Schizophrenia is associated with impaired AKT1-GSK3β signaling. This study provides convergent evidence that individuals with schizophrenia have reduced levels of AKT1 protein and decreased phosphorylation of GSK3β at Ser9 in peripheral lymphocytes and brain tissues. A significant association was found between schizophrenia and an AKT1 haplotype linked to lower AKT1 protein levels. Additionally, individuals with schizophrenia showed greater sensitivity to the sensorimotor gating-disrupting effects of amphetamine, which was attributed to AKT1 deficiency. These findings support the hypothesis that alterations in AKT1-GSK3β signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential susceptibility gene. Consistent with this, haloperidol treatment in mice increased regulatory phosphorylation of AKT1, potentially compensating for impaired signaling in schizophrenia. The study also found that AKT1 levels were lower in the frontal cortex and hippocampus of individuals with schizophrenia compared to controls. No differences were observed in other kinases tested. Phosphorylation of GSK3β at Ser9 was significantly lower in individuals with schizophrenia, consistent with reduced AKT1 levels. An AKT1 haplotype associated with lower AKT1 protein levels was preferentially transmitted to individuals with schizophrenia, suggesting a genetic contribution to the disorder. These findings are consistent with the role of AKT1-GSK3β signaling in mood disorders and support the idea that genetic and biochemical abnormalities are shared between schizophrenia and bipolar disorder. The study also examined the effects of haloperidol on AKT1 phosphorylation in mice, finding a stepwise increase in phosphorylation of total AKT, which may compensate for impaired signaling in schizophrenia. These results suggest that antipsychotic medications could modulate AKT-GSK3β signaling, potentially influencing schizophrenia pathogenesis. The findings highlight the importance of intracellular signaling pathways in neuropsychiatric disorders and suggest that targeting these pathways may be a promising therapeutic approach.Schizophrenia is associated with impaired AKT1-GSK3β signaling. This study provides convergent evidence that individuals with schizophrenia have reduced levels of AKT1 protein and decreased phosphorylation of GSK3β at Ser9 in peripheral lymphocytes and brain tissues. A significant association was found between schizophrenia and an AKT1 haplotype linked to lower AKT1 protein levels. Additionally, individuals with schizophrenia showed greater sensitivity to the sensorimotor gating-disrupting effects of amphetamine, which was attributed to AKT1 deficiency. These findings support the hypothesis that alterations in AKT1-GSK3β signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential susceptibility gene. Consistent with this, haloperidol treatment in mice increased regulatory phosphorylation of AKT1, potentially compensating for impaired signaling in schizophrenia. The study also found that AKT1 levels were lower in the frontal cortex and hippocampus of individuals with schizophrenia compared to controls. No differences were observed in other kinases tested. Phosphorylation of GSK3β at Ser9 was significantly lower in individuals with schizophrenia, consistent with reduced AKT1 levels. An AKT1 haplotype associated with lower AKT1 protein levels was preferentially transmitted to individuals with schizophrenia, suggesting a genetic contribution to the disorder. These findings are consistent with the role of AKT1-GSK3β signaling in mood disorders and support the idea that genetic and biochemical abnormalities are shared between schizophrenia and bipolar disorder. The study also examined the effects of haloperidol on AKT1 phosphorylation in mice, finding a stepwise increase in phosphorylation of total AKT, which may compensate for impaired signaling in schizophrenia. These results suggest that antipsychotic medications could modulate AKT-GSK3β signaling, potentially influencing schizophrenia pathogenesis. The findings highlight the importance of intracellular signaling pathways in neuropsychiatric disorders and suggest that targeting these pathways may be a promising therapeutic approach.