The presynaptic component of the serotonergic system is required for clozapine's efficacy

Prem N. Yadav, Atheir I. Abbas, Martilias S. Farrell, Vincent Setola, Noah Sciaky, Xi Ping Huang, Wesley K. Kroeze, Latasha K. Crawford, David A. Piel, Michael J. Keiser, John J. Irwin, Brian K. Shoichet, Evan S. Deneris, Jay Gingrich, Sheryl G. Beck, Bryan L. Roth

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)638-651
Number of pages14
Issue number3
StatePublished - Feb 2011
Externally publishedYes


  • antipsychotic drugs
  • clozapine
  • pet1
  • schizophrenia
  • serotonin

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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