madman
Super Moderator
Nitrous Oxide: an emerging novel treatment for treatment-resistant depression (2022)
Darin F. Quach, Victoria C. de Leon, Charles R. Conway
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, its current use in psychiatry, putative mechanisms of action, and future directions highlighting knowledge gaps and other potential utilities in the field of psychiatry.
1. Antidepressants: past and present
2. Nitrous oxide: the basics
3. Nitrous oxide: another antidepressant option?
4. Mechanism of action in TRD
5. Comparison between nitrous oxide and ketamine
6. Future directions
Recent studies demonstrating the potential utility of N2O as a novel therapeutic for depression have been extremely promising (Table 1). Additional insight regarding dose, tolerability, and duration of response was gained in a recent Phase 2 trial [17]. However, further studies are needed to determine whether these results can be replicated and to further clarify treatment guidelines (e.g., optimal dosage, dosing schedule, “maintenance” schedule, etc.). Ongoing studies regarding the mechanistic details of ketamine's action have been helpful for conceptualizing potential mechanisms of action for N2O. Nevertheless, how N2O works as an antidepressant is currently largely unknown; hence, future studies utilizing nitrous oxide in both preclinical and clinical models will be crucial. Perhaps a clinical study comparing N2O to ketamine may also be of interest to investigate the context in which each is optimally effective. One possible area of exploration may include attempting to correlate euphoric experiences observed with N2O inhalation and subsequent antidepressant response. The possibilities of N2O use in other disorders such as post-traumatic stress disorder or bipolar disorder are currently under investigation [40,41]. Another area of interest may be studying the impact of N2O on suicidality, especially given the rapid anti-suicidal effect of ketamine in previous studies [42].
Considering its overall safety and tolerability, relative ease of use, and favorable results from initial studies in the treatment of both TRD and MDD, it is reasonable to propose the eventual potential use of N2O as an adjunctive treatment modality in addition to oral antidepressant therapy. At this stage of development, a larger, multi-center trial of inhaled nitrous oxide is warranted. If this trial is successful, one could envision the eventual development of a specialty clinic for delivery of N2O or perhaps eventual incorporation into a private practice setting under medical supervision similar to many dental practices.
Darin F. Quach, Victoria C. de Leon, Charles R. Conway
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, its current use in psychiatry, putative mechanisms of action, and future directions highlighting knowledge gaps and other potential utilities in the field of psychiatry.
1. Antidepressants: past and present
2. Nitrous oxide: the basics
3. Nitrous oxide: another antidepressant option?
4. Mechanism of action in TRD
5. Comparison between nitrous oxide and ketamine
6. Future directions
Recent studies demonstrating the potential utility of N2O as a novel therapeutic for depression have been extremely promising (Table 1). Additional insight regarding dose, tolerability, and duration of response was gained in a recent Phase 2 trial [17]. However, further studies are needed to determine whether these results can be replicated and to further clarify treatment guidelines (e.g., optimal dosage, dosing schedule, “maintenance” schedule, etc.). Ongoing studies regarding the mechanistic details of ketamine's action have been helpful for conceptualizing potential mechanisms of action for N2O. Nevertheless, how N2O works as an antidepressant is currently largely unknown; hence, future studies utilizing nitrous oxide in both preclinical and clinical models will be crucial. Perhaps a clinical study comparing N2O to ketamine may also be of interest to investigate the context in which each is optimally effective. One possible area of exploration may include attempting to correlate euphoric experiences observed with N2O inhalation and subsequent antidepressant response. The possibilities of N2O use in other disorders such as post-traumatic stress disorder or bipolar disorder are currently under investigation [40,41]. Another area of interest may be studying the impact of N2O on suicidality, especially given the rapid anti-suicidal effect of ketamine in previous studies [42].
Considering its overall safety and tolerability, relative ease of use, and favorable results from initial studies in the treatment of both TRD and MDD, it is reasonable to propose the eventual potential use of N2O as an adjunctive treatment modality in addition to oral antidepressant therapy. At this stage of development, a larger, multi-center trial of inhaled nitrous oxide is warranted. If this trial is successful, one could envision the eventual development of a specialty clinic for delivery of N2O or perhaps eventual incorporation into a private practice setting under medical supervision similar to many dental practices.
