Treatments for major depression

We read with interest Steven Marwaha and colleagues' Review of novel treatment options for major depressive disorder.1Marwaha S Palmer E Suppes T Cons E Young AH Upthegrove R Novel and emerging treatments for major depression.Lancet. 2022; 401: 141-153Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar Like ketamine, nitrous oxide (laughing gas) is an N-methyl-D-aspartate-receptor antagonist.2Sanders RD Weimann J Maze M Biologic effects of nitrous oxide: a mechanistic and toxicologic review.Anesthesiology. 2008; 109: 707-722Crossref PubMed Scopus (262) Google Scholar The similarity between the presumed mechanism of action of nitrous oxide and ketamine supports the possible effectiveness of nitrous oxide as a rapid-onset antidepressant. Although promising as a treatment, ketamine can have considerable undesirable side-effects such as confusion, dissociation, other psychomimetic effects, and substance abuse potential. Unlike ketamine, nitrous oxide has an excellent safety profile in major surgery, obstetrics, dentistry, and emergency care. PN has completed two randomised clinical trials demonstrating efficacy of nitrous oxide in severe treatment-resistant depression.3Nagele P Duma A Kopec M et al.Nitrous oxide for treatment-resistant major depression: a proof of concept trial.Biol Psychiatry. 2015; 78: 10-18Summary Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 4Nagele P Palanca BJ Gott B et al.A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression.Sci Transl Med. 2021; 13eabe1376Crossref PubMed Scopus (29) Google Scholar Both studies found that nitrous oxide significantly improved depressive symptoms versus placebo up to 1 week after inhalation (both p<0·01). We anticipate the treatment benefits of nitrous oxide can be accentuated with a four-cycle treatment programme. We are therefore conducting an ongoing trial to further evaluate the optimal nitrous oxide dose and regimen in a broader population of people with major depressive disorder (NCT03869736). Nitrous oxide is on the WHO list of essential medications and is available virtually anywhere in the world. It is inexpensive and can be simply and safely delivered by any trained clinician, and in more convenient locations such as a ward, an electroconvulsive therapy suite, clinic, or emergency room. The hope is that nitrous oxide can provide rapid onset of antidepressant effect during the time whereby the therapeutic benefit of any newly commenced traditional antidepressant or non-pharmacological therapy has its delayed effect. PSM and JK are funded in part by Australian National Health and Medical Research Council investigator grants. JK has received unrelated research funding from Janssen Cilag, Boehringer Ingelheim, and Servier. PN receives funding from the US National Institute of Mental Health, American Foundation for Prevention of Suicide, and Brain Behavior Foundation; and has previously filed for intellectual property protection related to the use of nitrous oxide in major depression. PSM, JK, and PN have received project grant funding from the Australian and New Zealand College of Anaesthetists (ID 18-032). Treatments for major depression – Authors' replyAlain Braillon and colleagues outline several judgements about novel treatments for depression and argue that treatment-resistant depression does not have reliable research criteria. Although we are aware of the debate concerning multiple treatment-resistant depression1 definitions, their specificity, and precision, we used the widely accepted definition of not responding to at least two treatments that is consistent with approximately 50% of definitions that are used in the literature.2 We believe this was a pragmatic and reasonable choice, as the alternative is to not investigate therapy for people who have not responded to serial treatments before having an internationally agreed research criterion (clearly desirable). Full-Text PDF