Upregulation of the kynurenine pathway has been associated with several etiologies of psychosis, an indication that increased levels of pathway intermediates might be involved in eliciting some psychotic features. In schizophrenia, tryptophan 2,3-dioxygenase (TDO2) was previously identified in postmortem frontal cortex as the enzyme likely responsible for the reported increase in pathway activity in the brain. For this follow-up study of postmortem anterior cingulate gyrus, we have found evidence of increased TDO2 activity in schizophrenia at three different levels of regulation: mRNA, protein, and metabolic product. The results were unaffected by neuroleptic status or smoking history. To make the distinction between mental disorders with psychosis and those without, this study included patients with bipolar disorder and major depression. Compared to the control group, the HPLC, RT-PCR, and immunohistochemistry results show significant elevation of (1) kynurenine in schizophrenia (1.9-fold, P = 0.02), and in bipolar disorder (1.8-fold, P = 0.04), primarily in the bipolar subgroup with psychosis (2.1-fold, P = 0.03); (2) TDO2 mRNA in schizophrenia (1.7-fold; P = 0.049); and (3) the immunohistochemistry values for the density of TDO2-positive white matter glial cells in schizophrenia (P = 0.01) and in major depression (P = 0.03) as well as the density and intensity of glial cells (in both gray and white matter) stained for TDO2 in bipolar disorder (P = 0.02). Unlike the results for schizophrenia and bipolar disorder, the increase in TDO2 protein in the major depression group was not associated with an increase in kynurenine concentration.