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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 18 of 18. This is the beginning of the thread.
Posted by SLS on June 22, 2011, at 13:37:45
DRUG BOOSTS GROWTH FACTOR TO JUMP-START RAPID ANTIDEPRESSANT RESPONSE Little-known enzyme pivotal -- NIH-funded study in mice
A study in mice has pinpointed a pivotal new player in triggering the rapid antidepressant response produced by ketamine <http://www.nimh.nih.gov/science-news/2010/experimental-medication-lifts-depression-symptoms-in-bipolar-disorder-within-an-hour.shtml>;. By deactivating a little-known enzyme, the drug takes the brakes off rapid synthesis of a key growth factor thought to lift depression, say researchers supported by the National Institutes of Health.
"Other agents that work through this pathway and block the enzyme may also similarly induce anti-depressant-like effects and hold promise for development of new treatments," said Lisa Monteggia, Ph.D., of the University of Texas Southwestern Medical Center, Dallas, a grantee of the NIH's National Institute of Mental Health.Monteggia, Ege Kavalali, Ph.D., and colleagues reported their findings online June 15, 2011 in the journal Nature.
Unlike currently available antidepressants that take weeks to work, ketamine can lift mood within hours. Yet adverse side effects of this animal anesthetic -- and sometime club drug <http://www.drugabuse.gov/infofacts/clubdrugs.html>; -- preclude it from becoming a practical treatment. So researchers have been studying its mechanism of action, in hopes of developing safer alternatives that work the same way.
Earlier studies <http://www.ncbi.nlm.nih.gov/pubmed/20686454>; had shown that the growth factor, called brain-derived neurotrophic factor (BDNF <http://www.nimh.nih.gov/science-news/2006/depression-model-leaves-mice-with-molecular-scar.shtml]>, produces antidepressant-like effects. To find out if BDNF is involved in ketamine's action, the researchers gave the drug to mice genetically engineered to lack BDNF. Unlike in control mice, ketamine failed to produce a fast-acting antidepressant-like response in such BDNF knockout mice exposed to experimental situations that trigger depression-like behaviors. This and other tests confirmed that ketamine's rapid antidepressant effects depend on rapid synthesis of BDNF in the brain's memory center, or hippocampus <http://www.nimh.nih.gov/health/brain-basics/brain-basics.shtml#WorkingBrain>;.
The researchers determined that this happens so quickly -- within 30 minutes -- because time-consuming intermediate steps have already been completed. It only requires the translation <http://www.genome.gov/glossary/index.cfm?id=200>; of BDNF mRNA<http://www.genome.gov/glossary/?id=123>;, an intermediate form, into the final protein <http://www.genome.gov/glossary/index.cfm?id=169>;. By contrast, conventional antidepressants are thought to work through a much more lengthy and indirect process that requires, among other things, the birth of new neurons <http://www.nimh.nih.gov/science-news/2003/creation-of-new-neurons-critical-to-antidepressant-action-in-mice.shtml>; and their integration into circuits.
Ketamine achieves this boost in BDNF levels by first blocking a protein on neurons (brain cells) called the NMDA receptor <http://www.nimh.nih.gov/science-news/2007/faster-acting-antidepressants-closer-to-becoming-a-reality.shtml>;. The Texas team discovered that this blockade, in turn, deactivates an enzyme called eukaryotic elongation factor 2 (eEF2) kinase, which restrains BDNF synthesis. So ketamine (and presumably other agents that similarly turn off the enzyme) effectively takes the brakes off of this antidepressant mechanism.
"Selectively inhibiting the eEF2 kinase was sufficient to trigger a rapidly acting antidepressant response in control mice but not in mice lacking BDNF," explained Monteggia.The researchers discovered that the boost in BDNF occurs while neurons are in their default mode - not doing anything in particular. But the cells continue communicating via a low level of background chatter, spontaneously releasing chemical messengers that bind to receptors. So when ketamine blocks NMDA receptors, it prevents their naturally occurring messenger chemical, glutamate, from binding to them.
"Interference with such spontaneous neurotransmission to trigger production of a protein represents a novel mode of drug action," Monteggia noted. "It may also hold clues to what goes awry in the brain in disorders like depression."
Although BDNF levels fall off sharply following the transient increase triggered by ketamine, she says evidence may also support a role for BDNF in the drug's longer-term antidepressant effects. The exact role of another enzyme implicated in ketamine's antidepressant action remains to be determined, in light of the new findings. Yale researchers reported last fall that the drug triggered increased connections between neurons via effects on the enzyme, called mTOR <http://www.nimh.nih.gov/science-news/2010/rapid-antidepressant-works-by-boosting-brains-connections.shtml>;.
"This discovery of a novel pathway involved in mediating fast-acting antidepressant action holds hope for development of new rapid-acting medications," said Monteggia.The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website <http://www.nimh.nih.gov/index.shtml>;.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit <www.nih.gov>.
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REFERENCE:
NMDA receptor blockade at rest triggers rapid behavioral antidepressant responses. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. Nature. 2011 Jun 15. doi: 10.1038/nature10130. [Epub ahead of print] PMID:21677641
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IMAGE INFORMATION:
URL - <http://www.nimh.nih.gov/images/news-items/monteggia-ketamine.jpg>;
Caption - When in their default (resting) state, neurons that mediate ketamine's action engage in the brain's equivalent of background chatter. They spontaneously spray out (orange) the chemical messenger glutamate (green circles), which binds to NMDA receptors (black ovals) on adjoining neurons. This activates the enzyme eEF2 kinase, which suppresses synthesis of BDNF, a growth factor that has antidepressant effects. Treatment with ketamine blocks the binding of the neurotransmitter to the receptors (blue dots on black ovals), which inactivates the enzyme, taking the brakes off translation of BDNF into protein. This jump-starts a fast-acting antidepressant effect.
Source: Lisa Monteggia, Ph.D., University of Texas Southwestern Medical Center
Posted by Laney on June 22, 2011, at 19:41:13
In reply to Ketamine mechanism: Rapid AD response., posted by SLS on June 22, 2011, at 13:37:45
So has anyone here on PB tried Ketamine? What have the results been?
Scott, have you tried it and if so, what do you think?
Thanks!
Laney
Posted by SLS on June 23, 2011, at 6:20:11
In reply to Re: Ketamine mechanism: Rapid AD response., posted by Laney on June 22, 2011, at 19:41:13
> So has anyone here on PB tried Ketamine?
I haven't. It is available as a "street drug", but I still would not try it. The antidepressant effect is very brief.
> What have the results been?
It works. The NIH has confirmed this.
The article I posted helps to elucidate how ketamine works so that neuroscientists can identify new compounds that accomplish the same thing using a "short-cut" that more directly affects the necessary enzyme activity. I would try such a new drug in a heartbeat.
- Scott
Posted by Phillipa on June 23, 2011, at 10:38:39
In reply to Re: Ketamine mechanism: Rapid AD response. » Laney, posted by SLS on June 23, 2011, at 6:20:11
Weren't the first studies kind of a surprise as they gave ketamine IV in a strutured hospital enviornment and discovered the ad effect? Phillipa
Posted by hyperfocus on June 23, 2011, at 16:51:26
In reply to Ketamine mechanism: Rapid AD response., posted by SLS on June 22, 2011, at 13:37:45
Amitriptyline is an AD that has pronounced long-term positive effects on BDNF production. Curiously, nortriptyline does not. This is unfortunate because the side-effects of amitriptyline are very harsh and not many people can tolerate therapeutic doses of it, so not many doctors are willing to prescribe it ahead of SSRIs and newer drugs. BDNF may also be a factor in fibromyalgia so it could explain why amitriptyline is effective in treating these conditions.
http://www.ncbi.nlm.nih.gov/pubmed?term=amitriptyline%20BDNF&itool=QuerySuggestion
I'm partial to the theory that treating depression and MI has more to do with repairing and regrowing areas of the brain that are damaged and have atrophied, than raising or lowering neurotransmitter levels.
http://www.neurotransmitter.net/depressionfactors.html
Posted by SLS on June 23, 2011, at 18:14:49
In reply to Re: BDNF in depression and fibromyalgia, posted by hyperfocus on June 23, 2011, at 16:51:26
> Amitriptyline is an AD that has pronounced long-term positive effects on BDNF production.
If I read the article properly, an inhibitor of the eukaryotic elongation factor 2 (eEF2) enzyme would produce an immediate increase in BDNF production along with an immediate antidepressant response. We will have to see if it is necessary to combine a eEF2 inhibitor with a regime of other psychotropics to sustain the antidepressant effect long-term.
- Scott
Posted by SLS on June 23, 2011, at 18:23:19
In reply to Re: BDNF in depression and fibromyalgia, posted by hyperfocus on June 23, 2011, at 16:51:26
> I'm partial to the theory that treating depression and MI has more to do with repairing and regrowing areas of the brain that are damaged and have atrophied,
I am currently of the same belief.
I had thought to combine fish oil omega-3 with phosphatidylserine to enhance the repair processes. Unfortunately I react negatively to these substances.
> than raising or lowering neurotransmitter levels.
It might be that these mechanisms facilitate long-term changes in BDNF production downstream - sort of like a domino effect.
- Scott
Posted by hyperfocus on June 23, 2011, at 20:05:13
In reply to Re: BDNF in depression and fibromyalgia » hyperfocus, posted by SLS on June 23, 2011, at 18:23:19
The interesting thing is I've found that the effect of amitrip on my day-to-day functioning is best when in the range 150-225mg. Anything higher makes me feel much, much worse. I can't even take drugs like metformin and glimiperide that affect the liver metabolism of amitrip. Tianeptine has also gotten a lot of praise for it's neurotrophic properties but I find tianeptine not to have any significant improvement on my overall day-to-day condition and can actually make me feel a whole lot worse under certain conditions. Apathy is a major negative side-effect for me on tianeptine yet I cannot deny it's immediate next-day memory-boosting effects. Fish oil, flaxseed oil or anything with significant Omega-3 also seems to exert this pronounced negative day-to-day negative effect on me.
I've always suspected that while these drugs and supplements exert their effects on neurogenesis and neuroplasticity, they can actually make our day-to-day symptoms considerably worse. Do you thing this is possible - drugs that do actually repair brain structures but also make us feel much worse? Maybe we should look towards always taking these neurotrophic drugs and trying to combat their adverse effects on our symptoms some other way?
Posted by jhj on June 24, 2011, at 0:16:05
In reply to Re: Ketamine mechanism: Rapid AD response. » Laney, posted by SLS on June 23, 2011, at 6:20:11
There is already a drug similar to ketamine in phase II being developed by Naurex
Posted by SLS on June 24, 2011, at 5:13:12
In reply to Re: BDNF in depression and fibromyalgia » SLS, posted by hyperfocus on June 23, 2011, at 20:05:13
> The interesting thing is I've found that the effect of amitrip on my day-to-day functioning is best when in the range 150-225mg. Anything higher makes me feel much, much worse.
That is interesting. It's almost like the therapeutic window that exists for nortriptyline. I never understood why nortriptyline should demonstrate this effect and not amitriptyline.
> Fish oil, flaxseed oil or anything with significant Omega-3 also seems to exert this pronounced negative day-to-day negative effect on me.
Fish oil has twice exacerbated my depression within 6 hours of taking my first dose. Strange. A biochemist friend of mine and I both have come to suspect that there is something pharmacological going on here. That some people become manic on fish oil would seem to indicate such. Of course, I really don't know. It's just a hunch. Real scientific, eh?
> I've always suspected that while these drugs and supplements exert their effects on neurogenesis and neuroplasticity, they can actually make our day-to-day symptoms considerably worse. Do you thing this is possible - drugs that do actually repair brain structures but also make us feel much worse? Maybe we should look towards always taking these neurotrophic drugs and trying to combat their adverse effects on our symptoms some other way?
Pretty creative. I wish Zyprexa didn't carry with it such a metabolic liability. It would seem to me to be a good choice to fit your protocol.
Personally, I have never taken a drug that initially exacerbated my depression that later went on to produce an improvement. I was so disappointed when both fish oil and phosphatidylserine made me feel worse. I had thought that combining these two substances with lithium would enhance neuroplasticity and make me feel better.
So much for my personal theories. Maybe it would work for someone else.
- Scott
Posted by SLS on June 24, 2011, at 5:15:03
In reply to Re: Ketamine mechanism: Rapid AD response. » SLS, posted by jhj on June 24, 2011, at 0:16:05
Posted by Hombre on June 24, 2011, at 5:32:38
In reply to Ketamine mechanism: Rapid AD response., posted by SLS on June 22, 2011, at 13:37:45
But is it the production of BDNF that causes the antidepressant effect, or the neurons that (re)grow in the hippocampus and frontal lobe (yes, in the frontal lobe as well)? I never heard that just producing BDNF will cause an antidepressant response.
Because exercise will produce lots of BDNF, so much so that the kids in Naperville, IL do a special PE class before school if they are having trouble. In fact, all the kids are required to do PE, and they can choose from a number of activities, as long as they get their heart rate up to a certain level. These kids outperformed countries like Korea, Japan, and Singapore in several tests of math and science.
Lots of studies on this by Dr. Charles Hillman at U of I. Also the guy who wrote "why zebras don't get ulcers" from Stanford.
I will say this, the cognitive effects of depression and chronic stress/anxiety are profound, but rarely discussed.
I found that after receiving successful treatment, I was able to integrate a foreign language that I'd studied while super depressed. At the time, I was struggling big time, but now I find words and phrases flowing out of some corner of my brain.
I had studied very hard, but nothing seemed to stick. Even after over a year of not using that foreign language, when it came time to use it, I surprised myself. I'm sure there are psychological factors at play i.e. being more confident, but that doesn't explain why I was able to remember things I thought I'd completely lost.
Posted by SLS on June 24, 2011, at 5:47:45
In reply to Re: Ketamine mechanism: Rapid AD response., posted by Hombre on June 24, 2011, at 5:32:38
> But is it the production of BDNF that causes the antidepressant effect,
That is what the authors of the paper suggest.
> I will say this, the cognitive effects of depression and chronic stress/anxiety are profound, but rarely discussed.
I might get a few negative replies to saying this, but for many people with depression, the cognitive impairments are the prominent symptoms. They are nothing short of DEMENTIA.
--------------------------------"DEMENTIA
Also found in: Medical, Legal, Encyclopedia, Wikipedia, Hutchinson 0.01 sec.
de·men·tia (d-mnsh)
n.1. Deterioration of intellectual faculties, such as memory, concentration, and judgment, resulting from an organic disease or a disorder of the brain. It is sometimes accompanied by emotional disturbance and personality changes."
---------------------------
DEMENTIA is a generic term as described above and need not be of the Alzheimers type.Your observations regarding the speaking of a foreign language mirrors my own.
- Scott
Posted by zonked on June 24, 2011, at 9:25:58
In reply to Re: Ketamine mechanism: Rapid AD response. » Hombre, posted by SLS on June 24, 2011, at 5:47:45
> I might get a few negative replies to saying this, but for many people with depression, the cognitive impairments are the prominent symptoms. They are nothing short of DEMENTIA.They are up there with everything else for me. Nothing's more frustrating than feeling like CRAP 24/7 *plus* things like "um, um, what was I saying again?" and feeling prematurely aged. Especially if you remember being pretty quick at one time.
Scott, I hope you continue to improve. My cognitive symptoms have reduced substantially since I began to respond to Nardil, although they aren't completely resolved (I suspect Klonopin plays a role in this.)
For now, I'm fine; but eventually I would like to replace Klonopin with Xanax XR (Xanax doesn't "slow me down" as much as Klonopin does, if that makes any sense.)
How are you tolerating low dose Lithium?
-z
Posted by SLS on June 24, 2011, at 11:07:57
In reply to Re: Ketamine mechanism: Rapid AD response. » SLS, posted by zonked on June 24, 2011, at 9:25:58
> > I might get a few negative replies to saying this, but for many people with depression, the cognitive impairments are the prominent symptoms. They are nothing short of DEMENTIA.
> They are up there with everything else for me. Nothing's more frustrating than feeling like CRAP 24/7 *plus* things like "um, um, what was I saying again?" and feeling prematurely aged. Especially if you remember being pretty quick at one time.
>
> Scott, I hope you continue to improve.Thanks. I will. (That's a promise). I hope Latuda (lurasidone) does more for me than Abilify did. Even if it works only equally well, the Latuda does not seem to produce weight gain like Abilify can.
> My cognitive symptoms have reduced substantially since I began to respond to Nardil, although they aren't completely resolved (I suspect Klonopin plays a role in this.)
Perhaps. However, I would give Nardil and your brain enough time to heal in order to assess your remaining cognitive difficulties. It is still early for you.
> For now, I'm fine; but eventually I would like to replace Klonopin with Xanax XR (Xanax doesn't "slow me down" as much as Klonopin does, if that makes any sense.)
I have been on both drugs. I find Klonopin to be mentally slowing and depressogenic as well. Xanax is more of a mood brightener in addition to being an anxiolytic. Ativan is neutral. It can make a good anxioylytic without mood brightening or depressogenic effects.
>
> How are you tolerating low dose Lithium?
>
> -z
The 300mg of lithium I am taking is tolerable enough such that I wouldn't know I was taking it. 450mg flattened me out somewhat, but not too badly.
- Scott
Posted by desolationrower on June 24, 2011, at 20:39:51
In reply to Re: BDNF in depression and fibromyalgia » hyperfocus, posted by SLS on June 24, 2011, at 5:13:12
> > The interesting thing is I've found that the effect of amitrip on my day-to-day functioning is best when in the range 150-225mg. Anything higher makes me feel much, much worse.
>
> That is interesting. It's almost like the therapeutic window that exists for nortriptyline. I never understood why nortriptyline should demonstrate this effect and not amitriptyline.
>i think i posted a study here once that the norep reuptake pump is not as saturated as the 5ht pump. Also, don't discount statstical flukes+hysterysis/suggestion/placebo.
> > Fish oil, flaxseed oil or anything with significant Omega-3 also seems to exert this pronounced negative day-to-day negative effect on me.
>
> Fish oil has twice exacerbated my depression within 6 hours of taking my first dose. Strange. A biochemist friend of mine and I both have come to suspect that there is something pharmacological going on here. That some people become manic on fish oil would seem to indicate such. Of course, I really don't know. It's just a hunch. Real scientific, eh?
>NSAIDs work on pain w/in hours, so atleast the affect on COX-enzyme metabolites could occur that quickly (i'm assuming fats absorbed from GI track, lymph system, blood are primary source of trigs used to create those molecules)
> > I've always suspected that while these drugs and supplements exert their effects on neurogenesis and neuroplasticity, they can actually make our day-to-day symptoms considerably worse. Do you thing this is possible - drugs that do actually repair brain structures but also make us feel much worse? Maybe we should look towards always taking these neurotrophic drugs and trying to combat their adverse effects on our symptoms some other way?
making yoru brain plastic makes it succeptable to change both good and bad. it lets you fix things, but you can re-fubar them, too.
> Pretty creative. I wish Zyprexa didn't carry with it such a metabolic liability. It would seem to me to be a good choice to fit your protocol.
>
> Personally, I have never taken a drug that initially exacerbated my depression that later went on to produce an improvement. I was so disappointed when both fish oil and phosphatidylserine made me feel worse. I had thought that combining these two substances with lithium would enhance neuroplasticity and make me feel better.
>
> So much for my personal theories. Maybe it would work for someone else.
>
>
> - Scott-d/r
Posted by Lamdage on June 26, 2011, at 11:05:52
In reply to Re: Ketamine mechanism: Rapid AD response. » SLS, posted by Phillipa on June 23, 2011, at 10:38:39
> Weren't the first studies kind of a surprise as they gave ketamine IV in a strutured hospital enviornment and discovered the ad effect? Phillipa
I agree! I think there are some kewl new things being started. MDMA is picked up again against PTSD, Lsd, too.
Seems like research is agressive again and they may soon stop to overwhelm us with 5.000 different all the same sh*tty prozacs (sry a lil ranting is good for mental health!)Im happy they are doing decent research again and hope that we will encounter some elite drugs in the future. I wish theyd be working on a bigger variety of Maoi, too!
Posted by Lamdage on June 26, 2011, at 11:15:30
In reply to Re: Ketamine mechanism: Rapid AD response., posted by Lamdage on June 26, 2011, at 11:05:52
Ps Ketamine sounds awesome to me for in between meds in hospital settings. When the washout period prohibits the use of the new AD.
I wish i had something like it for my venlafaxine/bupropion -> phenelzine switch.
This is the end of the thread.
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