Evidence by condition / Depression and treatment-resistant depression
Ketamine and esketamine (Spravato) for depression
What the trials show for esketamine nasal spray (Spravato) and intravenous ketamine in depression and treatment-resistant depression, how Spravato is given under its REMS, what it costs, and the FDA's warning on compounded ketamine.
Strength of evidenceFDA-approved
A product is approved by the US Food and Drug Administration for this use, after phase 3 trials. How we grade
- Esketamine nasal spray is FDA-approved for treatment-resistant depression after phase 3 trials, including one where it beat a newly started antidepressant alone at 28 days and one where continuing it roughly halved relapse in people who had responded. (U.S. Food and Drug Administration, Drugs@FDA, 5 Mar 2019; U.S. Food and Drug Administration, Drugs@FDA, 2026; American Journal of Psychiatry, 2019; JAMA Psychiatry, 2019)
- Intravenous racemic ketamine is not FDA-approved for depression, but a 403-patient randomised trial found it noninferior to electroconvulsive therapy for treatment-resistant depression without psychosis. (U.S. Food and Drug Administration, 10 Oct 2023; New England Journal of Medicine, 2023)
Not medical advice. This page reports what published research, regulators and drug labels say, checked 26 Oct 2026. Talk to a doctor about your own situation; nothing here is a reason to start, stop or change a treatment on your own.
What the research shows
Clinical trialAmerican Journal of Psychiatry, 2019
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
In 227 adults with treatment-resistant depression, esketamine spray plus a new antidepressant improved depression scores 4.0 points more than the antidepressant plus a placebo spray at 28 days.
Clinical trialJAMA Psychiatry, 2019
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial
Among people in stable remission on esketamine, 26.7% relapsed if they continued it and 45.3% if switched to placebo.
Clinical trialNew England Journal of Medicine, 2023
Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression
In 403 patients referred for ECT, 55.4% responded to IV ketamine and 41.2% to ECT; ECT caused a temporary dip in memory that ketamine did not.
Clinical trialAmerican Journal of Psychiatry, 2018
Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial
In 80 depressed adults with suicidal thoughts, one ketamine infusion cut suicidal ideation more than midazolam within 24 hours.
Clinical trialArchives of General Psychiatry, 2006
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression
In a placebo-controlled crossover trial of 18 adults with treatment-resistant depression, one infusion lifted mood within hours, but the effect faded for most within a week.
Clinical trialBiological Psychiatry, 2000
Antidepressant effects of ketamine in depressed patients
The first placebo-controlled trial of ketamine for depression: in 7 patients, one infusion cut depression scores within 72 hours.
Each study links to its own page with the design, size, results and limits, checked against PubMed.
Risks to know
More sedation.
The SPRAVATO label says use with CNS depressants, for example benzodiazepines, opioids and alcohol, may increase sedation, which should be closely monitored. In trials 48% to 61% of patients on Spravato developed sedation. (Janssen Pharmaceuticals, via DailyMed (US National Library of Medicine), 24 Sep 2026)
More sedation; respiratory depression has been reported with Spravato.
The SPRAVATO label says use with CNS depressants, including opioids, may increase sedation, and that respiratory depression has been observed after marketing, which is why patients are monitored for at least 2 hours after each dose. (Janssen Pharmaceuticals, via DailyMed (US National Library of Medicine), 24 Sep 2026)
May raise blood pressure; the label asks for close monitoring.
The SPRAVATO label says use with MAOIs may increase blood pressure and should be closely monitored. A 2022 review of 39 patients given ketamine with an MAOI found blood pressure and heart rate rises, clinically significant in 1 patient, and no hypertensive crisis or serotonin syndrome, but the authors say the sample was small and doses low. (Janssen Pharmaceuticals, via DailyMed (US National Library of Medicine), 24 Sep 2026; Journal of Clinical Psychiatry, Veraart JKE, Smith-Apeldoorn SY, Kutscher M, et al., 2022)
Check your medicines · Screening checklist
Lawful ways to get it
Spravato (esketamine nasal spray)FDA-approved
- The current label approves Spravato for two uses in adults: treatment-resistant depression, either on its own or with an oral antidepressant, and depressive symptoms in major depressive disorder with acute suicidal thoughts or behaviour, together with an oral antidepressant. The label states that its effectiveness in preventing suicide or reducing suicidal thoughts or behaviour has not been demonstrated, and that it is not approved for children. (U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026)
- Under the Spravato REMS, the drug may only be dispensed and given in healthcare settings certified in the programme, never taken home. A certified outpatient setting must have a prescriber on site during administration and monitoring, staff and a pulse oximeter to monitor patients, and must watch each patient for at least 2 hours for sedation, dissociation, breathing problems and changes in vital signs, then file a Patient Monitoring Form within 7 days. Outpatients are enrolled in the REMS with a healthcare provider before the first dose. (U.S. Food and Drug Administration, REMS@FDA, 24 Jun 2026; U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026)
- The FDA does not publish a list of certified Spravato treatment settings. The manufacturer's website offers a search tool for healthcare offices certified to administer Spravato and says there are about 3,000 such centres in the US; the label says the REMS programme (spravatorems.com, 1-855-382-6022) lists certified pharmacies. A patient can also ask their own psychiatrist or doctor, who may be able to offer it in their office. (Janssen Pharmaceuticals (manufacturer's website), current page; U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026; U.S. Food and Drug Administration, REMS@FDA, 24 Jun 2026)
- The label contraindicates Spravato in people with aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arteries) or an arteriovenous malformation, a history of intracerebral haemorrhage, or hypersensitivity to esketamine or ketamine. It raises blood pressure at all recommended doses, peaking about 40 minutes after a dose and lasting about 4 hours. (U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026)
Intravenous ketamine clinicsLegal, off-label
- Ketamine itself is FDA approved only as an intravenous or intramuscular anaesthetic. The FDA stated in October 2023 that ketamine is not FDA approved for the treatment of any psychiatric disorder, that it has not determined ketamine is safe and effective for depression, anxiety, PTSD or OCD, and that compounded ketamine products, including oral forms, have not been evaluated for safety, effectiveness or quality. It warned that using them without monitoring by a health care provider may put patients at risk of serious adverse events. Intravenous ketamine clinics for depression are therefore prescribing off-label. (U.S. Food and Drug Administration, 10 Oct 2023)
- Ketamine, its salts, isomers and salts of isomers are Schedule III controlled substances under federal law (21 CFR 1308.13); esketamine, sold as Spravato, is one of those isomers and its label lists it as Schedule III. (eCFR (Office of the Federal Register), current; U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026)
- The FDA lists the known safety concerns of ketamine products as abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression (slowed breathing) and lower urinary tract and bladder symptoms. (U.S. Food and Drug Administration, 10 Oct 2023)
Clinical trialsClinical trials
- A listing on ClinicalTrials.gov means the sponsor registered the study, not that the US government evaluated it. (U.S. National Library of Medicine (NIH), Oct 2023)
What it costs
- In its June 2019 final evidence report the Institute for Clinical and Economic Review (ICER) judged esketamine 'low value for money' at its announced list price of $32,400, and put a fair value-based price at $17,700 to $25,200 a year, a 25 to 52 percent discount. (Institute for Clinical and Economic Review, 20 Jun 2019)
- We found no peer-reviewed or official source for what off-label ketamine infusions cost, so we give no figure. Ask a clinic for the full price of a course in writing before you start.
- Ask any trial team whether taking part costs anything, which expenses such as travel or lodging are reimbursed, and whether your insurance covers what the research does not. (National Institute on Aging (NIH), current page)
Recruiting trials for depression and treatment-resistant depression
86 trials were recruiting on ClinicalTrials.gov on 26 Oct 2026, 49 with US sites, testing any psychedelic or ketamine; 49 of them test Ketamine. The first 3 are below; the full list, by state, is on its own page.
Phase 3Ketamine / esketamineNCT07227454
A Study to Evaluate the Efficacy and Safety of Esketamine for Reduction of Symptoms of Major Depressive Disorder (AVENUE)
- Conditions:
- Depressive Disorder, Major
- Sponsor:
- Janssen Research & Development, LLC
- Who:
- ages 12 Years to 17 Years, 258 participants planned
- Also in:
- Brazil, Hungary, Italy, Romania, Spain, Taiwan
- University of Alabama at Birmingham, Birmingham, Alabama
- Children's National Medical Center, Washington D.C., District of Columbia
- Peachford Hospital-Atlanta Behavioral Research, Atlanta, Georgia
- Endeavor Health Evanston Hospital, Evanston, Illinois
- Johns Hopkins University, Baltimore, Maryland
- Boston Childrens Hospital, Boston, Massachusetts
- and 4 more US sites on the registry record
Phase 3Ketamine / esketamineNCT07716098
A Study of Esketamine Nasal Spray Versus Placebo Spray in Adult Participants With Treatment-resistant Depression
- Conditions:
- Depressive Disorder, Treatment-Resistant
- Sponsor:
- Janssen Research & Development, LLC
- Who:
- ages 18 Years and over, 348 participants planned
- Also in:
- Japan, Taiwan
- Anderson Clinical Research, Redlands, California
- Artemis Institute for Clinical Research, San Diego, California
- Psych Atlanta, P.C., Marietta, Georgia
- Psychiatric Medicine Associates LLC, Skokie, Illinois
- Neurobehavioral Research Inc, Cedarhurst, New York
- The Medical Research Network, LLC, New York, New York
- and 1 more US site on the registry record
Phase 3Ketamine / esketamineNCT06713616
PCORI Comparative Effectiveness Study-Esketamine (Spravato) vs. Ketamine-Equivalence Study
- Conditions:
- Depression
- Sponsor:
- Yale University
- Who:
- ages 18 Years and over, 400 participants planned
- Mood Institute, Milford, Connecticut
- Yale School of Medicine, New Haven, Connecticut
- Emory University, Atlanta, Georgia
- Athena Care, Nashville, Tennessee
- Houston Center for Advanced Psychiatric Treatment, Bellaire, Texas
- Seattle NTC, Seattle, Washington