Nitrous oxide (NO) 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 (NO) 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 NO had significant antidepressant effects, with maximum antidepressant effects observed 24 h after administration. However, the antidepressant effects of NO 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 NO administration leads to antidepressant effects in adolescents with depression at 24 h, (2) determine whether combined NO and SSRI administration (commenced after NO 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 NO 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 NO 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 NO 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 NO compared with placebo at 24 h after administration. Additionally, we expect that subjects treated with NO 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.