Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy.

Treatment-resistant major depression (TRMD) affects 15-30% of people with major depressive disorder. N-methyl-d-aspartate receptors (NMDARs) have become targets for treating depression, with most research focusing on ketamine, though its psychotomimetic and other side effects may limit its use. A recent pilot clinical trial tested nitrous oxide, an NMDAR antagonist that works through a different mechanism than ketamine, in patients with severe TRMD. This paper reviews TRMD as a subtype of MDD, the development of ketamine as a fast-acting antidepressant, and clinical and basic science studies supporting the possible use of nitrous oxide as a rapid antidepressant.

Study at a glance

Abstract

Major depressive disorder (MDD) remains a huge personal and societal encumbrance. Particularly burdensome is a virulent subtype of MDD, treatment resistant major depression (TMRD), which afflicts 15-30% of MDD patients. There has been recent interest in N-methyl-d-aspartate receptors (NMDARs) as targets for treatment of MDD and perhaps TMRD. To date, most pre-clinical and clinical studies have focused on ketamine, although psychotomimetic and other side effects may limit ketamine's utility. These considerations prompted a recent promising pilot clinical trial of nitrous oxide, an NMDAR antagonist that acts through a mechanism distinct from that of ketamine, in patients with severe TRMD. In this paper, we review the clinical picture of TRMD as a subtype of MDD, the evolution of ketamine as a fast-acting antidepressant, and clinical and basic science studies supporting the possible use of nitrous oxide as a rapid antidepressant.