Systematic Review of Ketamine and Esketamine for TRD: Evidence and Implications

Ketamine and Esketamine: Systematic Review Offers Consolidated Evidence for Treatment-Resistant Depression

A systematic review published on August 30, 2026, in OpenAlex (W7205010749) synthesizes the existing published studies on ketamine and esketamine for treatment-resistant depression (TRD). This review does not introduce new clinical trial data but is significant for providing a consolidated, critical appraisal of the current evidence base, which is essential for clinicians, researchers, and policymakers navigating the rapidly evolving landscape of psychedelic-assisted therapies.

Mechanisms, Efficacy, and Safety: What the Review Reveals

The review finds that both ketamine and esketamine—an enantiomer of ketamine and the active ingredient in the FDA-approved nasal spray Spravato—demonstrate rapid-acting antidepressant effects in patients with TRD. Most included studies report a significant reduction in depressive symptoms within hours to days of administration, contrasting with the delayed onset of traditional antidepressants. The review highlights that the mechanism of action is believed to involve N-methyl-D-aspartate (NMDA) receptor antagonism, leading to downstream effects on glutamatergic signaling and synaptic plasticity, though the precise pathways remain incompletely understood.

Safety profiles are generally favorable in the short term, with the most common adverse events being dissociation, transient blood pressure increases, and mild perceptual disturbances. However, the review notes that most studies are limited to acute or short-term follow-up, and there is a paucity of data on long-term safety, dependence potential, and cognitive effects. The review also underscores that efficacy appears robust in the short term, but relapse rates are high without maintenance dosing or adjunctive therapy.

Policy and Research Implications: Shaping Guidelines and Regulatory Decisions

This systematic review is likely to influence clinical guidelines and regulatory discussions regarding the use of ketamine and esketamine in TRD. The U.S. Food and Drug Administration (FDA) approved esketamine (Spravato) for TRD in 2019, but off-label ketamine use remains under scrutiny due to the lack of large-scale, long-term randomized controlled trials. The review’s synthesis of published data may prompt regulatory agencies in other jurisdictions to reconsider their stance on ketamine and esketamine, especially as more real-world evidence accumulates.

Importantly, the review identifies several research gaps, including the need for head-to-head trials comparing ketamine and esketamine, studies on optimal dosing regimens, and investigations into long-term safety and effectiveness. A non-obvious insight highlighted is the lack of standardized outcome measures across studies, complicating meta-analyses and comparative effectiveness research—a barrier that could delay guideline harmonization and insurance reimbursement decisions.

Risks, Unknowns, and the Path Forward

Despite promising short-term efficacy, the review emphasizes that risks and unknowns remain substantial. The potential for misuse, psychological dependence, and neurocognitive side effects warrants caution, particularly in unsupervised or non-clinical settings. The review also notes that most published studies have excluded patients with comorbid substance use disorders or severe medical conditions, limiting generalizability to broader clinical populations.

Another underappreciated risk is the variability in clinical protocols, including differences in dosing, administration routes, and adjunctive psychotherapy, which may affect both efficacy and safety outcomes. This heterogeneity complicates the translation of research findings into standardized clinical practice and could lead to inconsistent patient care if not addressed in future studies and guidelines.

Looking Ahead: Consolidated Evidence as a Catalyst for Progress

The 2026 systematic review provides a critical foundation for advancing the clinical and regulatory landscape of ketamine and esketamine in TRD. By consolidating efficacy and safety data, it not only guides current clinical practice but also highlights the urgent need for harmonized research protocols, longer-term studies, and real-world data collection. Stakeholders—including clinicians, researchers, regulators, and payers—should leverage these insights to inform responsible adoption, policy development, and the design of future trials. As the field evolves, systematic reviews like this will remain essential for bridging evidence gaps and ensuring patient safety.

Reviewed by Dr. Alex M. Greene, MD, PhD (Clinical Psychiatry), August 31, 2026. Research synthesized from primary literature and regulatory sources.