Posted by SLS on February 9, 2001, at 17:02:06
In reply to re: , posted by Eric on February 9, 2001, at 14:41:47
Hi Eric.
> The reason to get a little excited about Zeldox is not due to the fact it is another new anti-psychotic. The reason to get a little excited about this new medication is due to the fact it is the ONLY neuroleptic on the market in the USA which has automatic built in antidepressant properties.
>
> Zeldox is reported to have built in, moderate serotonin and norephinephrine reuptake properties in addition to its anti-psychotic properties. What this means is that this drug could possibly be used all by itself to treat some cases of depression. None of the other anti-psychotics have serotonin or norephinephrine reuptake capability built into them. Thus, none of the other anti-psychotics used in the USA have any significant anti-depressant properties.I am excited for the same reasons as are you. However, I never considered the possibility that ziprasidone would be consistently and robustly effective as an antidepressant. I guess we'll see.
Where did you get your information regarding the effects of ziprasidone on the reuptake of the monoamines? Is it a reuptake inhibitor? Is the effect at the transporter relavent at clinical dosages?
Perhaps just as important is that ziprasidone does produce increases in extracellular levels of dopamine. I found one study that indicated that ziprasidone did not influence the reuptake of norepinephrine. However, zotepine did. Regarding serotonin, ziprasidone stimulates 5-HT1a somato-dendritic autoreceptors which *inhibit* the firing of serotonergic neurons. It is my opinion at this point that some depressions are actually the result of *too much* serotonergic activity. By inhibiting serotonergic neuron firings by both 5-HT2a antagonism and 5-HT1a agonism, ziprasidone may produce a synergy to inhibit those serotonergic neurons that would otherwise inhibit dopaminergic pathways in meso-cortical and pre-frontal cortical areas of the brain; those which seem to be involved with mood. The result might be an increase in mood elevating dopaminergic activity. (Or perhaps better put, a return to normal mood). This is presumed to occur as the result of an increase in the *release* of dopamine. Increases in extracellular norepinephrine might occur the same way. Neither of these properties are exclusive to ziprasidone. It is zotepine that seems to be unique in its ability to bind to norepinephrine transporter. Ziprazidone will probably show itself to be superior to the other neuroleptics for treating the negative symptoms of schizophrenia.
Olanzapine (Zyprexa) by itself has produced potent antidepressant responses in some people. However, I don't know as to how long this improvement tends to last.
- Scott--------------------------------------------
Neuropharmacology 1998 Jul;37(7):937-44 Related Articles, Books
Elevation of extracellular cortical noradrenaline may contribute to the antidepressant activity of zotepine: an in vivo microdialysis study in freely moving rats.Rowley HL, Kilpatrick IC, Needham PL, Heal DJ
CNS Biology, Knoll Pharmaceuticals Research and Development, Nottingham, UK. Helen.Rowley@knoll.co.uk
The antipsychotic, zotepine, as well as possessing affinity for dopamine D1- and D2-1ike receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.5% and prevented the 50 mM KCl-stimulated increase in NA levels. Zotepine (0.5-1.5 mg kg(-1) i.p.), evoked biphasic, dose-dependent rises in extracellular NA with maximal increases observed at 60 min (+ 171.0%) and 240 min (+ 211.5%) post-treatment. The increases in NA levels were sustained for up to 100 min post-dosing. Clozapine (10.0 mg kg(-1) i.p.), resulted in a smaller, transient increase in NA levels (+ 72.0%) which lasted for 20 min post-treatment. Neither ziprasidone (3.0 mg kg(-1) i.p.) nor olanzapine (1.0 mg kg(-1) i.p.) influenced extracellular NA. Systemic treatment with the antidepressant desipramine (0.3 mg kg(-1) i.p.) resulted in a prolonged elevation of NA levels over 240 min (maximal increase of + 354.3%), whilst local infusion of nisoxetine (1-100 microM) through the dialysis probe increased NA levels in a concentration-dependent manner (up to 587.8% of control values). These data suggest that the inhibition of NA uptake by zotepine and its subsequent prolonged elevation of extracellular cortical NA may underlie the reported antidepressant properties of zotepine in schizophrenic patients.
PMID: 9776389
poster:SLS
thread:53408
URL: http://www.dr-bob.org/babble/20010131/msgs/53620.html