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Dr. Bob is Robert Hsiung, MD,
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Posted by jrbecker on March 9, 2006, at 15:26:20
http://www.nimh.nih.gov/press/stardgene.cfm
NIMH
Science Update
March 8, 2006Gene Influences Antidepressant Response
Whether depressed patients will respond to an antidepressant depends, in part, on which version of a gene they inherit, a study led by scientists at the National Institutes of Health (NIH) has discovered. Having two copies of one version of a gene that codes for a component of the brain's mood-regulating system increased the odds of a favorable response to an antidepressant by up to 18 percent, compared to having two copies of the other, more common version.Since the less common version was over 6 times more prevalent in white than in black patients — and fewer blacks responded — the researchers suggest that the gene may help to explain racial differences in the outcome of antidepressant treatment. The findings also add to evidence that the component, a receptor for the chemical messenger serotonin, plays a pivotal role in the mechanism of antidepressant action. The study, authored by National Institute of Mental Health (NIMH) researchers Francis J. McMahon, M.D., Silvia Buervenich, Ph.D., and Husseini Manji, M.D., along with collaborators at several other institutions, was posted online March 8 and will appear in the May, 2006 American Journal of Human Genetics.
"To our knowledge, this is the first demonstration of significant association between genetic variation and outcome of antidepressant treatment," said Manji, director of the NIMH's Mood and Anxiety Disorders Program. "It brings us closer to the day when clinicians will be able to make more informed decisions about which medication to prescribe for an individual patient. Right now, it still involves a lot of trial-and-error."
In the initial phase of the NIMH-funded STAR*D (Sequenced Treatment Alternatives for Depression) trial, about 47 percent of the 2,876 participants experienced some improvement with the serotonin selective reuptake inhibitor (SSRI) citalopram (Celexa). The NIH scientists set out to find genetic factors that might help to explain why some patients fared better than others.
They screened genetic material from 1,953 of the STAR*D patients, a sample with a higher percentage of responders (69 percent), in part because patients who were doing well tended to stay in contact longer and were more likely to allow a blood sample to be drawn. The researchers looked for associations between treatment response and 768 known sites of variability in 68 suspect genes - sites where letters in the genetic code vary across individuals.
They found the strongest connection in the gene that codes for the serotonin 2A receptor, one of several proteins to which serotonin binds when brain cells communicate.
Located on cells in the brain's thinking center (cortex), the serotonin 2A receptor regulates circuits implicated in depression. Antidepressants, including citalopram, reduce the number of serotonin 2A receptors in animal cortex over the course of a few weeks — the same time-frame required for the drugs to work in humans — suggesting that the receptors are important in the drugs' mechanism of action.
Everyone inherits two copies of the serotonin 2A receptor gene, one from each parent. A tiny glitch in the gene's chemical sequence results in some people having an adenine (A) at the same point that other people have a guanine (G). So an individual can have gene types AA, AG or GG. Overall, the prevalence of the A version was 38 percent, compared to 62 percent for the G version in this sample. Fourteen percent had AA gene type, 43 percent AG and 43 percent GG. Since the site of variation is located in a stretch of genetic material with no known function, the researchers suspect that it may be just a marker for a still-undiscovered functional variation nearby in the gene.
Based on scores on a depression rating scale, close to 80 percent of patients who had AA responded to the antidepressant, compared to about 62 percent of those with GG. Thus, patients with the AA gene type were 16-18 percent more likely to benefit from the medication. Even patients with AG showed some increased benefit.
But this only applied to white patients, in whom the A version was more than six times more frequent than in black patients. There was no significant association between gene type and treatment outcome in black patients, who tended to fare less well in the trial overall.
"We now have to consider genetic factors as well as psychosocial issues in our attempts to explain why antidepressants do not help our black patients as much as they should," McMahon said. "Although the new findings cannot yet guide treatment decisions, they help make a compelling case for a key role of the serotonin 2A receptor in the mechanism of antidepressant action."
Also participating in the study were: A. John Rush and Madhukar Trivedi, University of Texas Southwestern Medical Center; Gonzalo Laje, NIMH; Dennis Charney, Mount Sinai Hospital; Robert Lipsky, National Institute on Alcohol Abuse and Alcoholism (NIAAA); Alexander Wilson, Alexa Sorant, and George Papanicolaou, National Human Genome Research Institute (NHGRI); Maurizio Fava, Massachusetts General Hospital; and Stephen Wisniewski, University of Pittsburgh.
TopPosted: 03/08/2006
Posted by bipolarspectrum on March 9, 2006, at 18:23:07
In reply to Serotonin 2A gene affects antidepressant response, posted by jrbecker on March 9, 2006, at 15:26:20
Posted by linkadge on March 9, 2006, at 20:56:24
In reply to Is this the so-called suicide gene?? (nm), posted by bipolarspectrum on March 9, 2006, at 18:23:07
Certain patterns of 5-ht2a expression seem to occur in the brains of suicide victoms. Depressed suicide brains tend to have upregulated 5-ht2a receptors in the frontal cortex. But, antidepressant treatments differentially regualte 5-ht2a expression. For instance, ECT does not downregulate 5-ht2a receptors in the frontal cortex. I read a few studies saying it does the opposite.
Another thing to keep in mind is that even non-serotonergic antidepressants can regulate the expression of 5-ht2 system, like desipramine.
Even melatonin can downregulate 5-ht2a receptors.http://biopsychiatry.com/des5ht2.htm
So I'm not sure that I'd agree with the assumption that 5-ht2 dysregulation was a consequence of "low serotonin"
From what I have read, 5-ht2a upregulation and downregulation seemed to be a marker of the activity of the HPA axis.
I remember reading a report that showed that a certain 5-ht2a receptor gene was associated with a better response to mirtazapine over paxil. I would like to read that study with and this one together to see how they compare.
Linkadge
Posted by River1924 on March 10, 2006, at 1:13:44
In reply to Re: Is this the so-called suicide gene?? » bipolarspectrum, posted by linkadge on March 9, 2006, at 20:56:24
I find the idea of depressed suicide brains morbidly comic.
The article is interesting. A bit over my head and I'm never sure with something as complex and chaotic as a brain and the body and experience.... how science even comes to any conclusions about "normal" in one small area of something as large as the frontal cortex... no saying something as singular as each person's interior life.
I'm lucky, I guess. And, perhaps, emotionally unambitious. If I am not suicidal, I don't count that as being depressed. But it has become predictable... I will stop an SSRI or TCA and in 7 days, suicidal thoughts will start to circulate like moons around my cognition. Within 10 -12 days, the "suicial ideation" is no longer just verbal electrical randomness... it has become something (there is no work in English) total, larger than "me." At first, "I" am separate from it but it swallows me up. I feel (again there is no word in English) something I can't call pain, it isn't a sensation, but at the same time "it" is almost unbearable and becomes more so. What is happening and where, I can not say but I can not stand it as days pass.
Luckily, every SSRI and some TCA's work for me and "it" goes away and, then, I no longer desire to commit suicide. By all measures of science, I may still be depressed but if "it" goes away... life is bearable and sometimes okay.
I can give metaphors for "it": pain comes closest I suppose but that really refers to something physical. My perception of existence changes and I see through whatever the opposite of rose colored glasses is... but, really, that is just a side effect of "it."
To me, there are two kind of people in the world: those who have been swallowed up by "it", who have felt "it", and those who haven't.
I stopped desipramine three or four days ago. I know my thinking is becoming bleaker but I have hope that... maybe, just maybe... the suicidal thoughts won't start to circle my other thoughts, my other actions, my walking, my eating, my socializing. I can keep them out there and continue in a rational way for three or four more days but then it begins to become dangerous.
Is something leaving my system or entering it? Some ratio of this or that? A joy opiate leaking out some drain or "it" (whatever "it" is) leaking in and poisoning me, some toxic substance telling my entire body to commit suicide. A cell instructs itself to die, a process called apoptosis. For me, my experience is like my entire body filling up with instructions for apoptosis.
I hear some people stop their meds and life goes on more or less in a civil way. I hope that happens that way this time. Stranger things have happened.
If you can shed any light on this experience of "it": this feeling of my entire body being coded for apoptosis against my reason, I'd be happy. Even words, vocabulary... it is all helpful.
Otherwise, thanks. Where else can I ramble on about "it" and not be thought paranoid or possessed by demons? When I was young and tried to get myself off this earth, I recall people telling me it was "a cry for help." It always seemed like a glib dismissal and egocentric (as if my suicide attempt had anything to do with someone else.)
Later... I'll be fine (or, if not, I'll go back on one AD or the other.)
River.
This is the end of the thread.
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