Nitrous oxide (N(2)O) and subsequent open-label SSRI treatment of adolescents with depression (NOTAD): study protocol for a randomised controlled trial

BACKGROUND: The first line of pharmacological treatment for severe depressive disorders in young people is selective serotonin reuptake inhibitors (SSRIs). However, beneficial clinical effects are rarely observed before several weeks into treatment. Nitrous oxide (N(2)O) has a long-standing safety record for pain relief and has been used in adults and young people. In adults with severe treatment-resistant depression, a single dose of N(2)O had significant antidepressant effects, with maximum antidepressant effects observed 24 h after administration. However, the antidepressant effects of N(2)O have never been investigated in adolescents with a confirmed diagnosis of depression in a prospective trial. The aims of this study are to (1) investigate whether a single inhaled N(2)O administration leads to antidepressant effects in adolescents with depression at 24 h, (2) determine whether combined N(2)O and SSRI administration (commenced after N(2)O intervention) provides a clinically significant improvement in mood over and above the benefits from SSRI administration alone, and, (3) investigate whether the effect seen following N(2)O administration can be used as a predictor of SSRI treatment response. METHODS/DESIGN: In this study, we will use a single-blind, randomised, placebo-controlled design. Patients aged between 12 and 17 years with major depressive disorder will be recruited. This study will consist of two phases: phase A and phase B. During phase A, participants will be randomised to receive either inhaled N(2)O or placebo (air) for 1 h. In phase B, participants will receive open-label pharmacological treatment with the SSRI fluoxetine and will be followed over a 12-week period. Participants will undertake mood assessments at 2 and 24 h after N(2)O or placebo administration (phase A) and weekly during the 12-week follow up in phase B. DISCUSSION: We expect an antidepressant effect from a single dose of inhaled N(2)O compared with placebo at 24 h after administration. Additionally, we expect that subjects treated with N(2)O will also show greater improvements than the placebo group after 6 and 12 weeks into fluoxetine treatment because of potential additive antidepressant effects. Such findings would be of clinical importance because currently children and adolescents often do not experience any symptom alleviation for several weeks following the initiation of SSRIs. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12616001568404. Registered on 14 November 2016. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-017-2342-4) contains supplementary material, which is available to authorized users.