Abstract
There is an ongoing need to identify novel pharmacological agents for the effective treatment of depression. One emerging candidate, which has demonstrated rapid-acting antidepressant effects in treatment-resistant groups, is nitrous oxide (N(2)O)-a gas commonly used for sedation and pain management in clinical settings and with a range of pharmacological effects, including antagonism of NMDA glutamate receptors. A growing body of evidence suggests that subanaesthetic doses of N(2)O (50%) can interfere with the reconsolidation of maladaptive memories in healthy participants and across a range of disorders. Negative biases in memory play a key role in the onset, maintenance, and recurrence of depressive episodes, and the disruption of affective memory reconsolidation is one plausible mechanism through which N(2)O exerts its therapeutic effects. Understanding N(2)O's mechanisms of action may facilitate future treatment development in depression. In this narrative review, we introduce the evidence supporting an antidepressant profile of N(2)O and evaluate its clinical use compared to other treatments. With a focus on the specific memory processes that are thought to be disrupted in depression, we consider the effects of N(2)O on memory reconsolidation and propose a memory-based mechanism of N(2)O antidepressant action.