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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 15 of 15. This is the beginning of the thread.
Posted by SLS on November 2, 2000, at 7:50:25
http://www.drkoop.com/news/stories/october/hs/mood_swings.html
Depression Drug May Help Treat Brain Diseases
Oct. 9, 2000
Lithium Factsheet
Medications for Mania and Bipolar Disorder
About Lithium Overdose
Charnicia E. Huggins
Reuters Health InformationNEW YORK -- Lithium, currently used to treat symptoms of bipolar disorder, or manic-depressive illness, may someday be used to treat degenerative brain conditions such as Alzheimer's or Parkinson's diseases, researchers suggest.
Dr. Gregory J. Moore, from Wayne State University School of Medicine in Detroit, Michigan and his colleagues analyzed the effect of lithium on 10 individuals with bipolar mood disorder. Bipolar disorder is a chronic condition characterized by emotional 'cycles' of manic highs and depressive lows.
After 4 weeks of lithium treatment, 8 of the 10 study participants experienced an average 3% increase in their total brain gray-matter volume, the investigators report in the October 7th issue of The Lancet. The gray matter is the outer layer of the brain involved in thinking and processing information.
"This is the first time a drug has been proven to increase gray matter in the human brain," Moore stated.
"This has possible future implications for the treatment of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases," Moore told Reuters Health. "Specifically, if one can prevent neurons from dying or even increase the number or size of neurons in the brain after there has been some neuronal degeneration, one could potentially slow down, halt, or even reverse some of the effects of these devastating diseases."
The researcher cautioned that even though these study results may be exciting, they "should be considered preliminary until larger numbers of (individuals) can be studied and until the findings can be replicated by other laboratories."
SOURCE: The Lancet 2000;356:1241-1242.
Posted by Sunnely on November 2, 2000, at 21:45:22
In reply to Article: Lithium increases brain volume ?, posted by SLS on November 2, 2000, at 7:50:25
>
> http://www.drkoop.com/news/stories/october/hs/mood_swings.html
>
>
> Depression Drug May Help Treat Brain Diseases
> Oct. 9, 2000
>
>
> Lithium Factsheet
> Medications for Mania and Bipolar Disorder
> About Lithium Overdose
>
>
>
> Charnicia E. Huggins
> Reuters Health Information
>
> NEW YORK -- Lithium, currently used to treat symptoms of bipolar disorder, or manic-depressive illness, may someday be used to treat degenerative brain conditions such as Alzheimer's or Parkinson's diseases, researchers suggest.
>
> Dr. Gregory J. Moore, from Wayne State University School of Medicine in Detroit, Michigan and his colleagues analyzed the effect of lithium on 10 individuals with bipolar mood disorder. Bipolar disorder is a chronic condition characterized by emotional 'cycles' of manic highs and depressive lows.
>
> After 4 weeks of lithium treatment, 8 of the 10 study participants experienced an average 3% increase in their total brain gray-matter volume, the investigators report in the October 7th issue of The Lancet. The gray matter is the outer layer of the brain involved in thinking and processing information.
>
> "This is the first time a drug has been proven to increase gray matter in the human brain," Moore stated.
>
> "This has possible future implications for the treatment of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases," Moore told Reuters Health. "Specifically, if one can prevent neurons from dying or even increase the number or size of neurons in the brain after there has been some neuronal degeneration, one could potentially slow down, halt, or even reverse some of the effects of these devastating diseases."
>
> The researcher cautioned that even though these study results may be exciting, they "should be considered preliminary until larger numbers of (individuals) can be studied and until the findings can be replicated by other laboratories."
>
> SOURCE: The Lancet 2000;356:1241-1242.++++++++++++++++
Hi Scott,
Not sure about this study. These are the same type of patient population that are so sensitive to the adverse effects of lithium such as acute delirium, confusion, further memory impairment, and worsening movement disorder.
Of course, I could be wrong. Just my own 2 cents.
Posted by SLS on November 2, 2000, at 23:29:53
In reply to Re: Article: Lithium increases brain volume ?, posted by Sunnely on November 2, 2000, at 21:45:22
> Hi Scott,
>
> Not sure about this study. These are the same type of patient population that are so sensitive to the adverse effects of lithium such as acute delirium, confusion, further memory impairment, and worsening movement disorder.
>
> Of course, I could be wrong. Just my own 2 cents.
Sunnely,I just thought the findings were interesting. I'm definitely acquiring a taste for salt, though. One thing that is somewhat corroborative is that lithium is capable of inhibiting apoptopic substances and promoting an increase in neurotrophic substances.
On an unrelated matter; in 1984, a clinical researcher psychiatrist, formerly a professor at NYU, told me in confidence that lithium produced some benefit in the treatment of neuroblastoma. For some reason, I got the impression that this was supposed to be a secret. I know the secret nature of this "fact" sounds funny, this guy was brilliant. I believe he was one of the first (if not the first) to identify the schizoaffective presentation as a distinct disorder. He wrote a book about it.
- Scott
Posted by Emmanuela on November 3, 2000, at 1:00:22
In reply to Re: Article: Lithium increases brain volume ?, posted by SLS on November 2, 2000, at 23:29:53
Scott - would you please explain what means:
inhibiting apoptopic substances and promoting an increase in
neurotrophic substances.I don't know for which side to root.
Thanks.
Emmanuela
Posted by danf on November 3, 2000, at 9:26:20
In reply to Article: Lithium increases brain volume ?, posted by SLS on November 2, 2000, at 7:50:25
After initial evaluation of this study..
let's see, a 3% change in gray matter volume using an MRI... 3% certainly approaches the resolution capability of an MRI..
So Lithium is neurotrophic ?
How about the cells swell a bit ( a few % ) when on Li ?
Posted by SLS on November 3, 2000, at 11:54:37
In reply to Re: Article: Lithium increases brain volume ?, posted by Emmanuela on November 3, 2000, at 1:00:22
> Scott - would you please explain what means:
> inhibiting apoptopic substances and promoting an increase in
> neurotrophic substances.
>
> I don't know for which side to root.
>
> Thanks.
>
> Emmanuela
Hi Emmanuela.apoptopic = promotes the programmed aging and death of cells. Neurotoxic.
neurotrophic = promotes the maintenance of nerve cells and the growth of new nerve cells and connections.
- Scott
Posted by SLS on November 3, 2000, at 12:18:23
In reply to Re: Article: Lithium increases brain volume ?, posted by danf on November 3, 2000, at 9:26:20
> After initial evaluation of this study..
>
> let's see, a 3% change in gray matter volume using an MRI... 3% certainly approaches the resolution capability of an MRI..
>
> So Lithium is neurotrophic ?
>
> How about the cells swell a bit ( a few % ) when on Li ?
Hi DanF.Obviously, I posted the wrong URL. Sorry. I think the post included a copy of the full article.
Why MRI? Did you read the article in the Lancet?
Lithium affects the processes by which the cell (cytoplasm) communicates with the nucleus to direct the transcription of specific genes. Two measurable consequences of this change in transduction is a decrease in the synthesis of neurotoxic substances (peptides?) and an increase in the synthesis of neurotrophic and neuroprotective substances.
* HK Manji is considered to be one of the most brilliant researchers who has ever worked at the NIH in the field of neuropsychobiology. I think he is probably second only to Robert M. Post.
----------------------------------------------Enhancement of hippocampal neurogenesis by lithium.
----------------------------------------------
Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects?
----------------------------------------------
Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness.
----------------------------------------------Signalling pathways in the brain: cellular transduction of mood stabilisation in the treatment of manic-depressive illness.
----------------------------------------------
Posted by danf on November 3, 2000, at 13:12:43
In reply to Re: Article: Lithium increases brain volume ?, posted by SLS on November 3, 2000, at 12:18:23
This seems to be almost a miss the forest for the trees kind of thing.
I read the abstract, could not get the full text.
We know that Li works to stabilize mood lability. It has been used for a long time & it works & works well. We also know that Bipolar MD disorder is in general progressive if untreated.
We also know that there is an imbalance in neural regulation, of some type with BMDD, that Li corrects in at least some aspects.
we also know that Li does not do a lot for seizure control.
The logical extension of this is that the continued neural imbalance eventually causes some permanent changes in neural architecture. By prevention / correction of the imbalance, one would asume that the progressive permanent changes are blocked.
By following this model, one would assume that the protective features of Li are secondary & not primary.
We also would assume that there are changes in neural metabolic activity as a result of the changes in neural net activity.
Just finding altered metabolic activity does not help decide or prove whether the Li protective effect is primary or secondary.
So where does this leave us ? Given time & more research, the best fit theory will win out...
One bad result of our current system of grant supported research is that controversy gets money & results in published reports. Some times the reports are good, sometimes of little worth for the intended information. So we have to look at them all to see if they appear to fit with other known data, & judge critically.
The fact that Li is protective in some situations (BP MDD ), does not mean that it will automatically stimulate or promote healing of injured or damaged neurons under other circumstances.
Posted by B Day on November 3, 2000, at 13:18:16
In reply to Article: Lithium increases brain volume ?, posted by SLS on November 2, 2000, at 7:50:25
Great, just what I needed...more brains just like the one I got.
B
Posted by SLS on November 3, 2000, at 14:27:27
In reply to Re: Article: Lithium increases brain volume ?, posted by danf on November 3, 2000, at 13:12:43
Dear DanF,
This doesn't sound like you. :-)
Lithium does a SH_T-LOAD of things, very few of which I think can be discounted as not in some way contributing to its therapeutic effects. Unlike the anticonvulsant mood-stabilizers, I don't think lithium works to "stabilize" axonal propagation of action potentials.
Lithium has an acute antimanic effect. It may not be as rapid as Depakote, but it is certainly too fast to attribute it to changes in G-protein receptors. It is the inhibition in the synthesis of these receptors that is thought to help account for lithium's prophylactic properties. Perhaps the putative changes in the secretion of neurotropic peptides has a place here as well.
It seems plausible to me that chronic exposure of neuronal tissue to neurotrophin could account for a number as small as 3%.
I don't feel one way or the other about the results of this one study. I just thought it was interesting.
Correct me if I'm wrong, but I believe you frequently verbalize that "we", in general, don't have enough of a grasp of what goes on in the brain with regard to affective-disorders to so quickly embrace or reject explanations as to what is going on there.
> So where does this leave us ? Given time & more research, the best fit theory will win out...
No way!
> The fact that Li is protective in some situations (BP MDD ), does not mean that it will automatically stimulate or promote healing of injured or damaged neurons under other circumstances.
I'm not sure that this was stated as the implication of their results. If you happen upon the article, please post the salient points.
It is possible that neurotropins foster an increase in neurites and dendritic connections to circumvent the dysfunctional neurons, and not necessarily reanimate necrotic tissue. I imagine that anything that promotes an increase in the plasticity of the brain would encourage some rather creative ways for it to deal with injury.
One of the most vigorously studied aspects of the treatment of Parkinson's disease is to try to arrest the condition, not necessarily heal damaged terminals. Inducing an increase in endogenous neuroprotective substances may help to accomplish this.
Don't neurotrophins help in the regeneration of nerves in the spinal chord?
- Scott
Posted by danf on November 3, 2000, at 17:35:46
In reply to Re: Article: Lithium increases brain volume ?, posted by SLS on November 3, 2000, at 14:27:27
scott,
thanks again for this most excellent discussion.
I agree that Li does not stabilize axonal propagation, hence it is not a good anticonvulsant.
One of the real questions is, does Li really do a whole lot of things or does it stabilize a part of the neural net, & by changing that regulatory activity of part of the net, change the whole net ?
In other words is it a simple effect on a complex part, or a complex effect on a simple part ?
This study wanted to imply that gray matter tissue was increased. A 3 % volume change is well within the possible range of a solute /solvent shift, rather than something more complex, requiring active metabolic changes..
> Correct me if I'm wrong, but I believe you frequently verbalize that "we", in general, don't have
> enough of a grasp of what goes on in the brain with regard to affective-disorders to so quickly
> embrace or reject explanations as to what is going on there.& I still agree very much with that.
Perhaps you misunderstood me...
What ever theory fits the data best in the end, is the one most accepted.
There are some other writers that think, Li may promote healing ???
One of the major problems with brain injury & disease is that adult human brains are not very plastic. If alternate neural pathways exist, they may be put to use to make up for damaged ones.
There is little evidence that new pathways are ever formed in the adult brain.
Injured spinal cords ??? a real tuffie.. I think we are more likely to learn how the brain works with mental disorders Than to get a severed spinal cord to work again.
Posted by SLS on November 3, 2000, at 20:57:57
In reply to Re: Article: Lithium increases brain volume ?, posted by SLS on November 2, 2000, at 23:29:53
> On an unrelated matter; in 1984, a clinical researcher psychiatrist, formerly a professor at NYU, told me in confidence that lithium produced some benefit in the treatment of neuroblastoma. For some reason, I got the impression that this was supposed to be a secret. I know the secret nature of this "fact" sounds funny, but this guy was brilliant. I believe he was one of the first (if not the first) to identify the schizoaffective presentation as a distinct disorder. He wrote a book about it.
Something to chew on for awhile.Do the following two abstracts support the notion that lithium may represent a treatment for neuroblastoma?
I think so.
- Scott
----------------------------------------------------: Exp Cell Res 1994 Apr;211(2):332-8 Related Articles, Books
Lithium induces apoptosis in immature cerebellar granule cells but promotes survival of mature neurons.D'Mello SR, Anelli R, Calissano P
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8143780&dopt=Abstract
----------------------------------------------------: Eur J Neurosci 1996 Sep;8(9):1994-2005
Maturation-dependent modulation of apoptosis in cultured cerebellar granule neurons by cytokines and neurotrophins.
de Luca A, Weller M, Frei K, Fontana A
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8921290&dopt=Abstract
----------------------------------------------------
Posted by SLS on November 6, 2000, at 8:25:31
In reply to Re: Article: Lithium increases brain volume ?, posted by SLS on November 3, 2000, at 20:57:57
Hey Dan,
Check this out:
This abstract makes a good argument for continued inquiry to be made in the use of lithium in the treatment of neurodegenerative disorders like Parkinson's and Alzheimers Dementia. It also suggests that the neurotrophic and neuroprotective properties of lithium be used to treat mood disorders, regardless of the primary treatment. This abstract states that lithium is the most potent of available medications to increase the amount neurotrophic substances and decrease the amount of neurodegenerative substances.
A 3% increase in cortical volume may not be so far-fetched.
- Scott-------------------------------------------------------------
J Clin Psychiatry 2000;61 Suppl 9:82-96 Related Articles, Books,
Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness.Manji HK, Moore GJ, Chen G
Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Mich 48201, USA. hmanji@med.wayne.edu
Although mood disorders have traditionally been conceptualized as "neurochemical disorders," considerable literature from a variety of sources demonstrates significant reductions in regional central nervous system (CNS) volume and cell numbers (both neurons and glia) in persons with mood disorders. It is noteworthy that recent advances in cellular and molecular biology have resulted in the identification of 2 novel, hitherto completely unexpected targets of lithium's actions, discoveries that may have a major impact on the future use of this unique cation in biology and medicine. Chronic lithium treatment has been demonstrated to markedly increase the levels of the major neuroprotective protein bc1-2 in rat frontal cortex, hippocampus, and striatum. Similar lithium-induced increases in bc1-2 are also observed in cells of human neuronal origin and are observed in rat frontal cortex at lithium levels as low as approximately 0.3 mM. Bc1-2 is widely regarded as a major neuroprotective protein, and genetic strategies that increase bc1-2 levels have demonstrated not only robust protection of neurons against diverse insults, but have also demonstrated an increase in the regeneration of mammalian CNS axons. Lithium has also been demonstrated to inhibit glycogen synthase kinase 3beta (GSK-3beta), an enzyme known to regulate the levels of phosphorylated tau and beta-catenin (both of which may play a role in the neurodegeneration observed in certain forms of Alzheimer's disease). Consistent with the increases in bc1-2 levels and inhibition of GSK-3beta, lithium has been demonstrated to exert robust protective effects against diverse insults both in vitro and in vivo. These findings suggest that lithium may exert some of its long-term beneficial effects in the treatment of mood disorders via underappreciated neurotrophic and neuroprotective effects. To date, lithium remains the only medication demonstrated to markedly increase bc1-2 levels in several brain areas; in the absence of other adequate treatments, an investigation of the potential efficacy of lithium in the long-term treatment of several neurodegenerative disorders is warranted. Additionally, we suggest that a reconceptualization of the use of lithium in mood disorders may be warranted-namely, that the use of lithium as a neurotrophic/neuroprotective agent should be considered in the long-term treatment of mood disorders, irrespective of the "primary" treatment modality being used for the condition.
Publication Types:
Review
Review, tutorialPMID: 10826666, UI: 20284917
Posted by danf on November 6, 2000, at 16:48:52
In reply to Re: Article: Lithium increases brain volume ?, posted by SLS on November 6, 2000, at 8:25:31
Thanks, Scott...
Yes, interesting.
Time & further studies will show whether this is a primary or secondary effect of Li, & if it will be of benefit in degenerative states.
There seems to be little if any contraindication to testing it. The difficulty is in timing & duration of treatment to determine effectiveness.
Posted by danf on November 7, 2000, at 7:21:56
In reply to Re: Article: Lithium increases brain volume ?, posted by danf on November 6, 2000, at 16:48:52
> Thanks, Scott...
Li, Na & KNa is predominatly an extra cellular ion, K intracellular.
Na high concentrations outside the cell, low inside. K high, concentrations inside the cell, low outside. part of the life force of cells are metabolic pumps that maintain these concentration differences. The different concentrations cause an electric potential to exist across the membrane. When a nerve cell is depolorized, Na & K ions go thru the cell walls to try to attain equal concentrations.
Li which is not a "normal" life related ion has no specific metabolic controls ( as do Na & K ). When Li is present, it interferes with both the steady state ratios of Na & K ( Na & K 'pumps' ) as well as passage of the Na & K ions thru the membrane. It does this at low concentrations.
This corrsponds with therapeutic levels of Li used to treat bipolar.
At high concentrations, Li kills the cells by inactivating the 'pumps'.
There are no Li receptors. It does not have a complex molecular shape that binds to receptors of other molecules, as do neuro transmitters.
This is the end of the thread.
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