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Dr. Shitij Kapur and Dr. Philip Seeman
answers a few questions about this month's
new hot paper in the field of Psychiatry/Psychology
From
•>>November 2002
Field: Psychiatry/Psychology
Article Title: "Does fast dissociation from the dopamine D-2 receptor explain the action of atypical
antipsychotics?: A new hypothesis"
Authors: Kapur,
S;Seeman, P
Journal: AMER J PSYCHIAT
Volume: 158
Page: 360-369
Year: MAR 2001
* CAMH, Clarke Div, 250 Coll St, Toronto, ON M5T 1R8, Canada.
* Univ Toronto, Dept Pharmacol, Toronto, ON, Canada.
* Univ Toronto, Dept Psychiat, Toronto, ON, Canada.
* CAMH, Clarke Div, PET Ctr, Toronto, ON M5T 1R8, Canada.
* CAMH, Schizophrenia Program, Toronto, ON M5T 1R8, Canada.
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Why do you think your paper is highly cited?
Because schizophrenia occurs in about 1% of the world population
with an additional 2% or 3% of individuals with other forms of
psychosis (as in Alzheimer's disease or in manic-depressive
disorder), the treatment of psychosis is a major issue for medicine
and psychiatry. Because there are many new types of antipsychotic
medications that have
been developed in the last few years, physicians have a considerable
choice. These newer antipsychotic medications are attractive to
patients and physicians, because the new drugs cause less side
effects (stiffness, Parkinsonian-like rigidity, and breast swelling)
compared to the traditional antipsychotics such as chlorpromazine or
haloperidol. This article may be highly cited because it provides a
new way of thinking about the mechanism of these newer so-called
atypical drugs, atypical because they elicit less Parkinsonism. It
may have garnered particular attention because it provides an
alternative way of thinking about mechanism—different from the
prevailing ideas of serotonin-dopamine interaction.
Does
it describe a new discovery or new methodology that's useful to
others?
This paper crystallizes the idea, brewing for the past few years,
that the new atypical antipsychotics bind to the dopamine D2
receptor more loosely than the traditional
antipsychotics. So the contribution of this paper was to bring these
ideas together and present a hypothesis that links bench
observations in the test tube to clinical observations at the
bedside. The main claim is that even though different drugs bind to
the same receptor, if they dissociate from the receptor faster after
having bound to it, it leads to different functional outcome.
What
were some of the circumstances that led you to do this research?
The research arose from the problem of trying to explain why
clozapine only blocked 40% of D2 receptors in the brains of
patients, while all the other traditional antipsychotics blocked a
consistent 60% to 80% of the D2 receptors. We directly tested,
therefore, the speed of dissociation of radioactive antipsychotics
from the human cloned dopamine D2 receptors in test tubes. We found
(Ref. 1) thatradio-clozapine and radio-quetiapine came off D2 in
less than 30 seconds, in contrast to radio-haloperidol or
radio-chlorpromazine which
stayed on the receptor for more than 25 or 30 minutes, a glaring
difference. These studies showed that atypical antipsychotics (the
ones that do not give rise to motor side effects) differ from the
typical antipsychotics (the ones that do give rise to motor side
effects) in the rate of their dissociation from the dopamine d2
receptor.
Ref. 1: P.
Seeman and T. Tallerico, "Rapid release of antipsychotic drugs from dopamine D2 receptors: An explanation for low receptor occupancy and early clinical relapse upon drug withdrawal of clozapine or quetiapine,"
Amer. J. Psychiat. 156: 876-884, 1999.
Could
you summarize the significance of your paper in layman's terms?
The paper has significance at different levels of analysis. At a
molecular level it points out that even though two drugs bind to the
same site in the brain—if their rate of binding and dissociation
is not the same—they will have different effects. But, the concept
also hints at how this may have implications for treatment of
patients. Because some compounds remain attached to the receptors
for a long time (even after they have disappeared from the blood) it
may be possible to give some drugs in a once-in-two-days regimen
[see ref 2]. However, these ideas are still at the research stage,
and although such a regimen will diminish the side effects, it is
essential for the patients, their families and the physicians to
ensure that the patients do not stop their medication altogether,
because a serious relapse of the psychosis will occur.
REF. 2: G.
Remington, S. Kapur, S. Shammi, and P.
Seeman,
"Extended dosing as an alternative to intermittent or targeted
antipsychotic
therapy: Rationale and pilot study,"
Schizophrenia Res. 49 (1-2, supplement): 243, 2001. 
Shitij Kapur, M.D., FRCPC, Ph.D.
Canada Research Chair in Schizophrenia
and Therapeutic Neuroscience
Associate Prof. Psychiatry
University of Toronto.
Philip
Seeman, M.D., Ph.D.
Professor, Departments of Pharmacology and
Psychiatry
University of Toronto.
Read an interview
with Dr. Philip
Seeman discussing the Special
Topic of Schizophrenia in
ESI Special Topics.
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ESI Special Topics,
November 2002
Citing URL - http://www.esi-topics.com/nhp/comments/november-02-Kapur-Seeman.html
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