Quote (S3th @ Oct 6 2014 12:19am)
SSRIs don't work due to increasing serotonin, they work after 3-4 weeks due to enhancing neurogenesis, synaptogensis, and overall neuronal survival and neurite outgrowth.
Scientists think SSRIs might promote synaptogenesis and neurogenesis but there isn't full proof that it does.
Unless something came out this year saying otherwise.
And to state "It typically begins due to some type of low grade systemic inflammation or stress." I assume is talking about Atypical Depression and none of the other forms, correct?
Well, SSRIs increase both BDNF & TrkB expression.. that's obvious, as serotonin will bind to a variety of receptors, in particular Gs & Gq ones will cause CREB expression through distinct pathways (cAMP vs Ca2+). Moreover, there's been several reports indicating long term usage of antidepressants upregulate the functioning of the cAMP-PKA-CREB pathway in both the hippocampus and neocortex.
BDNF signaling causes those changes I outlined. They've also shown SSRIs covalently modify histone proteins, altering chromatin packaging and overall gene expression.. which persists after treatment stops.
There's also been a study, here:
http://www.ncbi.nlm.nih.gov/pubmed/12907793?dopt=Abstract&holding=npg -- that demonstrates inhibition of neurogenesis prevents the behavioral amelioration of SSRIs, adding more veracity to the theory.
Many studies have corroborated the findings of SSRI induced increase in overall neurogenesis, neuronal precursor cell proliferation, and BDNF expression.
They've also shown that SSRI use causes a shift in the expression of miR16, which increases levels of S100Beta.. this is mostly an astrocytic specific neurotrophic factor, increasing glial cell proliferation and influencing neurite outgrowth/cell shape, and protects astrocytes. This brings me to the tripartite synapse then, involving astrocytes in antidepressant action, typically overlooked. For instance, SSRIs stimulate astrocytes to to produce neurotrophic factors and protect from glial cell loss that occurs via depression & stress. There's also some studies showing SSRIs signal via 5HT2A & B receptors on astrocytes to increase FGF and EGF production, both of which are growth factors.. and they also favor an ERK pathway, which is robustly involved in mood and neurogenesis.
I mean, there's really not much extrapolation that needs to be done to see this.. too much mechanistic insight. The only thing missing is actually administering the drug for a prolonged period of time then examing the brains and noting the structular changes altogether, which simply hasn't been tested.. but there's enough insight from other studies to say that as all the related and necessary pieces for that to occur has been tested.