CONTEXT The biological basis for the development of major depressive disorder (MDD) remains incompletely understood. OBJECTIVE To quantify brain serotonin (5-hydroxytryptamine 5-HT) turnover in patients with MDD. DESIGN Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated. SETTING Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. PARTICIPANTS Studies were performed in 21 patients fulfilling the DSM-IV and International Statistical Classification of Diseases, 10th Revision diagnostic criteria for MDD and in 40 healthy volunteers. INTERVENTIONS Treatment for patients consisted of SSRI administration for approximately 12 weeks. MAIN OUTCOME MEASURES Brain serotonin turnover before and after SSRI therapy. RESULTS Brain serotonin turnover was significantly elevated in unmedicated patients with MDD compared with healthy subjects (mean SD internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 4.4 4.3 vs 1.6 2.4 nmol/L, respectively; P = .003). Analysis of the influence of the 5-HTT genotype in MDD indicated that carriage of the s allele compared with the l allele was associated with greater than a 2-fold increase in brain serotonin turnover (mean SD internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.5 4.7 vs 2.7 2.9 nmol/L, respectively; P = .04). Following SSRI therapy, brain serotonin turnover was substantially reduced (mean SD internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.0 4.0 nmol/L prior to treatment vs 2.0 3.3 nmol/L following therapy; P = .008). CONCLUSIONS Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD.Arch Gen Psychiatry. 2008;65(1):38-46-->