Can Laughing Gas (Nitrous Oxide) Help People With Treatment-Resistant Depression?
Thoughtful woman at home - copyspace getty  In up to a third of patients with major depression, standard medications that block receptors for the key neurotransmitters, serotonin and norepinephrine, are not effective. Beyond this, it may take several weeks to months before the beneficial effects of the medication are realized. While unique brain network disruptions may provide a potential explanation for the treatment failure, looking at alternative pathways and receptors that may have more immediate effects represent more recent advances for so-called treatment-resistant depression, or depression that does not improve with standard medications and therapy. This recent approach has included ketamine, a drug which blocks the NMDA receptor, now shown to be a possible factor in those with treatment-resistant depression. The treatments, which may be delivered by intravenous infusions or as a nasal spray (Esketamine) are done in an office-based setting the under the supervision of a psychiatrist, as well as other medical professionals based on risk factors and underlying medical history. Patients must be observed for about 2 hours until the sedative effects of the medication wears off. Ketamine has been quite effective for many patientsleading to relief within a few hours after the infusion or treatment itselfbut its beneficial effects subside after several weeks resulting in the need for repeat infusions/treatments. Now, researchers from Washington University School of Medicine in St. Louis and the University of Chicago are using a unique approach that also takes advantage of blocking the NMDA receptor. It involves a one-hour treatment inhaling a mixture of nitrous oxide, aka laughing gas, along with oxygen, offering potential advantages over ketamine. (Nitrous oxide is commonly used as an anesthetic in dental surgery, since it is able to provide short term pain relief and sedation lasting only minutes.) What the researchers found in a Phase 2 clinical trial is that symptoms of depression improved within a few hoursand lasted for several weeksafter treatment with inhaled nitrous oxide and oxygen. The findings were published today in the journal Science Translational Medicine. A large percentage of patients dont respond to standard antidepressant therapies  the patients in this study had failed an average of 4.5 antidepressant trials  and its very important to find therapies to help these patients, said Charles R. Conway, MD, Professor of Psychiatry at Washington University and one of the studys senior investigators said in a press release. That we saw rapid improvements in many such patients in the study suggests nitrous oxide may help people with really severe, resistant depression.  Conway, and his co-senior investigator, Peter Nagele, MD, Professor and Chair of the Department of Anesthesia & Critical Care at the University of Chicago, have been investigating the utility of nitrous oxide as an antidepressant over the past decade. In 2015, they published a proof-of-concept study demonstrating that inhaled nitric oxide (50% nitric oxide/50% oxygen administered over 1 hour) had rapid and significant antidepressant effects in patients with treatment-resistant depression, compared to a placebo. Beneficial effects were seen at 2 hours and even up to 24 hours post treatment. Three patients had full remission, with nausea and paradoxical anxiety as the main adverse effects. Compared with ketamine, nitrous oxide also has a relatively rapid onset of antidepressant action (within about 2 hours) but does not result in so-called psychotomimetic side effects seen with ketamine (delusions, hallucinations, illusions), which may be the result of nitric oxides effects lasting only a matter of minutes. Our primary goals in this study were twofold: to determine whether a lower dose of nitrous oxide might be just as effective as doses wed tested previouslyand it was for most patientsand we also wanted to see how long the relief lasted, said Nagele. In a proof-of-concept study several years ago, we assessed patients for 24 hours. In this study, we continued to assess them for two weeks, and most continued to feel better.  The researchers recruited 24 patients for this small study. Each participant received 3 treatments, about one month apart. For the first treatment, participants were treated with a mixture of 50% nitrous oxide and 50% oxygen for 1 hour. For the second treatment, each participant was treated with a mixture of 25% nitrous oxide and 75% oxygen. Finally, during the third treatment, as a placebo, participants breathed only oxygen, with no nitrous oxide. During the study, many of those who were taking antidepressants were allowed to continue taking these medications during the study period. You cant really get a better comparison group than when you compare a person to himself or herself, said Nagele. Serving as your own control is ideal. The alternative is studying the effects of a drug in two similar groups of people in which you either get one treatment or another. But the problem with that is that you need much larger numbers of patients before you really can draw conclusions.  The study found that nitrous oxideboth at 25% and in a 50% mixture with oxygen  improved symptoms of depression in 17 of the study participants. While there was a slightly greater antidepressant effect noted in participants after the 50% mixturewith positive effects lasting up to 2 weeks after the treatment, the 25% mixture had much fewer adverse events, the main one being nausea. That said, the researchers concluded that the 25% mixture was nearly as effective as the 50% mixture in relieving symptoms of depression, but with significantly fewer side effects such as nausea, haziness, and headache. In a small number of patients, treatment effects lasted up to 4 weeks. Some patients experience side effectsits a small subset, but its very real  and the main one is that some people get nauseated, said Conway. But in our study, only when people got the 50% dose did they experience nausea. When they received 25% nitrous oxide, no one developed nausea. And that lower dose was just about as effective as the higher dose at relieving depression.  Of the 20 study participants, 55% (11 of 20) described a significant improvement in at least half of their depressive symptoms, and 40% (8 of 20) were noted to be in remission (no longer were clinically depressed) after completing the 3 treatments in the study, each one month apart. The study also found that 85% (17 of 20) of the study participants experienced a major improvement in their symptoms and were able to be reclassified from having severe to moderate depression. That said, the researchers still noted that nitrous oxide did not have a beneficial effect in some of the study participants, and the reasons behind this lack of treatment effect were not clear. Needless to say, every patient is unique, Conway emphasized, and the lack of efficacy is still not unexpected. While as many as one-third of those who take antidepressants dont experience clinical improvement in their depressive symptoms, its important to note that ketamine (and nitrous oxide) have both shown promise in those with treatment-resistant depression. Conway and Nagele feel that these approaches may offer hope and be breakthroughs for people with treatment-resistant depression, but they believe nitrous oxide may have some practical advantages. One potential advantage to nitrous oxide, compared with ketamine, is that because its a volatile gas, its anesthetic effects subside very quickly, Conway said. Its similar to what happens in a dentists office when people drive themselves home after getting a tooth pulled. After treatment with ketamine, patients need to be observed for two hours following treatment to make sure they are ok, and then they have to get someone else to drive them.  Since the elimination half-life of nitrous oxide is about 5 minutes, one might envision potential advantages to large scale adoption of this drug in the outpatient setting compared to ketamine (with an elimination half-life of up to 2.5 hours), if large scale trials continue to demonstrate efficacy. To better understand the effects seen in the present study, it will be important to conduct a large, multicenter study involving hundreds of patients, comparing the effects of ketamine as well as nitrous oxide to placebo. On a deeper level, understanding the genetic profiles of people with treatment-resistant depression, including their unique brain network disruptions may help medical professionals select an optimal approach to therapy in the near future. There is hope for those who suffer from treatment-resistant depression, said Conway. While the results of this study are relatively preliminary, they demonstrate clinical benefit and require further study on a larger scale.  One limitation of the research involved the study design itself, with each study participant the recipient of all three treatments: 25% mixture, 50% mixture and a placebo over a 3-month period. This is in contrast to a randomized placebo controlled clinical trial, in which one group receives the treatment or drug and the other group is given a placebo. By allowing the researchers to use patients as their self-control instead of comparing them to other patients, it may have biased or even confounded the results due to a lingering effect of one treatment that could have influenced the outcome of the next treatment. Finally, one possible safety-related concern raised by Conway and Nagele in their 2015 study involves vitamin B 12 inactivation by nitrous oxide. While a single treatment will not likely lead to hematologic or neurological complications, the authors wrote that the risk for such complications is substantially higher when nitrous oxide administrations are repeated within short periods of time. Megaloblastic anemia and myelopathy have also been reported among persons who chronically abuse nitrous oxide as well as in patients with chronic disturbances of folate metabolism. They do caution that it is likely that for its sustained antidepressant effect, nitrous oxide must be administered several times, which would increase the risk for such complications. That said, Conway explained that the effects of recurrent dosing of nitrous oxide will need to be investigated in ongoing trials. (He has not observed B12 deficiencies thus far, emphasizing that the trials his research group has conducted to date were not repetitive dosing trials.) What we do know is that nitrous oxide is a drug of abuse (whippets). As a result, its important to consider that its abuse potential might reduce or limit its clinical utility in major depressive disorder. That said, the authors explain that their research was not designed to address this possible concern related to the drugs abuse potential. Treatment refractory depression can be quite a disabling condition, explained Dr. Scott Krakower, a child and adolescent psychiatrist at Zucker Hillside Hospital in Glen Oaks, New York. While there are treatments that may help, including pharmacology and ECT, treatment has turned toward looking at certain agents which inhibit NMDA receptors.  Ketamine has shown promising data and is readily available in clinical treatment centers. More recently, nitrous oxide has been reviewed as a potential agent which would could also help with this condition. There has been less data proving efficacy with this agent, although more research is to be done, offered Krackower. If data continues to show improvement with this compound, it may present as an efficient and widely available viable agent which practitioners could access and use. Like other substances in it's class, there is an abuse potential, so benefits would also have to outweigh the harm. he added.