About this term
- Quick definition
- An NMDA-receptor antagonist used at low doses for treatment-resistant depression. Esketamine (Spravato) is FDA-approved as a nasal spray; intravenous racemic ketamine is used off-label in specialty clinics. Both produce antidepressant effects within hours rather than weeks.
- Full clinical definition
- Ketamine has been used as an anesthetic since the 1960s. At subanesthetic doses (roughly one-tenth the anesthetic dose), it has rapid antidepressant effects in many patients with treatment-resistant depression. Esketamine is the S-enantiomer of ketamine, formulated as a nasal spray and FDA-approved in 2019 for treatment-resistant depression and in 2020 for major depression with acute suicidal ideation. It's delivered only in certified REMS clinics with at least two hours of post-dose monitoring. Off-label intravenous racemic ketamine is delivered as a 40-minute infusion in specialty clinics, typically as a series of six infusions over two to three weeks followed by maintenance.
- Epidemiology and evidence base
- The first randomized controlled trial of intravenous ketamine in depression showed a rapid and substantial reduction in depressive symptoms within hours of a single infusion (Berman et al., Biological Psychiatry, 2000). Subsequent trials of esketamine nasal spray showed similar rapid effects and supported FDA approval (Daly et al., JAMA Psychiatry, 2018; TRANSFORM-2, Popova et al., Am J Psychiatry, 2019). Roughly 50 to 70 percent of patients with treatment-resistant depression respond to a course of esketamine or IV ketamine in published series.
- What a course can look like
- A patient with depression that hasn't responded to two antidepressants begins esketamine in a certified clinic. They self-administer the nasal spray under direct observation, then sit in a recliner for two hours while staff monitor blood pressure and dissociation. Many patients describe a brief sense of detachment or floating that resolves within an hour. Treatment is twice weekly for the first four weeks, then weekly, then every one to two weeks for maintenance. An oral antidepressant is continued throughout.
- Why the careful framing
- Ketamine produces effects very different from those of standard antidepressants: rapid onset, dissociation during the dosing window, and a need for in-clinic monitoring. It isn't a first-line treatment and isn't used in place of standard antidepressants for most patients. The misuse potential, the bladder toxicity reported with chronic high-dose recreational use, and the cost of treatment all argue for delivery in a structured clinical setting rather than at home.
- How clinicians assess it
- Screening covers prior treatment trials, cardiovascular history (because of the transient blood pressure rise during dosing), substance use history, and a check for active psychosis or uncontrolled bipolar mania. Treatment is delivered only by clinicians and clinics that meet REMS or specialty-clinic standards.
- Treatment implications
- Esketamine is FDA-approved for adults with treatment-resistant depression (after at least two failed antidepressant trials in the current episode) and for major depression with acute suicidal ideation, both used together with an oral antidepressant. Common acute side effects include dissociation, dizziness, nausea, sedation, and a transient rise in blood pressure. Most commercial insurers and Medicare cover esketamine with prior authorization. Off-label IV ketamine is rarely covered and is usually paid out of pocket.
- Related terms
- Treatment-resistant depression. ECT. TMS. Antidepressant. Active suicidal thoughts.
- Related articles
- Depression treatment, explained.
Sources
- Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000.
- Daly EJ, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018.
- Popova V, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study (TRANSFORM-2). Am J Psychiatry. 2019.
- Fu DJ, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: ASPIRE I. J Clin Psychiatry. 2020.
- McIntyre RS, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021.