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Nancy A. Melville

June 7, 2012 (Phoenix, Arizona) — The administration of 6 low-dose intravenous infusions of the fast-acting drug ketamine over 2 weeks shows efficacy in improving symptoms in patients with treatment-resistant depression, new research shows.

Ketamine, an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, is best known in medicine as an anesthetic but also has some notoriety as a street drug, sometimes dubbed "Special K" and taken for its psychedelic effects.

However, the drug has gained interest among researchers for its potential as a unique, rapid-onset antidepressant capable of quickly improving symptoms in severe or treatment-resistant depression.

"[Ketamine] may rapidly reverse prefrontal cortex–based deficits in depression at the neurocircuitry level, leading to an amelioration of clinical symptoms," said study investigator James W. Murrough, MD, a research fellow in Mount Sinai's Mood and Anxiety Disorders Program in New York City.

http://img.medscape.com/thumbnail_library/ht_120607_dr_james_w_murrough_120x156.png

Dr. James Murrough

Dr. Murrough presented the study findings here at the New Clinical Drug Evaluation Unit (NCDEU) 52nd Annual Meeting.

Significant Symptom Reduction

A recent study by Dr. Murrough and colleagues published in Clinical Pharmacology and Therapeutics showed that in low doses, ketamine appears to "enhance the strength of cortical synapses through NMDAR- and AMPAR-dependent and neurotrophic mechanisms."

Most studies to date, however, have looked at the drug only in terms of a single-dose treatment, and the effects were measured over the course of hours or a week.

In an effort to evaluate the drug's effect in repeated administrations over the course of 2 weeks, the investigators conducted a study involving 24 patients with treatment-resistant depression.

After undergoing a washout of antidepression medication, patients were treated with a series of 6 intravenous infusions of low-dose ketamine (.5 mg/kg, which is about one quarter of the 2 mg/kg typically used as an anesthetic), administered 3 times a week over the 2 weeks. The patients were then monitored for up to 3 months or until a relapse.

The results showed a significant decrease in depression during the 2-week treatment phase, with an overall improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to postinfusion number 6 of 22.8 points (mean baseline MADRS score, 32.1 ± 6.0; endpoint MARDS score, 9.3 ± 11.3).

As many as 70.8% (17 of 24 participants) had a reduction of 50% or more in their MADRS score at the study's endpoint, compared with baseline. The remaining 29.2% (7 of 24) were considered nonresponders.

The median time to relapse in the follow-up phase was 20 days (range, 4 days to >3 months). Four participants did not relapse during the 3-month follow-up; the estimated risk of remaining relapse-free for up to 83 days was .25 ± .11.

"The cumulative rate of relapse was 75%, which is about what you would expect — you stop the treatment and people relapse, so we need to figure out some kind of maintenance strategy, and in doing so, it would be interesting to look at those patients who didn't relapse," Dr. Murrough told Medscape Medical News.

As has been previously shown, improvement in depression symptoms with ketamine was rapid and statistically significant, as demonstrated in an improvement in MADRS score from baseline to 2 hours of 18.9 ± 6.6 (decrease from 31.8 to 12.9, P < .001).

About 40 minutes into the infusion, a minority of patients begin to feel some of the sedative or cognitive impairment effects of the drug, but Dr. Murrough said that in all cases, those effects resolved in less than 1 hour after the infusion.

Importantly, it became evident which patients would be nonresponders within 4 hours after the first infusion, and the separation between the two was large at 24 hours after the first infusion (8.35 ± 4.2 vs 18.8 ± 5.5, P = .002).

"We knew within 2 hours basically who would respond to the overall 2-week course of ketamine, which is remarkable," Dr. Murrough said.

"With standard antidepressant therapies, you often have to wait 1 to 2 months before you know whether they are working, so this really has major public health implications if it holds up."

The patients' response status at the study's endpoint was strongly predicted by their response to the first ketamine administration.

Need for More Research

Although the findings shed light on a potentially important and effective new treatment approach with ketamine, the results will need to be tested in more robust studies, said Carlos A. Zarate, Jr, MD, chief of the Experimental Therapeutics and Pathophysiology Branch in the National Institute of Mental Health's Division of Intramural Research Program.

"I would say the research is interesting and promising, but that 20 days is a bit short," Dr. Zarate told Medscape Medical News.

"Larger sample sizes, longer duration of follow-up, and a comparison group are needed to know for sure. But as I said, this is a promising line of research to pursue."

Owing to its fast-acting nature, ketamine has been evaluated for use in emergency departments to treat extremely depressed or suicidal patients.

In one recent study, researchers with Yale University School of Medicine found that when treated with a single subanesthetic IV bolus of ketamine (.20 mg/kg over 1 to 2 minutes), the suicidal ideation of 14 suicidal patients in an emergency department completely resolved within 40 minutes, and the improvements were sustained over 10 days.

New Generation of Antidepressants

Paul E. Holtzheimer, MD, agreed that the findings on the 2-week low-dose administration are intriguing, but he said that ketamine's true value for treatment-resistant depression could lie in the insights it provides for development of a similar, more optimized drug.

"I personally think it's unlikely that ketamine itself will become a standard treatment for depression, but given that we know very well how it works in the brain as an NMDA glutamate receptor antagonist, it provides clues to a potential drug target that hasn't been exploited fully yet," said Dr. Holtzheimer, an associate professor of psychiatry and surgery and director of the Mood Disorders Service at Dartmouth Medical School and Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

"I think what we're learning from ketamine will hopefully be very helpful in developing new antidepressant medications that could have a more rapid onset," he told Medscape Medical News.

"If you can give it orally or through a patch or some other administration continuously, you may be able to maintain the effect over time."

Dr. Murrough agreed that the ketamine findings may indeed help blaze trails into areas of depression treatments, but he argued that the drug itself could have important value in helping patients not later, but now.

Urgent Need

"Our feeling is the utility of clinical research on ketamine is 2-fold. First, it can indeed help open new avenues of drug discovery, and in better understanding its mechanism, maybe we can develop a new generation of more effective, rapidly-acting antidepressant treatments."

"But the fact is, new treatments for patients with severe depression are urgently needed now, and there's no reason to think this couldn't be developed into an actual treatment that could be given, for instance, in hospital-based settings," he said.

"For patients in such settings with severe depression who have not responded to previous treatments, the options are pretty limited, and right now, a main approach is electroconvulsive therapy (ECT), but ketamine could represent a more benign but possibly equally effective choice."

Aside from its use as an anesthetic, ketamine is currently used in the treatment of chronic pain, so there is a precedent in using the drug off label, Dr. Murrough said.

He noted that although the need to administer the drug intravenously is an obstacle to more widespread use, the Mount Sinai research team is also exploring the possibility of administering the drug as a nasal spray.

"In the limited research on ketamine, it looks like it is quite robust in its effect and very well tolerated, so I think we would be hard-pressed to argue that we shouldn't consider turning it into a treatment," Dr. Murrough said.

The project was supported in part by grant UL1RR029887. Dr. Murrough is supported by a Career Award (K23MH094707) from the National Institute of Mental Health. Coauthor Dennis S. Charney has been named as an inventor on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the US Food and Drug Administration for this indication, Dr. Charney and Mount Sinai School of Medicine could benefit financially. Dr. Zarate reports that he is involved in a patent application for the use of ketamine. Dr. Holtzheimer reports that he is a consultant for St. Jude Medical Neuromodulation and for Cervel Neurotech. Dr. Holtzheimer recently received an honorarium for giving a talk to investigators at a Johnson and Johnson symposium on mood disorders.

New Clinical Drug Evaluation Unit (NCDEU) 52nd Annual Meeting. Presented May 20, 2012.

 

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