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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 5 of 5. This is the beginning of the thread.
Posted by SLS on February 23, 2003, at 20:12:42
Hi.
Will raising the dosage of Abilify get rid of the sedation some people experience when initiating treatment with low dosages?
I recently started Abilify. My doctor started me off at 20mg. He said that we might as well start this high because, in his experience, the intensity of side-effects produced by neuroleptics is nearly the same at high dosages as low dosages. I have been at this dosage for over a week. The only side-effects I have thus far experienced are mild to moderate insomnia, slightly blunted cognition, mild headache, and perhaps dry mouth. They are at worst minor annoyances that seem to be dissipating.I have begun to think that for those people whom experience sedation, their dosage of Abilify might be too low. Abilify acts as an agonist (stimulator) of presynaptic dopamine DA2 autoreceptors. These presynaptic receptors tend to attract and bind dopamine, along with various drugs, significantly more strongly than do postsynaptic receptors. When stimulated, these autoreceptors instruct the neuron to reduce it's rate of synthesis and release of dopamine. This usually results in sedation or somnolence.
The best example of the presynaptic DA agonist sedation phenomenon is the drug, apomorphine. Apomorphine is a non-selective DA agonist that produces arousal, excitement, and amphetamine-like stereotypical behavior at moderate and higher dosages. However, at low dosages, it produces profound sedation due to its preferential stimulation of presynaptic autoreceptors.
I feel that these facts yield a hypothesis: Raising the dosage of Abilify will abolish the sedation experienced by some people at low dosages.
For some people, Abilify produces sedation at low dosages in a manner similar to apomorphine due to preferential presynaptic DA receptor agonism. This sedation is perhaps amplified by the ability of Abilify to act as a postsynaptic antagonist in the presence of dopamine. Perhaps raising the dosage beyond a certain threshold would change the balance between presynaptic and postsynaptic stimulation in favor of the latter to mitigate or abolish sedation. It is possible, however, that the synaptic dynamics of some individuals prevent this net reversal from occurring.
I will stop this post here so I that I can watch Bruce perform on the Grammys.
Bye...
- Scott
Posted by Thomas123 on February 23, 2003, at 21:00:55
In reply to Abilify produces sedation at low dosages only?, posted by SLS on February 23, 2003, at 20:12:42
There are a few holes in your theory. 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.
Two, it is just false that one gets the same side-effects from high dosages as from low dosages. 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.
How I understand Abilfiy is it is a weak dopamine agonist. It binds strongly to dopamine D2 receptors blocking access by dopamine to the receptor but gives less of a charge than dopamine thereby toning down dopaminergic output.
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
Posted by Thomas123 on February 24, 2003, at 0:07:42
In reply to Re: Abilify produces sedation at low dosages only?, posted by SLS on February 23, 2003, at 22:13:46
The prescribing information for Abilify states somnolence is the only side-effect which is dose related. It is about 8.5% for 15 milligrams, 7.5 percent for 20 milligrams and 15% for 30 milligrams. See www.abilfiy.com. I was unable to cut and paste from the PDF.
Your post says for neuroleptics side-effects aren't dosage related. This is false. EPS go up with typical neuroleptics when dosage is increased. Atypical neuroleptics have many actions. Increase dosage and side-effects will go up with them. Sleepiness comes from antihistaminergic and anticholigneric actions as much as from blockade of dopamine receptors. Haldol is a very powerful dopamine antagonist but lacks sedative properties because it is only a dopamine antagonist. Even if Clozaril and Seroquel are only transiently on the receptor if there is a lot of Clozaril or Seroquel in the system there will be a new neurolpetic molecule around to pop on the receptor when the old one pops off.
These boards have talked about a sleepiness associated with Abilify but the fact remains this is an uncommon side-effect for Abilfiy according to the published studies.
Abilfy isn't transiently on the receptor. It has a very low dissociation constant. It is on for a long time. It is third generation drug. Increase the dosage enough and it will totally displace dopamine from the receptor and there will be a decreased agonization of dopamine receptors given that Abilify is a weaker agonist than dopamine.
Low dosages by agonizing presynatpic receptors weakly increase the release of dopamine from terminals relative to the agonization of dopaminergic autoreceptors by dopamine and thereby have a stimulatory affect.
There is really no angle in trying to tease out a differential effect between pre and post synaptic dopamine receptors as presynaptic receptors are D2 receptors and the same kind of receptor which must be blocked to obtain an antipsychotic effect. One has to look at net effects.
Best of luck, of course.
Posted by lostforwards on October 21, 2004, at 7:27:58
In reply to Re: Abilify produces sedation at low dosages only?, posted by Thomas123 on February 23, 2003, at 21:00:55
I've got a serious case of apathy and anhedonia after being on 3mg Risperidal, for bp, and suffering parkinsonian to the point that I had difficulty breathing, muscle stiffness, and td-like movements in my hands.
It's been 3 weeks and hasn't gone away.
do you know what might've caused this?
( I was thinking d2 upregulation )
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