Pam Harrison

April 25, 2016

PHILADELPHIA — With limited evidence the anesthetic ketamine is effective for the short-term treatment of depression and almost no long-term safety and efficacy data, US psychiatrists are troubled by the rapidly growing trend of off-label prescribing.

"This is really an unusual situation in which a drug that was approved as an anesthetic is available to be prescribed by any physician," Charles Nemeroff, MD, PhD, professor and chairman, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, told Medscape Medical News.

"And while we are used to prescribing things off label all the time — obviously, medications find other uses — to take a drug like ketamine, which is an anesthetic and a well-known drug of abuse, especially when there are no data on its long-term effectiveness or its safety, is very worrisome."

Dr Nemeroff raised these and other concerns about the off-label use of ketamine here at Anxiety and Depression Association of America (ADAA) Conference 2016 and was later interviewed by Medscape Medical News.

Psychiatric Side Effects, Bladder Toxicity

The original suggestion that ketamine might have antidepressant properties came from animal studies undertaken years ago. N-methyl-D-aspartate (NMDA) receptor antagonists appeared to have positive effects in animal models of depression.

Later, investigators made a serendipitous observation that some patients with depression experienced a rapid improvement in symptoms when treated with ketamine. In a seminal randomized, double-blind study published in 2006 (Arch Gen Psychiatry. 2006;63:856-864), Carlos Zarate, MD, chief, Section of Treatment of Mood Disorders, National Institute of Mental Health, Bethesda, Maryland, and colleagues confirmed that a single IV dose of an NMDA antagonist produced robust and rapid antidepressant effects within 2 hours following infusion and that effects remained significant over the course of 1 week.

Since then, the literature on ketamine has been spotty. In a meta-analysis of ketamine and other NMDA antagonists published in 2015 (Am J Psychiatry. 2015;172:950-966), Dr Nemeroff and colleagues identified only 12 randomized clinical trials in which ketamine had been used to treat depression, either as monotherapy or as augmentation in conjunction with other psychotropic agents or with electroconvulsive therapy (ECT).

The meta-analysis was undertaken by an offshoot of the American Psychiatric Association's Task Force for Novel Biomarkers and Treatments, which is charged with developing an advisory statement on the appropriate use of ketamine. The group is chaired by Dr Nemeroff.

The meta-analysis, which involved fewer than 200 patients, supported the efficacy of ketamine in depression. A single IV infusion of subanesthetic doses of the drug produced rapid antidepressant responses that peaked within 1 day of administration.

However, the therapeutic benefit quickly dissipates over time. The investigators also found that the anesthetic commonly produces dissociative and psychotomimetic side effects.

Two recent studies showed that recreational ketamine use is associated with bladder toxicity. As reported by Medscape Medical News at the time, investigators from the University of York, in the United Kingdom, found that ketamine damages the bladder lining. The study raised concerns that this effect may affect the drug's clinical potential.

Proliferation of Ketamine Clinics

"That the encouraging results from published ketamine trials would generate excitement is certainly understandable [and] it is [also] perhaps understandable that infusion centers, employing ketamine as an alternative to ECT, have rapidly appeared across the nation," the investigators note in their meta-analysis.

"However, the available data do not support ketamine infusions as an ECT alternative for acute treatment of depression. The fleeting nature of ketamine's therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution," they add.

Fueling the drive behind the appearance of ketamine clinics across the United States is the fact that current antidepressants do not work that well, and even when they do, it takes time for their effects to kick in.

"There are two main reasons why ketamine has generated so much interest," Gerard Sanacora, MD, PhD, professor of psychiatry, Yale University, New Haven, Connecticut, told Medscape Medical News.

"First, current antidepressants, although quite effective for many people, still leave almost two thirds of our patients in a situation where they do not have a complete response, and about one quarter to one third of patients gain little benefit," he added.

"Secondly, even when these medications are effective, it can take up to several months before patients get complete benefit, and that's a long time for a patient to be suffering."

ECT can offer relatively rapid relief from depression, Dr Sanacora added. But many patients refuse ECT out of concern for potential memory impairment.

Relapse rates following ECT approach 50% in the 6 months after undergoing ECT, according to Dr Nemeroff. By way of comparison, relapse rates approach almost 90% 4 weeks after patients receive serial ketamine infusions.

Desperate Patients

Driven by desperate patients and their families, many healthcare providers in the United States have responded to the early, favorable reports about ketamine and have provided treatment with few questions asked.

But it is not just patients who are driving ketamine use. According to the Ketamine Advocacy Network, the cost of a single injection of the drug ranges from $400 to $800, and some physicians in affluent areas charge as much as $2000 per shot.

"There is significant economic gain for providers, and we should not ignore the fact that most third-party payers are not going to reimburse patients for this," Dr Nemeroff said.

Currently, no drug is indicated for the rapid treatment of major depressive disorder or for any other mood disorder, said Dr Sanacora.

"That said, there are situations when I think a trial of ketamine could be an appropriate treatment option," he added.

The key word here is "appropriate." At Yale University, physicians such as Dr Sanacora do offer ketamine for depression, but only for carefully selected patients who have been thoroughly apprised of the risks and the benefits associated with the treatment.

Ketamine may also be an appropriate treatment option for patients with treatment-refractory depression who refuse ECT but who are in need of a rapid treatment response because of acute suicidality or an inability to care for themselves.

A "Better Ketamine" in the Wings?

Ketamine researcher James Murrough, MD, Icahn School of Medicine at Mount Sinai, in New York City, reported at the ADAA meeting that 24 patients with clinically significant suicidal ideation who received a single infusion of ketamine experienced a significant improvement in scores on the Montgomery-Åsberg Depression Rating Scale‒Suicidal Ideation (MADRS-SI) at 24 hours compared with control patients who received midazolam. Perhaps predictably, the treatment effect was no longer significant at 7 days.

"What we need is a better ketamine," Dr Zarate told Medscape Medical News.

He noted that the National Institute of Mental Health may have found a more effective molecule than ketamine. Study results are awaiting publication.

But Dr Zarate also sees a role for ketamine — or something like it — provided it is offered exclusively in specialty clinics where experts have worked through all possible treatment options and patients still have not responded to any form of therapy.

There is some hope that more intelligent use of IV ketamine in treatment-resistant depression may provide longer-term effects. In one recent double-blind, randomized, dose-frequency study led by Jaskaran Singh, MD, and published online April 8 in the American Journal of Psychiatry, patients received IV ketamine at a dose of 0.5 mg/kg of body weight given over 40 minutes or IV placebo either two or three times a week for up to 4 weeks.

Patients who discontinued double-blind treatment after at least 2 weeks because of lack of efficacy could enter an optional 2-week, open-label phase in which they received ketamine on the same schedules.

In the twice-weekly group, the mean change in the MADRS score at day 15 was -18.4 for ketamine vs -5.7 for placebo. In the thrice-weekly group, the mean change in the MADRS score was -17.7 for ketamine and -3.1 for placebo.

Similar changes in the MADRS score were observed during the open-label phase. Both regimens were generally well tolerated.

"It's easy for us to philosophize on the ethics of using a drug off label, but when you're seeing a patient in front of you who has failed all prior therapies, there really aren't many options left," Dr Sanacora said. He participated in the study by Dr Singh and colleagues.

"So I think ketamine has the potential to really benefit some people, but we really do have to be cautious about the risks associated with its use. Used in a controlled way, however, I think ketamine could have great clinical benefit," he said.

Dr Nemeroff, Dr Sanacora, and Dr Murrough have each disclosed a number of ties with industry.

Anxiety and Depression Association of America (ADAA) Conference 2016: Symposium 355, presented April 2, 2016.

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