Esketamine (Spravato)

Class

NMDA receptor antagonist (S-enantiomer of ketamine)

Mechanism

Noncompetitive NMDA receptor antagonist leading to rapid glutamatergic modulation and synaptic plasticity enhancement, which may underlie its rapid antidepressant effects

FDA-Approved Use

Treatment-resistant depression (TRD); depressive symptoms in major depressive disorder (MDD) with acute suicidal ideation or behavior

Off-Label Use

Augmentation in treatment-resistant bipolar depression; adjunctive treatment in other mood disorders

Formulation

Intranasal spray

Titration

56 mg intranasally 1–2 times weekly during induction, titrated to 84 mg as tolerated; maintenance dosing typically weekly to biweekly

Dose Range

56–84 mg intranasally per administration

Kinetics

Rapid absorption intranasally with peak plasma concentration within 20–40 minutes; short half-life (~7–12 hours)

Common AEs

Dissociation, dizziness, nausea, sedation, increased blood pressure, headache

Serious/Rare AEs

Potential for abuse; hypertension; sedation-related falls

Monitoring

Administer only in certified REMS clinics; monitor blood pressure and mental status for at least 2 hours post-dose

Black Box Warning

Risk of sedation and dissociation; potential for abuse and misuse

Considerations

Limited evidence for use in traumatic brain injury (TBI) and neurodegenerative disorders; caution advised due to risk of sedation and blood pressure fluctuations. Avoid in patients with uncontrolled hypertension, significant cardiovascular disease, or aneurysmal vascular disease. Use cautiously in elderly patients given increased sensitivity to sedation and cardiovascular effects.