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

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.

Keywords: NMDA receptors; antidepressant; hippocampus; ketamine; metaplasticity; suicide.

Figure 1

The scheme lists symptoms of depression according to changes in brain networks underlying emotion, motivation and cognition. Sleep disturbances may reflect homeostatic corrective efforts.

Figure 2

The graph shows the age of onset of MDD in the 79 patients evaluated in the TRMD clinic. The bars show the mean age of onset of MDD in these subjects according to family history including family members with MDD and bipolar disorder (BP). This figure has been adapted and modified from data presented in Ref. (25).

Figure 3

The graph shows the number of antidepressant trials documented in 79 patients evaluated in the TRMD clinic. Based on chart review and clinical interview, all trials listed in this graph had adequate dose and duration of antidepressant treatment.

Figure 4

The list includes various effects of nitrous oxide that could contribute to antidepressant and other CNS effects. Supporting studies are described in the text.