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Letter to the EditorFull Access

Impairment of Phosphatidylinositol 3-Kinase Signaling in Schizophrenia: State or Trait?

Published Online:1 Jun 2010https://doi.org/10.1176/appi.ajp.2010.10010103

To the Editor: In their article, published in the April 2010 issue of the Journal, Szabolcs Kéri, M.D., Ph.D., D.Sc., et al. (1) showed that neuregulin 1-dependent activation of phosphatidylinositol 3-kinase signaling was impaired in schizophrenia patients, which was connected to P50-evoked response and thereby influenced sensory gating in patients with first-episode schizophrenia. Phosphatidylinositol 3-kinase and phosphoinositide-dependent protein kinase-1 signaling inhibit glycogen synthase kinase-3β. Our workgroup found increased anxiety behavior in phosphoinositide-dependent protein kinase 1 hypomorphic mice (2) and stress-resistant behavior in glycogen synthase kinase-3β knock-in mice, supporting the role of phosphatidylinositol 3-kinase signaling in anxiety and stress (3). However, Dr. Kéri et al. did not examine the influence of neuroleptic treatment on phosphatidylinositol 3-kinase activity. The highly effective atypical antipsychotics olanzapine and clozapine in contrast to haloperidol have been shown to activate the protein kinase B (AKT) glycogen synthase kinase-3β axis (4). These effects might explain heterogenous findings on the P50-evoked response in schizophrenia patients, which seems to normalize after treatment with clozapine and olanzapine but not after typical drugs (5).

Berlin, Germany

The author reports no financial relationships with commercial interests.

References

1 Kéri S , Beniczky S , Kelemen O : Suppression of the P50 evoked response and neuregulin 1-induced AKT phosphorylation in first-episode schizophrenia. Am J Psychiatry 2010; 167:444–450 Link, Google Scholar

2 Ackermann TF , Hörtnagl H , Wolfer DP , Colacicco G , Sohr R , Lang F , Hellweg R , Lang UE : Phosphatidylinositide dependent kinase deficiency increases anxiety and decreases GABA and serotonin abundance in the amygdala. Cell Physiol Biochem 2008; 22:735–744 Crossref, Medline, Google Scholar

3 Ackermann TF , Kempe DS , Lang F , Lang UE : Hyperactivity and enhanced curiosity of mice expressing PKB/SGK-resistant glycogen synthase kinase-3 (GSK–3). Cell Physiol Biochem 2010 (in press) Crossref, Google Scholar

4 Aubry JM , Schwald M , Ballmann E , Karege F : Early effects of mood stabilizers on the Akt/GSK-3beta signaling pathway and on cell survival and proliferation. Psychopharmacology 2009; 205:419–429 Crossref, Medline, Google Scholar

5 Light GA , Geyer MA , Clementz BA , Cadenhead KS , Braff DL : Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry 2000; 157:767–771 Link, Google Scholar