Evidence map›Paper›PMID 15258717›Full record

ArticlePsychopharmacology2004

The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine.

D M Weiner, H Y Meltzer, I Veinbergs, E M Donohue, T A Spalding, T T Smith, N Mohell, S C Harvey, J Lameh, N Nash and 9 more

Abstract read
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In one paragraph

Article in Psychopharmacology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
80citing papers in PubMed, 4 pooled it
5.2field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

80 citing papers in PubMed, 4 syntheses or guidelines pooled it, 249 citations in OpenAlex.

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20 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors at 3 institutions in 1 country.

D M WeinerACADIA Pharmaceuticals, Inc., 3911 Sorrento Valley Boulevard, San Diego, CA, USA. dweiner@acadia-pharm.com
H Y Meltzer
I Veinbergs
E M Donohue
T A Spalding
T T Smith
N Mohell
S C Harvey
J Lameh
N Nash
K E Vanover
R Olsson
K Jayathilake
M Lee
A I Levey
U Hacksell
E S Burstein
R E Davis
M R Brann
Acadia Pharmaceuticals (United States) · USVanderbilt University · USEmory University · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

rationaleClozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described. OBJECTIVES AND

methodsTo comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay.

resultsProfiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone.

conclusionsThe muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

Indexed as

AnimalsCHO CellsClozapineCricetinaeDose-Response Relationship, DrugHippocampusHumansMiceMice, Inbred C57BLMuscarinic AgonistsNIH 3T3 CellsReceptor, Muscarinic M1ClozapineMuscarinic AgonistsnorclozapineReceptor, Muscarinic M1

Identifiers

PMID15258717
OpenAlexW2046479063

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.