Is Off-label repeat prescription of ketamine as a rapid antidepressant safe? Controversies, ethical concerns, and legal implications

Ketamine, a dissociative anaesthetic and phencyclidine derivative with known abuse liability, has shown rapid antidepressant effects in some clinical trials for treatment-resistant depression, but methodological flaws and possible reporting bias may have influenced those findings. Regulatory agencies have not approved ketamine for depressive disorders, and a Canadian review did not recommend its prescription. Off-label repeat prescribing raises ethical concerns, especially given the comorbidity of substance abuse with depression and the lack of evidence ruling out long-term abuse risk. Two clinical vignettes illustrate ethical principles—autonomy, nonmaleficence, fidelity, and consequentialism—relevant to off-label ketamine use. Clinicians should exhaust standard antidepressant therapies before considering ketamine.

Study at a glance

Abstract

BACKGROUND: Depressive disorders are a common form of psychiatric illness and cause significant disability. Regulation authorities, the medical profession and the public require high safety standards for antidepressants to protect vulnerable psychiatric patients. Ketamine is a dissociative anaesthetic and a derivative of a hallucinogen (phencyclidine). Its abuse is a major worldwide public health problem. Ketamine is a scheduled drug and its usage is restricted due to its abuse liability. Recent clinical trials have reported that ketamine use led to rapid antidepressant effects in patients suffering from treatment-resistant depression. However, various flaws in study designs, and possible biased reporting of results, may have influenced those findings. Further analyses of ketamine use are needed to ensure patient safety. DISCUSSION: The use of ketamine in research and treatment of depressive disorders is controversial. Recently, mental health professionals raised ethical concerns about an ongoing ketamine trial in the UK. Also, a Canadian agency reviewed the existing evidence and did not recommend prescribing ketamine to treat depressive disorders. Findings obtained from tightly controlled research settings cannot be easily translated to clinical practice as substance abuse is commonly comorbid with depressive disorders. An effective antidepressant should reduce severity of depressive symptoms without liability problems. Although the US FDA has not approved the use of ketamine to treat depressive disorders, some psychiatrists offer off-label repeat prescription of ketamine. Prescribing ketamine for treating depressive disorders requires substantial empirical evidence. Clinicians should also consider research findings on ketamine abuse. Depressive disorders can be chronic conditions and the current evidence does not rule out the risk of substance abuse after repeat prescription of ketamine. Off-label ketamine use in treating depressive disorders may breach ethical and moral standards, especially in countries seriously affected by ketamine abuse. This article presents two real-world clinical vignettes which highlight ethical principles and theories, including autonomy, nonmaleficience, fidelity and consequentialism, as related to off-label ketamine use. CONCLUSION: We urge clinicians to minimise the risk of harming patients by considering the empirical evidence on ketamine properties and attempting all standard antidepressant therapies before considering the off-label use of ketamine.