Ketamine and esketamine can relieve depressive symptoms relatively quickly in some adults whose illness has persisted despite treatment. Their clinical value depends on what follows the initial improvement: sustained functioning, acceptable adverse effects, a workable maintenance plan and continuing psychiatric care.
Rapid response, remission and lasting recovery are different outcomes. A patient may improve substantially without becoming well, and an early response can be lost. Treatment should be judged against the person’s symptoms, daily functioning, risks and available alternatives.
On this page
Different medicines and different treatment models
Racemic ketamine contains two mirror-image molecular forms, R-ketamine and S-ketamine. Esketamine is the S form. Both act at NMDA receptors, but their formulations, routes of administration and clinical evidence differ. They are dissociative anaesthetic drugs, pharmacologically distinct from classic serotonergic psychedelics such as psilocybin. Proposed effects on synaptic plasticity do not by themselves establish how an individual patient’s depression will respond.1
| Treatment | What is being offered | Important distinction |
|---|---|---|
| Intravenous ketamine | A monitored infusion, commonly studied as a course of treatments. | Its use for depression is off-label in the UK and US; anaesthetic licensing does not establish a depression indication. |
| Intranasal esketamine | A specific licensed nasal spray administered under clinical supervision. | Evidence and authorisation apply to that product and its specified indications. |
| Ketamine-assisted psychotherapy | Drug administration combined with an explicitly described psychotherapy approach. | Evidence for the drug does not establish the added benefit of every psychotherapy package. |
These categories cannot be treated as interchangeable. Oral preparations, compounded nasal products and supervised intravenous treatment can differ in exposure and monitoring. In particular, a compounded ketamine product does not inherit the evidence or approval of Spravato, the esketamine nasal spray.23
Benefits compared with other treatments
In the ELEKT-D trial, 403 adults with treatment-resistant major depression without psychosis were randomised to ketamine or electroconvulsive therapy (ECT); 365 began their allocated treatment. After the three-week treatment phase, response occurred in 55.4% of ketamine recipients and 41.2% of ECT recipients. Response meant at least a 50% reduction on a self-report depression scale. Ketamine met the trial’s prespecified criterion for noninferiority.4
This supports ketamine as a clinically relevant option in a selected population. It does not establish that ketamine is preferable to ECT for every severe depressive illness. The study was open-label, excluded psychotic depression and evaluated particular treatment schedules. ECT was associated with a greater short-term decline in memory recall, followed by improvement during follow-up; ketamine was associated with dissociation. The choice requires attention to urgency, prior response, physical health, cognitive concerns and patient preference.
Esketamine also has evidence against an active comparator. In ESCAPE-TRD, 676 adults received either esketamine nasal spray or extended-release quetiapine, each alongside an SSRI or SNRI antidepressant. Remission at week eight occurred in 27.1% and 17.6%, respectively. The study was open-label with blinded outcome raters. Its result supports an advantage over that particular augmentation strategy under trial conditions; it does not compare esketamine with every reasonable next treatment.5
Negative findings and the limits of a rapid response
The esketamine evidence is not uniformly positive. The UK product information records Japanese and predominantly Chinese randomised studies in which the primary four-week depression outcome did not significantly separate esketamine plus an oral antidepressant from the control treatment. Differences in populations, design and placebo response may matter, but explanations offered after a negative result do not make that result disappear.6
A separate trial administered ketamine or saline during surgical anaesthesia to 40 adults with depression, substantially concealing the subjective drug experience. It found no statistically significant advantage for ketamine on depression ratings over the first three days. The small sample, surgical setting and broad confidence interval limit what can be inferred. It raises a question about context and masking; it does not overturn the full evidence from awake patients receiving repeated treatment.7
For an individual patient, a rapid mood change should therefore prompt reassessment rather than an assumption of recovery. Sleep, motivation, concentration and the ability to resume ordinary responsibilities may change at different rates. Improvement that lasts only until the next appointment has a different practical meaning from sustained recovery with manageable treatment demands.
Maintenance and relapse prevention
Maintenance evidence is particularly relevant because the initial effect may not persist. In SUSTAIN-1, patients first received esketamine with an oral antidepressant. Those who achieved stable remission or response could then be randomised to continue esketamine or switch to placebo nasal spray while continuing the antidepressant. Among stable remitters, relapse occurred in 26.7% continuing esketamine and 45.3% switched to placebo during the maintenance phase.8
This was an enriched withdrawal design: it asked about continuing treatment in people already benefiting from it. Those percentages are not the likelihood that any new patient will recover. They also do not establish a universal maintenance duration. Follow-up should address recurrence, adverse effects, treatment burden and what happens when treatment stops.
A treatment plan should specify how benefit will be measured, when insufficient response will trigger a change of approach, who will provide continuing care, and how deterioration between appointments will be managed. Travel, time away from work, accompaniment and the cumulative cost of repeated visits can influence whether an otherwise effective treatment is sustainable.
Where psychotherapy fits
Supportive clinical care, psychotherapy after an infusion, and psychotherapy organised around the altered state are different interventions. A 2026 scoping review identified 47 reports of ketamine or esketamine combined with psychotherapy for depression or depressive symptoms; only four were randomised trials. Much of the literature consisted of observational work and individual case reports. Descriptions of the psychotherapy varied considerably.1
A small study randomised 28 initial ketamine responders to cognitive behavioural therapy or treatment as usual. The primary clinician-rated outcome did not show a statistically significant group-by-time interaction, although some secondary findings favoured therapy. This was a preliminary test of sustaining improvement, not definitive evidence of an added effect.9 At present, a clinic should describe its psychotherapy method and the evidence supporting the proposed combination. Claims of necessary emotional breakthroughs or guaranteed resolution of trauma exceed what these data establish.
Safety requires active monitoring
Clinical assessment includes cardiovascular and respiratory health, psychiatric history, substance use, pregnancy considerations and other medicines. Acute effects can include dissociation, dizziness, nausea and sedation. Blood pressure may rise. The US Spravato label also warns about respiratory depression and requires observation for at least two hours, including assessment of respiratory status. Readiness to leave depends on clinical stability.10
Repeated treatment requires attention to urinary symptoms, cognition and signs of misuse. Risks reported with frequent nonmedical ketamine use cannot simply be assigned the same frequency in monitored treatment, but they cannot be ignored. Combining ketamine with sedating substances can increase risk, and unsupervised compounded products raise additional concerns about dosing and monitoring.2
Improvement in depressive symptoms should not be represented as proven prevention of suicide. The US esketamine label explicitly distinguishes its indication for depressive symptoms associated with acute suicidal thoughts or behaviour from evidence of preventing suicide or reducing suicidal behaviour. A continuing risk assessment and appropriate level of care remain necessary.10
Licensing and access in the UK and US
As checked on 11 October 2026, US labelling permits Spravato for adult treatment-resistant depression either alone or with an oral antidepressant. The UK indication for treatment-resistant depression specifies combination with an SSRI or SNRI. The UK product also has a separate short-term indication, with an oral antidepressant, for rapid reduction of depressive symptoms constituting a psychiatric emergency.106
Licensing and NHS funding are separate assessments. NICE TA854 does not recommend esketamine nasal spray for treatment-resistant depression, citing uncertainties affecting the clinical and cost-effectiveness assessment. That recommendation should not be confused with a claim that no patient can benefit, or with a prohibition on all specialist use.11
The central clinical question is whether a particular treatment offers a worthwhile, sustainable improvement for a particular patient. Reliable care connects the initial intervention with reassessment, relapse planning and access to other effective treatments when the response is insufficient.
References
- Swainson J, Grewal P, Polard S, Borle C, Gutierrez G, Zhang Y, Winkler O, Burback L, Khullar A, McIntyre RS, Brietzke E, Soares CN. A scoping review: ketamine or esketamine when used to assist psychotherapy or in combination with psychotherapy for the management of depression in adults. Npj Ment Health Res. 2026. doi:10.1038/s44184-026-00226-1.
- US Food and Drug Administration. Compounding Risk Alerts: ketamine products for psychiatric disorders. Alert dated 10 October 2023; accessed 11 October 2026.
- Oxford Health NHS Foundation Trust. Ketamine for treatment-resistant depression. Interventional Psychiatry Service; accessed 11 October 2026.
- Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. N Engl J Med. 2023;388:2315–2325. doi:10.1056/NEJMoa2302399.
- Reif A, Bitter I, Buyze J, et al. Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. N Engl J Med. 2023;389:1298–1309. doi:10.1056/NEJMoa2304145.
- Janssen-Cilag Ltd. Spravato 28 mg nasal spray, solution: Summary of Product Characteristics. UK product information, sections 4 and 5; accessed 11 October 2026.
- Lii TR, et al. Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nat Ment Health. 2023. doi:10.1038/s44220-023-00140-x.
- 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: A Randomized Clinical Trial. JAMA Psychiatry. 2019;76:893–903. doi:10.1001/jamapsychiatry.2019.1189.
- Wilkinson ST, Rhee TG, Joormann J, et al. Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial. Psychother Psychosom. 2021;90:318–327. doi:10.1159/000517074.
- Janssen Pharmaceuticals, Inc. Spravato (esketamine) US prescribing information. Revised March 2026; DailyMed updated 22 September 2026. Accessed 11 October 2026.
- National Institute for Health and Care Excellence. Esketamine nasal spray for treatment-resistant depression (TA854). Published 14 December 2022; current recommendation and review checked 11 October 2026.