Posted by Larry Hoover on October 9, 2007, at 8:33:24
In reply to Re: Glutamate receptor type/suicidal induction? » Larry Hoover, posted by Bob on October 8, 2007, at 23:54:32
> > I haven't read the full-text yet, but this discovery might prove useful for screening depressives for this adverse effect of citalopram, or perhaps, other antidepressants.
> >
> > Full-text:
> > http://ajp.psychiatryonline.org/cgi/content/full/164/10/1530
> >
> > Abstract:
> > Am J Psychiatry. 2007 Oct;164(10):1530-8.
> > Genetic markers of suicidal ideation emerging during citalopram treatment of major depression.
> > Laje G, Paddock S, Manji H, Rush AJ, Wilson AF, Charney D, McMahon FJ.
> > Genetic Basis of Mood and Anxiety Disorders, NIMH, 35 Convent Dr., Rm. 1A207, Bethesda, MD 20892-3719. gonzalo.laje@nih.gov.
> >
> > OBJECTIVE: Suicidal ideation is an uncommon symptom than can emerge during antidepressant treatment. The biological basis of treatment-emergent suicidal ideation is unknown. Genetic markers may shed light on the causes of treatment-emergent suicidal ideation and help identify individuals at high risk who may benefit from closer monitoring, alternative treatments, or specialty care. METHOD: A clinically representative cohort of outpatients with major depressive disorder who enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were treated with citalopram under a standard protocol for up to 14 weeks. DNA samples from 1,915 participants were genotyped for 768 single-nucleotide polymorphisms in 68 candidate genes. Allele and genotype frequencies were compared between the 120 participants who developed treatment-emergent suicidal ideation and those who did not. RESULTS: Two markers were significantly associated with treatment-emergent suicidal ideation in this sample (marker rs4825476, p=0.0000784, odds ratio=1.94; permutation p=0.01; marker rs2518224, p=0.0000243, odds ratio=8.23; permutation p=0.003). These markers reside within the genes GRIA3 and GRIK2, respectively, both of which encode ionotropic glutamate receptors.CONCLUSIONS: Markers within GRIK2 and GRIA3 were associated with treatment-emergent suicidal ideation during citalopram therapy. If replicated, these findings may shed light on the biological basis of this potentially dangerous adverse event and help identify patients at increased risk.
> >
> >
> > Lar
>
> I don't understand what the suicidal ideation had to do with glutamate receptors.I just read the full-text. This was a prospective study. It means they didn't have any particular hypotheses to test. They collected as much data as they could, and then studied it all, to see if anything popped up. They took blood samples of roughly half the participants, ahead of time, and seeing that some participants developed what they defined as treatment-emergent suicidal ideation, they went looking for any association with the gene variants they'd thought might be involved.
Here's the list of gene variants they went fishing with: "Sixty-eight genes were chosen for study from among a larger list of plausible candidates, which has been detailed elsewhere. Genes were selected to sample five broad signaling pathways of potential importance in antidepressant effects: serotonin (20 genes), glutamate (16 genes), dopamine (three genes), norepinephrine (four genes), and neurotrophins (four genes), along with selected genes in other pathways (21 genes)."
Of those 68 gene variants they considered (one limitation is that they only checked 68, and these specific 68), two gene variants, identified by what they call "markers", i.e. specific strings of genetic code, were shown to be signicantly more common among those subjects who reported even the slightest signs of new suicidal ideation. The highest likelihood was seen when both gene variants were present, suggesting an additive effect. There was also an interaction with citalopram dose, with greater likelihood at higher doses. Subjects with this suicidal response were much less likely to respond to the medication (although many did).
None of the identified subjects dropped out of the study. None of the identified subjects attempted suicide. There were two attempted suicides among the entire study population, but only one had had a blood sample collected for analysis. Although he denied any suicidal ideation (and thus was not captured for the analysis above), this subject had both gene variants predisposing to suicidality.
For the record, the specific receptors coded for by these candidate genes are:
"A marker in the first intron of GRIK2 on chromosome 6 (marker rs2518224), which encodes the kainate-sensitive ionotropic glutamate receptor GluR6, was associated with treatment-emergent suicidal ideation..."
"A marker in the third intron of GRIA3 on chromosome X (marker rs4825476), which encodes the α-amino-5-hydroxy-3-methyl-4-isoxazole propionic acid-sensitive ionotropic glutamate receptor AMPA3, was associated with treatment-emergent suicidal ideation..."
I hope I answered your question, but if not, ask more questions.
Lar
poster:Larry Hoover
thread:787922
URL: http://www.dr-bob.org/babble/20071009/msgs/788041.html