Background: Phosphoinositide 3-kinase (PI3-K) signaling plays a crucial role in neuronal growth and plasticity. Recently, we demonstrated that suicide brain is associated with decreased activation and expression of selective catalytic and regulatory subunits of PI3-K. The present investigation examined the regulation and functional significance of compromised PI3-K in suicide brain at the level of upstream phosphatase and tensin homologue on chromosome ten (PTEN) and downstream substrates 3-phosphoinositide-dependent kinase 1 (PDK1) and Akt. Methods: Messenger RNA expression of Akt1, Akt3, PTEN, and PDK1 by competitive reverse transcription polymerase polymerase chain reaction; protein expression of Akt1, Akt3, PTEN, PDK1, phosphorylated Akt1 (Ser473 and Thr308), phosphorylated PDK1, and phosphorylated PTEN by Western blot; and catalytic activities of Akt1, Akt3, and PDK1 by enzymatic assays were determined in prefrontal cortex and hippocampus obtained from suicide subjects and nonpsychiatric control subjects. Results: No significant changes in the expression of Akt1 or Akt3 were observed; however, catalytic activity of Akt1, but not of Akt3, was decreased in prefrontal cortex and hippocampus of suicide subjects, which was associated with decreased phosphorylation of Akt1 at Ser473 and Thr308. The catalytic activity of PDK1 and the level of phosphorylated PDK1 were also decreased in both brain areas without any change in expression levels of PDK1. On the other hand, messenger RNA and protein expression of PTEN was increased, whereas the level of phosphorylated PTEN was decreased. Conclusions: Our study demonstrates abnormalities in PI3-K signaling at several levels in brain of suicide subjects and suggests the possible involvement of aberrant PI3-K/Akt signaling in the pathogenic mechanisms of suicide. © 2010 Society of Biological Psychiatry.