Ketamine for Depression in Serious Illness: Evidence, Safety, and Practical Approaches.
Paul Noufi, Joshua B Borris, Danielle Chammas, Cara L Mcdermott, Nneka N Ufere, Jason A Webb, Daniel Shalev
Journal of pain and symptom management August 1, 2026 Peer reviewed DOI: 10.1016/j.jpainsymman.2026.04.604 via PubMed
Summary
Ketamine and esketamine are effective rapid-acting antidepressants for patients with serious illnesses experiencing depression and suicidal thoughts. Intravenous ketamine shows moderate-to-large effects within 1-24 hours, with a number needed to treat of three in the first week. Esketamine nasal spray has similar early efficacy and is FDA-approved for treatment-resistant depression. However, evidence specific to serious illness is limited, primarily consisting of small studies that do not address long-term management.
Study at a glance
| Design | Palliative Care Rounds |
|---|---|
| Population | patients with serious illnesses experiencing depression and suicidal ideation |
| Key finding | Ketamine and esketamine provide strong evidence as rapid-acting antidepressants, particularly when urgent symptom relief is needed. |
Abstract
Patients with serious illnesses and short prognoses often experience depression and suicidal ideation. Traditional antidepressants are limited by delayed onset, creating a need for rapidly acting therapies. In this Palliative Care Rounds, we examine the evidence for ketamine/esketamine's efficacy as antidepressants, including evidence specific to people with serious illnesses. In psychiatric studies, intravenous ketamine produces rapid (1-24 hours), moderate-to-large antidepressant effects lasting one to two weeks, with a number needed to treat of three in the first week. Esketamine nasal spray demonstrates similar early efficacy and is U.S. Food and Drug Administration-approved for treatment-resistant depression and major depression with suicidal ideation. Evidence in serious illness is limited to several perioperative cancer trials and small open-label studies, which show short-term reductions in depressive symptoms and suicidal ideation but do not address long-term management or maintenance dosing. Safety across serious illness studies is generally favorable, with transient dissociation, hypertension, and somnolence the most common adverse effects; serious adverse events remain rare. Ketamine and esketamine offer the strongest evidence among rapid-acting antidepressants and may be preferred when urgent symptom relief is needed. However, rigorous psychiatric trials in serious illness are lacking. Clinicians should consider prognosis, access to Risk Evaluation and Mitigation Strategies-certified esketamine programs or equivalent regulatory frameworks outside the U.S., and the need for an appropriate maintenance regimen when integrating ketamine into palliative care depression management.