Esketamine for Treatment-Resistant Depression

What patients considering esketamine treatment should know about its history, benefits, treatment schedule, side effects, and long-term outlook

For people whose depression has not improved after several standard treatments, esketamine can offer a different path. Sold in the United States as SPRAVATO, esketamine is a prescription nasal spray used in a certified medical setting. It works through the brain’s glutamate system rather than relying primarily on serotonin or norepinephrine, and some patients experience meaningful improvement much sooner than they did with conventional antidepressants.

Esketamine is not a first-line treatment, a take-home medication, or a guaranteed cure. It is a structured course of care that requires careful screening, monitored treatment visits, and an ongoing plan to protect recovery. This overview explains where esketamine came from, who may be a good candidate, what treatment is like, and what current research says about benefits and risks.

When did esketamine enter the market

The US Food and Drug Administration approved SPRAVATO in March 2019 for adults with treatment-resistant depression, initially in combination with an oral antidepressant. Treatment-resistant depression generally means that a person has not had an adequate response to at least two antidepressant treatments of sufficient dose and duration during the current depressive episode.

In August 2020, the FDA added an indication for depressive symptoms in adults with major depressive disorder who have acute suicidal ideation or behavior, again with an oral antidepressant. This indication is important but sometimes misunderstood: improvement in depressive symptoms does not mean esketamine has been proven to prevent suicide or eliminate suicidal thoughts. Emergency assessment, hospitalization when appropriate, and a comprehensive safety plan remain essential.

In January 2025, the FDA expanded the treatment-resistant depression indication so that SPRAVATO could be used either by itself or together with an oral antidepressant. That change gives clinicians more flexibility, including for patients who cannot tolerate or do not want to continue a daily oral antidepressant.

How is esketamine used

Esketamine is self-administered as a nasal spray while a healthcare professional supervises. It cannot be taken home. Because it can temporarily cause sedation, dissociation, breathing problems, and increases in blood pressure, the patient remains under observation for at least two hours after each dose. Patients need a ride home and should not drive, operate machinery, or do anything requiring full alertness until the next day after a restful sleep.

The schedule may differ for the short-term indication involving acute suicidal ideation or behavior. Treatment frequency should always be decided by the prescribing clinician based on response, tolerability, medical history, and the approved labeling.

How has esketamine helped patients

Clinical trials show that esketamine can reduce depressive symptoms in some patients who have not improved with standard medications. The change may begin within a day for some people, although clinicians usually judge the initial course over several weeks rather than after one visit. Benefits can include lower symptom severity, improved functioning, and a better chance of reaching response or remission.

The evidence also shows that treatment does not work for everyone. In a major 32-week study comparing esketamine nasal spray with extended-release quetiapine, both added to a continuing antidepressant, 27.1% of patients assigned to esketamine were in remission at week 8 compared with 17.6% assigned to quetiapine. The esketamine group also had better outcomes through week 32. These are group averages, not a promise of what any individual patient will experience.

For patients who respond, continuing treatment can reduce the risk of relapse. In a randomized maintenance study, patients who continued esketamine plus an oral antidepressant relapsed less often than patients switched to placebo nasal spray while continuing the oral antidepressant. This finding helps explain why esketamine is often planned as induction followed by individualized maintenance rather than as a brief one-time intervention.

Who may be a good fit

A strong candidate is usually an adult with a confirmed diagnosis of major depressive disorder whose current episode has not improved enough after at least two appropriately selected and adequately tried antidepressants. A good fit is also someone who can attend repeated clinic visits, arrange transportation, tolerate a two-hour monitoring period, and participate in follow-up care.

Esketamine may be especially worth discussing when depression remains severe, functioning is substantially impaired, or conventional treatments have caused unacceptable side effects. The decision should still be individualized. A clinician will review the accuracy of the diagnosis, prior medication doses and durations, psychotherapy history, bipolar or psychotic symptoms, substance-use history, blood pressure and cardiovascular risk, pregnancy considerations, and practical barriers such as transportation and insurance requirements.

Who may need another approach

Esketamine is contraindicated in people for whom a rise in blood pressure or intracranial pressure poses a serious risk, including certain aneurysmal vascular disorders, arteriovenous malformation, or a history of intracerebral hemorrhage. It may also be unsuitable or require additional caution for people with uncontrolled hypertension, significant cardiovascular or cerebrovascular disease, active psychosis, serious substance-use concerns, pregnancy, or an inability to comply with monitored visits.

Screening matters because symptoms that look like unipolar depression can occur in bipolar disorder, substance-induced conditions, trauma-related disorders, medical illness, or medication effects. Esketamine should be one part of a complete psychiatric evaluation, not a shortcut around one.

What side effects can occur

Most side effects occur around the treatment session, peak during the observation period, and improve the same day. In the FDA clinical-trial data for treatment-resistant depression using esketamine with an oral antidepressant, common reactions included dissociation in about 41% of patients, dizziness in 29%, nausea in 28%, sedation in 23%, vertigo in 23%, reduced sensation or numbness in 18%, anxiety in 13%, lethargy in 11%, increased blood pressure in 10%, and vomiting in 9%. Rates vary by study, indication, dose, and whether esketamine is used alone or with another antidepressant.

These percentages overlap. One patient may report more than one effect, so they cannot be added together to calculate the percentage of people who experience any side effect. The most honest summary is that temporary treatment-day effects are common, while serious complications are much less common and are the reason dosing occurs only in a certified, monitored setting.

Important risks and monitoring

• Sedation and impaired alertness. Some patients become very sleepy; rare cases of reduced consciousness have occurred.
• Dissociation. A temporary sense of detachment, altered perception, or feeling disconnected from oneself or the surroundings can occur.
• Blood pressure increases. Blood pressure is checked before dosing and again afterward; clinically significant increases may require longer monitoring or medical evaluation.
• Respiratory depression. Breathing and oxygen saturation are monitored during treatment because post-marketing cases have been reported.
• Abuse and misuse. Esketamine is a Schedule III controlled substance. Patients with a substance-use history require careful risk assessment and monitoring.
• Worsening mood or suicidal thoughts. As with other antidepressant treatment, clinicians monitor for clinical worsening and emerging suicidal thinking, particularly in younger adults and during treatment changes.

What do we know about long-term consequences

Long-term evidence is reassuring but not complete. The final SUSTAIN-3 extension study followed more than 1,100 participants who had entered through earlier esketamine trials. Median exposure was about 46 months, and some patients were treated for as long as 79 months. Depression improvement was generally maintained among continuing participants, and investigators reported no new safety signal. The most common adverse events across long-term follow-up included headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis.

However, SUSTAIN-3 was open-label and included people who had already participated in esketamine studies. Patients who benefited and tolerated treatment were more likely to remain, so the results cannot tell us exactly how every new patient will fare over many years. Continued surveillance is important.

Current therapeutic-dose studies have not shown the same pattern of bladder injury or progressive cognitive impairment associated with heavy, repeated illicit ketamine misuse. Even so, clinicians should ask about urinary symptoms, cognition, liver concerns, tolerance, cravings, and changes in effectiveness during long-term care. The safest conclusion is that supervised esketamine has an increasingly substantial multi-year safety record, but it is not yet a medication with decades of depression-treatment data.

What is the prognosis

Prognosis varies. Some patients do not respond during the first month. Others improve but need ongoing weekly or every-other-week treatment to stay well. A smaller group may remain stable while gradually spacing treatments, and some eventually discontinue. Stopping after a good response can be followed by relapse, especially in people with recurrent or severe treatment-resistant depression, so discontinuation should be planned rather than abrupt or driven only by a temporary improvement.

The best outlook usually comes from combining medication management with psychotherapy, sleep and substance-use assessment, treatment of medical contributors, social support, and a written relapse-prevention plan. Progress should be measured with both symptom scales and real-life goals such as returning to work, reconnecting with family, restoring daily routines, or regaining interest and motivation.

Questions to ask before starting

• Have my previous antidepressant trials been adequate in dose and duration?
• What improvement should we look for, and when will we decide whether treatment is working?
• How will blood pressure, sedation, dissociation, and breathing be monitored?
• What is the plan if I improve, and how long might maintenance treatment continue?
• Which costs are covered, and what transportation arrangements will I need?
• What should I do if my depression or suicidal thoughts worsen between visits?

The bottom line

Esketamine changed depression care by offering a rapid-acting, glutamate-based option for adults who have not benefited enough from conventional antidepressants. For a carefully selected patient, it may reduce symptoms, restore functioning, and help maintain recovery. It also requires a serious commitment to supervised dosing, monitoring, and long-term planning. A consultation with a qualified psychiatric clinician can determine whether the potential benefits outweigh the risks for a particular person.

If you or someone you know is in immediate danger or may act on suicidal thoughts, call 911 or go to the nearest emergency department. In the United States, call or text 988 for the Suicide and Crisis Lifeline.

Medical disclaimer

This article is for general education and does not provide medical advice, diagnosis, or treatment. Indications, contraindications, and dosing can change. Decisions about esketamine should be made with a licensed clinician using the current FDA prescribing information and the patient’s individual medical history.

References

1. SPRAVATO (esketamine) nasal spray full prescribing information. Janssen Pharmaceuticals, Inc. Prescribing information.
2. National Library of Medicine. DailyMed drug label for SPRAVATO esketamine hydrochloride nasal spray.
3. Reif A, et al. Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. New England Journal of Medicine. 2023;389:1298-1309. DOI.
4. Daly EJ, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression. JAMA Psychiatry. 2019;76:893-903. DOI.
5. Zaki N, et al. Long-term safety and maintenance of response with esketamine nasal spray in participants with treatment-resistant depression. Neuropsychopharmacology. 2023;48:1225-1233. DOI.
6. Final SUSTAIN-3 report. Safety and efficacy with esketamine in treatment-resistant depression after long-term use. 2025. Full text.