Mechanism
Racemic ketamine (R + S enantiomers) delivered intravenously or intramuscularly; broader receptor activity beyond NMDA, including opioid and monoaminergic effects.
S-enantiomer only (esketamine); higher NMDA-receptor affinity, delivered as an intranasal spray absorbed through nasal mucosa.
Evidence
Large off-label evidence base including meta-analyses in TRD, bipolar depression, suicidal ideation, and PTSD; not FDA-approved for psychiatric use.
FDA-approved (2019) for TRD and (2020) for depressive symptoms with acute suicidal ideation, based on pivotal Phase III trials with adjunct oral antidepressant.
Onset
Antidepressant effect often within hours after the first infusion; peaks over an induction series of 6 sessions.
Response typically within 24 hours to 1 week; induction is twice-weekly for 4 weeks per FDA label.
Duration
Days to several weeks per session; maintenance highly variable by protocol.
Structured maintenance: weekly for weeks 5–8, then every 1–2 weeks per FDA label and REMS program.
Side effects
Dissociation, transient blood-pressure elevation, nausea, dizziness; bladder toxicity is a concern only at recreational-use frequencies.
Dissociation, sedation, dizziness, nausea, blood-pressure elevation; mandatory 2-hour in-clinic monitoring after every dose per REMS.
Access
Off-label at specialty clinics; typically $400–$800 per infusion; almost never covered by insurance; wide protocol variability.
REMS-certified centers only; commonly covered by commercial insurance and Medicare with prior authorization; standardized dosing.
Best for
Patients who want protocol flexibility, do not meet TRD criteria required by Spravato, cannot access a REMS site, or have not tolerated intranasal delivery.
Patients meeting FDA TRD criteria (failure of ≥2 antidepressants), with insurance coverage, and who can commit to the twice-weekly in-clinic schedule.
Limits
Cost paid out of pocket, variable clinic quality, no standardized maintenance protocol, off-label regulatory status.
Rigid FDA-mandated schedule, 2-hour monitoring window, prior-authorization delays, must remain on an oral antidepressant per label.
