Schizophrenia is associated with abnormalities in glucose metabolism that may lead to insulin resistance and a 3 fold higher incidence of type II diabetes mellitus. The goal of the present studies was to assess the role of insulin-dependent Akt signaling in schizophrenia and in animal and cellular models of insulin resistance. Our studies revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the dorsolateral prefrontal cortex (BA46) of medicated schizophrenics relative to control patients using post-mortem brain material. We found ∼50% decreases in the content and autophosphorylation levels of IRβ and ∼76–78% decreases in Akt content and activity (pSer⁴⁷³-Akt). The inhibition of IRβ signaling was accompanied by an elevated content of glycogen synthase kinase (GSK)-3α and GSK-3β without significant changes in phospho-Ser^21/9 GSK-3α/β levels. A cellular model of insulin resistance was induced by IRβ knockdown (siRNA). As in schizophrenia, the IRβ knockdown cells demonstrated a reduction in the Akt content and activity. Total GSK-3α/β content remained unaltered, but phospho-Ser^21/9 GSK-3α/β levels were reduced indicating a net increase in the overall enzyme activity similar to that in schizophrenia. Insulin resistance phenotype was induced in mice by treatment with antipsychotic drug, clozapine. Behavioral testing showed decreases in startle response magnitude in animals treated with clozapine for 68days. The treatment resulted in a functional inhibition of IRβ but the Akt activation status remained unaltered. Changes in GSK-3α/β were consistent with a net decrease in the enzyme activity, as opposed to that in schizophrenia. The results suggest that alterations in insulin-dependent Akt signaling in schizophrenia are similar to those observed in our cellular but not animal models of insulin resistance. In animal model, clozapine ameliorates IRβ deficits at the GSK-3α/β level, which may justify its role in treatment of schizophrenia. Our studies suggest that aberrant IR function may be important in the pathophysiology of schizophrenia.