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

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).