Researchers Consider Benefits of Ketamine for Depression

A recently proposed ethical framework for providing the dissociative anesthetic ketamine (Ketalar, JHP Pharmaceuticals, others) to treat severe, unrelieved symptoms of major depression identifies and addresses three primary ethical concerns: lack of effective treatment for these patients, insufficient data on the safety and efficacy of this off-label use, and the misuse potential of ketamine.

Ilina Singh, EdD, Department of Psychiatry, University of Oxford, Oxford, UK, and colleagues argue for providing the treatment, while warning of practical and ethical challenges that can arise even after safe and effective drug administration.

"Patients who achieve a dramatic beneficial response to ketamine might face a serious fall in morale after rapid relapse; and patients with suicidal thoughts or ideation might be harmed by the false assurance of an abrupt, but potentially brief, reduction in suicidality," Singh and colleagues point out.

In an accompanying commentary, Christopher James Ryan, MBBS, MHL, Discipline of Psychiatry and the Centre for Values, Ethics and the Law in Medicine, University of Sydney, Australia and Colleen Loo, MBBS, MD, School of Psychiatry, University of New South Wales, Sydney, Australia elaborated on this concern.

"After initial relief, patients could experience declining responses and, desperate to recapture improvement, they could pressure clinicians, unconstrained by research protocols, into increasing their frequency or dose," Ryan and Loo indicated.

The argument by Singh and colleagues references principles of responsible research in novel neurotechnologies developed by the UK Nuffield Council of Bioethics. They emphasize the importance of two principles in particular: a clearly identified need, and a treatment that is both safe and efficacious. The first condition is apparent, Singh and colleagues indicate, in that severe depression is associated with increased risk of suicide, suicidal ideation is difficult to manage without effective treatment, and, they indicate, "treatment resistance can contribute to a dangerous sense of hopelessness."

The evidence for safety and efficacy is less clear, they acknowledge, as there are few controlled trials of the treatment for mood disorders, and little interest by manufacturers in sponsoring such trials for a drug available as a generic. The data on safety come largely from use as an anesthetic, and provide little information on the effects of repeated dosing.

Given these circumstances, Singh and colleagues accept the need to extrapolate data from imperfect sources, and they encourage additional observational and single-case studies "as a necessary adjunct to the randomized controlled trials, and as an independently valid and valuable source of evidence for treatment safety and efficacy."

Singh and colleagues suggest that the clinician's task in weighing benefit against risk involves three key interests: autonomy, innovation and professional integrity. In the first, they explain that protection of autonomy in the treatment of severe depression is both an ethical duty, to uphold the patient's expressed desire for treatment, and a clinical goal, to promote or restore patient autonomy.

As innovation can lead to better tolerated and more effective therapies, it should be a key interest in weighing patient need against potential harm, according to Singh and colleagues. "Therefore, off-label use of ketamine for treatment-resistant depression in single cases can contribute to innovation and to justice."

Regarding professional integrity, Singh and colleagues advise "a heightened degree of humility and responsibility" when clinicians prescribe the treatment.

"This will help to prevent...a promising depression therapy from being stopped or delayed by clinical mistakes that increase policy makers' concerns about the drug and decrease public trust.”

The ethical basis for ketamine treatment in depression was published April 5 online in The Lancet Psychiatry.