The solution to treatment-resistant depression may be in your dentist’s office

If you’ve ever gone to the dentist and received laughing gas, you’re familiar with the faintly sweet smell and giggly after-effect of nitrous oxide. The dentist’s office suddenly looks brighter and friendlier. You’re tranquil — if a bit giddy.

Discovered in 1772 by chemist Joseph Priestley, nitrous oxide is used as a short-term anesthetic during surgery (too much exposure is fatal) as well as a recreational drug by some.

The results of a Phase 2 trial, published Wednesday in Science Translational Medicine, suggest laughing gas may have a new purpose: giving relief to the 30 percent of people with an intractable form of Major Depressive Disorder called Treatment-Resistant Depression. That’s over half a million people in the United States alone with a potentially fatal illness for whom traditional medication doesn’t work.

Co-author Peter Nagele, chair of The University of Chicago’s Department of Anesthesia & Critical Care, tells Inverse he thinks nitrous oxide treatments could have monumental, life-saving implications.

“Several weeks after the study concluded, we had patients in remission,” he says.

How the discovery was made — Building off a successful Phase 1 trial, Nagele and colleagues investigated the efficacy of nitrous oxide in 28 patients with treatment-resistant depression.

Participants underwent one three-hour inhalation session per month for three months. The participants were separated into three groups:

• One which received nitrous oxide at 50 percent concentration
• One which received it at 25 percent concentration
• One placebo group

The Phase 1 trial only investigated the effectiveness of nitrous oxide at 50 percent concentration, and only for 24 hours following exposure. While the 50 percent concentration appeared to be extremely effective, some participants experienced side effects like nausea.

In the Phase 2 trial, researchers wanted to see if 25 percent concentration would be just as effective with reduced symptoms, as well as if the positive effects could last beyond 24 hours.

What they found — By the end of the study, 85 percent of patients had improved, 55 percent had a treatment response, and 40 were in remission.

“Mainstream psychiatry has two formal endpoints,” Nagele says. “Treatment response means that your depressive symptoms are basically cut in half or more.”

For example, a patient would take a test like the Hamilton depression rating scale, which calculates your symptom and assigns you a number.

“Let's say your depression score is 24,” Nagele explains, “then, in order to claim that the patient had a treatment response, you must fall below 12 points; that is considered a formal response.”

Remission he adds, “is defined on the Hamilton scale, as being below seven points.”

“It means you have such a strong improvement that actually you're no longer considered to have treatment-resistant depression,” he explains.

The effects of the nitrous lasted between two and four weeks.

What’s more, the 25 percent concentration was just as effective as the 50 percent concentration, but participants had a fourfold decrease in adverse side effects like sedation and nausea.

Why it worked — Despite the name, laughing gas isn’t the first thing you’d think of when it comes to an antidepressant. For one, as anyone who has stumbled out of a dentist’s office can attest, it can be pretty sedating.

But for those who understand chemistry, its promise is clear. Specifically because of another potential therapy for treatment-resistant depression: ketamine

Nagele has worked with nitrous oxide as an anesthesiologist for decades. Prior to this study, he understood that — much like ketamine — nitrous oxide is an antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors. Importantly, these are different receptors than serotonin and/or norepinephrine receptors, which are what traditional antidepressants target.

In medicine, an antagonist is a substance that stops the action of another substance. In this case, nitrous oxide inhibits activity in glutamate receptors which influence neural communication, memory formation, and regulation. These neurotransmitters are thought to influence different conditions, including anxiety, schizophrenia, and depression.

“I heard about the success of ketamine for treatment-resistant depression and I just sort of connected the dots,” he says.

As for stumbling out of the dentist’s office, Nagele says that kind of sedation is unlikely with these treatments, especially at the 25 percent concentration.

“At the dentist, they are trying to keep you calm but also make sure you don’t feel pain,” he says. “That concentration is like 70 percent. 25 percent is very mild.”

Why it’s promising — While psychedelics and psychedelic-adjacent drugs including ketamine have shown incredible promise for treatment-resistant depression, many of them are still mired in legal barriers to access. They’re also fairly intense — not everyone is looking to hallucinate or experience “ego death” just because they don’t respond to traditional SSRIs.

Nitrous oxide treatments could be a simple means of using an already FDA-cleared drug to treat one of the most difficult to treat and fatal mental health disorders.

Nagele also envisions these treatments being used in emergency rooms.

“Right now, if someone comes to the emergency room with really strong suicidal thinking, there's not a lot that we can offer them,” he says. “But this may be a fast onset, effective treatment for a patient.”

What comes next? — Naegle would like to see nitrous oxide treatments follow in ketamine’s footsteps. “Ketamine infusion is off-label, but it's legal,” he says. “We have not started a formal program, but we are thinking about it. I think we would be the first in the country.”

Nitrous oxide may not work for every single person with treatment-resistant depression, Nagele says, “but for the ones who do get the benefit, it would be great.”

Abstract: Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were −0.75 points on the HDRS-21 at 2 hours (P = 0.73), −1.41 points at 24 hours (P = 0.52), −4.35 points at week 1 (P = 0.05), and −5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were −0.87 points at 2 hours (P = 0.69), −1.93 points at 24 hours (P = 0.37), −2.44 points at week 1 (P = 0.25), and −7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.