One in 16 young Australians is currently experiencing depressive symptoms, which underlines the significant prevalence of depressive disorders in minors [
1]. Approximately 6.3% of Australians aged between 16 and 24 years have experienced an affective disorder in the last 12 months [
1]. Selective serotonin reuptake inhibitors (SSRIs) are frequently used for the pharmacological treatment of depressive disorders. SSRIs are amongst the most frequently prescribed antidepressants and are known to increase the availability of the neurotransmitter serotonin (5-HT) in the brain, which is thought to contribute to their antidepressant effects. However, the complete mechanism of action of SSRIs is still not fully understood. In particular, the question why antidepressant effects are often observed only after a delay of several weeks into treatment, despite the fact that single doses of SSRI administration can lead to significant changes in activation of brain regions that are known to be associated with mood and emotion regulation (i.e., the amygdala, hippocampus and prefrontal cortex) [
2]. The described delay in the onset of antidepressant effects after SSRI administration can put young patients at risk for exacerbation of low mood and other associated depressive symptoms, such as self-harm or suicide. Thus, two major child and adolescent health issues are highlighted and must be urgently addressed: first, whether there is a treatment strategy that can bridge the gap between the initiation of SSRIs and observed (possibly also additional) clinical benefits, and second, the need to investigate the predictors of response to SSRI treatment, which in turn could save significant time allocated to treatments with little or no effect.
Strong biological and recent clinical evidence has suggested that nitrous oxide (N
2O) has significant antidepressant effects in adults, in particular in patients with treatment-resistant depression (TRD) [
3]. The underlying mechanism of action of N
2O is thought to be through the
N-methyl-
d-aspartate (NMDA) receptor, because N
2O serves as an antagonist of this particular receptor [
4‐
6]. Numerous animal studies and human trials have investigated the use of NMDA antagonists in targeting behaviours or symptoms that may be associated with depression. For example, in murine models, the administration of ketamine, which, like N
2O, is an NMDA antagonist and anaesthetic, showed a reduction in depression-like behaviour, such as increased mobility in the forced-swim test, shorter latencies in the novelty-suppressed feeding test and a reduction in learnt helplessness [
7,
8]. In this context, authors of a recent systematic review of studies investigating the use of ketamine to treat TRD in humans suggested it to be associated with a rapid onset of antidepressant effects [
9]. Similarly, in a trial where inhaled N
2O was administered in adults with TRD, Nagele et al. [
3], found a significant improvement in depressive symptoms as rated by the 21-item Hamilton Depression Rating Scale (HDRS) at 2 and 24 h and 1 week (in a subset of participants) following administration. These findings are significant because in the underlying neurobiology of depression, the NMDA receptor is thought to play a decisive role [
8,
10,
11]. NMDA antagonists, such as N
2O and ketamine, work by blocking the NMDA receptor, which inhibits a further inhibiting interneuron (GABAergic), resulting in a release of glutamate. Whilst the blocking of the NMDA receptor leads to this sequential effect which impacts three neurons, it has been hypothesised that the blocking of the NMDA receptor leads primarily to an almost immediate antidepressant effect [
12‐
15]. The mechanism of action of SSRIs differs from that of the NMDA antagonists, because it may take a period of weeks following administration before the desensitisation of central nervous system 5-HT receptors occurs, which has been hypothesised to lead to an increase of 5-HT within the synaptic cleft (i.e., antidepressant effect). Therefore, the use of N
2O, a safe inhalational anaesthetic, has the potential to be a novel, fast-acting and non-intrusive treatment strategy for patients with severe depressive disorders while awaiting onset of SSRI antidepressant activity. Furthermore, in the hospital setting, N
2O has been used for several decades with an excellent record with regard to safety and effectiveness.
Whilst the described mechanisms of action in depression of NMDA antagonists and SSRIs are not fully understood, animal models have shown that the administration of NMDA antagonists is associated with changes in specific brain areas which are also related to mood, such as the hippocampus and the prefrontal cortex [
16]. Most notably, such areas are also highly 5-HT-modulated areas of the brain [
4,
17]. Given the significant overlap in neurocircuits, an increase in brain function in terms of improved top-down control in mood-related neurocircuits may be used to explain any possible additive treatment effects of the administration of both N
2O and SSRIs (e.g., fluoxetine), as well as for investigating N
2O as a potential predictor of SSRI response. Whilst the significant antidepressant effects of N
2O in a cohort of adults with TRD has been shown [
3], such research questions have never been investigated in minors.