The activation of the Akt/PKB signalling pathway in the brains of clozapine-exposed rats is linked to hyperinsulinemia and not a direct drug effect

Psychopharmacology (Berl). 2014 Dec;231(23):4553-60. doi: 10.1007/s00213-014-3608-0. Epub 2014 May 7.


The second generation antipsychotic drug clozapine is a much more effective therapy for schizophrenia than first generation compounds, but the reasons for this are poorly understood. We have previously shown that one distinguishing feature of clozapine is its ability to raise glucagon levels in animal models and thus causes prolonged hyperinsulinemia without inducing hypoglycaemia. Previous studies have provided evidence that defects in Akt/PKB and GSK3 signalling can contribute to development of psychiatric diseases. Clozapine is known to activate Akt/PKB in the brain, and some studies have indicated that this is due to a direct effect of the drug on the neurons. However, we provide strong evidence that elevated insulin levels induced by clozapine are in fact the real cause of the drug's effects on Akt/PKB and GSK3 in the brain. This suggests that the elevated levels of insulin induced by clozapine may contribute to this drug's therapeutic efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Brain / drug effects
  • Brain / metabolism*
  • Clozapine / pharmacology*
  • Glycogen Synthase Kinase 3 / metabolism
  • Hyperinsulinism / metabolism*
  • Male
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Schizophrenia / drug therapy
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology


  • Antipsychotic Agents
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Clozapine