Ketamine and Esketamine for Severe Depression: Efficacy and Safety in Acute Suicidality (Brazil, 2026 Review)

Rapid-Acting Interventions for Severe Depression and Suicidality

A 2026 integrative review published in Brazil synthesizes clinical and safety outcomes for ketamine and esketamine in adults experiencing severe or treatment-resistant depression with acute suicidality. The review, which included 15 primary studies after screening 567 records, confirms that both intravenous ketamine and intranasal esketamine can produce rapid reductions in depressive symptoms and suicidal ideation—often within hours or by the first day post-administration. This rapid onset distinguishes these agents from traditional antidepressants, which typically require weeks to achieve full effect.

However, the review highlights that while initial anti-suicidal effects are robust, the evidence for sustained benefit with repeated dosing is inconsistent. For instance, one trial of repeated ketamine infusions failed to demonstrate superiority over placebo for suicidality endpoints, underscoring the need for cautious interpretation of early response data.

Mechanism of Action and Clinical Context

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and its S-enantiomer esketamine, are believed to exert antidepressant and anti-suicidal effects through modulation of glutamatergic neurotransmission and downstream synaptic plasticity. These mechanisms are distinct from those of selective serotonin reuptake inhibitors (SSRIs) and other conventional antidepressants, offering a potential pathway for rapid symptom relief in crisis situations.

In clinical practice, ketamine is most often administered intravenously in controlled settings, while esketamine is available as an intranasal spray approved in several jurisdictions for treatment-resistant depression. The review emphasizes that these interventions are intended as adjuncts in acute settings, not as substitutes for comprehensive psychiatric care, safety planning, or hospitalization when indicated.

Policy and Research Implications

The findings of this review have significant implications for clinical guidelines and regulatory policy. While ketamine and esketamine are increasingly incorporated into emergency protocols for severe depression and suicidality, the lack of consistent superiority over placebo for repeated dosing and suicidality endpoints raises questions about their optimal role in longitudinal care. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and Brazil's Agência Nacional de Vigilância Sanitária (ANVISA) have approved esketamine for treatment-resistant depression, but not specifically for acute suicidality, reflecting ongoing uncertainty about risk-benefit balance in this population.

One non-obvious insight from the review is that the rapid anti-suicidal effect may be most clinically meaningful as a bridge to longer-term interventions, rather than as a standalone solution. This positions ketamine/esketamine as crisis-phase adjuncts, potentially reducing immediate risk while comprehensive care is mobilized—a nuance sometimes overlooked in policy debates and media coverage.

Risks, Adverse Events, and Unknowns

Common adverse events associated with ketamine and esketamine include dissociation, dizziness, nausea, sedation, and transient increases in blood pressure. These effects are typically short-lived but can be distressing or medically significant in vulnerable patients. The review underscores that, despite the promise of rapid symptom relief, there is insufficient evidence to support routine or unsupervised use outside of controlled clinical environments.

Long-term safety remains a critical unknown. The review notes that repeated dosing regimens have not consistently outperformed placebo for suicidality, and there is limited data on the potential for dependence, cognitive effects, or other sequelae with chronic use. This gap in evidence highlights the importance of ongoing monitoring and research, particularly as off-label and non-clinical use of ketamine expands globally.

Looking Forward: Integrating Rapid-Response Therapies into Care Pathways

The 2026 review concludes that ketamine and esketamine represent valuable rapid-response options for selected patients with severe depression and acute suicidality, but they do not replace standard suicide prevention strategies or longitudinal psychiatric care. Future research should prioritize head-to-head trials, real-world effectiveness studies, and long-term safety monitoring to clarify their place in clinical practice.

For clinicians, policymakers, and researchers, the key challenge is to integrate these agents into evidence-based care pathways that maximize benefit while minimizing risk. As regulatory frameworks evolve and new data emerge, a cautious, data-driven approach will be essential to ensure patient safety and optimize outcomes in this high-risk population.

By Dr. Mariana Silva, MD, PhD (Universidade de São Paulo). Reviewed by Dr. Pedro Almeida, MD, MSc, on 2026-10-15. Sources: OpenAlex W7222527346; FDA esketamine label; ANVISA guidelines.