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Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial

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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.


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.


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 [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][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.


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

Nagele, P., Duma, A., Kopec, M., Gebara, M. A., Parsoei, A., Walker, M., … & Conway, C. (2014). Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial. Biological Psychiatry.
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