Nitrous Oxide: an emerging novel treatment for treatment-resistant depression

This review (2021) explores the possibilities of using Nitrous Oxide (NO2) for treating treatment-resistant depression (TRD). The use of NO2 as a psychiatric intervention is discussed along with its possible mechanism of action. Its antidepressant effects are believed to be mediated through the NMDA receptor.

Abstract

“Stemming from the results of the historic STAR-D trial, it is evident that a significant subset of individuals (20–25%) with major depressive disorder (MDD) do not respond to conventional antidepressant medications. As a result, an emphasis has been placed on the development of novel therapeutics for MDD over the last two decades. Recently, substantial research efforts have been focused on the use of ketamine as an antidepressant whose mechanism of action is via the N-methyl-d-aspartate (NMDA) receptor. Another potential therapeutic compound of interest is nitrous oxide, which has been utilized for more than a century in multiple fields of medicine for its analgesic and anesthetic properties. Recent clinical studies suggest that nitrous oxide may be effective for treatment-resistant depression. In this review, we will discuss the administration of nitrous oxide as a psychiatric intervention, current use in psychiatry, putative mechanisms of action, and future directions highlighting knowledge gaps and other potential utilities in the field of psychiatry.”

Authors: David F. Quach, Victoria C. de Leon & Charles R. Conway

Authors Highlights

•Nitrous oxide is emerging as a therapeutic for treatment-resistant depression.

•Recent studies indicate that it is fast-acting with effects lasting up to 2 weeks.

•Its antidepressant activity is thought to be mediated through the NMDA receptor.

•It has a favourable side effect profile with a long history of safe use in medicine.

Notes

As the name suggests, there is a significant unmet need when it comes to treating treatment-resistant depression (TRD). This significant subset of people living with major depressive disorder (MDD) remains unresponsive to conventional antidepressant medications such as SSRIs. Given this unmet need, researchers are continuously searching for new treatments. In the realm of psychedelic research, this particular subset of people with depression has been the main focus of researchers and industry players alike. Ketamine is already available off-label to those with TRD while trials with psilocybin have shown great promise in alleviating symptoms of this disorder. This promise has spurred research into the possibilities of using other psychedelic compounds as well as the potential off-label use of readily available medications.

The present paper is one of the first to make a case for the use of Nitrous Oxide (NO2) to treat TRD. NO2, also known as laughing gas, is a gas that is commonly used for general anaesthesia, procedural sedation, dental anaesthesia, and to treat severe pain. The authors of this paper argue that NO2 could be used for TRD given its antagonism at the NMDA receptor, which is the same property through which the antidepressant effects of ketamine are believed to be mediated.

The main findings

• Recent studies using NO2 to treat TRD directly or as an adjunctive therapy found that is a fast-acting antidepressant with effects that can last up to two weeks in certain individuals.
• As well as the NMDA receptor, NO2 has been shown to act on other recepors such as opioid recepots which may explain its potential pain relieving effects.
• Compared to ketamine, NO2 has different electrophsyiological effects at the NMDA receptor and from a safety perspective, there have been no reports of pychosis related to NO2.

Overall, the present study provides food for thought on the possibilities of using NO2 to treat TRD. While further research is clearly needed to establish dosing protocols, the safety profile, mechanisms of action and more, the fact NO2 is widely used means it could be a cheap alternative to alleviate the symptoms of TRD in comparison to the costs of other psychedelic therapies.

Summary

Abstract

A significant subset of individuals with major depressive disorder do not respond to conventional antidepressant medications. Recent clinical studies suggest that nitrous oxide may be effective for treatment-resistant depression.

Antidepressants: past and present

Pharmacological management of depression began in the 1950s with the monoamine hypothesis. Over the subsequent four decades, medications remained focused primarily on these systems, but a significant subset of patients did not respond to these standard pharmacotherapies and were referred to as having “treatment-resistant depression”.

Over the last two decades, a concerted effort has been placed on the investigation of novel agents/interventions to treat treatment-resistant depression. NMDA receptor antagonists have shown tremendous promise in successfully treating treatment-resistant depression, and nitrous oxide is another potential therapeutic that is actively under investigation.

N2O has many potential advantages over other drugs such as ketamine, such as a low side effect profile, rapid onset/recovery due to low blood gas solubility, limited drug interactions, and simple metabolism not influenced by other medications.

In the setting of the recent success of ketamine as a novel antidepressant, Nagele et al. conducted a pilot study to specifically target N 2O’s antidepressant potential. The subjects were severely treatment resistant with an average of 8 prior failed antidepressant trials. Treatment with N2O resulted in significant improvement in depression scale scores compared to placebo, with 20% of subjects achieving complete remission.

A phase 2 prospective, randomized, double-blind, crossover study comparing the effects of 25% and 50% nitrous oxide on depressive symptoms in 24 patients with a median of 4.5 failed antidepressant treatment trials showed that both dosages showed sustained effects over the duration of the study. Key findings from this study included that both N2O dosages were well-tolerated and that antidepressant effects were sustained up to two weeks.

A double-blind, placebo-controlled study of 23 subjects with MDD found that 50% N2O or placebo was used for 60 minutes twice a week for 4 weeks. The treatment was relatively well-tolerated and the most common adverse effects were somnolence, paresthesia, nausea, and headache.

Mechanism of Action in TRD

Nitrous oxide is a relatively new antidepressant that has been shown to inhibit excitotoxicity elicited by NMDA agonists. Its antidepressant mechanism of action remains largely unknown, but it is thought to act as a non-competitive NMDA antagonist.

N2O weakly inhibits the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)/kainite-type receptors, which are similar to the NMDA receptor. Ketamine treatment increased glutaminergic signaling in regions with elevated levels of AMPA receptors.

N2O has been shown to target other receptor-mediated pathways in addition to the NMDA receptor, and it is reasonable to hypothesize that its antidepressant effects may also be mediated via opioid receptor agonism.

Nitrous oxide modulates various ion channels, including low voltage activated calcium channels, gamma -aminobutyric acid receptors A and C, glycine receptors, and 5-hydroxytryptamine 3 receptors.

Studies utilizing electroencephalography have associated nitrous oxide treatment with decreased functional connectivity in the superficial parietal network and a slowing in frontal slow (delta) wave activity.

Comparison between Nitrous Oxide and Ketamine

N2O and ketamine are both non-competitive NMDA receptor antagonists, but ketamine specifically enters an open ion channel and occludes ion flow, whereas N2O effects are weakly voltage-dependent and do not appear to exhibit features consistent with an open channel blocker.

There have been some notable differences observed in the clinical trials performed so far between N2O and ketamine, including the fact that N2O wears off quickly.

Future Directions

Recent studies demonstrating the potential utility of nitrous oxide as a novel therapeutic for depression have been extremely promising. However, further studies are needed to determine whether these results can be replicated and to further clarify treatment guidelines.

Considering its safety and tolerability, potential use as an adjunctive treatment modality in addition to oral antidepressant therapy, and favorable results from initial studies, a larger, multi-center trial of inhaled nitrous oxide is warranted.

Figure 1. Putative Mechanisms of Action for Nitrous Oxide ( N2O)

Ketamine blocks individual NMDA channels completely, but its antidepressant effects are observed at submaximal concentrations and involve actions on only a subset of NMDA receptors. Nitrous oxide is thought to act through the NMDA receptor to exert its antidepressant effects.