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Nagele P, Duma A, Kopec M, Gebara MA, Parsoei A, Walker M, Janski A, Panagopoulous VN, Cristancho P, Miller JP, Zoumski CF, Conway C. 
“Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial”. 
Biological Psychiatry. 2014.

BACKGROUND: NMDA receptor antagonists, such as ketamine, have rapid antidepressant effects in patients with treatment-resistant depression (TRD). We hypothesized that nitrous oxide, an inhalational general anesthetic and NMDA receptor antagonist, may also be a rapidly acting treatment for TRD.

METHODS: In this blinded, placebo-controlled crossover trial 20 TRD patients were randomized to a 1-hour inhalation of 50 nitrous oxide/50 oxygen or 50 nitrogen/50 oxygen (placebo control). Primary endpoint was the change on HDRS-21 24 hours after treatment.

RESULTS: Mean duration of nitrous oxide treatment was 55.6 2.5 (SD) minutes at a median inspiratory concentration of 44 (37 45, IQR). In two patients nitrous oxide treatment was briefly interrupted and in three discontinued. Depressive symptoms improved significantly at 2 hours and 24 hours after receiving nitrous oxide compared to placebo (mean HDRS-21difference at 2 hours: -4.8 points, 95 CI -1.8 to 7.8 points, p= 0.002; at 24 hours: - 5.5 points, 95 CI -2.5 to -8.5 points, p< 0.001; comparison between nitrous oxide and placebo: p< 0.001). Four patients (20) had treatment response (reduction ≥50 on HDRS); three patients (15) a full remission (HDRS ≤ 7 points) after nitrous oxide, compared to one patient (5) and none after placebo (odds ratio [OR] for response 4.0, 95 CI 0.45 35.79; OR for remission 3.0, 95 CI 0.31 28.8). No serious adverse events occurred; all adverse events were brief and of mild to moderate severity.

CONCLUSIONS: This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with treatment-resistant depression.
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