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Glutamate for MDD! Mainstream Washington Post article


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I found this article very readable:

http://www.washingtonpost.com/wp-dyn/conte...6092501387.html

Also, Googling on glutamate and depression brings up documentation over the past several years pointing to the glutamate connection as well. As always, the Northern Europeans are light years ahead of the Americans on clinical research.

What good does it do for a country, winning Noble prizes and such, if we can't even manage bringing a known MDD remedy to market in synch with other countries?

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The scientific article announcing this was released last month. I don't have a ready link, but the gist is that volunteers were given small injections of Ketamine, and experience relief from severe depression within a few hours. The effect last for only, and precisely, 7 days. Repetition of the Ketamine injection on schedule provided sustained relief.

Now, getting a weekly injection is not a convenient nor cost effective treatment method. And ketamine has both a high abuse potential, and the danger of causing psychosis. No doubt, the researchers are looking for both alternative methods of delivery, as well as daughter compounds or metabolites that could be used instead.

I think your conclusion that the US research establishment is somehow incompetent and clueless on glutamate research is unfair and unsubstantiated. First, this new use for Ketamine hasn't been previously reported by Europeans. I did a quick survey of PubMed, and find that since January at least 110 articles have been published on various aspects of glutamate pathways and applications. Over 40 of these citations are in publication for September 2006. Obviously the entire scientific establishment is attacking this problem tooth and nail.

a.m.

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much of the current ocd research seems to point to a glutamate over transmission problem as well. the oc foundation newsletter reprinted a yale study investigating the efficacy of three different possible glutatamate modulating agents. i don't know if i can find a link of that online, since they only seem to have the latest newsletter, but to wit the three agents they cited were

a ) riluzole (Ritulek)

b ) n-acetyl cysteine (an amino acid supplement you can find at any vitamin store)

c ) Ceftriaxone (an FDA approved antibiotic)

all three trials pointed to potential success in being effective glutamate modulating agents. (this is in the Winter 2006 issue of the OC Foundation newsletter btw, if you can find a copy somewhere)

a couple weeks later, as i was randomly looking through the journals in the central library, i came across a study in the Journal of Psychiatry showing success with riluzole in patients with MDD. i gave a copy of the oc foundation newsletter to my pdoc the last time i saw him, and he seemed pretty interested in it, but i think he said he couldn't currently prescribe riluzole and Ceftriaxone because they didn't fall under the approved list of drugs for conditions he could treat. i'll have to ask him about the riluzole again though.

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i dont know about this whole thing, but i havent heard of MSG (monosodium glutamate, a common salt form of glutamate) having any medicinal benefits... quite the contrary actually.

i think ketamine is an NMDA antagonist (n-methyl d aspartate) which is a type of glutamate (and aspartate) receptor, but there are other ones such as AMPA receptors that are affected by lamictal actually (or was that kainate receptor.. i forget.)...

id like to see more research, and i think ketamine would make anyone feel better:) but that doesnt make it an antidepressant ;)

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i don't think anybody's claiming that glutamate helps. i thought that was pretty clear from the beginning, but i didn't read the Washington Post article. all the stuff i've read (especially the Yale study reprinted in the OC Foundation newsletter) is looking for medicines to reduce glutamate transmission. that's what all three drugs in their study promised to do to some extent. it was only a couple of days ago that i made the connection to monosodium glutamate, or glutamate being an amino acid at all. (but isn't that like nature to make something that tastes good to us fuck up our mental illnesses some more? well mine at least)

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I can't find the report from this year. Here is one from 2000.

Biol Psychiatry. 2000 Feb 15;47(4):351-4. Links

Antidepressant effects of ketamine in depressed patients.Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH.

Abraham Ribicoff Center Clinical Neuroscience Research Unit of the Connecticut Mental Health Center, New Haven 06519, USA.

METHODS: Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) ....

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looks like nobody's interested in examining glutamate's role in MI right now. or i'm just being pissy because this thread hasn't gotten the response i imagined it could. anyway, here's the abstract i mentioned earlier - from the american journal of psychiatry - about using Riluzole (a glutamate modulating agent) in the treatment of MDD. i'm guessing there would be less hackles raised with riluzole, then ketamine

http://ajp.psychiatryonline.org/cgi/conten...tract/161/1/171

An Open-Label Trial of Riluzole in Patients With Treatment-Resistant Major Depression

Carlos A. Zarate, Jr., M.D., Jennifer L. Payne, M.D., Jorge Quiroz, M.D., Jonathan Sporn, M.D., Kirk K. Denicoff, M.D., David Luckenbaugh, M.S., Dennis S. Charney, M.D. and Husseini K. Manji, M.D., F.R.C.P.C.

OBJECTIVE: This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in patients with recurrent major depression. METHOD: After a 1-week drug-free period, subjects 18 years or older with a diagnosis of recurrent major depression and a Montgomery-

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hiya SP-

i hope this reply takes your thread in the direction you were hoping which sounds like away from the scientific principles of the substance and more towards the reasons we don't use it here...

i think that we are afraid to study it and learn more, and potentially use it, because the drug companies have such a strangle hold on politics in this country. anything natural or non-traditionally pharmacutical would fall under the catagory of "no can do" by the people funding the political campaigns. i think it is a wider issue that points to the corruption in our government, including even our own health care.

why are we not studying medical marijuna (spelling)? why are we not studying theraputic esctasy? i think the medical establishment is afraid of what these substances could do to their money engines, and discourage politicians from freeing-up laws that would allow for more study.

especially the medical marijuna (spelling). why are they so against that? it seems like a lot of people, including some doctors i met in germany, benefit from it medically.

this is just my opinion. this option needs further study and is being blocked by the big pharma companies because it would take away from zoloft and paxil sales.

loon

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We're not studying medical marijuana and (for the most part) not studying therapeutic ecstasy because it's almost always impossible to get funding and ethics board / FDA approval for it. It's not a conspiracy by the medical establishment so much as the decision, on the part of a lot of individual researchers, to not tank their careers by investing time and money into planning studies they'll never be allowed to run.

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looks like nobody's interested in examining glutamate's role in MI right now. or i'm just being pissy because this thread hasn't gotten the response i imagined it could. anyway, here's the abstract i mentioned earlier - from the american journal of psychiatry - about using Riluzole (a glutamate modulating agent) in the treatment of MDD. i'm guessing there would be less hackles raised with riluzole, then ketamine

MI researchers aren't stupid, nor un-ambitious. If you feel no one is adequately researching APPLIED medications and glutamate, then it is because they judge that the science of glutamate is not at the point of being used at the clinical level. Not result of some conspiracy or incompetence.

In fact, it could be that 100's of researchers have trials underway, but are not at the point of publishing results. "You can't know what isn't published yet".

I, on the other hand, am encouraged by what you have pointed out about glutamate receptors and influence. Again, I'll remind you that something like 100 articles about glutamate have been published this calendar year, with 4 months left to go.

a.m.

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[sarcastic nonsense removed]

In any event, I'd bet that glutamate is in its infancy of study anyways, and what we do know is that the NMDA/AMPA stuff controls some very basic processes in the brain.

For example, NMDA receptors need to be activated to perform long-term potentiation, as well as for its opposite, the pruning process of long-term depression (don't confuse that with MDD).

So, if you go block NMDA receptors, depending on various factors in the blockade, you could decrease the brain's abilities to store new memories in long-term, and also to remove old memories from long-term. That conclusion was just hypothetical, of course, and research is slowly starting to show evidence for it.

There have been people out there who think that blocking the NMDA system could help us depressives by in fact, making us stupider. Well, moreover, people with cognitive-based depression who have an issue learning too much "long-term helplessness".

Wouldn't be sure it'd have any applications in PTSD given that NMDA blockade would just keep old traumatic memories in, but I'm going off the deep end in terms of hypotheticalness.

OTOH, as pointed out here, NMDA activity in schizos is often seen to be diminished... wouldn't surprise me, since NMDA receptor blockade is well-known to cause increases in dopamine. So yes, NMDA blockade wouldn't be too suitable for anybody who's schizo or otherwise psychosis prone.

in any event, null0trooper knows one hell a lot more about this NMDA stuff than I do, so maybe he'll jump in at some point and help out.

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in any event, null0trooper knows one hell a lot more about this NMDA stuff than I do, so maybe he'll jump in at some point and help out.

Not so much the NMDA receptor stuff, although some of the research has looked interesting. But yeah,

I've made a point to read up on the high-dosage use of dextromethorphan ;)

The subjective experience from repeated dissociative use seems to be not a blockade of memory

formation but an alteration of the storage encoding. If that is the case, memory-retention would be

affected by both the current medication state and the medication state at the time of learning.

On the bright side, some of those awful memories stored as a kid (or last week) could be kept buried

so long as you kept taking your medication. On the dark Side: Run out and oops! back come the bad

memories! In the meantime, all the coping strategies you picked up in therapy are scrambled because

the pharmacologically-altered pathways they were stored in are missing their chemical decoder key.

So the brain makes do with what it can call up and you hope it's good.

Come to think of it, that DOES sound like a middle ground between DID and schizophrenia.

Any volunteers?

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Not so much the NMDA receptor stuff, although some of the research has looked interesting. But yeah,

I've made a point to read up on the high-dosage use of dextromethorphan ;)

The subjective experience from repeated dissociative use seems to be not a blockade of memory

formation but an alteration of the storage encoding. If that is the case, memory-retention would be

affected by both the current medication state and the medication state at the time of learning.

Dextromethorphan is a bizarre creature as far as NMDA antagonists go... I guess you could say it's the Rennaissance man of the family... having direct effects on NMDA, DA, 5HT, Sigma/PCPR, and NE... and not doing any one of them all that powerfully (NMDA antagonism is its strongest suit, but it's not even remotely near ketamine in that department).

That aside, I'd like to know what your definition of "repeated dissociative use" is. There's low-dose chronic ("therapeutic") use, as well as intermittent high-dose (recreational) use of varying frequency.

I assume you're speaking of the more recreational usage, and in particular, changes in memory state encoding that occur during periods of intoxication. Of course, you might also mean that periods between uses will also have altered memory encoding.

On the bright side, some of those awful memories stored as a kid (or last week) could be kept buried

so long as you kept taking your medication. On the dark Side: Run out and oops! back come the bad

memories! In the meantime, all the coping strategies you picked up in therapy are scrambled because

the pharmacologically-altered pathways they were stored in are missing their chemical decoder key.

So the brain makes do with what it can call up and you hope it's good.

Depends on dosage and frequency, again. I have no idea if low-dose therapeutic use of NMDA antagonists would behave anything like high-dose intermittent recreational usage (which given the popularity of rec. use of ketamine and PCP, and to some extent, dextromethorphan, is probably much more well-studied than therapeutic use!).

I would assume that having cognitive-behavioral therapy performed while intoxicated on PCP may be somewhat counterproductive in terms of use of therapy-learned mechanisms outside times of intoxication. Then again, I'm sure there are, or at least have been, psychiatrists who would disagree with me on that.

And in any event, to "run outside of your medication world" is something that's scary with the idea of leaving any psychotropic medication behind, and NMDA antagonists would be no exception, whether or not your idea applies to acute intoxication or chronic low-dose usage.

Come to think of it, that DOES sound like a middle ground between DID and schizophrenia.

Any volunteers?

Your proposal is dangerously tempting for me, at least the schizophrenia part. I could make do with the subtle delusions of denial that others seem to have... delusions that keep them sane, after all, if we were all 100% grounded into reality without any idealism, this world would be an ugly place.

...now if you'll excuse me, I have to convince my hysterical mother that giving the phone to my father (who's down here visiting me) will not result in him yelling at her. As tempted as he might be to.

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That aside, I'd like to know what your definition of "repeated dissociative use" is. There's low-dose chronic ("therapeutic") use, as well as intermittent high-dose (recreational) use of varying frequency.

Recreational use. I don't recall it being reported as being strongly dissociative within the OTC recommended

dosing (unless you are on Wellbutrin - that whole enzyme inhibition deal.) There's an entire spectrum of

dosage-dependent effects that could be "recreational", even therapeutic... and of course there are some

folks who use it an awful lot.

I would assume that having cognitive-behavioral therapy performed while intoxicated on PCP may be somewhat counterproductive in terms of use of therapy-learned mechanisms outside times of intoxication. Then again, I'm sure there are, or at least have been, psychiatrists who would disagree with me on that.

And in any event, to "run outside of your medication world" is something that's scary with the idea of leaving any psychotropic medication behind, and NMDA antagonists would be no exception, whether or not your idea applies to acute intoxication or chronic low-dose usage.

Dose-dependency is always an issue - there might be a psychologically or psychiatrically

therapeutic range between standard OTC dosing and acute intoxication. But, there might not be.

Would there really be a unique and useful psy. effect?

Would it be possible to create a reproduceable dosage schedule or is it too individually variant?

It comes back to very expensive studies on a very cheap medication with low margins and high

FDA and DEA resistance for ketamine, dextromethorphan, or PCP. (How can the company make

a big profit after the approval process is paid for, and how do we keep it away from the dopers?)

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It comes back to very expensive studies on a very cheap medication with low margins and high

FDA and DEA resistance for ketamine, dextromethorphan, or PCP. (How can the company make

a big profit after the approval process is paid for, and how do we keep it away from the dopers?)

I do believe that PCP is US DEA Schedule II, and not manufactured legally in any meaningful quantity. Much like was done with the cancer/nausea drug Marinol/drabinol (synthetic THC, i.e. pharmaceutical ganja), it is possible for the FDA to allow sanctioned manufacture (Marinol is Schedule III and pot is Schedule I) and have it sold at exorbitant prices.

Whether PCP is useful as therapeutic treatment at any dose, is of course, a value judgement.

Also, note that I'm relatively pro-pharma (especially as far us CBers here go!) and anti-conspiracy theory.

And as far as the low-profit dextromethorphan and ketamine are concerned, of course no drug company is going to try and get them tested as MI drugs/adjuncts. That's what regular clinical (generally academic) research trials are for... both of these drugs have some support in adjunct treatment of depression, and may well go the way of teaching an old dog new tricks, as was done with aspirin.

Ketamine is an inexpensive drug with an already extant recreational use history, and neither of those things seem to stop it from finding new life as a human anesthetic in "rapid sequence induction" (i.e., knock the patient out, stick tubes down his throat, and quickly) of emergency anesthesia.

Lack of FDA indications don't seem to stop docs from prescribing things, anyways. Most AAPs, for example, are approved for treatment of acute (<6 mo.) mania, but not for prophylaxis and mood stabilization in bipolars. That doesn't stop pdocs for prescribing it for these purposes, and in many bipolars, AAPs work wonders as mood stabilizers. Of course, it also ends up being a trainwreck for other bipolars (such as myself), so a few truckloads of salt are warranted before jumping off the deep end of FDA-indicated uses.

Then again, I suppose that some companies ARE trying to subvert the downsides to the unprofitable use of current NMDA antagonists - There is at least one new NMDA antagonist on the market now, Memantine, which I doubt is cheap (though I'm sure it's a hell of a lot more powerful on the NMDA antagonist than say, dextromethorphan).

In the end, I doubt marketability and fiscal feasibility will be barriers to the use of NMDA drugs in various treatment settings. Either there will be no marketing necessary (new uses for older compounds, the only profit going to the makers of generics, and of course to the patients for whom these drugs work), or marketing and approval will be funded by the use of new NMDA drugs that can command high market prices.

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Then again, I suppose that some companies ARE trying to subvert the downsides to the unprofitable use of current NMDA antagonists - There is at least one new NMDA antagonist on the market now, Memantine, which I doubt is cheap (though I'm sure it's a hell of a lot more powerful on the NMDA antagonist than say, dextromethorphan).

Compared to DXM, not cheap at all. Then again, as you pointed out, DXM is NOT very specific for NMDA receptors.

It's a trade-off.

In the end, I doubt marketability and fiscal feasibility will be barriers to the use of NMDA drugs in various treatment settings. Either there will be no marketing necessary (new uses for older compounds, the only profit going to the makers of generics, and of course to the patients for whom these drugs work), or marketing and approval will be funded by the use of new NMDA drugs that can command high market prices.

If one or more NMDA-specific drugs show a lot of promise and bring decent profits, of course ketamine and DXM might

be brought in specifically as inexpensive adjuncts (barring complications with P450 isoenzymes). Look at the serotonergics -

the SSRIs have brought in the big bucks but the older/cheaper TCAs and MAOIs are still in use if not expanded use.

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null--

The point you made with SSRIs vs. TCA/MAOI families hits home. One of Cymbalta's clinical pre-marketing campaigns was "looking at depression from a new perspective", which I assume would be from both serotonin and norepinephrine rather than just serotonin.

Oh, as if that was such a new idea. The TCAs and MAOIs had been doing that for about 40 years.

And if you want "new perspective", look at the 5HT blockers (namely trazodone and Remeron). Been on the market for ages, but never caught on since they both tend to knock patients out cold. They block the serotonin receptors that are associated with negative effects ("5HT3" is associated with nausea and vomiting for example).

The SSRIs/SSNRIs just happen to be a hell of a lot safer, despite their relatively crude action of flooding every nook and cranny of your body with serotonin. Including the vomit-inducing 5HT3 neurons in your CTZ, among other receptors as well.

As far as the specific use of DM and ketamine in depression, I doubt they'll catch on, if only the latter... ketamine's effects leave as soon as they come on, which I suppose would require a time-release formula. Which requires another patent. Which can make someone some profit. Which isn't a hindrance to its fate, per se.

DM faces a struggle to become adjunct due to its multipharmcology (it works on any neurotransmitter you can think of) and that it's one of the many drugs that inhibit the liver's ubiquitous 2D6 enzyme... meaning it'll interact with a lot of things, including grapefruit juice. On the other hand, it's common, OTC, cheap, and for most people, safe at the doses used for coughs. Now if only we can get the makers of Robitussin in on this just as Bayer cashed in on the aspirin benefits...

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DM faces a struggle to become adjunct due to its multipharmcology (it works on any neurotransmitter you can think of) and that it's one of the many drugs that inhibit the liver's ubiquitous 2D6 enzyme...

You're thinking of Wellbutrin; bupropion competitively binds to 2D6 as a substrate, whereas DXM is used as a generally

nontoxic test of 2D6 function. Obviously, you'd not want any other 2D6 substrates horning in on the isoenzyme action

if you can avoid it (another P450 cheat-sheet) as that would slow metabolism down all around.

Grapefruit juice targets 3A4. Do not wash erythromycin down with grapefruit juice (or amphetamine, but that's a pH issue)

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You're thinking of Wellbutrin; bupropion competitively binds to 2D6 as a substrate, whereas DXM is used as a generally

nontoxic test of 2D6 function. Obviously, you'd not want any other 2D6 substrates horning in on the isoenzyme action

if you can avoid it (another P450 cheat-sheet) as that would slow metabolism down all around.

Grapefruit juice targets 3A4. Do not wash erythromycin down with grapefruit juice (or amphetamine, but that's a pH issue)

Wellbutrin I know targets 2D6, but I do believe that the same enzyme is bound to by DM and is involved in its conversion to dextorphan (DO), in highfalutin chemical terms "O-demethylation". Which is a good reason why DM is used as a clinical test of 2D6 function. (I want to say they actually calculate function by checking the DM:DO ratio at timepoints?)

And thanks for bringing up the grapefruit juice correction, I knew it affected some enzyme and was wildly guessing. Interestingly, DM also undergoes minor but significant metabolism by 3A4, making grapefruit juice a minor concern again.

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