Ketamine for Depression in Serious Illness: Evidence, Safety, and Practical Approaches

Abstract

Patients with serious illness 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 1–2 weeks, with a number needed to treat of 3 in the first week. Esketamine nasal spray demonstrates similar early efficacy and is United States Food and Drug Administration-approved for treatment-resistant depression and major depression with suicidal ideation. Evidence in serious illness is limited to several peri-operative 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 US, and the need for an appropriate maintenance regimen when integrating ketamine into palliative care depression management.

A 68-year-old man with metastatic pancreatic cancer is admitted for uncontrolled pain and is found to have severe, treatment-resistant major depression (defined as inadequate response to at least two adequate antidepressant trials (1)) with prominent suicidal ideation. His prognosis is estimated at weeks to a few months. He has not experienced relief with two prior adequate antidepressant trials and cannot tolerate medication titrations requiring several weeks to take effect. The team is concerned that his depressive symptoms, particularly his intense, intrusive suicidal thoughts, are impairing his capacity for medical decision-making around his treatment. Given his short prognosis and the need for rapid symptom relief, the team considers whether ketamine could provide meaningful and rapid improvements in mood, suicidality, and pain.

Introduction

Ketamine is an anesthetic agent that functions as an antagonist of the N-methyl-D-aspartate (NMDA) receptor (2). It was initially approved by the U.S. Food and Drug Administration in 1970 as a dissociative anesthetic noted for its ability to produce a sensation of detachment from the body and environment without compromising airway reflexes or spontaneous respiration by the U.S. Food and Drug Administration (FDA) (3).

Research on ketamine as a psychiatric intervention was minimal until the early 2000s, when interest in the use of ketamine as an antidepressant grew exponentially (4–6). This interest was driven in part by ketamine’s unique properties compared to traditional antidepressants, including a robust reduction in suicidal ideation (SI) and rapid alleviation of depressive symptoms (within hours, rather than weeks). In 2019, intranasal s-ketamine (one enantiomer of racemic ketamine (7)) gained FDA approval for treatment-resistant depression (TRD) (8).

Ketamine can be safely administered through intravenous (IV), intramuscular (IM), oral, intranasal (IN), rectal, subcutaneous (SC), and epidural routes. The chosen route of administration affects patient comfort and convenience, bioavailability, metabolism, serum concentrations, and duration of effect. Table 1 summarizes the pharmacological profiles of ketamine in its common routes of administration as an antidepressant (2, 9–11).

Table 1.

Pharmacological profiles of various routes of administration of ketamine

Route	Dose	Bioavailability	Onset of Antidepressant Action*
Intravenous (IV)▲	0.1 – 0.5 mg/kg infusion over 40 minutes	100%	<4 hours
Intramuscular (IM)▲	0.1 – 0.5 mg/kg bolus	93%	<4 hours
Subcutaneous (SC)▲	0.1 – 0.5 mg/kg bolus	90% – 100%	<4 hours
Oral▲	50 – 300 mg/day	20% – 30%	Hours to days
Intranasal (IN)▲	50 – 150 mg	35% – 50%	<24 hours
Intranasal Esketamine	56 mg, 84 mg	48%	<24 hours

^▲:Racemic ketamine

^*:Onset of action reflects timing of assessments in relative studies and may not accurately reflect actual differences in effect time

In the palliative care setting, ketamine’s rapid antidepressant effects may offer relief to patients with limited prognoses and depression. Furthermore, it is already used by many palliative care clinicians for analgesia indications and has the potential to treat serious illness (defined as a health condition that carries a high risk of mortality, negatively impacts quality of life and daily function, and/or is burdensome in symptoms, treatments, or caregiver stress (12)) symptom complexes for patients with serious illness-related pain and psychiatric comorbidities like depression and anxiety. In this Palliative Care Rounds, we synthesize evidence from both general psychiatric studies and studies among individuals with serious illness to inform the potential use of ketamine as an antidepressant in the palliative care setting.

Ketamine as an antidepressant in the general population

What is the efficacy of ketamine as an antidepressant in the general population?

In 2000, Berman et. al published a landmark placebo-controlled, double-blinded, randomized controlled trial (RCT) that showed that the administration of a single subanesthetic dose of IV ketamine to individuals with major depressive disorder (MDD) produced a significant, rapid antidepressant effect (13). Since then, multiple RCTs, systematic reviews, and meta-analyses have shown a robust, but typically short-lived antidepressant effect for ketamine (14). The majority of this evidence is derived from studies of IV racemic ketamine.

Ketamine shows an onset of action on depressive symptoms that ranges between 1- and 24 hours post-infusion and persists between 1 and 2 weeks (15–17)^. Meta-analyses have found response rates (defined as a 50% reduction in symptoms) of 35–55% and remission rates (defined as resolution of depressive symptoms) of 25–35% (15). In a 2024 meta-analysis that included 14 studies on ketamine for TRD, the number needed to treat (NNT) was three in the first week post-treatment and nine at four weeks (18). Many of the trials from which these data are derived were conducted in individuals with treatment-resistant depression, a population whose depression has not responded to multiple prior psychopharmacologic agents. However, none of these studies focused on individuals with serious medical illness, and most explicitly excluded them.

Of particular interest is ketamine’s robust effect on SI. IV ketamine is associated with a moderate-to-large decrease in SI that occurs within hours of treatment and lasts between days and months (14, 19). This effect may be somewhat independent of ketamine’s effects on other depression symptoms (20). Most trials of ketamine for suicidality involve single doses and short-term outcomes (hours to days) (21), however, a recent observational study suggests that ketamine may have longer-term benefits in mitigating suicidal ideation (22). It is not known whether ketamine reduces the risk of suicide attempts or completed suicide.

Most ketamine clinical trials have assessed ketamine as a monotherapy (single agent) for treatment-resistant depression. However, a smaller body of data also examines its use as an augmentation agent delivered alongside a traditional antidepressant. For example, when added to escitalopram, IV ketamine was found to reduce time to treatment response significantly, with some patients in the treatment arm achieving improvement in symptoms within hours (23).

Ketamine is only now beginning to be integrated into depression treatment guidelines (24, 25). For example, although the 2016 U.S Department of Veterans Affairs and US Department of Defense Clinical Practice Guideline for Depression recommended against ketamine as an antidepressant, the 2022 guidelines recommend ketamine and esketamine for patients who do not respond to initial depression therapies (26).

At what dose, duration, and frequency is ketamine given to treat depression?

There is debate about the optimal frequency, duration, and dose of IV ketamine for depression. The most common initial dosing regimen is 0.5 mg/kg delivered over 40 minutes (27). A 2024 meta-analysis that compared different doses of IV ketamine for depression concluded that IV ketamine showed significant benefit at 0.2 mg/kg, 0.5 mg/kg, and 0.5–1 mg/kg, without a significant increase in efficacy at 1 mg/kg after 24 hours (28). There is a nonsignificant trend toward greater efficacy with 0.5 mg/kg (NNT =3) compared with 0.2 mg/kg (NNT=7), supporting the standard dose of 0.5 mg/kg used in most published trials. In general, repeated administrations of ketamine, at least in the short term (~6 doses), produce greater antidepressant effects and increase time to relapse (29). As such, when used as an antidepressant, ketamine is typically initially dosed twice or three times a week (27). A 2016 study did not find a difference in effect between twice- and three-times-weekly dosing over six weeks (30).

What is the evidence for non-intravenous ketamine as an antidepressant in the general population?

Few studies have examined the antidepressant effects of ketamine delivered intramuscularly, orally, or subcutaneously. The available data suggest that these alternative delivery modes may also be efficacious (18, 31, 32). Furthermore, little data exist supporting IV ketamine for depression when delivered as a slow infusion (as is often done in palliative care). In part, this reflects the logistical reality that a medication delivered over days intravenously is not aligned with paradigms of depression treatment, which is overwhelmingly delivered in an ambulatory context. However, one small open-label study (N=23) suggested the possible antidepressant efficacy of a low-dose ketamine infusion over 96 hours (33).

What about intranasal esketamine as an antidepressant in the general population?

Intranasal esketamine, marketed as Spravato, is approved in Europe and the United States (US) for TRD and MDD with SI (34, 35). In contrast to IV racemic ketamine, most intranasal esketamine studies are of its use as an augmenting agent alongside traditional antidepressants (36, 37). Combining esketamine with an oral antidepressant is more efficacious than antidepressant monotherapy, with a lower risk of relapse (38). For TRD, the NNT for esketamine is two at one to three days and eleven at four weeks, suggesting a robust initial advantage over placebo, which decreases over time (18). Intranasal esketamine is generally well-tolerated with an analogous adverse effect profile to racemic ketamine (34, 35). The use of intranasal esketamine in the US is limited by stringent safety requirements, including a mandatory Risk Evaluation and Mitigation Strategy (REMS) program, under which the drug is dispensed only to certified medical offices for specific patients enrolled in a registry. Patients self-administer the nasal spray in such a clinic and must be cleared for discharge by an administering provider after at least two hours of supervision (34, 35).

Ketamine as an antidepressant in people with serious illnesses

Evidence for the psychiatric use of (es)ketamine in serious illness care is more limited. Although ketamine was first introduced as an analgesic in the 1970s, its use in patients with serious illnesses did not begin until 1990, when it was found to alleviate cancer-related pain (39). However, only a few studies have evaluated ketamine’s effectiveness in treating depression and/or SI in people with serious illnesses (40–43). Furthermore, there are no meta-analyses on the effect of ketamine on psychiatric outcomes in people with serious illnesses (40, 41, 44–46).

What RCTs have been conducted on ketamine as an antidepressant in people with serious illness?

Five RCTs published between 2017 and 2024 evaluated IV ketamine or esketamine as an antidepressant in surgical oncology patients peri-operatively (47–52). In these studies, pre-operative ketamine improved depressive symptoms in the short-term post-operative period compared to placebo controls. Though none of the studies provided effect sizes, three provided sufficient statistical detail to calculate effect sizes, which were uniformly large (−1.28 to −1.46) (48, 50, 51). Two studies included longer-term three-month follow-up; one study found significant antidepressant effects in the ketamine group at month one but not at month three, while the second found ongoing effects at month three (50, 51). In contrast, in a 7-day study (N=417) comparing a control condition with high- and low-dose S-ketamine and racemic ketamine for surgical patients with cervical cancer, none of the comparators differed from the placebo control at day 7; however, only mildly to moderately depressed patients were included (52). Dosing in the studies ranged from 0.1 mg/kg to 0.5 mg/kg. Of note, in a study by Ren et al. of pre-operative colorectal cancer patients with depression (N=104) with three intervention groups dosed at 0.1, 0.2, and 0.3 mg/kg, only the 0.3 group achieved significance in reducing post-operative depressive symptoms compared to placebo (48). However, in a larger study (N=303) of pre-operative breast cancer patients with depression, 0.125mg/kg of ketamine or esketamine both outperformed the placebo control (50).

Outside of the surgical oncology setting, one RCT compared the effects of a single dose of IV ketamine (0.5 mg/kg) to a midazolam control in 37 patients with moderate-severe depression and newly diagnosed cancer (53). Ketamine significantly reduced both suicidal ideation and depressive symptoms with medium-large effect sizes over seven days of follow-up. Furthermore, in 2023, two open-label trials that included 20 and 10 patients with advanced cancer reported a rapid antidepressant effect of intranasal and subcutaneous ketamine within 7 days, with several patients achieving remission (54, 55). In one of these trials, the authors additionally report a ≥50% decrease in SI in 90% of participants (54). Several additional case reports and observational studies have examined different administrative routes of ketamine or esketamine in individuals with serious illness or have described its effects on non-specific psychological distress or requests for hastened death (41, 54–62).

What about psychiatric data from studies of ketamine for non-psychiatric indications in serious illness care?

Several studies of ketamine for cancer-related pain have included depression as a secondary outcome (51, 63, 64). None of these studies identified a significant effect of ketamine on depression. However, these studies either did not report baseline data or reported data demonstrating that their study population was largely non-depressed at baseline. As such, they are of greater utility in supporting the tolerability and safety of ketamine among individuals with serious illness than as indicators of ketamine’s efficacy or inefficacy as an antidepressant.

Safety and tolerability of ketamine as an antidepressant in people with serious illnesses

Ketamine and esketamine appear to have good safety and tolerability profiles in people with serious illnesses. The most common side effects include transient neuropsychiatric side effects such as dissociation, dizziness, and somnolence; cardiovascular side effects, including tachycardia and hypertension; and, more rarely, urinary side effects ranging from dysuria to cystitis (65).

Outside of the serious illness care context, ketamine has a favorable safety profile among individuals receiving it for psychiatric indications. In one systematic review of 36 trials, ketamine and esketamine were not associated with higher dropouts or adverse events compared to placebo (66). In a systematic review of medically serious adverse events in psychiatric studies of ketamine and esketamine, there were four such events among 3756 participants receiving the intervention: autonomic complications (transient blood pressure/heart rate/body temperature changes) in three, and a lacunar infarct in one patient six hours after intranasal esketamine (67). Psychiatrically, although ketamine is typically avoided in psychotic disorders and delirium for fear of further exacerbating agitation, it is otherwise unlikely to be harmful and may be helpful in other psychiatric illnesses that may mimic or present with depression, including bipolar affective disorder (66).

Though data are less robust in the serious illness context, ketamine appears to be safe among individuals with comorbid serious illnesses (particularly cancer) as well. In a recent systematic review of ketamine for cancer pain involving 35 studies and 2279 patients, ketamine was well tolerated and reduced adverse effects relative to opioids (68). Furthermore, across the studies about ketamine as an antidepressant in people with serious illness referenced above, ketamine and esketamine demonstrated high safety and tolerability.

In contrast, little guidance exists regarding the safety of ketamine or esketamine in patients with hepatic or renal disease. Though high doses of ketamine have been associated with hepatobiliary dysfunction, these findings are of unclear clinical significance in the context of subanesthetic dosing. Generally, ketamine and esketamine are used with caution in patients with mild to moderate hepatic impairment and are avoided in severe impairment, although the evidentiary basis for these practices is limited. In patients with renal disease, even those dependent on hemodialysis, ketamine has been used safely (69–71). Finally, in patients with cardiovascular disease, ketamine’s effect on blood pressure and heart rate may be of concern. However, with monitoring, most patients with cardiovascular disease can be safely treated with ketamine or esketamine (72–74).

Key gaps and unanswered questions

Existing surgical oncology trials are encouraging but limited to peri-operative settings, and no studies examine maintenance strategies, prognostic timelines, comparative effectiveness relative to other treatments, or the risk–benefit trade-offs of early initiation in patients with limited prognoses. There are no high-quality psychiatric trials (e.g., appropriately powered, double-blind, placebo-controlled or active-controlled randomized controlled trials) evaluating ketamine or esketamine for depression or suicidality in serious illness populations. Furthermore, the existing evidence base is largely confined to cancer populations; evidence for the treatment of depression and suicidality in other serious illness contexts, including advanced heart failure, end-stage renal or hepatic disease, and chronic obstructive pulmonary disease, is virtually nonexistent

Research comparing delivery routes, dosing schedules, and integration with behavioral interventions is urgently needed to guide safe, equitable access across palliative care settings. Because of the lack of palliative care-focused research, many psychiatric outcomes particularly relevant to the serious illness setting (e.g., demoralization) are unstudied or understudied. For example, while the wish to hasten death is a distinct and common phenomenon in this population, the evidence reviewed here focuses specifically on suicidal ideation as defined and measured in the ketamine literature.

Key recommendations for palliative care practice

Most data in the psychiatric literature focus on TRD. In the palliative care setting, we recommend that considerations such as prognosis, goals, and comorbid pain symptoms may be more meaningful than simply prior unsuccessful depression treatments in identifying patients who may benefit from ketamine or esketamine. Such an approach is likely to have a lower NNT than existing estimates in the psychiatric literature because it isn’t specific to individuals with TRD.

The evidence supporting ketamine’s antidepressant effects is sufficiently robust that, when possible, we recommend using ketamine or esketamine for rapid amelioration of moderate or severe depressive symptoms over other commonly used rapid-acting oral agents, particularly for patients with a prognosis of one month or less.

For patients with a prognosis of greater than one month, repeated or maintenance dosing is likely to be necessary to maintain ketamine/esketamine’s antidepressant effects. With a prognosis greater than one month, we recommend either ensuring a plan for maintenance dosing as part of the initial treatment decision-making or coupling the initiation of short-term ketamine/esketamine with the initiation of an oral antidepressant regimen.

The most robust data support IV ketamine boluses at 0.5mg/kg over 40–60 minutes or intranasal esketamine at 56mg to 84mg per dose kit. While these dosing and administration forms represent the most evidence-based options, they may pose significant administrative and logistical challenges in patients with serious illness. Limited data support the effectiveness of ketamine and esketamine delivered via slow IV infusions or via oral or subcutaneous routes; however, given the logistical challenges of standard administration in serious illness settings, these alternative routes may be considered on an individualized basis, weighing patient goals, prognosis, tolerability, and access. Additionally, access to centers or practitioners participating in the esketamine REMS programs, who are comfortable treating patients with serious illness, is likely a robust barrier to access, particularly for patients from rural communities. In settings where esketamine REMS access is unavailable, racemic IV ketamine represents a practical alternative with a robust evidence base. Long-term, palliative care programs should consider pursuing REMS certification or establishing referral relationships with certified centers to expand access for patients with serious illness. Finally, although esketamine was approved by the FDA for TRD in 2019, ketamine does not have FDA approval for depression. In August 2025 the FDA approved ketamine (KETARx) for surgical pain, the first approved indication beyond anesthesia. Therefore, ketamine may not be covered by patients’ insurance plans, creating a financial barrier to access (75). We recommend following existing psychiatric ketamine/esketamine protocols when feasible, but also utilizing alternative dosing and delivery methods (which are largely safe) to increase access among patients with serious illness.

Key Message:

Ketamine and esketamine offer rapid antidepressant and anti-suicidal effects unmatched by traditional agents. However, psychiatric evidence in serious illness is limited to primarily perioperative settings. Despite these gaps, ketamine may be appropriate for patients needing urgent relief, provided clinicians consider prognosis, safety, and the feasibility of an appropriate maintenance regimen.