Ketamine and esketamine (Spravato) for depression: state of practice

Two options in practice

Spravato (esketamine nasal spray):

• FDA-approved 2019 for TRD, 2020 for MDD with acute suicidality
• 56 or 84 mg twice weekly for weeks 1 to 4, then weekly weeks 5 to 8, then every 1 to 2 weeks maintenance
• Requires REMS-certified clinic with 2-hour monitoring post-dose
• Not driving for 24 hours after dose
• Costs $600 to $800 per dose plus clinic fees
• Insurance coverage improved but PA usually required
• Continues alongside oral antidepressant

IV ketamine:

• Off-label but standard of practice in dedicated ketamine clinics
• 0.5 mg/kg IV over 40 minutes typical starting dose
• Twice weekly for 2 weeks common induction
• Then weekly, biweekly, monthly maintenance
• Not covered by insurance in most cases; $400 to $800 per infusion
• Broader adoption in academic and community psychiatric practice

Mechanism and time course

NMDA receptor antagonism produces rapid glutamate surge, then downstream BDNF signaling, synaptogenesis, and long-term potentiation. Effect appears within hours (subjective mood shift) with peak effect around 24 hours. Duration typically 3 to 7 days after single dose. Repeated dosing extends effect.

Ketamine also acts on opioid receptors, sigma receptors, monoaminergic systems, and glutamate AMPA receptors, contributing to full effect.

Evidence base

Esketamine trials (Spravato):

• TRANSFORM-1, TRANSFORM-2, TRANSFORM-3: efficacy in TRD
• SUSTAIN-1: durability
• Effect size vs placebo modest but meaningful given TRD population

IV ketamine trials:

• Multiple RCTs support rapid antidepressant effect
• Larsen 2013 meta-analysis
• Sanacora 2017 practice guidelines
• Effect sizes larger than most conventional antidepressants for rapid response

Where these fit vs alternatives

Vs Auvelity (dextromethorphan-bupropion):

• Same broad NMDA-modulating family
• Auvelity is oral, outpatient, non-controlled
• Ketamine and esketamine are more effective and faster but require clinic infrastructure
• See our Auvelity state of practice

Vs ECT:

• Ketamine and esketamine often preferred as less invasive
• ECT remains gold standard for severe TRD, catatonia, and pregnancy
• Trials comparing ketamine and ECT show mixed results

Vs new atypical antidepressants (Auvelity, brexanolone/zuranolone):

• Different mechanisms
• Complementary rather than competing options

Where NOT to use

• Untreated psychosis (dissociative effects can worsen)
• Uncontrolled hypertension or heart disease
• Recent MI or unstable angina
• Substance use disorder (though evidence is evolving; some data suggests it can help)
• History of severe adverse reaction

Practical considerations

Access: Growing but still uneven. Major metro areas have multiple clinics. Rural areas underserved.

Insurance: Spravato coverage improved substantially since 2020. IV ketamine remains largely cash-pay.

Ongoing treatment: Most protocols require weekly to monthly maintenance for durable response. Discontinuation often produces relapse within weeks.

Common questions

Is ketamine addictive? Physical dependence is minimal at therapeutic doses used for depression. Psychological attachment can develop. Standard clinical use with intermittent dosing minimizes these concerns. Ketamine has recreational use potential separate from depression treatment.

How long does ketamine effect last? Single dose: 3 to 7 days typically. Repeated dosing: durable response can extend weeks to months. Most patients need maintenance dosing.

Is Spravato better than IV ketamine? No head-to-head trials. Effect sizes appear similar. Spravato has FDA approval, insurance coverage advantage, and REMS structure. IV ketamine has more established clinical experience and often lower per-dose cost.

Can Spravato be combined with other antidepressants? Yes, and this is standard. Spravato is used as an adjunct to an oral antidepressant, not as monotherapy.

Does insurance cover Spravato? Increasingly yes with prior authorization documenting TRD (2+ failed adequate antidepressant trials). Medicare Part B often covers.

Is there a home ketamine option? Compounded oral or nasal ketamine is offered by some telehealth companies. Not FDA-approved, not standardized, and increasingly subject to regulatory scrutiny. Standard of practice is clinic-based administration.

What are the psychedelic effects like? Mild to moderate dissociation for 30 to 60 minutes after dose. Typically described as floating, disconnected, or altered perception. Some patients find pleasant; some find distressing. Effect predicts antidepressant response somewhat but is not required.

Can it be used for PTSD or anxiety? Emerging evidence. IV ketamine for PTSD has trial data. Ketamine for anxiety has less established evidence. Off-label uses common but effect less predictable than for depression.

Sources

• Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: TRANSFORM-2. Am J Psychiatry. 2019;176(6):428-438.
• Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: SUSTAIN-1. JAMA Psychiatry. 2019;76(9):893-903.
• Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405.
• Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150-158.
• Spravato (esketamine) prescribing information. Janssen Pharmaceuticals; approved March 2019.