A Serotonin Transporter Gene Promoter Polymorphism (5-HTTLPR) and Prefrontal Cortical Binding in Major Depression and Suicide

Abstract

MAJOR DEPRESSION^1-25 and suicidal behavior^16,26-46 are independently related to altered serotonergic system indices in the brain, cerebrospinal fluid (CSF), and platelets.^47-51 Two questions arise: Do serotonergic abnormalities in major depression involve different brain regions compared with the diathesis for suicide? Second, what factors cause these alterations in serotonergic function? Genetic factors partly explain the risks for major depression⁵² and for suicide.^53,54 It is not known which genes are involved. Candidate genes that warrant investigation are those related to the serotonergic system. Genetic factors affect serotonergic activity, as indicated by the heritability of CSF levels of 5-hydroxyindoleacetic acid in nonhuman primates⁵⁵ and the reported association of suicidal acts and serotonergic indices, such as CSF levels of 5-hydroxyindoleacetic acid and the prolactin response to fenfluramine hydrochloride therapy, with an intronic polymorphism in the gene for tryptophan hydroxylase.^56-59 The most widely reported serotonergic abnormality in major depression and suicide involves the serotonin transporter (5-HTT).⁵¹ Fewer platelet 5-HTT sites and reduced platelet serotonin uptake have been reported.^49,51 Both functional imaging and postmortem brain studies indicate less 5-HTT binding in the brain in depressed patients.^60,61 Because platelet 5-HTT binding seems to be unrelated to levels of brain 5-HTT binding,^51,61 direct studies of the brain are necessary to determine the state of 5-HTT binding in major depression.