The Role of Ketamine in Depression

  • April Christensen MD, M.S.
  • Jennifer Pruskowski PharmD

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April Christensen MD1, Jennifer Pruskowski PharmD2

Background    Depression is common among seriously ill patients. While the mainstay of pharmacotherapy has been psychostimulants for those with a shorter prognosis (days to weeks) and selective serotonin reuptake inhibitors (SSRIs) for those with a longer prognosis (weeks to months), the efficacy of these medications has been mixed in palliative care populations (1-2). See Fast Facts#61 and #309. Ketamine has received attention from clinician experts for its potential to offer rapid relief in treatment-resistant depression (TRD), meaning depression which has not responded to at least two adequate trials of antidepressants (3-5). This Fast Factaims to provide a concise review of the role of ketamine to treat TRD in adults for experienced palliative care clinicians.

Pharmacology    Ketamine’s mechanisms of action are discussed in Fast Fact #132. It can be given off-label for depression intravenously (IV) or orally (usually the IV solution mixed into a palatable liquid) (6). However, oral ketamine undergoes extensive first-pass metabolism resulting in poor bioavailability (only 20%) (6-7). Intranasal ketamine or esketamine was recently approved for TRD and has a bioavailability of 45%. Ketamine has not been well studied in seriously ill adults with depression, except for an open label study and a few case reports (3,8-9). There is even less evidence to support its use for TRD in children.  Dose adjustments in renal and liver impairment are not felt to be necessary.

Intravenous    Themajority of randomized controlled trials (RCTs) of ketamine for TRD have examined otherwise healthy patients receiving one-time IV infusions of 0.5 mg/kg over 40 minutes as an adjuvant therapy with a follow-up of less than two weeks. In two meta-analyses, a single administration of IV ketamine significantly reduced depressive symptoms and suicidal thinking within one week (4,10). Response rates for a single infusion have been reported to be as high as 50-70%, which appears to be better than traditional antidepressants (11-13). However, the time to relapse is 1-3 weeks, necessitating repeat infusions (10,14). Most studies on single IV ketamine infusions have not reported any serious adverse events (10). Reported side effects generally resolve within four hours and include perceptual disturbances, confusion, blood pressure elevation, dizziness, and euphoria (13).

Intranasal    Esketamine (an S-isomer) has been approved as a nasal spray for TRD in conjunction with oral antidepressants. A double-blind RCT in 18 subjects showed a 44% response rate to a single dose of 50 mg intranasal ketamine compared to 6% for a placebo saline nasal spray (15). Onset was 40 minutes and lasted less than 3 days. Common side effects are “feeling unreal,” fatigue, and poor memory for up to four hours. Maintenance intranasal ketamine has been examined only in case reports (16).

Oral    A small, open-label study of oral ketamine in hospice patients demonstrated some improvement in a validated, patient-reported depression scale when dosed at 0.5 mg/kg for 28 days (3,17-18). The time to response was 1-2 weeks. However, four of the 14 patients withdrew before the completion of the study due to lack of response (3,17-18). Maintenance oral regimens have not been systematically studied in palliative care patients (19). Dizziness, delirium, hallucinations, nausea, vomiting, and headache are commonly reported side effects (6).

Other Considerations    Data on the long-term effects of ketamine are limited. However, there is concern for its potential to elicit urinary, hepatobiliary, and neuropsychiatric side effects if used greater than two weeks consecutively (6, 20-23). Its risk of misuse or addiction is relatively unknown (6, 20). Across methods of administration, ketamine’s effect on depression outlasts the side effect of euphoria. As needed benzodiazepines such as midazolam 1-5 mg IV or lorazepam 0.5 mg-2 mg IV are recommended for ketamine-induced delirium and hallucinations, the most common adverse drug reactions (24).

Clinical Use    Ketamine should only be used for severe TRD in adults after a thorough palliative-case assessment in which other potential diagnoses such as grief or adjustment disorder have been considered. Close collaboration with interdisciplinary team members is essential along with consideration and implementation of standard depression therapies including psychological counseling and first-line antidepressants (ex: SSRIs) as appropriate. Its use for TRD in the palliative care setting should be reserved for specialized palliative care or psychiatry clinicians with significant expertise with the medication who can closely collaborate with a clinical pharmacist (25).

At this time, available evidence has not established standard induction and maintenance protocols. Therefore, conservative doses should be utilized with a plan to titrate as tolerated (see table below). Clinicians should closely during any IV administration, any initial administration, and at any dose increase.

Intravenous0.5 mg/kg over 40 minutesInduction: q3 days for 6 infusionsMaintenance: q3 weeks or at time of relapse
Intranasal10-50 mgQ 3-7 days
Oral10-100 mgQday to 3 times per day

Cost    IV or oral ketamine is typically not covered by insurance, resulting in out-of-pocket costs to the patient or hospice. The cost of ketamine solution varies from $1 to $3 per mL depending on concentration and negotiated price. Therefore, costs of $400-$800 for single administrations of IV ketamine have been reported. Intranasal ketamine (esketamine) typically costs around $350 per administration.


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Conflicts of Interest: None reported

Authors’ Affiliations:  1Mayo Clinic, Rochester, Minnesota; 2University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Version History:  originally edited by Christopher Lawton MD; first electronically published in September 2019.

Fast Facts and Conceptsare edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin(PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’scontent. The full set of Fast Facts are available at Palliative Care Network of Wisconsinwith contact information, and how to reference Fast Facts.

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