Abstract
Clozapine, by virtue of its absence of extrapyramidal side effects and greater efficacy, revolutionized the treatment of schizophrenia, although the mechanisms underlying this exceptional activity remain controversial. Combining an unbiased cheminformatics and physical screening approach, we evaluated clozapine's activity at >2350 distinct molecular targets. Clozapine, and the closely related atypical antipsychotic drug olanzapine, interacted potently with a unique spectrum of molecular targets. This distinct pattern, which was not shared with the typical antipsychotic drug haloperidol, suggested that the serotonergic neuronal system was a key determinant of clozapine's actions. To test this hypothesis, we used pet1−/− mice, which are deficient in serotonergic presynaptic markers. We discovered that the antipsychotic-like properties of the atypical antipsychotic drugs clozapine and olanzapine were abolished in a pharmacological model that mimics NMDA-receptor hypofunction in pet1−/− mice, whereas haloperidol's efficacy was unaffected. These results show that clozapine's ability to normalize NMDA-receptor hypofunction, which is characteristic of schizophrenia, depends on an intact presynaptic serotonergic neuronal system.
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Acknowledgements
This study was supported by U19MH82441, RO1MH61887, RO1MH075047, the NIMH Psychoactive Drug Screening Program Contract, and the Michael Hooker Distinguished Professorship to BLR. Additional support was from GM71896 (to JJI and BKS) MH075047 to SGB, MH082611 to LKC and the Rogers Family Foundation (to MJK, JJI, and BKS). BKS thanks Tudor Oprea for a gift of the WOMBAT database and John Overington for early access to ChEMBL.
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Dr Roth in the past 24 months has been a consultant for Bristol Myers Squibb, Otsuka Pharmaceuticals, Merck, Medivation, Galenea Pharmaceuticals, the National Institutes of Health, Invitrogen, and Albany Molecular Researech, and has received royalty payments from licensing of 5-HT receptor patents (which are owned by UNC and Case Western Reserve University) to Galena Pharmaceuticals. Drs Shoichet and Irwin are co-founders of SeaChange, and Dr Keiser is an employee of SeaChange. The other authors declare no conflict of interest.
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Yadav, P., Abbas, A., Farrell, M. et al. The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy. Neuropsychopharmacol 36, 638–651 (2011). https://doi.org/10.1038/npp.2010.195
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DOI: https://doi.org/10.1038/npp.2010.195
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