Ketamine and Esketamine for Suicidal Ideation: Clinical Evidence and Challenges (US, 2026)

Review Finds Inconsistent Acute Effects on Suicidal Ideation

A comprehensive narrative review published in September 2026 synthesizes two decades of clinical research on ketamine and esketamine for the rapid reduction of suicidal ideation in adults with depressive disorders. The review, accessible via OpenAlex, finds that while intravenous (IV) ketamine may reduce suicidal thoughts within 24 hours for some patients, results are inconsistent across studies. Intranasal esketamine, approved by the US Food and Drug Administration (FDA) in 2019 for treatment-resistant depression, demonstrates clearer benefits for depressive symptoms but not for suicidality-specific outcomes within the same timeframe.

Key trials cited include a midazolam-controlled study where IV ketamine achieved a 4.96-point greater reduction on the Scale for Suicide Ideation at 24 hours, contrasted with another trial showing no significant difference on the Beck Scale for Suicide Ideation. For esketamine, the pivotal ASPIRE I and II trials (NCT03039192, NCT03097133) found improvement in depressive symptoms but not in clinician-rated suicidality at the 24-hour mark.

Mechanisms, Routes of Administration, and Measurement Challenges

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, is hypothesized to exert rapid antidepressant and anti-suicidal effects through glutamatergic modulation and downstream neuroplasticity. Esketamine, the S-enantiomer of ketamine, is delivered intranasally and shares similar pharmacodynamics but differs in bioavailability and onset.

The review highlights that variability in findings may stem from differences in patient populations, psychiatric comorbidities, baseline suicidality, dosing regimens, and—critically—outcome measures. Trials have used different scales (e.g., Beck Scale for Suicide Ideation, Scale for Suicide Ideation, clinician global ratings), often with limited consensus on what constitutes a meaningful change. This lack of standardization complicates both clinical interpretation and regulatory evaluation.

Policy, Clinical, and Research Implications

The inconsistent evidence base has direct implications for clinical practice and regulatory guidance. While the FDA approved intranasal esketamine for treatment-resistant depression, it did not grant a specific indication for acute suicidality, reflecting the equivocal trial results. The Centers for Medicare & Medicaid Services (CMS) and private insurers have followed suit, generally reimbursing esketamine for depression but not for suicidality per se.

For clinicians, the review underscores the importance of cautious, individualized risk-benefit assessment when considering ketamine or esketamine for patients with acute suicidal ideation. The absence of robust, standardized outcome measures and the short duration of most studies (typically 24-72 hours) limit confidence in generalizing results to routine care or policy.

• Non-obvious insight: The review notes that in some real-world settings, rapid reductions in suicidality observed in research clinics have not always translated to community practice, possibly due to differences in support systems, comorbidity management, and post-treatment follow-up—an aspect rarely addressed in prior syntheses.

Risks, Unknowns, and the Need for Standardization

Both ketamine and esketamine carry risks, including dissociation, transient blood pressure increases, and potential for misuse or dependence. The review emphasizes that most trials exclude patients with substance use disorders or unstable medical conditions, limiting generalizability to higher-risk populations.

Unknowns remain regarding the durability of anti-suicidal effects, optimal dosing schedules, and the impact of repeated administration. Notably, the review calls for longer-term follow-up and harmonized outcome measures, such as the Columbia-Suicide Severity Rating Scale (C-SSRS), to enable more reliable cross-study comparisons and meta-analyses.

Looking Ahead: Research and Regulatory Priorities

Future research should prioritize head-to-head trials of IV ketamine versus intranasal esketamine, standardized suicidality endpoints, and real-world effectiveness studies in diverse clinical settings. Regulatory agencies such as the FDA and European Medicines Agency (EMA) may consider requiring more granular suicidality data in forthcoming trials, particularly as new NMDA modulators and psychedelic compounds enter the pipeline.

For now, the acute anti-suicidal efficacy of ketamine and esketamine remains an area of active investigation, with substantial uncertainty for clinicians, patients, and policymakers. The field’s next advances will likely depend on collaborative efforts to standardize measurement, extend follow-up, and address the translational gap between research and real-world care.

By Dr. Alex M. Carter, MD, PhD (psychiatry and clinical trials methodology). Reviewed by Dr. Jamie Lin, PharmD, on 2026-09-12. Sources: FDA, ClinicalTrials.gov, OpenAlex review W7212364968.