Adjunctive dopaminergic enhancement of esketamine in treatment-resistant depression

Esketamine is a novel treatment for treatment resistant depression (TRD) and was approved by the FDA in early 2019. It antagonizes the NMDA receptor providing rapid improvement in symptoms with a complex mechanism of action primarily mediated through glutamatergic activation. Significant barriers exist to widespread use of esketamine including durability of response, particularly in the maintenance phase. Since it must be administered in combination with an oral antidepressant, investigating appropriate treatments to be given concomitantly may further improve outcomes and response duration. Specifically, due to dysfunction in dopaminergic pathways in many patients with MDD and TRD, addition of a prodopaminergic agent, such as bupropion, may provide additional benefit and durability of response. Historically, the addition of a dopaminergic agent to traditional treatment (e.g., SSRI, SNRI) has been shown to improve response in TRD. While we have anecdotal evidence to support adjunctive dopaminergic enhancement of esketamine response, robust data are limited. There are case reports that exhibit efficacy with the use of a MAO-I in combination with ketamine supporting at least in part a dopaminergic component. Additionally, there is mechanistic rationale for the use of dopaminergic agents with a NMDA antagonist. This includes co-localization of NMDA and dopamine receptors as well as increased glutamatergic signaling due to dopamine-induced phosphorylation of AMPAR. Recently, AXS-05, an oral combination of dextromethorphan and bupropion, has shown promise in both MDD and TRD clinical trials highlighting the potential validity of this mechanism. This paper describes how dopaminergic enhancement may increase efficacy and durability of response with esketamine, encouraging further research into this treatment option.