In an attempt to chemically estimate cerebral energy metabolism, creatine and creatinine was measured in cerebrospinal fluid and plasma of up to 135 patients with RDC diagnoses of major depressive disorders. A strong positive age effect and a significant subdiagnostic difference were detected for both substances in CSF, but not in plasma. Primary unipolar patients had higher concentrations than either secondary unipolar or bipolar patients. Further, the two CSF measures correlated highly significantly and positively with the CSF monoamine metabolites HVA and 5-HIAA and the purine metabolites hypoxanthine and xanthine. Results indicate alterations in energy metabolism to be involved in affective disorders as well as in the regulation of monoamine and purine turnover.