Posted by CamW. on July 29, 2002, at 16:39:59
In reply to Stop taking Zyprexa, posted by Shawn. T. on July 29, 2002, at 3:31:34
Shawn - I think that you have the concept of the roles of dopamine and serotonin receptors backwards. As research with MDL-100,907 and mirtazapine in schizophrenia has shown, the 5-HT2 receptor is not involved in the manifestation of the symptoms of schizophrenia.
Most leading researchers believe that it is the strength of the binding of antipsychotics to the dopamine-D2 receptors that differentiates the traditional antipsychotics from the newer ones.
I have commented on the work of Dr. Phil Seeman (who originated receptor site theory) and Dr. Shitij Kapur before on this site. Check the search function under Dr.Seemans name for my explanation of their work that was published in the American Journal of Psychiatry in the March 2001 issue(158:360-369 - "Does Fast Dissociation From the Dopamine-D2 Receptor Explain the Action of Atypical Antipsychotic?: A New Hypothesis"). This article was a follow-up of an article that Dr.Seeman had published in Clinical Neuroscience Research in early 2001 (pp 53-60 - "Antipsychotic Drugs, Dopamine Receptors, and Schizophrenia"). Both articles are excellent and well referenced.
For further evidence of D2 block rather than 5-HT2 block being resposible for antipsychotic effects (in a visual form) see:
Kapur S. "A New Framework for Investigating Antipsychotic Action in Humans: Lessons From PET Imaging". Molecular Psychiatry 1998; 3: pp 135-140.
and
Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P. "A Positron Emission Tomography Study of Quetiapine in Schizophrenia: A Preliminary Finding of an Antipsychotic Effect With Only Transiently High Dopamine-D2 Receptor Occupancy. Archives of General Psychiatry 2000; 57: pp 553-559.
and
Scherer J, Tatsch K, Schwarz J, Oertel WH, Konjarczyk M, Albus M: D2-Dopamine Receptor Occupancy Differs Between Patients With and Without Extrapyramidal Side Effects". Acta Psychiatrica Scandinavia 1994; 90: pp 266-268.
Also, if you check the following articles on fananserin and MDL-100907 respectively, you will find that these drugs, which both bind strongly to 5-HT2 receptors but are devoid of action at D2 receptors, have no antipsychotic activity. These following papers (actually, one is an article and one is a drug company report):
Truffinet P, Tamminga CA, Fabre LF, Meltzer HY, Riviere ME, Papillion-Downey C. "Placebo-Controlled Study of the D4/5-HT2A Antagonist Fananserin in the Treatment of Schizophrenia". American Journal of Psychiatry 1999; 156: pp 419-425.
Hoechst Marion Roussel (Company Report S). "Management Decisions on Priority Pipeline Products: MDL-100907". Frankfurt, Germany, 1999; pp 2-3.
If a drug company says a drug that they are testing doesn't work, it probably doesn't work.
As for 5-HT2 antagonism being responsible for a decreased incidence of EPS, this is probably wrong as well. Lack of EPS, and possibly a decreased incidence of raised prolactin levels, can be better explained by reversible D2 binding with the newer antipsychotics, as opposed to irreversible binding of conventional antipsychotics to D2 sites.
The reason I have all of these articles is that I took a serious interest in this after a lecture by Phil Seeman I attended in 2000. At the time he was just formulating the theory. As a matter of fact, he had completely changed his lecture while talking with another presenter on the way from the airport. It was really cool to see the gears working in such an intelligent and passionate man.
- Cam
poster:CamW.
thread:114125
URL: http://www.dr-bob.org/babble/20020725/msgs/114202.html