Over the last decade, increasing evidence has indicated that ketamine can have rapid, but short-lived, antidepressant effects when administered intravenously. This effect is often noticeable within hours of treatment and typically abates in about one week. Current FDA-approved antidepressants take several weeks to work. The fact that ketamine works so rapidly has led to new research elucidating the mechanisms underlying its antidepressant properties.

Ketamine is already approved by the FDA for use as an anesthetic. Doses used for anesthesia are considerably higher than those being studied to treat depression. Ketamine has a number of other effects, including dissociation (such as out-of-body experiences), hallucinations, delusions, and agitation. It can also cause cognitive impairment and has potential for abuse. Both ketamine and the related drug phencyclidine (PCP) are street drugs.

Because ketamine is already FDA approved, physicians can prescribe it for conditions other than those for which it is specifically approved. It is not uncommon for medications to be used for such “off-label” conditions. Many patients don’t respond to conventional treatments for depression and are desperate for new treatments. However, very little evidence exists to guide physicians in finding ways to sustain the short-term benefits of ketamine. This lack of information extends to the use of repeated administrations of the drug. Furthermore, there are potentially significant side effects with short-term and repeated use of ketamine. Despite these concerns, there is an increasing number of physicians who are willing to administer ketamine to individuals suffering from treatment-resistant depression. In fact, ketamine clinics are opening in many cities.

A recent consensus statement published in JAMA Psychiatry by the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments advises caution regarding the use of ketamine in the treatment of depression. This task force recommends that clinicians conduct a comprehensive review of an individual’s past psychiatric and medical history prior to administering ketamine in order to better assess the risk-to-benefit ratio for treatment. For example, given the potential for abuse, patients with a prior history of substance use disorders may be at increased risk for developing a ketamine use disorder.

Because of the acute effects of intravenous ketamine administration, the authors recommend monitoring the patient’s physical and mental status during and immediately after the infusion and having procedures in place to handle cardiovascular or respiratory complications. Clinicians should also be familiar with ways to manage patients who have marked behavioral changes, including severe agitation. They recommend careful documentation of current depressive symptoms and close follow-up of symptoms over time.

In addition, the authors review the potential side effects of ketamine following repeated administration and suggest that assessments of cognitive impairment, urinary discomfort, and substance use be considered when ketamine is used repeatedly. They point out that there are few data specifically addressing the effects of repeated use of ketamine in treating depression.

Some physicians are using alternative routes to administer ketamine, including oral ingestion, intranasal inhalation, and intramuscular injection. There are very limited data about the efficacy of these other methods of administration or of associated acute and longer-term side effects.

Importantly, the consensus statement emphasizes the need for ongoing systematic studies of ketamine for psychiatric indications and urges psychiatrists to enroll patients in these studies. The authors also call for a national registry of patients treated with ketamine so that its use, benefits, and complications can be evaluated more effectively and comprehensively.

Substantial research of ketamine and ketamine-inspired drugs is being conducted. Much more data about the acute and long-term administration of these various drugs will become available over the next several years. More definitive recommendations about the use of ketamine for depression in clinical settings must await completion of these studies.

In the interest of full disclosure: One of us (CZ) serves on the editorial board of JAMA Psychiatry and wrote an invited editorial that accompanied the consensus statement. This editorial emphasized optimism over the future of ketamine and ketamine-like drugs in psychiatry, but it also underscored the need for vigilance as psychiatry embarks on the clinical use of novel treatments that have substantial potential but also major and poorly understood risks. 

This post was written by Eugene Rubin MD, PhD and Charles Zorumski MD.

References

Sanacora, G., Frye, M.A., McDonald, W., Mathew, S.J., Turner, M.S., et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry, published online March 1, 2017.

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