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Tuesday, August 07, 2007 Why Ketamine Helps Fight DepressionStudying the club drug could bring about faster-acting and more-effective treatments. By Emily Singer
Last year, neuroscientists at the National Institute of Mental Health (NIMH) made headlines with a surprising result. They found that a single dose of ketamine--an anesthetic and club drug known as special K--could relieve depression in some patients in a matter of hours, rather than in the six or more weeks it typically takes for existing antidepressants to kick in. What's more, the drug was successful in a group that is usually extremely difficult to treat: patients who had failed to find relief after trying multiple antidepressant medications. Because of its hallucinogenic side effects, ketamine is unlikely to become a widely used antidepressant. But now researchers think they have discovered how ketamine exerts its fast-acting effect. Several pharmaceutical companies are already developing compounds that target this mechanism, one of which will be tested at the NIMH within the next few months. "In studying ketamine's effects, we may be heading down a path that leads us to treatments that might help the large numbers of depressed people who remain symptomatic despite available antidepressant treatments," says John Krystal, a neuroscientist at Yale University who also studies ketamine. Ketamine is an anesthetic approved by the Food and Drug Administration. It is also widely abused because it produces hallucinations and can trigger an out-of-body experience at higher doses. By understanding the mechanism underlying ketamine's antidepressant qualities, scientists hope to be able to develop novel compounds that mimic the beneficial effects without the accompanying hallucinations. In the brain, ketamine blocks a receptor known as the NMDA receptor, which plays a key role in brain signaling. But according to a new study by Husseini Manji, Carlos Zarate, and their colleagues at NIMH, that's just one part of the drug's biochemical influence. Blocking this receptor actually boosts the activity of another receptor, known as the AMPA receptor. This boost appears to be crucial for the drug's antidepressant effects: when the researchers blocked the AMPA receptors before administering ketamine to mice, the drug no longer stopped depressive behavior in an animal model of the disease. The findings were published last month in the journal Biological Psychiatry. The findings add to a growing body of evidence showing that compounds that trigger AMPA receptors eliminate depressive behavior in animal models of the disorder. While no such compounds have been tested yet in clinical trials for depression, several companies are developing molecules that target AMPA receptors for disorders including schizophrenia, Alzheimer's disease, and attention deficit/hyperactivity disorder (ADHD) and trials for Alzheimer's and ADHD are underway. Zarate and his colleagues are now planning a clinical trial of one such compound for depression. While scientists don't yet know exactly how ketamine works so quickly against depression or why it seems to be effective in a broader group of patients than currently available antidepressants are, they hypothesize that it boosts production of an important growth factor in the brain known as brain-derived neurotrophic factor. Popular antidepressants, such as Prozac, also boost this growth factor, but only after a complex series of chemical reactions. AMPA activation may circumvent this process, acting much more quickly. Directly targeting AMPA receptors may also bypass the drug's psychotic side effects, says Jeff Witkin, a neuroscientist at Lilly Research Labs, in Indianapolis. That's because the hallucinatory component of ketamine's effects is driven specifically by NMDA receptors, rather than by AMPA receptors. "In any other illness of depression's magnitude, patients aren't expected to just accept that their treatments won't start helping them for weeks or months," said NIMH director Thomas R. Insel in a statement released by NIMH. "The value of our research on compounds like ketamine is that it tells us where to look for more-precise targets for new kinds of medications that can close the gap." |
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Drugs to Grow Your Brain
06/02/2008
Comments
RedSevenOne on 08/07/2007 at 5:26 PM
18
Hello Susan Cahill
I note with some distress the following information released today.
[http://www.nih.gov/news/pr/jul2007/nimh-24.htm]
For your reference I give you this link
[http://www.cesar.umd.edu/cesar/drugs/ketamine.asp]
which will clearly explain my concerns and suggest that before there is widespread use promoted that you study the efficacy of rationalizing an already widely abused stimulant.
Best Regards
Martin G. Smith Ph.D - Co-ordinator
RedSeven Services - MATH Not METH
ABOTA*-ONAMISSION
[*A Bridge Over The Abyss]
CC: Dr. Nora D. Volkow
MATH Not METH - http://redsevenone.wordpress.com/
lkrndu on 08/08/2007 at 11:55 AM
18
I applaud Dr. Smith for the cool, academic tone of his warning to Technology Review. I will go much farther.
This article is irresponsible. It fails to note that 'club drug' users regularly off themselves by taking Ketamine, which is critically dose-dependent and too-frequently fatal in small overdoses.
The article implies great hope for the eventual fruits of this research, which I don't doubt in the least. But would it have been too much to ask that there have been even the smallest qualifier, such as to the impression that a SINGLE DOSE can 'cure' depression, and so it -- immediately?
The overall tone, the strongest implication of this article is that, right NOW, one might take Ketamine, have depression lift -- POOF -- and the worst that could happen would be to endure a few pesky hallucinations.
Bald-R-Dash.
I am appalled, and I'm under no academic restraint of politeness not to say so as loudly and as clearly as I possibly can. In my book, Technology Review is obligated at this point to publish, immediately and as or more prominently than it published the original article, a complete context for this research. And a very strong warning.
My sources, besides common sense, include private communications with responsible parties to neurobiological research, who use Ketamine in the course of their work as an animal anesthetic.
Sincerely,
Bob Tyson
Turin, Italy
DemiHampster on 08/08/2007 at 1:41 PM
1
wesc on 08/13/2007 at 1:13 PM
1
The huge safety factor is the reason why ketamine is used as an anasthetic in animals, military field medicine, and i believe most recently on the elderly and youngsters.
Deskdiva on 08/09/2007 at 10:05 AM
2
lkrndu on 08/10/2007 at 4:09 AM
18
A demi-hamster? How'd that lab rat widda furry tail get in here?? Well. Sit up, boy! That's right. Here, take your little dose 'o' Ketamine! Feel good? Oh. Oh-oh. Drat. Hallucinations must've got the better of 'im. Better luck next time.
Gosh, that was fun!
This is a very dangerous drug and again I call on TR to take responsibility for irresponsible journalism in how it has 'spun' this article.
I can see my middle-school students, dauntless and reckless, seizing on this as perfect license. And if that won't make anybody sit up, just wait until their PARENTS get into the act....
Deskdiva has it right. And survived to write about a terrifying experience. Then there are those who go out, screaming. Until they scream no more.
The graphic accompanying the article is shameful: the club-drug package. Stars and stripes, forever, right?
splink on 09/03/2007 at 3:02 PM
1
As a long-time sufferer of treatment-resistant major depression, and having taken 16 medications over the years, I can tell you that many can have drastic, terrible effects, even when taken exactly as prescribed. Ever heard of serotonin syndrome? I was unlucky enough to experience this when transitioning from one SSRI to another. It was as if every nerve in my body was firing simultaneously and uncontrollably: muscle tension, shaking, extreme pain, extreme overreaction and sensitivity to any stimulus, and definitely a profoundly unpleasant altered state of consciousness for the better part of a day. Other meds like several tricyclics caused severe cramps and muscle spasms that left me unable to eat, or even open my jaw. One dose of trazodone left me on my back for three days, feeling like I'd been hit by a truck. These are all approved antidepressants, administered to me as an outpatient and taken as prescribed or under the direct supervision of psychiatrists.
Nevertheless, after 18 years of struggle with this demon of a disease, and its ineffective and distressing treatments, I continue with new methods of treatment and look for new research ideas that may present clues to the mechanisms of my particular treatment-resistant variety. In the worst times, I wish I had the energy to bring death to myself. Such a vile, pathetic struggle of existence is what leads many to suicide, and to past drastic treatments like electro-convulsive therapy that do provide some immediate relief.
This is not hyperbole, as borne out by the numbers of depressives who also "off themselves," as Bob Tyson so callously put it. What is hyperbole is his statement that the article gave an "impression that a SINGLE DOSE can 'cure' depression... immediately." The specific word was "relief," and anyone such as myself that has suffered with this disease chronically knows that as much as can be hoped for is a little relief sometimes, and a *cure* is something we can't put hope in in our foreshortened lifetimes. Further, as I described above, we are well aware that many (and for me, most) treatments have severe side effects that make considering their use a careful weighing of possible benefit to further distress and destabilization of life through their bad effects. Am I going to go out and try some "Special K" to try to find relief on my own? Hell, no. Would I participate in a controlled study that uses sub-hallucinogenic levels of ketamine (this is the protocol) and looks for anti-depressive effects? Only after carefully looking at any other effects it may have, both short and long term. (Did I mention the liver damage that "safe" antidepressants like nefazodone and other medications have done over the years?) Participation would be with the hope that if not helping me, perhaps it will help others in the future by revealing mechanisms and the creation of other compounds.
The article was not about using ketamine as an antidepressant, as anyone that read through it with any care can see. It is about the clue provided by an unexpected effect of a ketamine dose, and research into compounds that directly act on the AMPA receptor and may be another mechanism for treatment of as yet untreatable varieties of depression-- hopefully without such a terrible trade-off as ketamine, and many *approved* antidepressants, present. Actually, for me, "trade-off" is not accurate. While causing many problems, none provided any significant benefit. Where's your outrage at my many terrible experiences with meds and 18 lost years of my life, Bob?