No consensus definition of treatment-resistant depression exists. Esketamine nasal spray won FDA approval in 2019, and psilocybin is not approved.
The treatment-resistant depression options on our record are one approved medicine, esketamine nasal spray, and one investigational drug, psilocybin. We read a definition review, the Food and Drug Administration (FDA) approval release and two clinical trials on October 13, 2026. Other options a clinician may raise sit outside those sources, so this page names them without rating them.
Treatment-resistant depression (TRD) has no single agreed definition, according to a 2020 review in Depression and Anxiety. The review was prepared for the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality, and it searched trials through July 5, 2019. It found that "no consensus definition existed for TRD."
For major depressive disorder, the most common definition required at least two prior treatment failures. It also required confirmation that each treatment was given at an adequate dose for an adequate duration. For bipolar disorder, the most common definition required one prior failure.
The review found no clear agreement on what counts as an adequate dose or an adequate duration. Only 17% of intervention studies enrolled samples that met the most frequently specified criteria. Read each trial's own definition before comparing results.
The FDA's March 2019 Spravato release uses similar wording. It describes TRD as major depressive disorder that has not responded to at least two antidepressant treatments at adequate doses for an adequate duration in the current episode.
Against that definition, this page covers two options. Esketamine nasal spray is FDA approved for use with an oral antidepressant in restricted settings, and psilocybin was tested in a phase 2 trial and is not approved. Choosing among them, and among options this page does not review, is a decision for a clinician.
Esketamine nasal spray, brand name Spravato, is the only option on this page with FDA approval. The FDA release of March 5, 2019 approved it "for the treatment of depression in adults who have tried other antidepressant medicines but have not benefited from them." The approval is for use in conjunction with an oral antidepressant.
Spravato is "only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS)." A health care provider must monitor the patient for at least two hours after each dose. The release headline says it is available only at a certified doctor's office or clinic.
The boxed warning on Spravato covers three risks: sedation and dissociation, abuse and misuse, and suicidal thoughts and behaviors.
The FDA evaluated efficacy in three short-term trials lasting four weeks and one longer-term trial of maintenance of effect. Only one of the three short-term trials met its statistical test against placebo.
One phase 3 trial, by Popova and colleagues in the American Journal of Psychiatry in 2019, ran at 39 outpatient centers. It enrolled adults with moderate to severe nonpsychotic depression who had not responded to at least two antidepressants in the current episode. Of 227 patients randomized, 197 completed the 28-day double-blind phase.
Every patient in that trial started a new oral antidepressant, and the comparison was esketamine spray against a placebo spray. At day 28, the esketamine group's Montgomery-Åsberg Depression Rating Scale (MADRS) score improved by more, with a difference of least squares means of -4.0 (95% confidence interval, or CI, -7.31 to -0.64).
Dissociation, nausea, vertigo, dysgeusia (altered taste) and dizziness were the five most common adverse events, and all five were more frequent with esketamine. Study drug was stopped because of an adverse event by 7% of the esketamine arm and 0.9% of the comparison arm. The events generally appeared shortly after dosing and resolved by 1.5 hours after dosing.
The trial abstract opens by noting that about one-third of patients with depression do not reach remission despite multiple antidepressants. This page reports the March 2019 release; labeling may have changed since, and later changes to Spravato labeling are not on our record. Our Spravato vs ketamine guide compares the two drugs.
Psilocybin is investigational for treatment-resistant depression and is not approved. The evidence on our record is one phase 2 double-blind trial by Goodwin and colleagues, published in the New England Journal of Medicine in 2022. The trial was funded by COMPASS Pathfinder.
Adults with TRD received one dose of a synthetic psilocybin formulation along with psychological support. The trial had three groups: 79 people at 25 mg, 75 at 10 mg and 79 at 1 mg, with the 1 mg group serving as the control. That adds up to 233 participants.
At week 3, the least-squares mean change in MADRS score was -12.0 at 25 mg, -7.9 at 10 mg and -5.4 at 1 mg. The 25 mg group differed from the 1 mg group by -6.6 (95% CI -10.2 to -2.9; P<0.001). The 10 mg group differed from the 1 mg group by -2.5 (95% CI -6.2 to 1.2; P=0.18), and that interval includes zero.
The authors described response and remission at week 3 in the 25 mg group as generally supportive. Sustained response at 12 weeks did not support the 25 mg dose.
Adverse events occurred in 179 of 233 participants, or 77%, and included headache, nausea and dizziness. The authors reported that "suicidal ideation or behavior or self-injury occurred in all dose groups."
The authors concluded that larger and longer trials are required, including comparison with existing treatments. Psilocybin and psilocyn are listed in federal Schedule I under codes 7437 and 7438 in Title 21 of the Code of Federal Regulations (21 CFR 1308.11). Our psilocybin for depression guide covers the trials and the law in more detail.
Options a clinician may discuss also include other medication strategies, psychotherapy and brain-stimulation treatments, which this page does not review. The sources behind this page do not report results for them, so we give no efficacy figures here.
For this site's own coverage, ketamine vs ECT compares ketamine with electroconvulsive therapy (ECT), and ketamine vs TMS compares ketamine with transcranial magnetic stimulation (TMS). Our SSRI alternatives guide looks at options beyond selective serotonin reuptake inhibitors (SSRIs). Our psilocybin vs antidepressants guide compares psilocybin with standard antidepressants.
Esketamine nasal spray is the legal prescription option on our record, given only at a certified doctor's office or clinic under the REMS. Our Spravato cost with insurance guide covers payment questions.
Psilocybin is a federal Schedule I substance, and legal access to it for depression on our record runs through clinical trials. Oregon, under Measure 109, and Colorado, under Proposition 122, allow adult access at state-regulated service centers. Those service centers are not depression treatment programs.
For state-by-state status, use our legal status by state tool. Our guide to whether psilocybin is legal in the US covers the federal picture. This site gives no sourcing advice for psilocybin or ketamine.
Bring a list of every antidepressant you have taken, with the dose and how long you took it. The most common TRD definition depends on two failures at adequate dose and duration, and the FDA wording ties those failures to the current episode. Ask whether your history meets that definition.
Ask whether Spravato fits your situation and which oral antidepressant it would be paired with. Ask which certified clinic near you offers it under the REMS. Ask how the two-hour monitoring period after each dose would fit your schedule and your trip home.
Ask how the clinic watches for the boxed-warning risks of sedation, dissociation, abuse, misuse and suicidal thoughts. Ask whether a psilocybin clinical trial is open to you, and how that trial defines TRD.
If you are in crisis now, go to our crisis resources page.
This page is not for readers looking for doses, preparation steps or a way to obtain psilocybin or ketamine, and it gives none. The legal routes on our record are a Spravato prescription in a REMS-certified setting or enrollment in a clinical trial.
Our answer would change if the FDA approved psilocybin for depression, or if larger and longer trials reported a response that held at 12 weeks. A change to Spravato labeling after March 2019 would also change the esketamine section.
For ketamine more broadly, read our ketamine guide. To find studies testing treatment-resistant depression options, search with our clinical trial finder.
The most common definition describes major depressive disorder that has not responded to at least two prior treatments, each given at an adequate dose for an adequate duration. The FDA's 2019 Spravato release uses similar wording and ties the failures to the current episode. A 2020 review found no consensus definition.
No. A 2020 review for the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality found that no consensus definition existed for TRD. It also found no clear agreement on adequate dose or duration. Only 17% of intervention studies enrolled samples meeting the most frequently specified criteria.
The FDA approved Spravato nasal spray on March 5, 2019, for depression in adults who have tried other antidepressant medicines without benefit. It is used together with an oral antidepressant and is available only through a restricted REMS system, with at least two hours of monitoring after each dose. Later labeling changes are not on our record.
No. Psilocybin is investigational, and the trial on our record is a 2022 phase 2 study. Psilocybin and psilocyn are listed in federal Schedule I under codes 7437 and 7438.
At week 3, a single 25 mg dose with psychological support lowered MADRS scores by 6.6 points more than a 1 mg control, while the 10 mg difference of 2.5 points had a P value of 0.18. Sustained response at 12 weeks did not support the 25 mg dose. Adverse events occurred in 77% of participants, and suicidal ideation or behavior or self-injury occurred in all dose groups. The authors called for larger and longer trials, including comparison with existing treatments.
Esketamine nasal spray (Spravato) is available by prescription at certified clinics under the REMS, used with an oral antidepressant. Psilocybin is Schedule I federally, and legal access for depression on our record runs through clinical trials. Oregon and Colorado allow adult psilocybin access at state-regulated service centers, which are not depression treatment programs. This site gives no sourcing advice.
Use the clinical trial finder on this site at /tools/find-clinical-trial to search for depression studies. Ask each trial team how it defines treatment-resistant depression, because the 2020 review found no consensus definition across studies.
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