A reliable method is described using high pressure liquid chromatography to measure creatine, creatinine, and urate in human cerebrospinal fluid (CSF) and blood; albumin was analyzed by routine methods. Creatine and creatinine serve as indices of one aspect of brain energy metabolism, the creatine-creatine phosphate (CrP) shuttle. CSF levels have been adjusted to a set blood level by analysis of covariance. The ratios between CSF and blood concentrations of urate and albumin are two sensitive indices of impaired blood-brain barrier (BBB) function. Analyses were performed on 41 male and 58 female inpatients with RDC major depressive disorders, with a mean age of about 40 years. The CSF creatinine and creatine levels were highly positively age-dependent; this factor as well as possible influences of body habits were removed by way of analysis of covariance from all measures in focus. We describe positive, highly significant correlations between creatinine and monoamine metabolites (HVA and 5HIAA) and purine metabolites (hypoxanthine and xanthine) in CSF, and a strong negative correlation between both BBB permeability measures and the noradrenalin CSF metabolite MHPG. CSF creatinine was negatively linked with suicidal ideation and increased appetite. The BBB tended to be the more permeable the less melancholic the depression. No measure appeared to be dependent on depressive state. Comparisons of depressive subgroups revealed a higher CSF creatinine concentration in sporadic unipolar patients according to Winokur. A particularly wide variance in the albumin ratio was found in pure unipolars. Pure unipolars with an impaired BBB had a more protracted onset, were more suicidal, had a higher erythrocyte sedimentation rate, and lower plasma cortisol levels than those without. Impaired BBB was further linked with a slower EEG rhythm and higher systolic blood pressure. Results suggest significant contributions of brain energy metabolism and deranged BBB permeability in accounting for some aspects of neuronal transmission and modulation as well as the symptomatology of depressive illness.