Published on 2 October 2026
Esketamine in treatment-resistant depression: what is known about its effects on work and social life, beyond symptoms?
The essentials
This systematic review set out to find the functional effects of intravenous ketamine and intranasal esketamine in adults with major depressive disorder or treatment-resistant depression. It included only 9 studies, all on esketamine in treatment-resistant depression: no controlled study of ketamine met the inclusion criteria. The outcomes measured are functional impairment (Sheehan Disability Scale, SDS) and work productivity (WPAI). Against placebo, the benefit on the SDS is significant in TRANSFORM-2 but not in three other studies; against extended-release quetiapine, productivity loss is smaller with esketamine over 32 weeks. The authors did not run a meta-analysis, citing the small number of studies and their heterogeneity, so no overall effect size is available. Most studies last four weeks, several analyses draw on the same trials, and the comparator is usually placebo. The last author has declared links with the manufacturer of esketamine. The signal is useful, but it remains descriptive.
Context
Trials of ketamine and esketamine mostly measure symptoms. Patients ask something else: whether they will get back to work, be able to concentrate, see the people close to them again. Efficacy trials cover these questions poorly.
This review brings together the randomised trials that measured these functional outcomes, to see whether the benefit on symptoms comes with a benefit in daily life.
The study at a glance
| Item | |
|---|---|
| Population | |
| Adults aged 18 and over; the criteria admitted major depressive disorder or treatment-resistant depression, but all 9 included studies concern treatment-resistant depression, one of them in people aged 65 and over (TRANSFORM-3); from 138 to 676 participants per study, with no pooled total sample | |
| Interventions | |
| Intranasal esketamine (28, 56 or 84 mg, most often twice a week for four weeks; flexible doses in ESCAPE-TRD), always combined with an antidepressant. Intravenous ketamine was eligible, but no study was included | |
| Comparators | |
| Placebo nasal spray combined with an antidepressant (7 studies); extended-release quetiapine combined with an antidepressant (2 studies) | |
| Outcomes | |
| Functional impairment at work and in social and family life (Sheehan Disability Scale, SDS, 8 studies); work productivity and activity impairment (WPAI and WPAI:D). Neither quality of life nor cognition is among the outcomes analysed | |
| Design | |
| Systematic review of randomised trials and of post hoc or secondary analyses of randomised trials, conducted according to PRISMA 2020, without meta-analysis; searches of PubMed, Embase and PsycInfo up to 1 February 2025; selection, data extraction and risk of bias assessment (RoB 2) carried out independently in duplicate; narrative synthesis | |
Quality check
| Item | Judgement |
|---|---|
| Literature search | Several databases |
| FindingThree databases searched (PubMed, Embase, PsycInfo), with selection and data extraction carried out independently in duplicate. | |
| Synthesis | Narrative |
| FindingNo meta-analysis, so no overall effect size and no confidence interval. | |
| Comparators | Rarely active |
| FindingSeven studies compare with placebo combined with an antidepressant, two with extended-release quetiapine. | |
| Funding | Not reported |
| FindingNot reported in the publication: it contains no section on the funding of the review. | |
| Competing interests | Declared |
| FindingThe last and corresponding author, McIntyre, declares speaker or consultation fees from Janssen, holder of the marketing authorisation for intranasal esketamine, and from Johnson & Johnson, among many companies. Three other authors declare interests. | |
Results
| Item | Authors’ finding |
|---|---|
| Functional impairment (SDS) | Inconsistent results against placebo |
| FindingIn TRANSFORM-2, a difference of -4.0 points at day 28 (95% CI -6.28 to -1.64), judged clinically relevant by the authors against a 4-point threshold. No significant difference in three studies (Chen 2023, Fedgchin 2019, Takahashi 2021). | |
| Work productivity (WPAI) | Improvement against quetiapine |
| FindingOver 32 weeks in ESCAPE-TRD (336 versus 340 patients): productivity loss reduced by 2.3 weeks (95% CI -3.9 to -0.7; p = 0.0045), presenteeism by 1.9 weeks (p = 0.0098), activity impairment by 1.3 weeks (p = 0.0172); no significant difference in absenteeism (-1.1 weeks; p = 0.2285). | |
| Ketamine | No controlled study included |
| FindingThe authors mention open-label real-world data, outside the scope of the review. | |
| Follow-up | From 4 to 32 weeks |
| FindingSix studies stop at four weeks. Effects beyond 32 weeks are not documented in this review. | |
Critical appraisal
| Item | Judgement |
|---|---|
| No meta-analysis | Effect not quantified |
| FindingWithout pooling, only study-by-study estimates are available, and they disagree on the SDS; the overall size of the benefit and its clinical relevance remain unknown. Even in TRANSFORM-2, the confidence interval includes values below the 4-point threshold. | |
| Heterogeneity | High |
| FindingMean age from 36.9 to 70.0 years depending on the study, placebo or quetiapine, SDS or WPAI, follow-up from 4 to 32 weeks. Several analyses draw on the same trials (two on the TRANSFORM-2 cohort): nine studies do not make nine independent trials. | |
| Competing interests | To weigh |
| FindingOne author is linked to the manufacturer of esketamine. This does not invalidate the review; it invites a reading of its conclusions with that in mind. | |
| Authors’ claims | Sometimes more assertive than the data |
| FindingThe conclusion in the body of the text stays cautious (“shows promise”), but the abstract states that esketamine “alleviates depressive symptoms and improves functioning”, and the authors consider that the absence of a high risk of bias ensures the reliability of the findings, despite three null studies on the SDS. | |
Level of evidence
The level of evidence assigned is Oxford CEBM 1a-: a systematic review of randomised trials, the minus sign marking troublesome heterogeneity, without meta-analysis. Confidence is moderate in the general direction of the signal for esketamine: the studies report functional improvement rather than deterioration, more consistently for work productivity than for the SDS.
It is low for the size of that improvement, its durability beyond 32 weeks, and how it compares with other strategies for treatment-resistant depression, a comparison limited here to extended-release quetiapine. For ketamine, this review provides no controlled data.
The colleague test
What an experienced colleague would say if you presented this study in two minutes, between two consultations.
“For esketamine, the signal points the right way, especially on work productivity. But only nine studies, often drawn from the same trials, short follow-up, nothing controlled on ketamine, and an author linked to the manufacturer. I keep the idea, and for decisions I rely on the efficacy trials.”
Translation for practice: this review adds to the file, it does not settle it.
What you can do with this
- What you can assess: alongside symptoms, measure the impact on work, social and family life before and during treatment, with one simple instrument used consistently (the Sheehan scale is the most widely used in the included trials).
- What you can tell a patient who asks whether they will work again: for esketamine, the available data lean that way, without allowing the overall benefit to be quantified or its duration guaranteed; for ketamine, this review provides no controlled data.
- What you can check: who may prescribe and dispense intranasal esketamine where you practise, since marketing authorisation, conditions of prescribing and reimbursement are separate decisions that each shape access; and whether ketamine used for depression would fall outside its authorised indications. In France, for example, intranasal esketamine is restricted to hospital use and its prescription to psychiatric specialists and departments, and the indications of the injectable ketamine consulted (anaesthesia, analgesia) do not include depression.
- What you can watch for: trials that take a functional outcome as their primary outcome, with an active comparator.
Frequently asked questions
Do ketamine and esketamine improve quality of life in depression?
This review does not measure quality of life: it covers functional impairment and work productivity. The 9 included studies, all on esketamine, report a more consistent benefit on work productivity against quetiapine than on the Sheehan scale against placebo. No controlled study of ketamine was included.
Why did the authors not run a meta-analysis?
They cite the small number of eligible studies and their heterogeneity in design and in the reporting of results. They also note that the instruments used to measure functioning are not standardised. They therefore produced a narrative synthesis.
Can esketamine be prescribed in office-based practice?
That depends on the local framework, which treats marketing authorisation, the conditions of prescribing and dispensing, and reimbursement as distinct questions. In France, for example, it cannot. Intranasal esketamine, authorised at European level on 18 December 2019, is restricted to hospital use and classified as a narcotic, and its prescription is restricted to psychiatric specialists and departments. The Haute Autorité de santé rates its actual clinical benefit as moderate, in combination with an SSRI or an SNRI, in adults under 65 with a severe major depressive episode that has not responded to at least two antidepressants from two different classes (reassessment of 17 July 2024). The indications of the injectable ketamine consulted (anaesthesia, analgesia) do not include depression. Source: French public medicines database (base de données publique des médicaments), consulted on 2 October 2026.
Do one author’s competing interests invalidate the review?
No, but they matter when reading it. Here, the absence of a meta-analysis leaves room for interpretation in the synthesis, and that is precisely where a competing interest can weigh.
Annotated bibliography
Source study. Ji IS, Cheng MCH, Teopiz KM, Dri CE, Wong S, Le GH, Rhee TG, Guillen-Burgos HF, Lo HKY, Zheng YJ, McIntyre RS. The effects of ketamine and esketamine on functional outcomes in major depressive disorder and treatment-resistant depression: A systematic review. Journal of Psychiatric Research. 2026;192:280-288. DOI: 10.1016/j.jpsychires.2025.10.056. PMID: 41176897. Funding: not reported in the publication. Declared competing interests: R.S. McIntyre, research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute, speaker/consultation fees from Lundbeck, Janssen, Johnson & Johnson, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Sage, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, MindMed, Neurocrine, Neurawell, Supernus, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie and Atai Life Sciences; K.M. Teopiz, fees from Braxia Scientific Corp; T.G. Rhee, supported in part by the National Institute on Aging (R21AG070666, R21AG078972, R01AG088647), the National Institute of Mental Health (R01MH131528), the National Institute on Drug Abuse (R21DA057540) and the Health Resources and Services Administration (R42MC53154-01-00), review committee member for the NIH, PCORI and SAMHSA, from which he has received honoraria, paid consultant to PCORI, advisory committee member for the International Alliance of Mental Health Research Funders (IAMHRF); H.F. Guillen-Burgos, research grant support from MinCiencias (Colombia) and UKRI (United Kingdom), speaker fees from Roche, Pfizer, Abbott, GSK and Synergy R&D. The publication prints no declaration for the other seven authors.
Editorial collections
Tags
Verified on 2 October 2026 against the full text of the publication and its supplementary material where available. This analysis underwent an independent double reading. The English version was checked for conformity on 2 October 2026, against the figures of the French version and against the source. How we verify what we publish
This analysis is intended for healthcare professionals. It does not constitute a prescribing recommendation and does not replace individual clinical judgment.
Analysis from Psychiatry Evidence Base, evidence-based psychiatry, explained with rigor.