The Role of Serotonin in the Pathophysiology of Depression: As Important As Ever

Featured Article: Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994;40: 288–95.1 Fifteen years have elapsed since we published this article focusing on the serotonin transporter (SERT)2 . Although developed as a review, this report ultimately included original data from a large study of drug-free depressed patients and controls showing that platelet [3H]imipramine binding, the ligand of choice for labeling serotonin transporters, was significantly decreased in depression. We also showed data indicating that the decreased platelet [3H]imipramine binding was specific for major depression. The high number of citations, including numerous citations even in 2009, reflects the ongoing importance of serotonin in depression. Since this report was published, remarkable advances have occurred in our understanding of the molecular neurobiology of serotonergic neurons, and in functional brain imaging studies, which have provided further evidence for a preeminent role for serotonergic circuits in the pathogenesis of major depression and suicide (1). These advances include (a) the development of specific positron-emission tomography ligands for the SERT and their use in detecting alterations in serotonergic circuits in patients with major depression and suicidality, as well as quantifying the magnitude of SERT occupancy associated with antidepressant treatment; (b) functional polymorphism in the promoter region of the gene that codes for SERT [solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4)], which has now been demonstrated to mediate, in part, the well-documented increased vulnerability to depression of adult individuals exposed to child abuse and neglect early in life; (c) the recognition that members of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants are not, in fact, homogeneous, but differ from each other in a number of important pharmacological properties; and (d) considerable progress in elucidating the molecular substrates of SSRI antidepressant action.