‘Cautious Optimism’ Marks Outlook for Ketamine, Mood Disorders

Ketamine for mood disorders—risks, benefits, pros, and cons—may be among the biggest stories in psychopharmacology today.

Dozens of articles on use of ketamine for major depression have appeared in Psychiatric News in the last two years—including a December 2017 report in the American Journal of Psychiatry (AJP) suggesting a single dose of the agent may be effective in treating suicidality—and hundreds of others have appeared in the medical and lay press.

Meanwhile, there has been a proliferation of ketamine infusion centers offering off-label treatment for mood disorders. The Ketamine Advocacy Network lists 25 centers around the country, but an online search suggests this number may be more likely in the hundreds. (The network acknowledges that providers of ketamine infusion may not be included on their list for a variety of reasons: extraordinarily high fees; practices or protocols not supported by multiple peer-reviewed studies; or marketing strategies that include claims unsupported by evidence, or serious factual errors about ketamine’s pharmacology or its mechanism of action.)

Gerard Sanacora, M.D., Ph.D., lead author on a consensus statement produced by an APA work group last year, says the promise of ketamine—and its potential perils—make for a unique situation.

“Here is a drug that may have some real benefit for patients, especially those who have not experienced satisfactory relief from standard treatments that are available,” he told Psychiatric News in an interview. “Yet it’s a drug that carries a little bit more baggage than is typical.”

Because it was first approved as an anesthetic in 1970, ketamine cannot be patented, so pharmaceutical companies have no incentive to undertake extensive clinical trials for it to be approved for a new indication. Moreover, ketamine has been used recreationally as a “party” drug, and carries with it the risk of abuse.

“With all this in mind, it was agreed that APA should develop some expert consensus with the understanding that there isn’t enough information to generate formal treatment guidelines,” Sanacora said.

“We took the approach that since we can’t offer firm treatment guidelines, we could at least highlight the potential risks and benefits and make people aware of both the potential for this drug and the concerns that surround it without overstepping the boundaries of what’s known.”

The consensus statement was the product of a work group of the APA Council on Research Task Force on Novel Biomarkers and Treatments. Work group members, in addition to Sanacora, included past APA Presidents Alan F. Schatzberg, M.D., and Paul Summergrad, M.D. Other authors on the consensus statement were Mark A. Frye, M.D, William McDonald, M.D., Sanjay J. Mathew, M.D., Mason Turner, M.D., and Charles Nemeroff, M.D.

A paucity of evidence regarding the effectiveness of ketamine for mood disorders informs the entire the consensus statement. “There still is relatively little high-quality peer reviewed published information beyond very short treatments,” Sanacora said.

The consensus statement cites an October 2015 paper in AJP that found seven published placebo-controlled, double-blind randomized clinical studies on ketamine hydrochloride infusion as a monotherapy for the treatment of depression, comprising 147 treated patients. Five studies have been done looking at ketamine as an adjunct to electroconvulsive therapy, according to the AJP report. At least one study has compared ketamine and placebo for obsessive-compulsive disorder.

The promise of ketamine for mood disorders is real. “There is evidence that in a significant proportion of patients who have not received satisfactory benefit from standard antidepressant treatment, ketamine can offer a very rapid antidepressant effect,” Sanacora said. “We are talking about within four hours.”

Perhaps the most exciting possible use for ketamine is in suicidal patients. A meta-analysis published in AJP last October found that a single infusion of ketamine appears to significantly reduce suicidal thoughts in depressed patients in as little as one day, with benefits lasting for up to one week. “If this potential is borne out, we don’t want to prevent people from getting that treatment,” he said.

But the risks are just as real. “There are changes in cardiovascular function including increases in heart rate and blood pressure consistent with doing a moderate level of exercise. For most people this isn’t going to be a real problem, but you need to screen patients who cannot maintain this level of cardiovascular challenge,” he said.

There are also psychological effects, including changes in cognition and perception that can last for a couple of hours after dosing. And the longer-term risk is for abuse of a drug that has a history of being used recreationally and is still prominently a drug of abuse in some parts of the world. “The question about long-term use of ketamine is whether we are putting patients at risk of addiction,” Sanacora said.

He noted that there have also been reports in the media of clinics offering take-home kits of self-administered ketamine—a practice Sanacora said creates the potential for drug diversion.

The work group consensus statement provides an overview and expert clinical opinion on six critical issues and considerations associated with the off-label use of ketamine treatment for mood disorders:

“However, there remain no published data that clearly support this practice, and it is strongly recommended that the relative benefit of each ketamine infusion be considered in light of the potential risks associated with longer-term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing administration,” Sanacora and colleagues wrote. “The scarcity of this information is one of the major drawbacks to be considered before initiating ketamine therapy for patients with mood disorders and should be discussed with the patient before beginning treatment.”

So, what does the future look like for the use of ketamine for patients with mood disorders?

Sanacora said one important development will be clinical trials of “mirror” molecules of ketamine, such as esketamine, which are scheduled for phase three trials in 2018. Some chemical compounds, such as ketamine, are composed of left and right molecules that mirror each other; the mirror image of ketamine, if found to be effective, can be marketed profitably by a pharmaceutical company.

More and longer-term trials of ketamine are also a must. Sanacora and colleagues wrote in the consensus statement: “Although economic factors make it unlikely that large-scale, pivotal phase 3 clinical trials for [the originally approved ketamine compound] will ever be completed, there are several studies with federal and private foundation funding to address some of these issues. It is imperative that clinicians and patients continue to consider enrollment in these studies. … A second means of adding to the knowledge base is to develop a coordinated system of data collection. … After such a registry is created all clinicians providing ketamine treatment should consider participation.” ■