Esketamine (Spravato)
Esketamine (Spravato) is an intranasal NMDA antagonist approved for treatment-resistant depression (TRD) in adults and for MDD with acute suicidal ideation/behavior as adjunctive therapy. In 2025, FDA expanded the TRD indication to include use as monotherapy. Administration is restricted to REMS-certified settings with post-dose observation.
- Mechanism of action
- S-enantiomer of ketamine; non-selective NMDA receptor antagonist with rapid-onset antidepressant effects, partly mediated by glutamate surge and downstream AMPA signaling.
- Administration route
- Intranasal, under clinician observation in a REMS-certified setting
FDA-approved indications (2026)
Treatment-resistant depression
Adults with MDD who have not responded to ≥2 antidepressants (adjunctive or monotherapy per 2025 label update).
MDD with acute suicidal ideation/behavior
Adjunctive therapy for rapid reduction of depressive symptoms.
Dosing: adult, renal, and hepatic
| Population | Dose |
|---|---|
| Induction phase (weeks 1–4) | 56 or 84 mg intranasally twice weekly. |
| Maintenance | Weeks 5–8: once weekly. Week 9 and beyond: every 1–2 weeks based on response. |
| Hepatic impairment | No adjustment in mild. Not recommended in severe (Child-Pugh C). |
| Renal impairment | No dose adjustment. |
Contraindications and boxed warnings
Contraindications
- Aneurysmal vascular disease (thoracic, abdominal, intracranial).
- Arteriovenous malformation.
- History of intracerebral hemorrhage.
- Hypersensitivity to ketamine/esketamine.
Boxed warnings
- Sedation and dissociation — monitor post-dose at least 2 hours.
- Abuse and misuse risk — Schedule III.
- Suicidal thoughts/behaviors — standard antidepressant warning.
- Available only through a restricted REMS program.
2026 guideline and pivotal trial position
APA 2024 and ACNP 2025 treatment guidance position esketamine as a reasonable option for TRD after ≥2 failed adequate antidepressant trials, with emphasis on REMS-compliant administration, suicide-risk assessment, and pre-dose BP screening. For acute suicidality, esketamine is positioned alongside short-course ketamine protocols as rapid-acting adjuncts bridging to definitive care.
TRANSFORM-2
Esketamine + newly initiated oral AD superior to placebo + oral AD in TRD.
SUSTAIN-1
Reduced relapse with continued esketamine in TRD responders.
ASPIRE-1 / ASPIRE-2
Rapid improvement in MADRS in MDD with acute suicidal ideation.
Cross-system reasoning
Esketamine administration requires psychiatry-primary care-pharmacy coordination around REMS scheduling, post-dose observation, driving restrictions, and BP monitoring (expect transient increases). Patients with uncontrolled hypertension, vascular anomalies, or prior intracerebral hemorrhage are excluded. Substance-use disorder history warrants careful risk-benefit discussion given the Schedule III status. Interactions with benzodiazepines and opioids modify dissociative response and should guide co-prescribing.
Key references
Related clinical reading
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This reference is for US-licensed physicians and is not a substitute for the full FDA prescribing information. Dosing in special populations, drug interactions, and emerging safety information should be verified against the current manufacturer label and society guidelines before prescribing.