Psychopharmacology

, Volume 177, Issue 1–2, pp 207–216 | Cite as

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
  • K. E. Vanover
  • R. Olsson
  • K. Jayathilake
  • M. Lee
  • A. I. Levey
  • U. Hacksell
  • E. S. Burstein
  • R. E. Davis
  • M. R. Brann
Original Investigation

Abstract

Rationale

Clozapine 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 methods

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

Results

Profiling 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.

Conclusions

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

Keywords

Muscarinic acetylcholine receptors Agonist N-desmethylclozapine Clozapine N-desmethylclozapine/clozapine ratios Schizophrenia Antipsychotic Cognition 

Notes

Acknowledgements

The authors would like to acknowledge the expert technical assistance of T. Son, J. Hendersen, D. Jackson, A. Bajpai, and C. Trotter. We thank M. Gustafsson for synthesis of N-desmethylolanzapine. Drs M. Geyer, L. Iversen, and A. Carlsson are acknowledged for their critical discussions. The in vivo experiments reported herein comply with the principles of laboratory animal care.

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • D. M. Weiner
    • 1
  • H. Y. Meltzer
    • 2
  • I. Veinbergs
    • 1
  • E. M. Donohue
    • 1
  • T. A. Spalding
    • 1
  • T. T. Smith
    • 1
  • N. Mohell
    • 1
  • S. C. Harvey
    • 1
  • J. Lameh
    • 1
  • N. Nash
    • 1
  • K. E. Vanover
    • 1
  • R. Olsson
    • 1
  • K. Jayathilake
    • 2
  • M. Lee
    • 2
  • A. I. Levey
    • 3
  • U. Hacksell
    • 1
  • E. S. Burstein
    • 1
  • R. E. Davis
    • 1
  • M. R. Brann
    • 1
  1. 1.ACADIA Pharmaceuticals, Inc.San DiegoUSA
  2. 2.Departments of Psychiatry and PharmacologyVanderbilt UniversityNashvilleUSA
  3. 3.Department of Neurology, Center for Neurodegenerative DiseasesEmory UniversityAtlantaUSA

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