From the Journals

APA task force urges caution in off-label use of ketamine for mood disorders

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Patient registry endorsed strongly

A clear need exists for better treatments for the up to one-third of patients with major depression who do not respond to currently available therapies. Ketamine, which can produce rapid antidepressant effects, holds promise for this population and is increasingly being used off-label.

However, clinical guidance is lacking, and the small studies done to date leave many knowledge gaps. Though ketamine is known to be an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, rodent studies show that its action, or perhaps that of its metabolites, on another glutamate pathway may primarily underlie its antidepressant effects. Also, researchers are trialling adjunctive agents such as clonidine to help mute the undesirable psychomimetic and cardiorespiratory effects of ketamine. As the science rapidly develops, more targeted rapid treatments may become available, an evolution that could fundamentally change many aspects of the practice of psychiatry.

Uncertainty created by the current limitations in knowledge permeates the consensus statement and appropriately so. The authors provide clinical guidance based on what data are available but call for caution and transparency when treating mood disorder patients with ketamine. Gaps in data can be ameliorated by the formation of a patient registry for coordinated data collection and safety monitoring.

Charles F. Zorumski, MD, and Charles R. Conway, MD, are professors of psychiatry at Washington University in St. Louis, where Dr. Zorumski also holds an appointment in the department of neuroscience. Dr. Zorumski reported serving on the scientific advisory board of Sage Therapeutics, which also has funded research conducted by both authors. Dr. Conway reported serving as an unpaid consultant to LivaNova. These remarks were drawn from invited commentary accompanying the consensus statement.



A new consensus statement on the use of ketamine as an off-label treatment for mood disorders provides psychiatrists some guidance for patient selection and evaluation, as well as dosing and duration of therapy. The statement was issued against the backdrop of newer studies showing ketamine’s rapid, though not durable, efficacy in treating depression and anxiety disorders.

From start to end, however, the statement urges caution and marks out areas for further study, citing a paucity of data on longer-term efficacy and safety and a literature largely made up of smaller studies.

Dr. Gerald Sanacora

Dr. Gerald Sanacora

In the statement, developed by the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments: Subgroup on Treatment Recommendations for Clinical Use of Ketamine, lead author Gerard Sanacora, MD, PhD, noted that, although ketamine has been used for more than 45 years as an anesthetic, there has been no postmarketing surveillance of its use in psychiatry, prompting an “urgent need for some guidance on issues surrounding the use of ketamine treatment in mood disorders” (JAMA Psychiatry. 2017 Mar 1. doi: 10.1001/jamapsychiatry.2017.0080).

Dr. Sanacora, professor of psychiatry at Yale University, New Haven, Conn., and his coauthors made clear that “this report is not intended to serve as a standard, guideline, clinical policy, or absolute requirement.” Rather, the document identifies the current state of the field and identifies factors to consider in determining the appropriateness of ketamine therapy.

When a clinician is considering giving ketamine to a patient, a preprocedural evaluation is recommended, both to assess whether ketamine is likely to benefit the patient and to evaluate potential risks. Recommended components include a comprehensive psychiatric diagnostic assessment, paying particular attention to substance use and psychosis history, if any; assessment of baseline symptom severity; history of prior antidepressant treatment; review of systems to assess risk factors; physical examination and laboratory screening that follows accepted guidelines for the anticipated level of sedation, with the recommended addition of a baseline urine toxicology screen; and records review and family corroboration with a particular eye to past substance use.

Finally, the informed consent process should ensure that the patient is aware not only of potential treatment risks, but also of the relatively limited data on the off-label use of ketamine for mood disorders. Thorough written documentation is recommended.

Regarding the appropriate amount of experience and training a clinician should have before administering ketamine, Dr. Sanacora and his coauthors noted that the subanesthetic doses of ketamine that are used to treat mood disorders have been found generally very safe in the limited studies that have been done. Typical peak plasma concentrations will not induce general anesthesia. However, systolic and diastolic blood pressure and heart rate elevations are not uncommon. The statement cites a study that found “blood pressure levels exceeding 180/100 mm Hg or heart rates exceeding 110 beats per minute in approximately 30% of the patients treated.”

Accordingly, the statement recommends that clinicians administering ketamine have Advanced Cardiac Life Support certification and be able to administer Drug Enforcement Administration Schedule III medications. Individual organizations, according to the statement, should follow accepted standards of practice for granting privileges to administer ketamine. A statement developed by the American Society of Anesthesiologists on granting privileges for conscious sedation to nonanesthesia professionals may be used for guidance.

The most-studied dose of ketamine in the treatment of mood disorders is 0.5 mg/kg, administered intravenously over 40 minutes. Though other routes, and lower doses, have been studied, Dr. Sanacora and his colleagues wrote that they consider that “insufficient benefit was provided in those studies to allow any meaningful analysis of any specific dose or route of treatment compared with the standard dose.”

The statement includes a strong recommendation to develop a site-specific–standard operating procedure for the administration of ketamine that incorporates the preprocedural evaluation. In addition, the procedure should assess baseline vital signs, include criteria for acceptable vital signs, and incorporate a “time-out” procedure before initiating ketamine treatment.

Also, standard operating procedures should include continued assessment of respiratory, cardiovascular, and mental status throughout the infusion. Stopping criteria should be clearly defined, as should a plan aimed at managing any cardiovascular or behavioral problems. Discharge procedures should include documentation of vital signs and mental status, ensuring that an adult caregiver can take the patient home, and a thorough review of discharge instructions.

The statement’s section on follow-up and assessments noted: “The existing data surrounding the benefits of repeated infusions of ketamine remain limited.” However, some studies have shown that twice-weekly infusions were as efficacious as infusions given three times a week. In terms of longer-term treatment, the data are sparse, wrote Dr. Sanacora and his coauthors. Some clinics, they said, are giving ketamine two or three times weekly for 2 or 3 weeks, then tapering or adjusting the regimen based on clinical response, but high-quality studies are lacking.” The scarcity of this information is one of the major drawbacks to be considered before initiating ketamine therapy for patients with mood disorders and should be discussed with the patient before beginning treatment,” they wrote.

The known risks of cognitive impairment and cystitis with more chronic high-frequency ketamine use, taken together with the significant potential for abuse, mean that ketamine should be discontinued if more than once-weekly dosing is required after 2 months of treatment. “The goal remains to eventually taper and discontinue treatment until more long-term safety data can be collected,” wrote Dr. Sanacora and his coauthors.

The statement, while acknowledging the hope and excitement that currently surround the use of ketamine for mood disorders, calls for further research that would include a patient registry and coordinated data collection to facilitate answering the many important questions remaining about ketamine’s efficacy and safety.

The report was neither endorsed nor promulgated as policy of the APA. Dr. Sanacora reported multiple relationships with pharmaceutical companies, as did all of his coauthors.

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