Posted by Cam W. on April 28, 2000, at 7:01:18
In reply to Re: Investigational drug assay and specific receptors., posted by PeterJ on April 28, 2000, at 2:21:30
Hey Fried & Peter - Many European psychiatrists say that the TCAs are still much better ADs than any of the new ones. The only problem with TCAs is that they bind to 5 main receptors (serotonin reuptake, norepinephrine reuptake, muscarinic/cholinergic-M1, alpha-adrenergic and histaminic-H1). This tends to produce a lot of the unbearable TCA side effects at therapeutic doses (esp. alpha-adrenergic - bloood pressure problems; M1-dry mouth, blurred vision; and H1-drowsiness and weight gain).Researchers found lower levels of a serotonin metabolite in the CSF of depressed people and that by increasing serotonin in the synaptic gap between cells depression resolved, thus the SSRIs. But, one can be depleted of serotonin and not be depressed (same goes for the depleletion of norepinephrine).
Then the NRIs started popping up (eg. bupropion, reboxetine) and the mixed SNRIs (eg venlafaxine and, to some extent, nefazodone). These too treated depression. Still, none of these antidepressants was as good as the TCAs in a majority of depression. Obviously, some other mechanisim of action for antidepressants was at work.
Some hypotheses are:
1) an upregulation of glucocorticoid receptors (GRs). This is seen with all antidepressants, except citalopram, which upregulates mineralocorticoid receptors (MRs). These two receptors are related and part of the HPA axis. MRs are almost always bound up with cortisol at a basal level and GRs bind more cortisol at higher stress levels. GR binding is not as efficient in people with depression.
2) a desensitization of ACTH receptors in the adrenal cortex, even though thae adrenal cortex keeps pumping out cortisol during depression (and an uncoupled HPA axis). This mechanism is probably addaptive.
3) a dysregulation of CRH release from the hypothalasmus and/or a problem with CRH-receptors in the pituitary. This could be caused by faulty signaling of the GRs. (cyclical process - so is this the chicken or the egg?).
4) Some minor problems with vasopressin (binding or release?) which works in conjunction with CRH to stimulate the pituitary to release ACTH and ß-endorphins. You need both of these processes for proper pituitary function and adrenal stimulation. This is probably why opiates resolve depression in the short term, before tolerance and addiction screw things up.
There are other things that are proposed to happen, but these are the main ones in the HPA axis. Depression is, yet it is not, a simple process.
BTW Peter - Some really cool posts, dude. The in vitro animal and human cell receptor binding studies do seem not to correlate precisely with in vivo actions (eg venlafaxine should not inhibit norepinephrine reuptake very well, as seem in vitro; but does when seen in vivo).
Sincerely - Cam W.
poster:Cam W.
thread:31294
URL: http://www.dr-bob.org/babble/20000420/msgs/31560.html