Nancy A. Melville

April 12, 2013

LA JOLLA, California — In the largest clinical trial to test the efficacy of ketamine for the treatment of depression, a single dose of the glutamate N-methyl-D-aspartate receptor antagonist was shown to be significantly more effective than midazolam in reducing treatment-resistant depression over 24 hours.

Most commonly used as an anesthetic agent, ketamine has shown promise in smaller studies as a novel antidepressant capable of offering fast-acting treatment for people with severe depression.

Whereas previous research on the drug's efficacy as an antidepressant largely involved placebo comparisons, the new study, presented here at the Anxiety and Depression Association of America (ADAA) 33rd Annual Conference, compared the drug to another anesthetic.

"The idea was that if ketamine resulted in superior antidepressant outcomes compared to midazolam, we could be more confident that ketamine did in fact possess specific antidepressant effects beyond what would be seen with a different anesthetic agent devoid of intrinsic antidepressant properties," said lead author James W. Murrough, MD, an assistant professor of psychiatry and neuroscience and associate director of the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai, in New York City.

Dr. James Murrough

"In this case, midazolam functioned as an active placebo."

Few Side Effects

For the 2-site study, conducted at Mount Sinai and Baylor College of Medicine, in Dallas, Texas, 72 psychotropic-medication-free patients with treatment-resistant major depression were administered a single 40-minute IV infusion of either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg).

The results showed that at 24 hours following the infusion, patients in the ketamine group (n = 47) had a response rate of 63.8%, compared with 28% in the midazolam arm (n = 25; P = .006).

After controlling for site differences, ketamine was shown to increase the odds of responding by a factor of 2.16 (95% confidence interval, 1.31 - 4.09).

Patients receiving ketamine showed a 16.5-point decrease in Montgomery-Ǻsberg Depression Rating Scale (MADRS) scores (P < .0001), compared with an 8.8-point decrease in the midazolam group (P < .0001).

Side effects, which included dizziness and headache, were more common in the ketamine group; however, both drugs were described as well tolerated. In addition, although ketamine infusion has been previously associated with psychosis symptoms, such symptoms were mild, Dr. Murrough told Medscape Medical News.

"Ketamine is known to cause transient psychoticlike symptoms and dissociation for a brief period while the drug is being administered," he said.

"In our study, we observed increases in measures of dissociation during the infusion of ketamine, which returned to normal levels within 4 hours of the start of the infusion and in most cases within minutes of the end of the infusion."

"However, we observed very little in the way of psychoticlike effects, probably because the dose we are using is very low."

Ketamine is also known to cause increases in blood pressure and heart rate. In the study, one ketamine patient experienced hypotension and bradycardia, but was fine after being kept overnight for monitoring.

Filling a Treatment Gap

In a previous study involving 24 patients and 6 IV infusions of low-dose ketamine (0.5 mg/kg), as reported by Medscape Medical News, Dr. Murrough and colleagues found antidepressant improvement with ketamine extending over 2 weeks.

He noted that an area of particular interest in understanding ketamine's effects on depression is the role of brain-derived neurotrophic factor (BDNF), which appears to show an increase in association with a response to the drug.

"In evaluating BDNF, we found an increase in BDNF levels from baseline, but only in the ketamine patients who responded," he said.

"We also saw a tight correlation in 13 ketamine patients between their plasma BDNF levels and their MADRS score at 4 hours, such that if they had a very low score after ketamine, they tended to show a very large increase in BDNF. In the midazolam group, there was no association."

"The findings are preliminary, but they are starting to suggest that this implicates BDNF in response to depression."

With most antidepressants taking weeks to have effect, the availability of a novel, rapid-acting antidepressant could be of critical value to patients with severe, treatment-resistant depression, but Dr. Murrough cautioned that the understanding of ketamine's safety and efficacy as an antidepressant is still in its infancy.

"There is increasing awareness of the research suggesting ketamine may have antidepressant effects in patients with treatment-resistant forms of depression," he said.

"There are currently very few treatment options for these patients, so clinicians are interested in any potential new treatment options. However, we know very little about the longer-term efficacy or safety of ketamine for the treatment of depression."

"Until more research is done, clinicians should carefully consider the risks and benefits before prescribing this for their patients. I personally would not recommend it at this time, however. It's not ready for prime time yet."

Encouraging Results

According to psychiatrist Scott Irwin, MD, the findings on ketamine are encouraging.

"Ketamine continues to prove to be a safe, rapid-acting, effective, and cheap antidepressant," said Dr. Irwin, an associate clinical professor of psychiatry at the University of California, San Diego.

"Further study is necessary to determine the best route or routes of administration, longevity of the effects, how to get and maintain longevity, and long-term side effects."

In the meantime, studies such as Dr. Murrough's help advance the understanding of such issues, he told Medscape Medical News.

"This study increases the evidence about what we already know about ketamine infusions for treatment-resistant depression over short periods of time, increasing the potential viability of ketamine for mainstream use in depression."

Dr. Murrough is supported by a Career Award from the National Institute of Mental Health. Coauthor Dennis S. Charney, MD, 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 were to receive approval from the US Food and Drug Administration for this indication, Dr. Charney and Mount Sinai School of Medicine could benefit financially. Dr. Irwin has disclosed no relevant financial relationships.

Anxiety and Depression Association of America (ADAA) 33rd Annual Conference. Abstract 403C. Presented April 6, 2013.

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