Now, a number of drug companies, as well as academic institutions, have seized on the glutamate system to test new antidepressant medications. One of the drugs being tested by Yale researchers is Riluzole, which is FDA-approved to treat Lou Gehrig's disease but has shown benefits in treating depression. Pfizer, AstraZeneca and other companies are testing other drugs that modulate glutamate.
Ketamine, which is sold as a generic and under the brand names Ketalar and Ketaject by Pfizer, is the subject of multiple trials.
"As of right now, the initial studies are promising in concept. But in terms of bringing ketamine to clinical practice, we still have some important unanswered questions," such as whether repeat doses work over time, Sanacora said. On the other hand, he said, if glutamate-altering drugs are shown to be effective, "they could be available fairly quickly. We could be looking at a new class of drugs in the next five years."
Chasing Glutamate In Alcoholism, Suicidal Behavior
Ketamine also has drawn interest from researchers studying alcohol addiction, largely because of findings indicating that the drug's negative effects are blunted, and positive effects more pronounced, in people with a family history of alcoholism.
Researchers at Yale and the West Haven VA are now conducting a study to gauge the effects of ketamine on mood and alcohol consumption in patients with both depression and alcohol dependence.
"Our hypothesis is that it might work particularly well on depression" in patients with both conditions, and that it also might "reduce cravings," said Dr. Ismene Petrakis, chief of psychiatry for the VA Connecticut Healthcare System and principal investigator on the study. "The thinking is that alcohol is a little like ketamine, so if you drink for many years and you're blocking your NMDA receptors, your body might compensate."
A prior study led by Petrakis indicated that underlying alterations in NMDA receptors may make some people less likely to get the "warning signs" to stop heavy drinking, the study suggested.
"If there's some underlying problem with NMDA receptors [in people with alcoholism], ketamine might be something that can address that," Petrakis said.
Krystal, of Yale, who began studying ketamine in relation to schizophrenia in 1989, said some hospitals and psychiatric facilities are now administering the drug on a "compassionate use" basis, when all other antidepressant treatments have failed. In Houston, for example, doctors affiliated with the Ben Taub General Hospital and the Baylor College of Medicine are giving ketamine to severely ill patients who have not responded to any other treatment.
A pilot study by Yale researchers found that a low dose of ketamine "rapidly reduced" suicidal thoughts in 20 patients who showed up in the emergency room with severe depression and suicidal ideation. A second study, by NIMH researchers, had similar results.
But more important than the drug itself, ketamine researchers said, is understanding more about the way it works.
"I think it is a great drug to tell us about the [glutamate] mechanism, but we have to wrestle with whether it's the best drug for depression," especially given dosing questions and the risks of abuse, Krystal said. "We view it still mostly as a research tool."
Charney said the ketamine PTSD study was underway, and it was too early to discuss results. Just last month, in another indication that the two FDA-approved drugs for treating PTSD were lacking, the Army announced plans to launch a multiyear study to evaluate the effectiveness of a range of medications that are being prescribed "off-label" to treat PTSD.
On the other hand, recent research has shown potential benefits of a drug called D-cycloserine (Seromycin), which is a partial blocker of the NMDA receptor. One study found that D-cycloserine reduced fear and anxiety in patients who were receiving exposure therapy, a technique used to treat PTSD.
As more veterans return home with PTSD, researchers say science needs to catch up — quickly. Krystal and others are hopeful that glutamate might be a new frontier.
"One of the challenges we have in the PTSD field is that there has been so little study of medications," Krystal said. "As prevalent as [the disorder] is, there is just not much research out there. That has to change."
This story was reported under a partnership with the Connecticut Health I-Team (www.c-hit.org).
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