Kathleen Louden

October 23, 2013

SAN FRANCISCO — Researchers have identified biomarkers that they hope will eventually help predict which patients with bipolar depression will respond to subanesthetic doses of ketamine.

An experimental blood test using pharmacometabolomics found patterns, or metabolic "fingerprints," that differ between people whose bipolar depression improved with intravenous ketamine and those who did not get better. Pharmacometabolomics uses sophisticated chemistry techniques to quantify and analyze metabolites that the body produces in response to drugs.

"This work is telling us what we should measure [in the blood]," study coauthor Irving Wainer, PhD, from the National Institute on Aging's Intramural Research Program in Baltimore, Maryland, told Medscape Medical News. "Then we'll develop the technology to predict, pretreatment, which patients will respond to ketamine treatment and find ways to individualize and optimize treatment with ketamine."

The research findings were presented here recently at the American Society of Anesthesiologists (ASA) 2013 Annual Meeting.

Rapid Antidepressant Effect

Recent studies of this investigational use of ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, show that many patients with treatment-refractory bipolar depression ( Biol Psychiatry, 2012;71:939-946) or other types of major depression respond rapidly to intravenous infusion of ketamine — typically in several hours.

However, 1 in 3 patients do not respond to this treatment at all, said another author of the new study, Michael Goldberg, MD, an anesthesiologist from Cooper University Health Care in Camden, New Jersey.

"It's not ethical to put everyone [with depression] on ketamine because it has risks. Hallucinations are common and may require other medications to counteract," Dr. Goldberg told Medscape Medical News.

Knowing before ketamine administration who would be least likely to benefit would spare them from exposure to the drug and its common dissociative side effects, he said.

Toward that end, the researchers collected blood samples from 22 patients with bipolar disorder and major depression both before and after a single intravenous infusion of 0.5 mg/kg of ketamine or a placebo; the patients then were crossed over to the alternate therapy after a 1-week drug washout.

Patients also received treatment with either lithium (n = 16) or valproate (n = 6) as a mood stabilizer and responded to this therapy, according to Dr. Goldberg. Response to ketamine was identified 230 minutes after infusion using the Montgomery-Åsberg Depression Rating Scale.

The investigators analyzed the metabolomic patterns in the blood samples using liquid chromatography/quadruple time-of-flight mass spectometry and capillary electrophoresis/laser-induced fluorescence.

They also reportedly identified the compound that ketamine breaks down into, which they called 2S, 6S hydroxynorketamine.

Quick Turnaround Test

In the group receiving comedication with lithium, patients who did not respond to ketamine treatment ("nonresponders") had significant post-treatment differences in 18 metabolites compared with ketamine responders, according to the abstract (P values not reported).

These included significantly increased levels of the fatty acids phenyllactic acid and monoglyceride and significantly decreased levels of trimethyl-L-lysine, lysophosphatidylethanolamine, and lysophosphatidylcholine.

The same trend was seen in the patients receiving valproate, but the number of patients in this group was not large enough to determine statistical significance, Dr. Goldberg stated.

Independently of the mood stabilizer, nonresponders also reportedly had significantly higher levels of the amino acid D-serine. In their abstract, the authors suggested a difference in the activity of the enzyme serine racemase between responders and nonresponders, possibly owing to an indirect change in NMDA receptor activity.

Although most patterns observed in metabolites were of fatty acids, some were metabolites of ketamine, Nagendra Singh, PhD, said during the oral presentation of the findings. Dr. Singh, who was not a coauthor of the study, will soon be joining Cooper University Health Care as a research associate.

Of 323 metabolites analyzed, only 2 were reportedly the same between the lithium and valproate groups.

"Two different mood stabilizers had very different metabolite patterns in their fatty acids, which was very interesting," Dr. Singh said. "This clearly demonstrates that lithium and valproate affect fatty acids differently."

The researchers speculated that patients with bipolar depression respond to ketamine on the basis of various endogenous factors, including fatty acid metabolism and the plasma levels of endogenous compounds involved in neurotransmission.

A limitation of the study, said Dr. Wainer, is that it was not designed prospectively for pharmacometabolomics. He described the pharmacometabolomic process as "time-consuming and costly."

Dr. Wainer said his team plans to limit future analyses to 5 or 6 metabolites.

"Our goal is to develop the technology so that there will be on-site rapid turnaround of blood test results," he said.

Not Ready for Routine Use

Commenting on the study for Medscape Medical News, Timothy Lineberry, MD, associate professor of psychiatry at Mayo Clinic, Rochester, Minnesota, said that identifying who will benefit from and have good response to ketamine is important.

Dr. Lineberry, who was not involved with the study, said that there are not yet enough research data for physicians to routinely use ketamine in clinical practice for this off-label purpose.

"There is also a need for identifying what are the psychological markers associated with response to ketamine and the particular diagnoses that will respond to treatment," he added.

The next patient population in which Dr. Goldberg said their research team plans to study pharmacometabolomics after ketamine infusion is those with post-traumatic stress disorder.

Dr. Goldberg disclosed that he, Dr. Wainer, and coauthor Marc Torjman, PhD, also of Cooper University Health Care, have filed a US patent on the creation and use of the metabolites, in conjunction with the National Institutes of Health. Dr. Lineberry and Dr. Singh report no relevant financial relationships.

American Society of Anesthesiologists (ASA) 2013 Annual Meeting. Abstract 2008. Presented October 13, 2013.


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