Posted by Brainbeard on July 17, 2009, at 5:32:24
Recently, I wrote a post about how 5HT2A-antagonism (blockade of the 2A serotonin subtype receptor) leads to dopamine and noradrenaline boosting (http://www.dr-bob.org/babble/neuro/20090701/msgs/904542.html). I suggested that dopamine depletion might be prevented by adding 5HT2A-antagonism to an SSRI.
Meanwhile, the situation seems to be more complex than I had hoped. Pure 5HT2A-blockers exist but are not clinically available. The most important reason for that seems to be that as a monodrug, they appear not to have the antidepressant qualities one would expect them to have. I think this reasoning is faulty, since the results of COMBINING a pure 5HT2A-blocker with an antidepressant might be impressive - preferably also adding a 5HT1A-agonist.
Anyway, the first option for a strong 5HT2A-blocker is one of the AAP's. Their relative affinity for the 5HT2A receptor can be seen from this chart: http://www.nature.com/npp/journal/v28/n3/fig_tab/1300027t1.html
Of course, almost all (A)AP's are relatively potent D2-antagonists, but they tend to be more potent 5HT2A-antagonists. I thought that when taken in low doses, an AAP like Risperdal or Ziprasidone (Geodon) would leave D2 alone while touching 5HT2A enough to reap therapeutical benefits. It turns out that this is not the case. Even low doses of AAP's will occupy D2-receptors significantly and antagonize them. I found a study that showed that only 1mg of Risperdal occupies 50% of D2 receptors already, while occupying 60% of 5HT2A-receptors (http://www.ncbi.nlm.nih.gov/pubmed/7530376). I also found a fantastically detailed study about Ziprasidone's binding properties for 5HT2A and D2: http://ajp.psychiatryonline.org/cgi/content/full/161/5/818. Some quotes:
'These studies indicated that single doses of 2040 mg of ziprasidone result in a dose-dependent dopamine D2 receptor occupancy of >60% at 5 hours, while the cortical 5-HT2 receptors are virtually saturated 4 hours after a single 40-mg oral dose'.
'Fischman et al. (15) used a single-dose (40 mg), within-subject design to study 5-HT2 receptor occupancy over time (418 hours) with [18F]setoperone PET. Their results indicated saturation of the 5-HT2 receptors at 4 and 8 hours after administration and a central half-life of 5-HT2 receptor occupancy of almost 20 hours'. That last bit is very interesting: despite its short half-life of 7 hours or less, Ziprasidone's effects on 5HT2A last almost 24 hours. So, for 5HT2A-blockade, it may not be necessary to dose more than once daily.
'At therapeutic doses, the separation of ziprasidones 5-HT2 and D2 receptor occupancies in our study (Figure 1) was 20%30%'.
So, 5HT2A- and D2-antagonism are never far removed from each other. At least not with Ziprasidone, and not with Risperdal either. The difference will be larger with Zyprexa, while Seroquel is not a potent 5HT2A-blocker at all.
Is this bad news? Not completely: it appears that D2-antagonism, together with 5HT2A-blockade, may actually lead to 5HT1A-activation which in turn leads to more cortical dopamine: http://pt.wkhealth.com/pt/re/jneu/abstract.00005064-200103050-00026.htm;jsessionid=KgRH6hCcp77J3YkgG1RnYYbknnmXq0mHlRRN3yrL7xn69qQ2NsWv!940204909!181195628!8091!-1.
Stahl also says somewhere that D2-antagonism may be necessary for the pro-dopaminergic effects of 5HT2A-antagonism.
What remains to be sorted out for me is what D2-antagonism actually entails and which parts of the brain are involved.
By the way, there is yet another drug that blocks 5HT2A, but actually it blocks 5HT2-receptors indiscriminately and is also a potent anticholinergic and antihistaminergic drug: cyproheptadine. I've found on the web that it can be used to counter SSRI-induced sweating, for instance. Its pharmacological profile isn't very attractive, though.
Any feedback or input would be appreciated.
To throw in a question (isn't one supposed to do that in a post?): Would D2-antagonism make me less religious?
poster:Brainbeard
thread:907193
URL: http://www.dr-bob.org/babble/neuro/20090701/msgs/907193.html