Clozapine: New research on efficacy and mechanism of action

Herbert Y. Meltzer*, Bijan Bastani, Luis Ramirez, Shigehiro Matsubara

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


Clozapine can produce greater clinical improvement in both positive and negative symptoms than typical antipsychotic drugs in neuroleptic-resistant schizophrenic patients. The clinical response may occur rapidly in some patients but is delayed in others. Clozapine has also been reported to produce fewer parkinsonian symptoms, to involve a lower risk of producing tardive dyskinesia, and to produce no serum prolactin elevations in man. It seems likely that these effects are the result of a common biological mechanism or related mechanisms, rather than unrelated effects. Other atypical antipsychotic drugs, such as melperone and fluperlapine, share at least some of these properties. A relatively low affinity for the D-2 dopamine (DA) receptor and high affinity for the 5-HT2 receptor, producing a high 5-HT2/D-2 ratio, best distinguishes atypical antipsychotics like clozapine from typical antipsychotic drugs. Through its weak antagonist action on D-2 DA receptors and a potent inhibitory effect on 5-HT2 receptors, as well as its abiltiy to increase DA and 5-HT release, clozapine may be able to permit more normal dopaminergic function in the anterior pituitary, the mesostriatal, mesolimbic and mesocortical regions. The numerous advantages of clozapine over typical neuroleptics are consistent with the primary importance of DA to the pathophysiology of schizophrenia. The secondary but still significant role of 5-HT in the action of clozapine may either be direct or via the effect of 5-HT on dopaminergic mechanisms. Some aspects of schizophrenia could be due to a dysregulation of the interaction between serotonergic and dopaminergic neurotransmission.

Original languageEnglish (US)
Pages (from-to)332-339
Number of pages8
JournalEuropean Archives of Psychiatry and Neurological Sciences
Issue number5-6
StatePublished - Jul 1989


  • Clozapine
  • Dopamine
  • Prolactin
  • Schizophrenia
  • Serotonin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Neuropsychology and Physiological Psychology
  • Psychiatry and Mental health

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