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Re: Andrew Question. Amisulpride vs Zyprexa

Posted by AndrewB on March 20, 2000, at 14:17:55

In reply to Andrew Question. Amisulpride vs Zyprexa, posted by JohnL on March 20, 2000, at 4:38:14


Both Zyprexa (olanzapine) and amisulpride are atypical antipsychotics with significant D2 receptor antagonist activity. You ask if Zyprexa, like amisulpride, antagonizes the presynaptic receptor if the dosage administered is reduced below a certain threshold. I really can’t say if this occurs but it is quite possible. I did some research and I couldn’t find any reference to Zyprexa’s actions at extremely low doses. I can speculate that even if Zyprexa does have amisulpride’s presynaptic action at such low doses, it does not necessarily possess amisulpride’s therapeutic value. Zyprexa has activity at a variety of other neurotransmitter sites (i.e. 5HT2) so at extremely low doses it is hard to say whether it would have utility for any depressive condition regardless of whether it has a presynaptic antagonistic action or not.

Amisulpride, sulpiride and other antipsychotics, having D2 antagonistic action, bind preferentially to the presynaptic autoreceptors at low doses. Likewise, Mirapex (pramipexole) and other D2 receptor agonists bind preferentially to the presynaptic autorecpetors. An explanation for this was offered by Scott Schofield in a previous post, the words in brackets are mine.

“(While at high doses dopamine agonists are energizing, sleepiness) is seen quite often when low doses of some direct dopamine agonists
are used. Presynaptic dopamine autoreceptors tend to be “stronger” than the
postsynaptic receptors at attracting the neurotransmitter. These autoreceptors,
when stimulated by the attachment of a natural neurotransmitter molecule or a
drug that mimics it, tells the presynaptic neuron to “power-down” by decreasing
the amount of dopamine being manufactured as well as releasing smaller
amounts of it. At low dosages, a greater ratio of the stronger presynaptic
autoreceptors are stimiulated as compared with those that are postsynaptic. The
consequence of this is a reduction in the number of postsynaptic dopamine
neurons firing and a resultant state of sedation. At higher dosages, basically all
of the receptors are stimulated, including the postsynaptic ones that cause the
stimulation otherwise associated with these drugs.

Amisulpiride works exactly in reverse. It is a dopamine receptor antagonist. It
sticks to the receptors without stimulating them. It therefore blocks the receptor
from capturing the dopamine that would otherwise stimulate it. At low dosages,
more presynaptic autoreceptors are blocked than are postsynaptic, so the first
neuron is convinced that it needs to manufacture and release more dopamine
while there are still enough open receptors on the second neuron to be
stimulated by it. This is what may account for its antidepressant effects. At
higher dosages, the receptors of the postsynaptic neuron are blocked, leading to
its inhibition. This is what is thought to be responsible for its anti-psychotic
properties and why it has been used for schizophrenia.” (Thanks Scott)

Zyprexa may however be an exception to the D2 drugs that have a preference for presynaptic activity at low doses. Some drugs apparently have different binding affinities to the post and pre synaptic receptors. For example some D2 drugs are both presynaptic agonists and postsynaptic antagonists, as strange as that sounds.

Andrew B




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