Posted by JohnX on October 15, 2001, at 23:53:02
In reply to Re: zyprexa dose » JohnX, posted by Cam W. on October 14, 2001, at 2:18:55
> John - Zyprexa™ (olanzapine) is mainly a postsynaptic dopamine-D2 (D2) receptor blocker (as well as blocking other postsynaptic dopamine, serotonin, and muscarinic receptors). An interesting theory was put forth by Dr. Phil Seeman (the guy who invented the receptor site theory) at an "Update on the Management of Psychosis" conference that I attended a couple of years ago. He claimed that the reason that it "appears" that the atypical antipsychotics have low binding constant is because they don't irreversibly bind to the postsynaptic D2 receptor, but rather they "tweak" this receptor. This allows for multiple tweakings of the receptor, leading to better modulation of dopamine neurotransmission, permitting an antipsychotic effect without motor side effects (EPS and TD), prolactin elevation, or secondary negative symptoms. He also said that this tweaking, in itself, is sufficient for the antipsychotic effect of the atypicals. He subsequently went on the publish this theory in two extrordinary articles:
>
> 1) Seeman, P. "Antipsychotic Drugs, Dopamine Receptors, and Schizophrenia", Clinical Neuroscience Research, 2001, 1: 53-60.
>
> 2) Kapur, S., Seeman, P. "Does Fast Dissociation From the Dopamine D2 Receptor Explain the Action of Atypical Antipsychotics?: A New Hypothesis", American Jounral of Psychiatry, 2001, 158: 360-369.
>
> In the second article, Kapur (a brilliant man - and speaker) and Seeman conclude that the blocade of the serotonin-2A (5-HT2A) and the dopamine-D4 (D4) receptor do not contribute to antipsychotic activity.
>
> But, at the Edmonton Schizophrenia 2001 Conference on Friday, Dr. Susan McGurk stated that the the dopamine-D1 receptor blockade by atypical antipsychotics may conceivably increase dopamine turnover in the prefrontal cortex, thus contributing to the increase in cognition see with these agents. She stated that the increase in dopamine in the prefrontal cortex offsets the decrease in cognition caused by the muscarinic-M1 (M1) receptor blocking action of Zyprexa. She also said that another explanation of a lack of cognitive dulling by Zyprexa could be due to the blocking of only select subtypes of the M1 receptor. Dr. McGurk also stated that the reason that Risperdal™ (risperidone) improves many areas of cognition better tha Zyprexa, is because Risperdal is devoid of M1 receptor blockade. Only Clozaril™ (clozapine) has shown to cause cognitive blunting due to it's built-in antimuscarinic action, due to it's blocking of acetylcholine receptors in frontal brain areas, which does not offset the Clozaril-induced increase in dopamine in this location.
>
> Another interesting bit of information that she shared (and that I wasn't aware of) was that the older typical antipsychotics have very little direct effect on cognition. I had always assumed that they did cause cognitive blunting. Dr. McGurk said that because typical antipsychotics cause EPS, people taking them usually need to take a muscarinic blocker like Cogentin™ (benztropine) or Artane™ (trihexyphenidyl), and it is these that cause the cognitive problems.
>
> As to Zyprexa dosing, Friday, Dr. Bill Honer, his plenary talk that I attended, commented on an article published last year in the European Journal of Pharmacology (? - I think - I haven't looked for it yet, and, of course, I missed writing down the author's and the journal names) which stated that maximal effective dosages of Zyprexa in psychosis were less in women (approx 13mg) than in men (approx. 17mg), above which, in most people, there will not be an increase in efficacy. Dr. Honer also stated that Zyprexa for augmentaion of unipolar depression or bipolar disorder, but not psychotic depression, usually required lower doses, but since it is difficult to predict how much less of a dose one would use in these two disorders because dosing with Zyprexa is very individualized. The way he approaches it is to start with 2.5mg or 5 mg of Zyprexa or 0.5 to 2mg of Risperdal (depending on the extent of response of the primary agent being used) and to increase slowly, as necessary.
>
> I hope that this rambling (and unabashed name-dropping) is of some help. - CamCam,
This is really good. Thanks for your time and
effort to piece this together.I ramble at least as well as you; no biggie.
More info the better!Regards,
john
poster:JohnX
thread:81232
URL: http://www.dr-bob.org/babble/20011015/msgs/81370.html