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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 14 of 14. This is the beginning of the thread.
Posted by SLS on December 16, 2004, at 7:20:20
U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH
NIH News
National Institute of Mental Health (NIMH)
http://www.nimh.nih.gov/FOR IMMEDIATE RELEASE
Tuesday, December 14, 2004
MUTANT GENE LINKED TO TREATMENT-RESISTANT DEPRESSIONA mutant gene that starves the brain of serotonin, a mood-regulating
chemical messenger, has been discovered and found to be 10 times more
prevalent in depressed patients than in control subjects, report
researchers funded by the National Institutes of Health's National
Institute of Mental Health (NIMH) and National Heart Lung and Blood
Institute (NHLBI). Patients with the mutation failed to respond well to
the most commonly prescribed class of antidepressant medications, which
work via serotonin, suggesting that the mutation may underlie a treatment-
resistant subtype of the illness.The mutant gene codes for the brain enzyme, tryptophan hydroxylase-2, that
makes serotonin, and results in 80 percent less of the neurotransmitter.
It was carried by nine of 87 depressed patients, three of 219 healthy
controls and none of 60 bipolar disorder patients. Drs. Marc Caron,
Xiaodong Zhang and colleagues at Duke University announced their findings
in the January 2005 "Neuron," published online in mid-December."If confirmed, this discovery could lead to a genetic test for
vulnerability to depression and a way to predict which patients might
respond best to serotonin- selective antidepressants," noted NIMH Director
Thomas Insel, M.D.The Duke researchers had previously reported in the July 9, 2004 "Science"
that some mice have a tiny, one-letter variation in the sequence of their
tryptophan hydroxylase gene (Tph2) that results in 50-70 percent less
serotonin. This suggested that such a variant gene might also exist in
humans and might be involved in mood and anxiety disorders, which often
respond to serotonin selective reuptake inhibitors (SSRIs) --
antidepressants that block the re- absorption of serotonin, enhancing its
availability to neurons.In the current study, a similar variant culled from human subjects
produced 80 percent less serotonin in cell cultures than the common
version of the enzyme. More than 10 percent of the 87 patients with
unipolar major depression carried the mutation, compared to only one
percent of the 219 controls. Among the nine SSRI-resistant patient
carriers, seven had a family history of mental illness or substance abuse,
six had been suicidal and four had generalized anxiety.Although they fell short of meeting criteria for major depression, the
three control group carriers also had family histories of psychiatric
problems and experienced mild depression and anxiety symptoms. This points
up the complexity of these disorders, say the researchers. For example,
major depression is thought to be 40-70 percent heritable, but likely
involves an interaction of several genes with environmental events.
Previous studies have linked depression with the same region of chromosome
12, where the tryptophan hydroxylase-2 gene is located. Whether the
absence of the mutation among 60 patients with bipolar disorder proves to
be evidence of a different underlying biology remains to be investigated
in future studies.The researchers say their finding "provides a potential molecular
mechanism for aberrant serotonin function in neuropsychiatric disorders."Also participating in the study were: Raul Gainetdinov, Jean-Marin
Beaulieu, Tatyana Sotnikova, Lauranell Burch, Redford Williams, David
Schwartz, and Ranga Krishnan, Duke University.In addition to grants from NIMH and NHLBI, the study was also funded by
the Human Frontiers Science Program and the Canadian Institute of Health
Research.NIMH and NHLBI are part of the National Institutes of Health (NIH), the
Federal Government's primary agency for biomedical and behavioral
research. NIH is a component of the U.S. Department of Health and Human
Services.
Posted by ed_uk on December 16, 2004, at 7:37:28
In reply to Gene Linked To Treatment-Resistant Depression, posted by SLS on December 16, 2004, at 7:20:20
Hi Scott,
I wonder whether taking an SSRI + L-Tryptophan might be an effective treatment strategy for people with the abnormal tryptophan hydroxylase gene who had failed to respond to SSRIs alone.
Ed.
Posted by Larry Hoover on December 16, 2004, at 8:07:35
In reply to Re: Gene Linked To Treatment-Resistant Depression » SLS, posted by ed_uk on December 16, 2004, at 7:37:28
> Hi Scott,
>
> I wonder whether taking an SSRI + L-Tryptophan might be an effective treatment strategy for people with the abnormal tryptophan hydroxylase gene who had failed to respond to SSRIs alone.
>
> Ed.As the enzyme has some activity, there are two ways to ensure optimal function of the existing enzyme. One is to ensure ample supplies of the substrate, as the velocity of the enzyme (to saturation) is a function of substrate concentration. The other is to ensure adequate cofactor concentration, which in this case, is tetrahydrobiopterin (BH4). A drug may be quite unnecessary.
Lar
Posted by MKB on December 16, 2004, at 8:35:39
In reply to Gene Linked To Treatment-Resistant Depression, posted by SLS on December 16, 2004, at 7:20:20
Posted by ed_uk on December 16, 2004, at 9:28:07
In reply to Re: Gene Linked To Treatment-Resistant Depression » ed_uk, posted by Larry Hoover on December 16, 2004, at 8:07:35
Hello Lar,
Hope you are well at the moment :-)
You make a good point in your post.It might still be useful to combine tryptophan with an SSRI because optimising the activity of the defective enzyme might not be sufficient to raise serotonin to an adequate level on its own.
Ed.
Posted by Larry Hoover on December 16, 2004, at 10:10:23
In reply to Hi Larry, posted by ed_uk on December 16, 2004, at 9:28:07
> Hello Lar,
>
> Hope you are well at the moment :-)Reasonably well, thanks. How about you?
> You make a good point in your post.
I do try. ;-)
> It might still be useful to combine tryptophan with an SSRI because optimising the activity of the defective enzyme might not be sufficient to raise serotonin to an adequate level on its own.
>
> Ed.Eventually useful, perhaps. However, having two independent variables precludes determining the relative contribution of each one.
I'm quite concerned that the first resort to treatment is medication, rather than optimization of whatever natural capacity the individual may have. To characterize the distinction more fully, the individual may have an innate functional deficiency in serotonin, possibly remedied by tryptophan enhancement. You could reasonably call the defect a functional deficiency in tryptophan (i.e. despite normal diet, insufficient tryptophan is available to optimize tryptophan hydroxylase activity). I doubt they have an SSRI deficiency. (slight sarcasm intended)
The other potential defect at this rate-determining step in serotonin synthesis is a functional deficiency in tetrahydrobiopterin. There is a well-characterized genetic flaw in the enzymes leading to BH4 synthesis, as well. Nutritional supplements and dietary vitamins are largely available in provitamin form. That is to say, they must themselves be transformed or activated by enzymes before they can serve in their coenzyme role. There has been some discussion on the alternate board about the utility of BH4 supplementation (it is a requirement for all hydroxylase enzymes), yet it is blessedly difficult to obtain. Taking folate just may not do the trick, for some people.
Despite the forgoing argument, you may find this particular thread interesting, vis a vis folate deficiency and antidepressant response: http://www.dr-bob.org/babble/alter/20041212/msgs/430007.html
Lar
Posted by ed_uk on December 16, 2004, at 10:46:10
In reply to Re: Hi Larry » ed_uk, posted by Larry Hoover on December 16, 2004, at 10:10:23
Hi Larry,
Thank you for the link :-)
>I'm quite concerned that the first resort to treatment is medication, rather than optimization of whatever natural capacity the individual may have.
I agree. The pharmaceutical industry is a very influential profit making business. A lot of the American Psychiatric Association's money is said to come from drug adverts. Many doctors are very dismissive of vitamins, I guess they aren't discussed much at medical school. About four years ago, I went to a conferance for people who were considering doing medicine at university. Various physicians and surgeons had prepared talks... people listened politely. A woman came to talk about the importance of diet and nutrition and some people were shouting 'boo boo'. It seems that potential medical students are anti-supplement before they even start medical school.
Perhaps if L-Tryptophan + BH4 (or folic acid if BH4 not available) was inadequate, adding an SSRI would make sense.
>I doubt they have an SSRI deficiency.
Me too. Last friday night I went to a bar with a friend who was already a bit drunk. I didn't enjoy myself, perhaps I was suffering from an alcohol deficiency!Regards,
Ed.
Posted by MKB on December 16, 2004, at 11:24:34
In reply to Re: Hi Larry » ed_uk, posted by Larry Hoover on December 16, 2004, at 10:10:23
>I'm quite concerned that the first resort to treatment is medication, rather than optimization of whatever natural capacity the individual may have. To characterize the distinction more fully, the individual may have an innate functional deficiency in serotonin, possibly remedied by tryptophan enhancement. You could reasonably call the defect a functional deficiency in tryptophan (i.e. despite normal diet, insufficient tryptophan is available to optimize tryptophan hydroxylase activity). I doubt they have an SSRI deficiency
AMEN!
Posted by linkadge on December 16, 2004, at 11:57:16
In reply to Re: Hi Larry » Larry Hoover, posted by MKB on December 16, 2004, at 11:24:34
"I doubt they have an SSRI deficiency"
This doesn't really make a lot of sence. Not every disease is caused by a deficiancy of one vitamin or mineral. I don't know how many times I've heard a naturalpath tell me that depression is not caused by a prozac deficancy, and then tell me to take St. John's Wort.
When a gene is messed up, then there exists the very real possability that, even in the presence of perfect nutrition and exercise, there still might be a problem.
Linkadge
Posted by SLS on December 16, 2004, at 13:58:25
In reply to Re: Gene Linked To Treatment-Resistant Depression » ed_uk, posted by Larry Hoover on December 16, 2004, at 8:07:35
> > Hi Scott,
> >
> > I wonder whether taking an SSRI + L-Tryptophan might be an effective treatment strategy for people with the abnormal tryptophan hydroxylase gene who had failed to respond to SSRIs alone.
> >
> > Ed.
>
> As the enzyme has some activity, there are two ways to ensure optimal function of the existing enzyme. One is to ensure ample supplies of the substrate, as the velocity of the enzyme (to saturation) is a function of substrate concentration. The other is to ensure adequate cofactor concentration, which in this case, is tetrahydrobiopterin (BH4). A drug may be quite unnecessary.
>
> Lar
>Why not just go with 5-HTP?
- Scott
Posted by MKB on December 16, 2004, at 14:24:32
In reply to Re: Gene Linked To Treatment-Resistant Depression, posted by SLS on December 16, 2004, at 13:58:25
Larry will probably address this and do a better job, but 5HTP does not work for some people as well as Tryptophan. From the reading I've done, it seems that 5HTP may do more circulating in your blood than in your brain, where you need it.
Posted by denise1904 on December 21, 2004, at 11:20:24
In reply to Gene Linked To Treatment-Resistant Depression, posted by SLS on December 16, 2004, at 7:20:20
Hi Scott,
How's it going and what are you trying now? :-)
Nine of 87 depressed patients having the gene doestn't sound like a big proportion to me, is this really significant or just a red herring do you think?
Denise
Denise
Posted by SLS on December 21, 2004, at 15:59:13
In reply to Re: to SLS - nine of 87 depressed patients??, posted by denise1904 on December 21, 2004, at 11:20:24
Hi Denise.
> How's it going and what are you trying now? :-)
I am doing very slightly better for having begun taking Parnate. I am benefiting from the initial stimulant-like effects. I am using Parnate temporarily until I can get a hold of mifepristone (RU-486). Yes - it is the infamous French abortion drug. Not only does it block progesterone receptors (the mechanism by which it works as an abortifacient), it also blocks cortisol receptors. I'm hoping it resets my HPA axis. Right now, the NIMH is studying it to treat bipolar depression. I don't know what their results are yet, as they have not published any results to my knowledge. The study is ongoing. Getting the drug involves a lengthy process of application to the FDA for a special treatment protocol. I'm pretty sure I will go through with it.
> Nine of 87 depressed patients having the gene doestn't sound like a big proportion to me, is this really significant or just a red herring do you think?
I think the salient findings of the study are that the people with the abberant gene are more likely to be treatment-resistant to SSRIs. Mood disorders seem to involve more than one gene. It is significant that perhaps one of these genes has been isolated.
- Scott
Posted by denise1904 on December 22, 2004, at 8:34:04
In reply to Re: to SLS - nine of 87 depressed patients?? » denise1904, posted by SLS on December 21, 2004, at 15:59:13
Hi Scott,
Glad to hear you're feeling a bit better, hope it lasts. Yes you told me you were planning on Mifepristone, if you do manage to get hold of it, are you hoping to take it regularly or just once a week or something?
I see what you mean about the gene and treatment resistance but what about people who haven't always been resistant (and I think you are one of those people having had a robust response a long time ago), would they have this gene do you think?
Denise
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