The concentration is much smaller than what is typically used in dentistry (50%-75%), lead author Dr. Peter Nagele of the University of Chicago told Reuters Health by email. "What surprised us a bit was that the risk of side effects was reduced four-fold compared to 50% N2O," he said.
Additional surprises, according to principal author Dr. Charles Conway of Washington University School of Medicine in St. Louis, who also commented by email: the high percentage of patients who responded and remitted and the sustained antidepressant benefits (two weeks after a single session and several patients still benefiting at four weeks).
As reported in Science Translational Medicine, in the phase 2 crossover study, 24 patients (median age, 39; 71%, female; 96%, white) with severe treatment-resistant major depression (TRMD) were treated in random order with a single one-hour inhalation of 50% N2O; an hour of 25% N2O; and an hour of placebo (air/oxygen). Treatments were separated by at least four weeks.
Participants had sustained and refractory depressive illness, with an average of 17.5 lifetime years of major depressive disorder (MDD), and had failed a median of 4.5 adequate-dose/duration antidepressant drug treatments.
The median Hamilton Depression Rating Scale, 21 items (HDRS-21) score at enrollment was 20.5, and the median Montgomery-Asberg Depression Rating Scale (MADRS) score was 30.
The primary outcome was the change on the HDRS-21.
Whereas N2O significantly improved depressive symptoms versus placebo, there was no significant difference between 25% and 50% concentrations.
The estimated HDRS-21 score differences between 25% N2O and placebo were −0.75 points on at two hours; −1.41 points at 24 hours; −4.35 points at one week; and −5.19 points at two weeks.
For 50% N2O, estimated differences versus placebo were −0.87 points at two hours; −1.93 points at 24 hours; −2.44 points at week one; and −7.00 points at week two.
Adverse events declined substantially with dose. Thus, the results suggest that whereas 25% N2O has comparable efficacy to 50% N2O in improving TRMD, the lower concentration has a markedly lower rate of adverse effects.
Drs. Nagele and Conway said the treatment is experimental at this point and needs verification with larger numbers of patients before it might be implemented in clinical practice.
Dr. Joshua Berman, a psychiatrist working in the Columbia Ketamine Program at Columbia University Irving Medical Center in New York City, commented on the study in an email to Reuters Health. "N2O is the latest potential depression treatment that may target the glutamate system. In this study, anywhere from a third to a half of the patients seemed to respond and the response was sustained for at least a period of weeks."
"Any treatment that can produce these kinds of results in a population with demonstrated treatment resistance is worth further exploration," he said.
Nonetheless, he noted, "The study was double blind, but the authors reported that the majority of patients were able to guess correctly whether they had received N2O or placebo. Given high rates of placebo response in depression, the problem of adequate blinding should be solved before undertaking larger studies."
"It is important to note that N2O is not without risks, including abuse potential," he added. "There is not a lot of data about the safety of repeated exposures on the level that may be required to maintain long term remission of depression."
Further, he noted, "At least some effects of N2O are known to diminish with repeated exposure. Since repeated exposures may be required for long-term effects, it is possible that it might be hard to maintain long-term responses."
SOURCE: https://bit.ly/3pUzbyW Science Translational Medicine, online June 9, 2021.
By Marilynn Larkin
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