Intranasal Esketamine for Treatment-Resistant Depression: Evidence and Policy Implications

Esketamine Demonstrates Rapid Efficacy in Treatment-Resistant Depression

Recent clinical evidence, as synthesized in a 2026 integrative review (OpenAlex W7221714332), shows that intranasal esketamine produces statistically and clinically significant reductions in depressive symptoms within hours for patients with treatment-resistant depression (TRD) and acute suicidal ideation. Randomized controlled trials and meta-analyses published between 2021 and 2026 consistently report improvements on the Montgomery-Åsberg Depression Rating Scale (MADRS) as early as two to four hours post-administration, with benefits persisting throughout four-week induction protocols when combined with first-line oral antidepressants. This rapid onset is particularly notable in psychiatric emergencies, where traditional monoaminergic antidepressants often require weeks to take effect.

Molecular Mechanisms Underpinning Esketamine's Effects

Esketamine's clinical impact is linked to its action as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, which initiates a cascade of glutamatergic signaling. This mechanism leads to neuroplastic changes via AMPA receptor activation, increased brain-derived neurotrophic factor (BDNF) secretion, and mammalian target of rapamycin complex 1 (mTORC1) pathway engagement. These molecular pathways are believed to underlie the rapid antidepressant and anti-suicidal effects observed in both clinical and preclinical studies. Notably, the review points out that these effects are distinct from those of conventional antidepressants, which primarily modulate monoamine neurotransmitters and have slower therapeutic onset.

Policy and Clinical Implications: Toward Acute Psychiatric Care Integration

Emerging evidence positions intranasal esketamine as a valuable tool for acute intervention in TRD and suicidal crises, with implications for clinical guidelines and access pathways. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have already approved esketamine for TRD, but the review highlights its particular utility in emergency psychiatric settings—an area where formal protocols remain underdeveloped. The need for rapid-acting interventions in emergency departments and psychiatric units is pressing, and esketamine's profile may support broader adoption and reimbursement for acute care indications.

• Clinical guidelines may evolve to recommend esketamine as a first-line intervention for acute suicidal ideation in TRD, provided that appropriate monitoring infrastructure is in place.
• Access remains uneven globally, with cost, infrastructure, and regulatory barriers impacting implementation outside major urban centers and high-income countries.
• Real-world data collection and post-marketing surveillance will be critical to refine eligibility criteria and optimize treatment protocols.

Risks, Monitoring, and Unresolved Questions

Esketamine is generally well-tolerated, but the review underscores the necessity of rigorous hemodynamic monitoring due to transient increases in blood pressure and heart rate. Adverse effects such as dissociation, nausea, and perceptual disturbances are relatively common but typically resolve within hours. Importantly, the review notes that while esketamine rapidly reduces suicidal ideation, sustained benefit requires integration with long-term maintenance therapy—highlighting a potential failure mode if follow-up care is inadequate. The risk of misuse and diversion, though lower than with some other controlled substances, remains an area of regulatory focus, especially as access expands.

Another non-obvious challenge is the potential for rapid relapse if esketamine is administered in isolation without a robust maintenance plan. This underscores the need for coordinated care pathways and careful patient selection, particularly in resource-limited settings where follow-up may be inconsistent.

Looking Ahead: Research and Implementation Priorities

Future research should focus on optimizing dosing schedules, identifying biomarkers for response prediction, and evaluating long-term safety in diverse populations. Policymakers and clinical leaders must address infrastructure and training gaps to ensure safe, equitable access to esketamine in both acute and outpatient settings. As new molecular insights emerge, there is potential for next-generation rapid-acting antidepressants with improved safety and efficacy profiles. For now, intranasal esketamine stands as a pivotal advance in the management of TRD and acute suicidality, provided its use is integrated within comprehensive, longitudinal care frameworks.

By Dr. Carolina Silva, MD, PhDReviewed by Dr. João Almeida, MD, October 2026How we research: This article synthesizes findings from peer-reviewed clinical trials, regulatory documents, and molecular studies published between 2021 and 2026, with direct reference to the integrative review cited above.