Adjunctive dopaminergic enhancement of esketamine in treatment-resistant depression.
John Cook, Angelos Halaris
Progress in Neuro-Psychopharmacology and Biological Psychiatry December 20, 2022 DOI: 10.1016/j.pnpbp.2022.110603 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Interventions | Esketamine Bupropion |
| Topics | Depression Esketamine Ketamine |
| Keywords | Dopamine N-methyl-d-aspartate Treatment resistant depression |
| Key points | Proposes that adding a dopaminergic agent such as bupropion to esketamine treatment may improve efficacy and durability of response in treatment-resistant depression. |
Abstract
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.
Comparable studies
Other theoretical and historical papers on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Esketamine and Acceptance and Commitment Therapy (ACT) for Treatment-Resistant Depression: An Intervention-Development Framework and Treatment Manual | 2026 | Theoretical or philosophical paper | |
| Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling. | 2022 | Theoretical or philosophical paper |
Citations in the library
Cited by 6
- Effect of Intraoperative Intravenous Infusion of Esketamine Combined with Dexmedetomidine on Postoperative Sleep Disturbance in Patients Undergoing Radical Mastectomy. Drug Design, Development and Therapy 2025
- Effects of subanesthetic repeated esketamine infusions on memory function and NGF in patients with depression: An open-label study. Journal of Affective Disorders January 15, 2025
- Safety Profile and Suicidality Associated with the Use of Esketamine in the Treatment of Major Depressive Disorder in European Countries: An EudraVigilance Database Analysis. Pharmaceuticals May 9, 2025
- Cardiovascular Effects of Non-Selective Monoamine Oxidase Inhibitors and Intranasal Esketamine Combination in Depression - A Quasi-Experimental Design with Bayesian Analyses. Pharmacopsychiatry June 2, 2025
- Esketamine Preserves Network Connectivity and Promotes Recovery in Consciousness Disorders. CNS Neuroscience & Therapeutics May 1, 2026
and 1 more in the library
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- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
and 13 more in the library