NITROUS OXIDE AS A THERAPEUTIC STRATEGY IN PSYCHIATRY: EVIDENCE IN TREATMENT-RESISTANT DEPRESSION AND NEUROBIOLOGICAL IMPLICATIONS

Abstract

Nitrous oxide (N₂O) is an agent with a long history in medicine, and its interest in psychiatry has recently been renewed due to advances in understanding the pathophysiology of depression, especially the role of the glutamatergic system and NMDA receptors. Treatment-resistant depression constitutes a significant clinical challenge, motivating the investigation of fast-acting therapeutic strategies, a context in which N₂O emerges as a promising alternative. The objective of this review was to critically synthesize the clinical and experimental evidence on the use of nitrous oxide in psychiatry, with an emphasis on treatment-resistant depression and its neurobiological implications. A literature review was conducted with a systematic search of international databases between 2000 and 2025, using descriptors related to nitrous oxide, psychiatry, treatment-resistant depression, and neurobiological mechanisms, including relevant clinical studies, experimental studies, and reviews. The findings indicate that N₂O, administered in subanesthetic doses, has a rapid antidepressant effect in patients with treatment-resistant depression, with an overall favorable safety profile, although with variability in the magnitude and duration of the response. The mechanisms involved appear to be multifactorial, encompassing modulation of NMDA and AMPA receptors, increased neurotrophic factors, alterations in brain connectivity, and interactions with multiple neurotransmitter systems, suggesting effects mediated by neuroplasticity processes. It is concluded that nitrous oxide represents a promising, yet still experimental, therapeutic strategy, whose definitive role in psychiatric practice depends on more robust and standardized future studies.