A single hour-long treatment that involves breathing a mixture of oxygen and nitrous oxide – also known as laughing gas – dramatically improved symptoms in people with treatment-resistant depression, according to news data from researchers at the Washington University School of Medicine. in St. Louis and the University of Chicago.
In a phase 2 clinical trial, researchers showed that symptoms of depression improve rapidly after treatment with inhaled nitrous oxide. Plus, they reported that the benefits can last for several weeks.
The results are published on June 9 in the journal Science Translational Medicine.
“A large percentage of patients do not respond to standard antidepressant treatments – the patients in this study failed an average of 4.5 antidepressant trials – and it is very important to find treatments to help these patients,” said Charles R. Conway, MD, professor of psychiatry at the University of Washington and one of the study’s principal investigators. “The fact that we saw rapid improvements in many of the patients in the study suggests that nitrous oxide may help people with really severe, resistant depression.”
Conway, and the study’s other co-principal investigator, Peter Nagele, MD, professor and chair of the Department of Anesthesia and Critical Care at the University of Chicago, and who previously held a position in the Department of Anesthesiology. from Washington University School of Medicine, have studied the potential of nitrous oxide as an antidepressant over the past decade.
Standard antidepressants affect the norepinephrine and serotonin receptors in the brain, but it often takes weeks for a person’s symptoms to improve. Nitrous oxide, however, interacts with different receptors on brain cells – the NMDA glutamate receptors – and tends to improve symptoms within hours when effective.
“Our primary goals in this study were twofold: to determine if a lower dose of nitrous oxide might be as effective as the doses we had tested previously – and that was for most patients – and we also wanted to see how many the relief lasted, “Nagele said. “In a proof-of-concept study several years ago, we evaluated patients for 24 hours. In this study, we continued to evaluate them for two weeks, and most continued to feel better.”
The study involved 24 patients. Each received three treatments approximately one month apart. During one session, the patients breathed for one hour gases composed of half nitrous oxide and half oxygen. During a second treatment, the same patients inhaled a 25% solution of nitrous oxide. A third treatment, the placebo, consisted of breathing only oxygen, without nitrous oxide.
“You can’t really get a better comparison group than when you compare a person to themselves,” Nagele said. “Being your own witness is ideal. The alternative is to study the effects of a drug on two similar groups of people in which you receive one or another treatment. But the problem with this is that you need a much larger number of patients before you can really draw any conclusions. “
The main findings of this study were that nitrous oxide – both 25% and in a 50-50 mixture with oxygen – improved depression in 17 of these study participants. The differences between a 25% mixture and a 50% mixture mainly concerned the duration of the antidepressant effects. While the 50% dose had greater antidepressant effects two weeks after treatment, the 25% dose was associated with 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 main one is that some people get nausea,” Conway said. “But in our study, it wasn’t until people were given the 50% dose that they felt nauseous. When they were given 25% nitrous oxide, no one developed nausea. . And that lower dose was about as effective as the higher dose in relieving depression. “
Of the 20 people who completed all of the study’s follow-up treatments and exams, 55% (11 of 20) experienced significant improvement in at least half of their depressive symptoms, and 40% (eight of 20) were considered to be in remission – meaning they were no longer clinically depressed – after breathing nitrous oxide solution for one hour.
Over the course of the study as a whole, after receiving both nitrous oxide dose levels and the placebo treatment, some 85% (17 out of 20) of the study participants experienced improvement. sufficiently significant for their clinical classification to be shifted by at least one category – for example, from severe to moderate depression.
Many of those who participated in the study also took antidepressants – drugs that for the most part had failed to relieve their depression – but were allowed to continue using these drugs while they were participating. in the study.
Up to a third of those who take antidepressants do not get better. Nitrous oxide and ketamine, another anesthetic drug that interacts with NMDA glutamate receptors, have recently shown promise in people with treatment-resistant depression. Conway and Nagele believe that both drugs may represent breakthroughs for people with treatment-resistant depression, but believe that nitrous oxide may have practical benefits.
“A potential advantage of nitrous oxide, over ketamine, is that, because it is a volatile gas, its anesthetic effects wane very quickly,” said Conway. “It’s similar to what happens in a dentist’s office when people drive home after having a tooth pulled. After ketamine treatment, patients should be observed for two hours after treatment to make sure they are okay, and then they should find someone else to lead them. “
Nagele and Conway said it was important that scientists soon conduct a large, multi-center study comparing the effects of ketamine and nitrous oxide to a placebo.
This work was supported by a NARSAD Award from the Brain & Behavior Research Foundation and the Taylor Family Institute for Innovative Psychiatric Research at the Washington University School of Medicine.