Esketamine for Perioperative Neuroprotection: Clinical Evidence and Future Directions

Esketamine’s Neuroprotective Potential in Perioperative Care

Recent clinical research has identified esketamine—a potent enantiomer of ketamine—as a candidate for neuroprotection during the perioperative period. The September 2026 review published in a Tier 1 venue (OpenAlex W7213559066) synthesizes evidence on esketamine’s mechanisms and its capacity to mitigate neurological complications associated with surgery, such as ischemia-reperfusion injury, neuroinflammation, and postoperative cognitive dysfunction. While esketamine is already approved in several jurisdictions for treatment-resistant depression, its perioperative applications remain investigational and are not currently reflected in regulatory guidance or clinical protocols.

Mechanisms Underpinning Esketamine’s Neuroprotective Effects

Esketamine exerts neuroprotective effects primarily through antagonism of N-methyl-D-aspartate (NMDA) receptors, which play a central role in excitotoxicity—a key driver of neuronal injury during surgical stress. In addition, the review details esketamine’s anti-inflammatory, anti-apoptotic, and antioxidant properties, which collectively reduce neuronal damage and support recovery. Compared to racemic ketamine, esketamine demonstrates higher potency, faster onset, and a more favorable side effect profile, including milder respiratory depression and fewer neuropsychiatric adverse events. These pharmacological advantages may make esketamine particularly suitable for vulnerable surgical populations, such as older adults at risk for postoperative delirium or cognitive decline.

Clinical Evidence and Implications for Research and Practice

Current clinical data on esketamine’s perioperative neuroprotective efficacy remain limited, with most studies focusing on surrogate endpoints—such as biomarkers of neuronal injury or short-term cognitive assessments—rather than long-term functional outcomes. Nevertheless, the review underscores a growing body of preclinical and early-phase clinical studies suggesting esketamine may reduce the incidence or severity of postoperative cognitive dysfunction (POCD), especially in high-risk surgical settings. Notably, the review points to a need for well-powered, randomized controlled trials (RCTs) with robust endpoints, such as functional recovery and quality of life, to clarify esketamine’s therapeutic value in this context.

• Trial Design Considerations: The review highlights that future RCTs should stratify patients by age, comorbidities, and surgical risk, as these factors influence both neuroprotection needs and drug tolerability.
• Protocol Integration: While esketamine’s use for depression is well-established, its perioperative application would require new dosing regimens, monitoring protocols, and interdisciplinary collaboration between anesthesiology and neurology teams.
• Regulatory and Ethical Implications: As of September 2026, no regulatory agency has approved esketamine for perioperative neuroprotection, and off-label use should be approached with caution pending further evidence.

Risks, Unknowns, and Real-World Barriers

Esketamine’s safety profile is generally favorable compared to racemic ketamine, but perioperative use introduces unique risks and uncertainties. Potential adverse effects include transient hypertension, dissociation, and—rarely—emergence reactions, which may complicate postoperative monitoring. The review notes that most existing studies are underpowered to detect rare or delayed neuropsychiatric outcomes, and there is limited data on drug interactions with commonly used anesthetics and analgesics. Importantly, the review surfaces a less-discussed failure mode: the potential for esketamine to mask early signs of neurological deterioration (e.g., subtle cognitive changes or delirium), which could delay critical interventions in the postoperative setting. This underscores the need for careful patient selection and vigilant monitoring in any future trials or clinical use.

Outlook: Opportunities and Next Steps for Stakeholders

Esketamine’s emerging role in perioperative neuroprotection represents a promising but as yet unproven frontier in surgical care. The review’s synthesis may inform the design of future multicenter trials and stimulate interdisciplinary dialogue on neuroprotection protocols. For now, esketamine’s legal status and clinical access remain unchanged; its perioperative use outside of research settings is not supported by regulatory guidance. However, the field is poised for rapid evolution if forthcoming trials demonstrate clear benefit on patient-centered outcomes. Stakeholders—including researchers, clinicians, and policy makers—should prioritize transparent reporting, patient safety, and rigorous endpoint selection as the evidence base develops.

How we research: This article was reviewed by Dr. Alex Lin, MD, PhD, on 2026-09-19. Sources include the original OpenAlex review and FDA and EMA regulatory guidance as of September 2026.