title: Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial.
abstract: BACKGROUND
  N-methyl-D-aspartate 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 N-methyl-D-aspartate receptor antagonist, may also be a rapidly acting treatment for TRD.
  
  
  METHODS
  In this blinded, placebo-controlled crossover trial, 20 patients with TRD were randomly assigned to 1-hour inhalation of 50% nitrous oxide/50% oxygen or 50% nitrogen/50% oxygen (placebo control). The primary endpoint was the change on the 21-item Hamilton Depression Rating Scale (HDRS-21) 24 hours after treatment.
  
  
  RESULTS
  Mean duration of nitrous oxide treatment was 55.6 ± 2.5 (SD) min at a median inspiratory concentration of 44% (interquartile range, 37%-45%). In two patients, nitrous oxide treatment was briefly interrupted, and the treatment was discontinued in three patients. Depressive symptoms improved significantly at 2 hours and 24 hours after receiving nitrous oxide compared with placebo (mean HDRS-21 difference at 2 hours, -4.8 points, 95% confidence interval [CI], -1.8 to -7.8 points, p = .002; at 24 hours, -5.5 points, 95% CI, -2.5 to -8.5 points, p < .001; comparison between nitrous oxide and placebo, p < .001). Four patients (20%) had treatment response (reduction ≥50% on HDRS-21) and three patients (15%) had a full remission (HDRS-21 ≤ 7 points) after nitrous oxide compared with one patient (5%) and none after placebo (odds ratio for response, 4.0, 95% CI, .45-35.79; OR for remission, 3.0, 95% CI, .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 TRD.
authors.affiliation: Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Electronic address: nagelep@wustl.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Nagele
authors.affiliation: Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Andreas
authors.initials: A
authors.lastname: Duma
authors.affiliation: Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Michael
authors.initials: M
authors.lastname: Kopec
authors.affiliation: Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Marie Anne
authors.initials: MA
authors.lastname: Gebara
authors.affiliation: Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Alireza
authors.initials: A
authors.lastname: Parsoei
authors.affiliation: Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Marie
authors.initials: M
authors.lastname: Walker
authors.affiliation: Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Alvin
authors.initials: A
authors.lastname: Janski
authors.affiliation: Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Vassilis N
authors.initials: VN
authors.lastname: Panagopoulos
authors.affiliation: Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Pilar
authors.initials: P
authors.lastname: Cristancho
authors.affiliation: Division of Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: J Philip
authors.initials: JP
authors.lastname: Miller
authors.affiliation: Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Zorumski
authors.affiliation: Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Conway
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003863:Depression / Q000188:drug therapy; D003865:Major Depressive Disorder / Q000188:drug therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009609:Nitrous Oxide / Q000009:adverse effects / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D009609:Nitrous Oxide
keywords: Major depression; Nitrous oxide; Treatment-resistant depression