Ketamine, Esketamine, and Scopolamine in TRD: Systematic Review Insights (2026)

Systematic Review Confirms Rapid Antidepressant Effects in TRD

A 2026 systematic review published in OpenAlex (W7214062646) confirms that ketamine and esketamine offer rapid antidepressant effects for adults with treatment-resistant depression (TRD), while scopolamine remains experimental. The review, conducted under PRISMA 2020 guidelines, analyzed randomized clinical trials (RCTs) published from 2000 to September 2025, focusing on efficacy, safety, and clinical applicability of these agents. Seven RCTs met inclusion criteria: two on intravenous ketamine, three on intranasal esketamine, and two on intravenous scopolamine.

Intravenous ketamine (0.5 mg/kg over 40 minutes) produced antidepressant effects within 110 minutes, with response rates up to 70% at 24 hours, but effects typically lasted only 1–2 weeks. Intranasal esketamine (56 or 84 mg twice weekly), administered alongside oral antidepressants, significantly reduced Montgomery–Åsberg Depression Rating Scale (MADRS) scores over four weeks and lowered relapse risk (hazard ratio 0.49). Scopolamine showed some rapid effects but lacked consistency in larger samples and did not have protocol-defined TRD populations.

Mechanisms and Clinical Context: How RAADs Differ

Ketamine and esketamine, both N-methyl-D-aspartate (NMDA) receptor antagonists, are distinguished by their administration routes and regulatory status. Ketamine is typically given intravenously in research and off-label clinical settings, while esketamine, the S-enantiomer of ketamine, is approved by the U.S. Food and Drug Administration (FDA) for intranasal use in TRD (see FDA NDA 211243). Both agents act rapidly, often within hours, in contrast to traditional antidepressants, which may take weeks.

Esketamine's approval was based on evidence of both acute efficacy and relapse prevention when used as maintenance therapy. The systematic review reinforces this distinction: ketamine offers the fastest onset, while esketamine demonstrates more robust maintenance and relapse prevention data. Scopolamine, an antimuscarinic agent, has shown promise in small trials but lacks the consistency and regulatory support of the other agents. Notably, the review highlights that scopolamine trials often included broader depressive populations, complicating direct comparisons and limiting policy relevance.

Policy and Research Implications: Shaping Guidelines and Access

The review's findings are likely to influence clinical guidelines and payer decisions regarding rapid-acting antidepressants (RAADs) in TRD. Ketamine's rapid but short-lived effects may support its use in acute crisis situations, such as imminent suicide risk, but its off-label status and need for intravenous administration limit widespread adoption. Esketamine, with FDA approval and maintenance data, is poised for broader integration into TRD treatment algorithms, especially where insurance coverage aligns with regulatory indications.

For policymakers and payers, the review provides a clearer rationale for distinguishing between acute and maintenance indications. It also underscores the need for infrastructure to deliver these therapies safely, including protocols for monitoring, risk management, and integration with existing mental health services. The review's direct comparison of onset, duration, and relapse prevention is a non-obvious decision criterion that can help clinicians and health systems tailor treatment pathways based on patient acuity and resource availability.

Risks, Limitations, and Knowledge Gaps

While ketamine and esketamine are generally well-tolerated in controlled settings, the review notes several risks and limitations. Both agents can cause dissociation, transient blood pressure increases, and potential for misuse, necessitating careful patient selection and monitoring. The short duration of ketamine's effect raises questions about repeated dosing, long-term safety, and potential neurocognitive impacts—areas where data remain limited.

Scopolamine's inconsistent efficacy and lack of large-scale, protocol-defined TRD trials restrict its clinical application. The review also highlights a real-world failure mode: logistical barriers to repeated intravenous or intranasal administration, which can undermine the theoretical benefits of rapid-acting agents in under-resourced settings. Further research is needed to clarify optimal dosing schedules, maintenance strategies, and long-term outcomes, particularly in diverse populations and real-world practice.

Looking Ahead: Evolving Standards in TRD Care

The systematic review sets a new benchmark for evidence-based use of RAADs in TRD, distinguishing between agents best suited for acute versus maintenance therapy. As additional data emerge and real-world experience accumulates, clinical guidelines and payer policies are likely to evolve, potentially expanding access to these therapies for patients with few other options. Ongoing trials and post-marketing surveillance will be critical for refining risk-benefit profiles and addressing knowledge gaps, particularly around long-term safety and health system implementation.

How we research: Reviewed and synthesized by Dr. Alex Morgan, MD, PhD (psychiatry, clinical trials specialist). Reviewed by Dr. Sarah Lin, PharmD, September 2026. Sources: OpenAlex systematic review (W7214062646), FDA NDA filings, trial registries.