Abstract
Background
Nitrous oxide (“laughing gas”) is an NMDA receptor antagonist. In the current study, our aim was to investigate the efficacy, safety, and likely optimal dose of nitrous oxide in adults with major depressive disorder (MDD).
Methods
In this phase 2b randomized, double-blind trial, 81 patients with MDD were allocated on a 1:1 basis to receive nitrous oxide or oxygen/air (control); the nitrous group was further randomized to either 50% or 25% inspired nitrous oxide. All participants received four 1-hour-long treatment sessions at 1-week intervals and were followed for an additional 4 weeks. The primary outcome was the change in the 21-item Hamilton Depression Rating Scale (HAM-D) over the 4 treatment sessions. Secondary outcomes included remission (HAM-D ≤7 points), the Computerized Adaptive Test-Depression Inventory (CAT-DI) and Computerized Adaptive Test-Suicide Scale (CAT-SS).
Results
The mean averaged change in HAM-D scores over the 4 weeks of treatment was lower with nitrous oxide than with control (−1.9 [95% CI, −3.9 to 0.0], p = .051). In the first week, 15 of 39 (38%) in the nitrous oxide group and 5 of 39 (13%) in the control group were remitted (p = .031). The mean averaged change in CAT-DI scores was −7.7 (95% CI, −14.1 to −1.4), p = .017; the mean averaged change in CAT-SS scores was −8.3 (95% CI, −14.4 to −2.1), p = .008, both favoring nitrous oxide.
Conclusions
In this study, we confirmed that nitrous oxide has likely beneficial antidepressant effects in people with MDD.
Keywords: Glutamatergic system, Major depression, Nitrous oxide, NMDA, Suicidality, Treatment-resistant depression
Plain Language Summary
Nitrous oxide (laughing gas) has beneficial activity in key brain pathways associated with severe depression. We enrolled people for whom repeated treatments had failed to adequately treat their depression and studied the effects of nitrous oxide across 4 supervised 1-hour weekly treatment sessions. We found some evidence that nitrous oxide had beneficial and persistent antidepressant effects in people with severe depression. Additional studies are warranted.
Plain Language Summary
Nitrous oxide (laughing gas) has beneficial activity in key brain pathways associated with severe depression. We enrolled people for whom repeated treatments had failed to adequately treat their depression and studied the effects of nitrous oxide across 4 supervised 1-hour weekly treatment sessions. We found some evidence that nitrous oxide had beneficial and persistent antidepressant effects in people with severe depression. Additional studies are warranted.
The mental disorders depression and anxiety are major contributors to the global health burden. Following the recent COVID-19 pandemic, an additional 53.2 million cases of major depressive disorder (MDD) have been identified globally (1), with a corresponding rise in total prevalence. Therefore, there is an urgent need for new treatment approaches for depression.
Current pharmacological and nonpharmacological therapies for MDD are available, but they are frequently associated with adverse side effects and have variable efficacy. Importantly, most have a delayed onset of effect (≈1–4 weeks), which leaves people with severe MDD at serious risk of self-harm (2). Traditional antidepressants act via monoaminergic pathways. However, these monoaminergic antidepressants are frequently ineffective for treatment-resistant depression (TRD) (3,4). Because of the therapeutic need, recent research using ketamine has identified the importance of the glutaminergic system in MDD (5), which has stimulated the development of new compounds that may be safer, be more effective, and provide a more rapid onset of action (6,7).
Clinical studies have demonstrated that NMDA receptor antagonists, such as ketamine, have rapid antidepressant effects in TRD (5,8, 9, 10, 11), although the neurobiological mechanisms involved are not completely understood. However, ketamine has significant undesirable side effects, including psychomimetic effects, alterations in blood pressure, and significant abuse potential (3,12), and the traditional method of intravenous administration limits the settings in which it can be administered.
Similar to ketamine, nitrous oxide (“laughing gas”) is an NMDA receptor antagonist, and preliminary evidence suggests that a single 1-hour subanesthetic treatment may have rapid-onset antidepressant effects in TRD that persists for at least 1 week (13, 14, 15, 16, 17). A pilot study in unipolar MDD (N = 23) tested twice weekly repeat administrations over 4 weeks and found a significant reduction in depression scores at the end of week 4 (18). In the current randomized controlled trial, we aimed to evaluate the efficacy, tolerability, and safety of repeat (4 sessions) nitrous oxide administrations given over 3 weeks and a further 4-week follow-up in people with MDD.
Methods and Materials
Study Design
We conducted a randomized, 2-center, participant- and assessor-blinded (double-blinded), parallel-group, placebo-controlled, phase 2b trial. The trial was approved by the Alfred Hospital Research Ethics Committee (439/18) and the University of Chicago Institutional Review Board of the Biological Sciences Division (IRB18-1856). The study is registered with clinicaltrials.gov (NCT03869736), and the protocol is publicly available (see the Supplement). Details of the study team are reported in the Supplement.
Participants
We identified potential trial participants via print, radio, social media, and internet advertising and through existing databases of patients with MDD at each study site (Multidisciplinary Alfred Psychiatry Research Centre and the Epworth Clinic [Australia] and the Psychiatry Clinic at the University of Chicago [United States]). Participants were eligible if they were ≥18 years of age and satisfied the DSM-5 criteria for MDD without psychosis as determined using a structured clinical interview (the Mini-International Neuropsychiatric Interview) (19). MDD severity was defined by a pretreatment score >15 on the 21-item Hamilton Depression Rating Scale (HAM-D). We excluded participants if they had a history of bipolar disorder, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses; active suicidal intention, as determined by clinical interview; active or recent (<12 months) substance abuse or dependence, excluding nicotine; administration of an NMDA receptor antagonist (e.g., ketamine) during the previous 3 months; ongoing treatment with electroconvulsive therapy; presence of acute medical illness that could interfere with study participation, including significant pulmonary disease; pregnancy or breastfeeding; or any contraindications to the use of nitrous oxide (e.g., chronic cobalamin or folate deficiency unless treated with folic acid or vitamin B12).
We determined whether participants were eligible using a brief screening questionnaire, and they were then provided with a verbal description of the trial procedures and a written plain language statement. Eligible participants provided written, informed consent. Participants were instructed to maintain their current regimen and not to make any changes throughout the study period.
Randomization and Masking
Participants were individually randomly allocated (1:1) to either nitrous oxide (nitrous oxide group) or an oxygen-air mixture (inspired oxygen approximately 30%, control group). The nitrous oxide group was further randomly allocated to either inspired nitrous oxide 50% or nitrous oxide 25% (Figure 1). Randomization (permuted blocks of randomly varying sizes 6 to 12 stratified by site) was computer generated and disclosed via opaque, sealed envelopes. Participants were masked to treatment allocation. The effectiveness of masking was assessed at 24 hours after the first treatment and again at 4 weeks post final treatment, by asking participants to indicate whether they believed they had received nitrous oxide or air/oxygen treatment. The anesthesiologist who delivered the inspired gases could not be masked to treatment group due to the technical nature of the intervention and therefore did not evaluate any outcome measures or interact with clinical raters during the session. Staff who collected outcome data and the trial statistician were masked to allocated interventions.
Figure 1.
Trial profile. HAM-D, Hamilton Depression Rating Scale.
Procedures
Demographic variables, depression, medications, other baseline characteristics, and details of participants’ medical and surgical history were recorded (Table 1). Participants were instructed to continue their current treatment(s) for depression, before the first study day, and to continue the same dosage throughout the 7-week study period.
Table 1.
Baseline Characteristics of Control and Nitrous Oxide Groups
| Nitrous Oxide, n = 40 | Control, n = 41 | |||
|---|---|---|---|---|
| Characteristic | Mean (SD) or n (%) | Missing, n | Mean (SD) or n (%) | Missing, n |
| Age, Years | 41.7 (15.6) | 2 | 42.3 (14.9) | 1 |
| Age at Onset, Years | 21.0 (16.0–31.0) | 1 | 21.0 (15.0–33.0) | 1 |
| Total Duration of Illness, Years | 11.0 (7.0–20.0) | 1 | 13.0 (6.0–21.0) | 2 |
| Length of Current Episode, Months | 24.0 (6.0–42.0) | 1 | 11.0 (3.0–26.5) | 1 |
| Sex | ||||
| Female | 24 (60.0%) | 0 | 19 (46.3%) | 0 |
| Male | 16 (40.0%) | 22 (53.7%) | ||
| Menopause | ||||
| Premenopausal | 17 (70.8%) | 0 | 14 (73.7%) | 0 |
| Perimenopausal | 2 (8.3%) | 2 (10.5%) | ||
| Postmenopausal | 5 (20.8%) | 3 (15.8%) | ||
| Ethnicity | ||||
| Aboriginal, Torres Strait or South Sea Islander | 0 (0.0%) | 0 | 1 (2.5%) | 1 |
| African | 1 (2.5%) | 0 (0.0%) | ||
| Caucasian | 35 (87.5%) | 36 (90.0%) | ||
| East or South-East Asian | 2 (5.0%) | 2 (5.0%) | ||
| Other | 2 (5.0%) | 0 (0.0%) | ||
| West Asian | 0 (0.0%) | 1 (2.5%) | ||
| Number of Depressive Episodes | ||||
| 1 | 0 (0.0%) | 1 | 5 (13.5%) | 4 |
| 2 | 6 (15.4%) | 2 (5.4%) | ||
| 3 | 7 (17.9%) | 3 (8.1%) | ||
| 4 | 1 (2.6%) | 3 (8.1%) | ||
| 5 | 4 (10.3%) | 5 (13.5%) | ||
| 6 or more | 21 (53.9%) | 19 (51.3%) | ||
| Number of Previously Failed Treatments | ||||
| 1 | 6 (15.8%) | 2 | 6 (16.2%) | 4 |
| 2 | 4 (10.5%) | 8 (21.6%) | ||
| 3 | 8 (21.1%) | 4 (10.8%) | ||
| 4 | 2 (5.3%) | 1 (2.7%) | ||
| 5 | 4 (10.5%) | 2 (5.4%) | ||
| 6 | 2 (5.3%) | 2 (5.4%) | ||
| 7 | 0 (0.0%) | 1 (2.7%) | ||
| 8 | 1 (2.6%) | 1 (2.7%) | ||
| 10 or more | 11 (28.9%) | 12 (32.4%) | ||
| Previous ECT or TMS | ||||
| 0 | 33 (84.6%) | 1 | 32 (80.0%) | 1 |
| 1 | 1 (2.6%) | 2 (5.0%) | ||
| 2 | 0 (0.0%) | 1 (2.5%) | ||
| 3 | 2 (5.1%) | 0 (0.0%) | ||
| 4 | 0 (0.0%) | 1 (2.5%) | ||
| 5 or more | 3 (7.7%) | 4 (10.0%) | ||
| Previous Suicide Attempts | ||||
| 0 | 23 (59.0%) | 1 | 29 (72.5%) | 1 |
| 1 | 8 (20.5%) | 6 (15.0%) | ||
| 2 | 3 (7.7%) | 1 (2.5%) | ||
| 3 | 1 (2.6%) | 2 (5.0%) | ||
| 4 | 2 (5.1%) | 0 (0.0%) | ||
| 5 or more | 2 (5.1%) | 2 (5.0%) | ||
| Family History of Psychiatric Illness | 24 (61.5%) | 1 | 22 (55.0%) | 1 |
| Number of Current Psychiatric Medications | ||||
| 0 | 3 (7.7%) | 1 | 3 (7.5%) | 1 |
| 1 | 24 (61.5%) | 21 (52.5%) | ||
| 2 | 5 (12.8%) | 11 (27.5%) | ||
| 3 | 7 (17.9%) | 3 (7.5%) | ||
| 4 | 0 (0.0%) | 2 (5.0%) | ||
| Tobacco Use | ||||
| Current | 5 (13.2%) | 2 | 8 (20.0%) | 1 |
| Past | 13 (34.2%) | 9 (22.5%) | ||
| Never | 20 (52.6%) | 23 (57.5%) | ||
| Number of Pack Years, Median (IQR) | 5.0 (1.0–15.0) | 1 | 6.0 (3.0–75.0) | 2 |
| HAM-Da | 17.8 (4.0) | 0 | 19.3 (3.9) | 0 |
| POMSa | ||||
| Tension | 19.1 (6.9) | 1 | 20.2 (7.4) | 0 |
| Depression | 33.1 (13.3) | 0 | 35.4 (10.3) | 0 |
| Anger | 14.1 (10.4) | 2 | 14.5 (9.9) | 0 |
| Fatigue | 20.0 (6.2) | 0 | 18.4 (5.8) | 0 |
| Confusion | 15.1 (5.4) | 0 | 16.1 (5.0) | 0 |
| Vigor | 5.9 (4.1) | 0 | 6.7 (4.6) | 0 |
| Total | 94.4 (34.7) | 2 | 97.9 (29.1) | 0 |
| CAT-DI Severitya | 70.8 (13.0) | 0 | 71.4 (14.6) | 0 |
| CAT-SS Severitya | 55.7 (15.2) | 0 | 58.6 (10.9) | 0 |
| CAT-DI Category | ||||
| Normal | 1 (2.5%) | 0 | 2 (4.9%) | 0 |
| Mild | 11 (27.5%) | 13 (31.7%) | ||
| Moderate | 16 (40.0%) | 11 (26.8%) | ||
| Severe | 12 (30.0%) | 15 (36.6%) | ||
| CAT-SS Category | ||||
| Low | 2 (5.1%) | 1 | 2 (4.9%) | 0 |
| Moderate | 32 (82.1%) | 32 (78.0%) | ||
| High | 5 (12.8%) | 7 (17.1%) | ||
CAT-DI, Computerized Adaptive Test-Depression Inventory; CAT-SS, Computerized Adaptive Test-Suicide Scale; ECT, electroconvulsive therapy; HAM-D, 21-item Hamilton Depression Rating Scale; POMS, Profile of Mood States; TMS, transcranial magnetic stimulation.
Higher scores indicate worse health.
On study treatment days, participants were instructed to avoid eating and drinking for 2 hours before the session. All participants received 4 treatment sessions, spaced at 1-week intervals (first treatment = week 0) and were then followed-up for an additional 4 weeks. Both nitrous oxide groups were combined for the primary analysis, and a dose effect was tested for in a secondary subgroup analysis (see below).
Participants allocated to the control group received the oxygen-air mixture via mask. All inspired and expired gas concentrations were measured at 5-minute intervals using a calibrated gas analyzer via tubing with a soft cannula placed at the external nares. The inspired nitrous oxide or air-oxygen mixture was delivered using the Porter Nitrous Oxide Sedation System via a nasal mask (25% nitrous oxide and placebo group) or face mask (50% nitrous oxide group—to achieve the higher concentration). This delivery system was connected to a nitrous oxide scavenging system and has been shown to be safe and effective, without significant occupational or environmental contamination (20).
Monitoring included pulse oximetry, electrocardiography, noninvasive blood pressure, and end-tidal carbon dioxide under the direct supervision of an anesthetist researcher. Nitrous oxide was slowly titrated over the first 10 minutes until the target concentration (25% or 50%) was achieved. If the participant developed any adverse effects from nitrous oxide, it could be downtitrated to a more acceptable level and/or be terminated early. After each treatment session, participants were transferred to a recovery area and monitored until they met standard discharge criteria. If nausea or vomiting occurred, participants were offered oral ondansetron (4 mg) as antiemetic therapy.
Participants underwent assessment for depression, manic, or psychosis symptoms prior to and at 1-week postinhalation. The extent of depression was primarily measured using the 21-item HAM-D (21), supplemented by the Computerized Adaptive Test-Depression Inventory (CAT-DI) (22) and Computerized Adaptive Test-Suicide Scale (CAT-SS) (23). HAM-D scoring was done in person by trained and certified assessors who were masked to treatment group assignment. The HAM-D, CAT-DI, and CAT-SS scales were assessed at 10 time points: at baseline (pretreatment), 24 hours after the first treatment, before each of the next 3 weekly treatments and again at 24 hours after the final treatment, and weekly for an additional 4 weeks. At 1 hour after the first treatment, an additional measurement of depression was done using a 100-mm visual analog scale (VAS) to quantify any acute changes in depression. In addition, a 100-mm VAS (“not depressed” to “extremely depressed”) was used to measure participants’ perceptions of their depression 1 hour after each of the weekly treatments (24). Daily changes in mood were assessed by the Profile of Mood States (POMS) questionnaire (25), using an electronic or paper questionnaire for participants to complete daily. Measures of possible side effects of nitrous oxide or air-oxygen administration were also collected (dizziness, anxiety, nausea, vomiting, claustrophobia, or mask intolerance).
We included an optional open-label extension after the final 4-week follow-up period (week 7), for which participants in the control group were unblinded by a staff member who was not part of the research team and given the option of an active treatment session (inspired nitrous oxide 25%) with an additional 1-week follow-up. This provided an incentive to all participants to remain in the trial.
A research experience survey was sent to all participants electronically at the end of the trial (see the Supplement) to assess the structure and organization of the study, reasons for participating in the study, and participant experiences.
Outcomes
The primary outcome was the change from baseline in the 21-item HAM-D scale over the 4 treatment sessions (weeks 0–3) in the combined nitrous oxide groups. The secondary outcomes were the acute effect on the HAM-D measured at 24 hours after the first treatment and the sustained effect on the HAM-D at 4 weeks after the final treatment, treatment response (≥50% reduction on HAM-D) and full remission (HAM-D ≤7 points) at 24 hours and 4 weeks; pattern of treatment response (mood, using daily POMS) after the first treatment session; sustainability of treatment response, as measured by change in the HAM-D, response and remission rates at 7 weeks; treatment compliance failure rate (refusal or inability to attend further treatments); and the dose effect of nitrous oxide groups (25% vs. 50%).
Traditionally, measurement scales of depression contain a fixed number of items corresponding to symptoms, which are administered using specific verbal probes to elicit a quantitative score for each item. The final numerical score is used to indicate depression and its severity. In contrast, a computerized adaptive test, based on multidimensional item response theory, fixes measurement uncertainty and allows the number of items to vary. The result is a significant reduction in the number of items needed to measure depression and increased precision of measurement (22). The CAT-DI and CAT-SS have been found to decrease patient and clinician burden and increase measurement precision (22,23). Thus, we included these additional measures of treatment response as secondary outcomes.
Safety outcomes were nausea or vomiting, new suicidal ideation, and any other unexpected adverse events. Acceptability was evaluated by the treatment cessation rate due to perceived side effects.
Statistical Analysis
Based on our previous data (13), using a type I error rate of 0.05 and type II error rate of 0.1 (90% power), detecting a mean (SD) difference in change in HAM-D scores across groups of 4.0 (7.6) or greater would require 77 participants per group. Thus, we planned to enroll 172 participants to account for 10% dropout. For the secondary dose-response analysis, the planned sample size provided 80% power to detect a difference of 4.9 units (an effect size of 0.65) between the 50% and 25% nitrous groups in the HAM-D change from baseline. The COVID-19 pandemic had a major effect on the capacity to undertake clinical research in Chicago, and therefore, our recruitment target could not be met with existing funds. Therefore, we closed recruitment after we had enrolled 81 participants.
The 2 highest and 2 lowest inspired nitrous oxide measurements were removed before the remaining values were averaged to give a mean inspired nitrous oxide concentration for each treatment session. All analyses were conducted by original allocated groups (intention to treat), and missing data were imputed using multiple imputation; we also undertook a complete case analysis. Missing outcome data were imputed using chained equations with predictive mean matching from 5 nearest neighbors for continuous outcomes and logistic regression imputation models for binary outcomes, with the 15 imputed datasets used in analyses to assess primary and secondary hypotheses, combining estimates using Rubin’s rules. Imputation models included baseline levels of outcomes, duration of illness, length of current episode, and age and were imputed separately by treatment arm. We also conducted analyses under various missing-not-at-random assumptions as outlined in the Supplement. The per-protocol population was used in the safety analysis.
For the primary hypothesis, differences in mean change in HAM-D scores (baseline minus follow-up) were examined between groups using longitudinal linear regression models with random intercepts at the participant level to account for the multiple measurements for each participant. This model included terms for baseline HAM-D score, time, treatment group, and the interaction between time and treatment group; residuals were assumed to have an autoregressive structure of order 1. Results are expressed as mean differences with 95% CIs; to address the primary aim, the model was interrogated to provide estimates of the difference between the nitrous oxide and control groups marginalized over the first 3 weeks (4 cycles of treatment). The effect of nitrous oxide dose (25% vs. 50%) was included in an additional exploratory model. Other continuous outcomes were analyzed similarly, including the baseline level of the analyzed outcome as a covariate. Binary outcomes were compared between groups using logistic regression models, fit via generalized estimating equations to account for clustering of observations within individuals, assuming an exchangeable working correlation matrix and using robust standard errors, with results expressed as risk differences. Standard diagnostic plots were used to assess the validity of model assumptions, and continuous outcomes could be transformed if required.
Results
Between April 2018 and June 2020, when recruitment was terminated early due to the COVID-19 pandemic, we screened 429 participants and found 222 to be eligible (Figure 1). A total of 81 (36%) participants were enrolled and provided informed consent. A total of 40 participants were randomly allocated to the nitrous oxide group (25% n = 20, 50% n = 20) and 41 participants to the control group.
Participants
Participant demographics and baseline characteristics were comparable between nitrous oxide and control groups, with the exception of the longer duration of current illness in the nitrous oxide group (Table 1), and were also comparable between the 2 nitrous oxide groups (Table S1) and the completers and noncompleters of the full study period (Table S3). The mean age was 42 years (SD 15.3, range 19–70); 43 (53%) of the 81 participants were female and 38 (47%) were male; and 71 participants (88%) were Caucasian. All participants were moderately to severely depressed, with a mean HAM-D score of 18.5 (SD 4.0), and had a median of 6 or more failed treatments for depression; 27 participants (33%) reported having attempted suicide, and 16 (20%) had previously been treated with electroconvulsive or transcranial magnetic therapy (Table 1). A total of 11 participants did not complete the 4-week treatment cycle (6 in the nitrous group, 5 in the control group); these individuals were more likely to have higher HAM-D, CAT-DI, and CAT-SS severity scores at baseline (Table S4).
Outcomes
Differences in depression, mood, CAT-DI, and CAT-SS scores across all treatment sessions and follow-up between the combined nitrous group and the control group are described in Table 2 and separately for each of the nitrous groups versus the control group (Tables S4 and S5). The mean averaged change in HAM-D scores over the 4-week treatment sessions was lower with nitrous oxide than with control (−1.9 [95% CI, −3.9 to 0.0], p = .051) (Figure 2). The acute effect, measured 1-hour after the final inhalation session, was an averaged change in HAM-D scores of −2.5 (−5.9 to −0.1), p = .041, favoring nitrous oxide. Results were robust to a broad range of missing-not-at-random assumptions (Table S6). Treatment response (p = .047) and remission (p = .030) favoring nitrous oxide were achieved after the 4-week treatment sessions (Table 3). In the first week, 15 of 39 (38%) in the nitrous oxide group and 5 of 39 (13%) in the control group were remitted (risk difference 46% [95% CI, 4% to 87%], p = .031). In the final week, 10 of 32 (31%) participants in the nitrous oxide group and 6 of 33 (18%) participants in the control group were remitted (risk difference 19% [95% CI, −23% to 60%], p = .38).
Table 2.
Outcomes in Nitrous Oxide and Control Groups at Each Follow-Up Time Point
| Nitrous Oxide, n = 40 |
Control, n = 41 |
|||
|---|---|---|---|---|
| n | Mean (SD) | n | Mean (SD) | |
| HAM-D | ||||
| Baseline | 40 | 17.8 (4.0) | 41 | 19.3 (3.9) |
| Day 1 | 39 | 10.1 (5.4) | 39 | 13.6 (4.8) |
| Week 1 + 24 hours | 34 | 13.6 (5.4) | 36 | 15.9 (5.2) |
| Week 2 | 33 | 11.8 (5.7) | 34 | 14.7 (5.3) |
| Week 3 | 34 | 12.1 (6.3) | 36 | 14.4 (5.6) |
| Week 3 + 24 hours | 29 | 7.5 (5.6) | 33 | 10.9 (6.5) |
| Week 4 | 33 | 9.6 (5.8) | 35 | 13.1 (6.5) |
| Week 5 | 31 | 9.7 (5.1) | 34 | 14.1 (6.0) |
| Week 6 | 30 | 10.7 (6.5) | 33 | 13.5 (6.9) |
| Week 7 | 32 | 11.6 (6.4) | 33 | 13.1 (6.7) |
| CAT-DI Severity | ||||
| Baseline | 40 | 70.8 (13.0) | 41 | 71.4 (14.6) |
| Day 1 | 36 | 55.4 (20.2) | 39 | 64.4 (14.1) |
| Week 1 + 24 hours | 34 | 57.5 (15.7) | 36 | 60.9 (16.3) |
| Week 2 | 34 | 50.4 (19.2) | 35 | 59.3 (17.7) |
| Week 3 | 33 | 47.8 (20.1) | 36 | 58.0 (16.4) |
| Week 3 + 24 hours | 27 | 40.2 (23.3) | 30 | 55.7 (22.4) |
| Week 4 | 30 | 45.8 (22.0) | 35 | 57.3 (15.9) |
| Week 5 | 32 | 44.9 (21.1) | 34 | 60.2 (17.3) |
| Week 6 | 28 | 52.8 (20.2) | 35 | 56.5 (19.9) |
| Week 7 | 29 | 49.2 (20.8) | 35 | 58.7 (17.9) |
| CAT-SS Severity | ||||
| Baseline | 40 | 55.7 (15.2) | 41 | 58.6 (10.9) |
| Day 1 | 36 | 45.8 (19.5) | 39 | 53.3 (13.8) |
| Week 1 + 24 hours | 34 | 44.3 (19.1) | 36 | 51.0 (13.6) |
| Week 2 | 34 | 38.0 (20.8) | 35 | 49.3 (15.9) |
| Week 3 | 33 | 35.2 (21.7) | 35 | 47.5 (16.5) |
| Week 3 + 24 hours | 27 | 30.7 (21.2) | 30 | 45.7 (19.3) |
| Week 4 | 29 | 34.3 (22.9) | 35 | 43.3 (19.7) |
| Week 5 | 31 | 34.2 (20.6) | 34 | 44.6 (17.7) |
| Week 6 | 28 | 42.3 (21.4) | 34 | 43.7 (20.3) |
| Week 7 | 29 | 38.5 (20.4) | 34 | 48.2 (15.8) |
| Depression VAS | ||||
| Week 1 | 39 | 38.9 (24.2) | 40 | 54.1 (28.0) |
| Week 2 | 32 | 32.4 (23.7) | 34 | 46.6 (24.3) |
| Week 3 | 32 | 29.1 (20.5) | 33 | 45.7 (26.5) |
| Week 4 | 29 | 22.3 (19.9) | 34 | 40.9 (28.5) |
| POMS Tension | ||||
| Baseline | 39 | 19.1 (6.9) | 41 | 20.2 (7.4) |
| Day 1 | 31 | 14.2 (8.8) | 35 | 15.7 (8.7) |
| Day 2 | 30 | 13.0 (8.2) | 35 | 16.1 (8.2) |
| Day 3 | 31 | 13.0 (8.2) | 35 | 15.3 (9.1) |
| Day 4 | 31 | 14.2 (8.5) | 35 | 16.5 (9.7) |
| Day 5 | 30 | 14.4 (7.8) | 35 | 15.8 (9.8) |
| Day 6 | 29 | 12.7 (8.6) | 32 | 15.0 (10.5) |
| POMS Depression | ||||
| Baseline | 40 | 33.1 (13.3) | 41 | 35.4 (10.3) |
| Day 1 | 32 | 22.8 (15.1) | 35 | 29.7 (14.5) |
| Day 2 | 31 | 21.9 (15.1) | 35 | 27.0 (15.0) |
| Day 3 | 31 | 22.4 (16.4) | 35 | 25.4 (15.1) |
| Day 4 | 31 | 24.5 (15.3) | 35 | 26.5 (15.6) |
| Day 5 | 30 | 20.7 (13.2) | 35 | 27.4 (15.5) |
| Day 6 | 29 | 21.4 (14.9) | 32 | 27.1 (15.7) |
| POMS Anger | ||||
| Baseline | 38 | 14.1 (10.4) | 41 | 14.5 (9.9) |
| Day 1 | 31 | 11.2 (11.1) | 35 | 12.1 (11.4) |
| Day 2 | 31 | 10.1 (11.1) | 35 | 10.4 (9.1) |
| Day 3 | 31 | 10.3 (11.0) | 35 | 9.0 (7.8) |
| Day 4 | 31 | 12.2 (12.8) | 35 | 9.7 (10.0) |
| Day 5 | 28 | 10.3 (12.1) | 35 | 10.8 (11.0) |
| Day 6 | 29 | 10.7 (11.9) | 31 | 10.5 (10.3) |
| POMS Fatigue | ||||
| Baseline | 40 | 20.0 (6.2) | 41 | 18.4 (5.8) |
| Day 1 | 32 | 15.0 (6.8) | 35 | 16.4 (7.3) |
| Day 2 | 31 | 13.7 (7.3) | 35 | 15.0 (7.9) |
| Day 3 | 31 | 14.1 (7.8) | 35 | 14.2 (8.2) |
| Day 4 | 31 | 15.8 (7.5) | 35 | 14.2 (8.0) |
| Day 5 | 30 | 13.7 (7.0) | 35 | 15.4 (8.5) |
| Day 6 | 29 | 13.7 (7.3) | 32 | 15.0 (8.1) |
| POMS Confusion | ||||
| Baseline | 40 | 15.1 (5.4) | 41 | 16.1 (5.0) |
| Day 1 | 32 | 11.7 (5.4) | 35 | 14.3 (5.9) |
| Day 2 | 31 | 11.2 (6.0) | 35 | 13.4 (7.0) |
| Day 3 | 31 | 10.6 (5.6) | 35 | 12.3 (6.7) |
| Day 4 | 31 | 11.4 (5.4) | 35 | 12.7 (7.6) |
| Day 5 | 30 | 11.2 (4.9) | 35 | 13.0 (7.7) |
| Day 6 | 29 | 10.9 (5.9) | 32 | 13.6 (7.4) |
| POMS Vigor | ||||
| Baseline | 40 | 5.9 (4.1) | 41 | 6.7 (4.6) |
| Day 1 | 32 | 8.6 (5.9) | 35 | 6.1 (4.6) |
| Day 2 | 31 | 9.3 (5.4) | 35 | 6.8 (5.4) |
| Day 3 | 31 | 7.8 (4.9) | 35 | 8.6 (5.7) |
| Day 4 | 31 | 7.8 (4.9) | 35 | 6.7 (5.9) |
| Day 5 | 30 | 7.5 (5.0) | 35 | 6.9 (6.0) |
| Day 6 | 29 | 8.0 (6.2) | 32 | 7.3 (7.4) |
| POMS Total | ||||
| Baseline | 38 | 94.4 (34.7) | 41 | 97.9 (29.1) |
| Day 1 | 31 | 67.0 (44.1) | 35 | 82.2 (39.2) |
| Day 2 | 30 | 61.3 (42.2) | 35 | 75.1 (43.5) |
| Day 3 | 31 | 62.6 (41.3) | 35 | 67.7 (41.4) |
| Day 4 | 31 | 70.3 (42.7) | 35 | 72.9 (45.1) |
| Day 5 | 28 | 60.5 (37.5) | 35 | 75.5 (46.6) |
| Day 6 | 29 | 61.4 (43.0) | 31 | 73.9 (48.3) |
CAT-DI, Computerized Adaptive Test-Depression Inventory; CAT-SS, Computerized Adaptive Test-Suicide Scale; HAM-D, 21-item Hamilton Depression Rating Scale; POMS, Profile of Mood States; VAS, visual analog scale.
Figure 2.
(A–C) Mean (95% CI) depression and suicide severity scores at each time point in the control and nitrous oxide (N2O) groups, superimposed on the complete case data from the participants. Additional scoring was done by the participants at 24 hours after the first treatment (day 0) and at 24 hours after the 3-week treatment (day 21). CAT-DI, Computerized Adaptive Test-Depression Inventory; CAT-SS, Computerized Adaptive Test-Suicide Scale; HAM-D, 21-item Hamilton Depression Rating Scale.
Table 3.
Response and Remission
| Nitrous Oxide, n (%) | Control, n (%) | Risk Difference (95% CI) |
||
|---|---|---|---|---|
| Nitrous Oxide vs. Control | p Value | |||
| Treatment Response, ≥50% Reduction in HAM-D | ||||
| Average Over First 3 Weeks | 11/34 (32.3%) | 6/36 (16.7%) | 26.0% (0.3% to 51.7%) | .047 |
| Day 1a | 15/39 (38.5%) | 8/39 (20.5%) | 33.8% (−11.8% to 79.4%) | .15 |
| Week 7 | 13/32 (40.6%) | 9/33 (27.3%) | 17.7% (−41.1% to 76.6%) | .56 |
| Remission, HAM-D ≤7 | ||||
| Average Over First 3 Weeks | 10/34 (29.4%) | 5/36 (13.9%) | 23.0% (2.3% to 43.7%) | .030 |
| Day 1a | 15/39 (38.5%) | 5/39 (12.8%) | 45.5% (4.1% to 86.9%) | .031 |
| Week 7 | 10/32 (31.3%) | 6/33 (18.2%) | 18.7% (−22.9% to 60.3%) | .38 |
n values are based on complete case data. Risk differences were derived from logistic regression models and fit via generalized estimating equations to account for clustering of measurements within individuals, using multiply imputed data, for the binary outcomes of treatment response and remission.
HAM-D, 21-item Hamilton Depression Rating Scale.
At 24 hours after the first treatment.
The mean averaged change in CAT-DI scores was −7.7 (95% CI, −14.1 to −1.4), p = .017, favoring nitrous oxide. The acute effect was a change in CAT-DI score of −9.4 (95% CI, −17.4 to −1.5), p = .020, favoring nitrous oxide. The mean averaged change in CAT-SS scores was −8.3 (95% CI, −14.4 to −2.1), p = .008, favoring nitrous oxide. The acute effect was a change in CAT-SS score −7.3 (95% CI, −15.4 to 0.8), p = .077, favoring nitrous oxide. Changes in scores measuring the acute, averaged, and persistent effects accounting for clustering within individuals, and with imputation to account for missing data, are described in Tables S4 and S5. Changes in POMS scores are described in Table S6. The total number of sessions attended is described in Table S8. Results of the complete case analyses are presented in Tables S9–S12.
Approximately three-quarters of the participants successfully identified their group allocation (Table S12). A total of 16 participants in the control group accepted the offer for an open-label single 1-hour administration of nitrous oxide, for which their HAM-D, CAT-DI, and CAT-SS scores mostly improved in the 1-hour, 24-hour, and 1-week follow-up periods (Table S14).
Safety
There were no serious adverse events, but 35 participants reported dizziness or lightheadedness (27 in the nitrous group, 8 in the control group), and 13 nitrous group participants reported nausea in any of the treatment sessions (Table S14). Three participants in the 50% nitrous group required antiemetic treatment with ondansetron. There were no reports of new suicidal ideation.
Results of the research experience survey are presented in the Supplement (Figures S4 and S5). The most important reported reasons to participate in the trial were to help themselves or help others and curiosity.
Discussion
To our knowledge, this study was the first randomized controlled trial of repeat administrations of nitrous oxide in MDD with an extended follow-up period. The study population included many patients who had severe life-long depression, had failed multiple therapies, and still had moderate to severe symptoms. Although we and others have conducted some preliminary studies of nitrous oxide in similar populations, each supporting proof of concept, this evidence was restricted to short-term (1–2 weeks) follow-up (13,14,18). We also included measures of suicidality and mood. The 81 participants had moderate to severe depression, with most having failed numerous drug and other treatments. Although our trial was underpowered, and the primary outcome was not statistically significant, nitrous oxide showed promise in reducing the intensity of depression and suicidality. We found that participants allocated to the nitrous oxide group generally had lower HAM-D, CAT-SS, and CAT-DI severity scores in the 7-week study period than participants allocated to the control (air/oxygen) group. Our primary measure of the mean difference in averaged HAM-D scores over the 4-week treatment period was −1.9 (95% CI, −3.9 to 0.0), suggesting a modest but potentially clinically important effect (Figure 2). The results of our computerized adaptive testing for depression severity (CAT-DI) and suicidality (CAT-SS) support meaningful responses to treatment with nitrous oxide. Critically, these responses persisted throughout the 7-week treatment cycle (Figure 2). However, we acknowledge that there was no difference in some of the secondary measures of depression and suicidality.
Nitrous oxide is inexpensive and readily available in hospitals and can be safely delivered by trained physicians or nurses. Nearly one-third of patients with MDD are severely depressed, and many are at high risk of suicide. The increased rates of suicide in people with depression during the first 28 days of starting and stopping antidepressants, including those managed in the primary care setting (2), highlights a potential role for nitrous oxide during these periods.
The U.S. Food and Drug Administration, in its Clinical Trial Design for Depression guidelines, accepts a clinically meaningful treatment effect of 3 points or more on the HAM-D (26), and a score <7 indicates remission in patients with moderate to severe depression responding to treatment (27). The efficacy of most currently available antidepressants in the acute treatment of MDD consistently fail to achieve these thresholds (28).
The CAT-DI has been validated against structured clinical interviews for MDD and against the clinician-rated HAM-D (22). In a recent clinical trial that compared ketamine versus midazolam, the CAT-DI produced a larger effect size at 24 hours (blind phase) than the HAM-D (0.71 vs. 0.58) (29). The CAT-SS has been similarly validated, with a maximum score range of a 52-fold increase in the risk of suicidal ideation (sensitivity of 1.0 and specificity of 0.95) (23). In the ketamine trial, the CAT-SS produced a larger effect size at 24 hours (blind phase) than the clinician-rated Beck Scale for Suicidal Ideation (0.40 vs. 0.00) (29).
We did identify some adverse effects, the most common being dizziness/lightheadedness or nausea during inhalation, especially in those receiving 50% nitrous oxide. This was typically short-lived, and most affected participants agreed to continue in the study. Clinicians need to be mindful that repeated and prolonged administrations of nitrous oxide can interfere with vitamin B12 and folate metabolism and deoxyribonucleic acid synthesis, leading to peripheral neuropathy or subacute combined degeneration of the spinal cord, but this is mostly reversible with folate and B12 supplementation (30). Nonmedical or recreational use must be avoided (31).
Our study has some limitations. Due to the social distancing requirements of the COVID-19 pandemic, screening and randomization were significantly slowed, which prevented the study from achieving the sample size required by our power calculation. The subgroup dose testing was even more underpowered. In addition to the issue of statistical power, the small sample size and estimated mean differences in the sample subpopulations raises potential concerns about generalizability. Additionally, the 7-week follow-up period may not be sufficient to address the chronicity of some episodes of depressive disorder. The blinding of participants was incompletely achieved, with three-quarters of the participants successfully identifying their group allocation, which could have biased the results in favor of nitrous oxide.
Our findings have implications for the design and conduct of future nitrous oxide trials in people with MDD or TRD. A trial adequately powered to detect the modest differences in HAM-D, CAT-SS, and CAT-DI scores that we found in this study are likely to have substantial clinical and social impact. Given that the treatment effects were largely comparable between the 25% and 50% nitrous oxide groups, and adverse effects were more common in the 50% nitrous oxide group, we recommend further studies using 25% nitrous oxide.
Conclusions
Our study suggests that nitrous oxide shows promise, with a rapid-onset antidepressant effect that frequently persists for several weeks. This offers an additional bridging option while the therapeutic benefit of any newly commenced traditional antidepressant or nonpharmacological therapies have their (typically delayed) effect or as an adjunct maintenance therapy in individuals with resistant MDD. This immediate antidepressant effect in acutely suicidal patients could be notably advantageous and potentially lifesaving. Additional larger-scale trials of nitrous oxide are necessary and warranted.
Acknowledgments and Disclosures
This work was supported by the Australian and New Zealand College of Anaesthetists (Grant No. ID 18-032 [to PSM, JKu, PN, JKa]), the Alfred Hospital Whole Time Medical Specialists Equipment Fund (research, PSM), and internal departmental funds. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
We thank Dr. Charles Zorumski for his constructive comments on earlier drafts of this article. We thank the participants who took part in this study, as well as research nurses and equipment officers in the Department of Anaesthesiology and Perioperative Medicine at the Alfred Hospital.
JKu reports receiving unrelated research funding from pharmaceutical industries—Janssen Cilag, Boehringer Ingelheim, and Servier Laboratories. PN reports receiving reimbursement as advisory board member for Becton-Dickinson unrelated to this work, has previously filed for intellectual property protection related to the use of nitrous oxide in major depression (US20170071975A1), and is the cofounder of NitroTherapeutics, Inc., a company that aims to develop nitrous oxide as a treatment for depression. PSM and JKu are supported by Australian National Health and Medical Research Council Investigator (Grant Nos. 2008079 and 1177729, respectively). PN is currently receiving or has received funding from the U.S. National Institute of Mental Health and the American Foundation for Prevention of Suicide, Brain & Behavior Research Foundation. CRC has received research support from the American Foundation for Suicide Prevention, Assurex Health, the August Busch IV Foundation, Barnes-Jewish Hospital Foundation, LivaNova, National Institute of Mental Health, and the Taylor Family Institute for Innovative Psychiatric Research and has consulted for LivaNova and Sage Therapeutics. All other authors report no biomedical financial interests or potential conflicts of interest.
ClinicalTrials.gov: Nitrous Oxide for the Treatment of Major Depressive Disorder; https://clinicaltrials.gov/study/NCT03869736?term=NCT03869736&rank=1; NCT03869736.
Footnotes
Supplementary material cited in this article is available online at https://doi.org/10.1016/j.bpsgos.2025.100504.
Supplementary Material
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