APA Task Force Addresses Off-Label Use of Ketamine

Despite escalating demand for clinical access to ketamine treatment and an increasing number of clinicians willing to provide it, big questions remain about the durability and safety of the anesthetic for the treatment of mood disorders. In a report published today in JAMA Psychiatry, the APA Council of Research Task Force on Novel Biomarkers and Treatments presents an overview on ketamine use and highlights critical issues for clinicians to consider about off-label use to help ensure patient safety.

The authors noted that the report is intended to complement a meta-analysis conducted by the Task Force in 2015. The report is broken down into the following sections:

• Patient Selection
• Clinical Experience and Training
• Treatment Setting
• Medication Delivery
• Follow-up and Assessments
• Efficacy of Longer-Term Repeated Administration
• Safety Measures and Continuation of Treatment
• Future Directions

“The rapid onset of robust, transient antidepressant effects associated with ketamine infusions has generated much excitement and hope for patients with refractory mood disorders and the clinicians who treat them. However, it is necessary to recognize the major gaps that remain in our knowledge about the longer-term efficacy and safety of ketamine infusions,” the authors wrote. “Although economic factors make it unlikely that large-scale, pivotal phase 3 clinical trials of racemic ketamine will ever be completed, there are several studies with federal and private foundation funding aiming to address some of these issues.

“It is imperative that clinicians and patients continue to consider enrollment in these studies when contemplating ketamine treatment of a mood disorder. It is only through these standardized clinical trials that we will be able to collect the data necessary to answer some of the crucial questions pertaining to the efficacy and safety of the drug.”

The authors also pointed to the value that a registry of patients treated with ketamine could offer for the field.

“Ketamine provides new excitement for psychiatry and offers the hope of much-needed novel and perhaps more effective treatments,” Charles Zorumski M.D., and Charles Conway, M.D., of Washington University School of Medicine, wrote in an accompanying editorial. “The consensus statement by Sanacora and colleagues, however, provides a sobering cautionary guide, especially as we move toward attempting to sustain the gains achieved by acute doses of ketamine. This consensus statement will not be the final word on this topic, and similar considerations will be needed for other novel treatments.”

For related information, see the Psychiatric News articles “Ketamine Clinics Attract Patients Despite Unknowns” and “APA Task Force to Address ‘What’s Next?’ for Ketamine.”

(Image: iStock/teetuey)

When Is Depression 'Treatment Resistant'?

What leads a clinician to conclude that a patient with depression is “treatment resistant” and thereby eligible for alternative nonpharmacological interventions—such as vagus nerve stimulation (VNS), electroconvulsive therapy (ECT), or transcranial magnetic stimulation (TMS)?

In an article appearing in the January issue of JAMA Psychiatry, Charles Conway, M.D., Mark George, M.D., and Harold Sackheim, Ph.D., wrote that the lack of a consensus definition around what constitutes treatment-resistant depression (TRD) “limits the ability to do comparative treatment research, to understand the biological underpinnings of TRD, and produces ambiguous medical insurance coverage issues.”

Drawing on data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the authors proposed a definition for TRD: failure to respond to two trials of an antidepressant prescribed at an adequate dose for an adequate duration of time.

Conway (pictured above), a professor of psychiatry and director of the Treatment Resistant Depression and Neurostimulation Clinic at Washington University, St. Louis, told Psychiatric News that in the absence of a consensus definition of TRD, patients often receive multiple trials of medication. “Our experience has been that when faced with patients who do not respond to a series of medications, clinicians typically continue to give more similar medications, despite there being no evidence to support that the fifth or sixth medication will work,” he said.

In STAR*D, patients with MDD received sequential treatment with antidepressants or psychotherapy using evidence-based antidepressant treatment strategies. At each stage of treatment, the likelihood that patients would respond decreased.

In the JAMA Psychiatry article, Conway and colleagues wrote that the “inflection point at which resistance markedly increased was level 3 (two adequate dose-duration treatments).” At that point, fewer than 1 in 5 patients remitted, they noted. “At subsequent trials (level 4) treatment failure rose to 90 percent,” Conway and colleagues wrote.

“After failure of two adequate dose-duration trials of antidepressants, augmentation strategy, or psychotherapy, a precipitous decrease to a remission rate of 5 percent or less was observed,” they wrote. “We believe this represents a starting point for operationally defining TRD.”

For more in-depth coverage on this subject, see the Psychiatric News PsychoPharm article “When Is Depression ‘Treatment Resistant’?”

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