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Re: Abilify produces sedation at low dosages only?

Posted by SLS on February 23, 2003, at 22:13:46

In reply to Re: Abilify produces sedation at low dosages only?, posted by Thomas123 on February 23, 2003, at 21:00:55

Hi Thomas.


> There are a few holes in your theory.

Most likely. The manner in which Abilify (aripiprazole) alters the dynamics of the DA synapse are probably quite complex.

> First of all presynaptic dopamine receptors when agonized reduce the release of dopamine. Presyaptic receptors are a feedback regulating mechanism. The idea is if there is a lot of dopamine in the synaptic cleft the dopamine will agonize a presynaptic receptor reducing the release of dopamine thereby lowering the amount of dopamine in the synaptic cleft.

I'm sure it was just an honest oversight on your part to have misread my post.

> Two, it is just false that one gets the same side-effects from high dosages as from low dosages.

I'm not so sure about that - at least not for the atypical neuroleptics. I suffered the same degree of weight-gain and somnolence starting at 10mg of Zyprexa as I did when I started at 2.5 in separate trials. I recently began a trial of Seroquel at 25mg. It knocked me on my ass for the first few days (somnolence). Three years ago, I began a trial of Seroquel; working up to 300mg within a week. I don't recall having any trouble with somnolence then, and the minor cognitive effects were no different between the two trials.

> Dosages which block more than 65% of dopamine D2 receptors result in EPS. One gets more than 70% of those D2 recptors blocked and it is apathy city.

This is absolutely wrong. ALL neuroleptics MUST transiently block at least 65% of postsynaptic receptors in order to produce a clinical antipsychotic effect. If your contention were to be correct, all of those people who respond to an antipsychotic always develop EPS. Surely, this is not the case. Scientists don't really know what properties or mechanisms of a neuroleptic confer atypicality. However, it seems to be related more to the dissociation constant of receptor binding (binding affinity) than to the number of receptors blocked. The term 'atypical' refers to the greatly reduced rate of EPS that these drugs express. Regarding the atypicals, with the exception of risperidone, I don't think the evolution of EPS increases greatly with increasing dosage or receptor occupancy. Seroquel only infrequently produces EPS, regardless of dosage, and has been assigned a risk of 0% for producing tardive dyskinesia in some of the medical literature.

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"Antipsychotic action occurs at about 65–80% D2 block, while extrapyramidal Parkinsonian signs and akathisia occur when at least 80% of D2 receptors are occupied (). The imaging data are primarily based on the binding of [11C]raclopride to the striatal D2 receptors in volunteers or patients. This binding primarily reflects D2 because there are negligible amounts of D3 and D4 receptors in the human striatum. At present, the measurement of D2 receptors in non-striatal regions of the brain is not feasible because these regions have low D2 densities."

http://www.acnp.org/g4/GN401000027/CH027.html

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- Scott

 

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