Seventeen patients with major affective disorder completed a 10-week, placebo-controlled, randomized trial of the serotonin reuptake inhibitor sertraline. Patients underwent positron emission tomography with 18F-deoxyglucose and were assessed with the Hamilton Depression Rating Scale at baseline and 10 weeks after treatment with sertraline or placebo. The middle frontal gyrus, an area previously characterized by decreased metabolic activity in depressive patients, showed relatively increased activity on both sides after sertraline when contrasted with temporal and some occipital areas. Sertraline was associated with a significantly increased relative metabolic rate in right parietal lobe and in left occipital area 19, and a decreased metabolic rate in right occipital area 18. Other areas that differed between controls and a larger cohort of 39 depressive patients--including medial frontal lobe, cingulate gyrus, and thalamus--also showed a normalization of metabolic rate after sertraline.