical for scientists to conduct a large, multicenter study comparing the effects of ketamine and nitrous oxide to a placebo as soon as possible. The NARSAD award from the Brain & Behavior Research Foundation and the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine helped fund this research.
