Context:The biological basis for the development of major depressive disorder (MDD) remains incompletely understood.Objective: To quantify brain serotonin (5-hydroxytryptamine ) 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. 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. Psychiatry. 2008;65(1):38-46 T HE ETIOLOGY OF MAJOR DEpressive disorder (MDD) has been linked to brain monoaminergic neuronal dysfunction.
Arch Gen1,2 Of particular interest is the role of brain serotonin (5-hydroxytryptamine [5-HT]) in MDD. The diversity of roles played by serotonin coupled with the lack of a demonstrated relationship between different clinical presentations and biochemical abnormalities has hampered the development of sensitive markers of the disease. Indeed, brain serotonin-releasing neurons subserve diverse although incompletely understood functions related to emotions and behavior, feeding and adiposity, 3 and light stimulation. 4 We have previously demonstrated influences of obesity and feeding 5 and season and sunlight 6 on brain serotonin turnover in humans. The principal means of intraneuronal metabolism of serotonin is via oxidative deamination by monoamine oxidase resulting in formation of 5-hydroxyindoleacetic acid (5-HIAA) (Figure 1). Deamination followed by reduction, conjugation with sulfate or glucuronide, and