The effects of serotonin polymorphisms and gender on cognitive control and brain function in major depression and healthy subjects.

Major depressive disorders (MDD) present a significant mental health concern to individuals and to our society and there is strong evidence that women are diagnosed with MDD twice as much as men. Cognitive functioning is the main outcome variable of this project. However, there is a considerable degree of variation with respect to cognitive impairments in MDD. The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is critical for the regulation of mood and seems to be involved in the modulation of a v ariety of cognitive functions. A relatively common polymorphism (5-HTTLPR) of the serotonin transporter promoter region of the 5-HT gene is associated with risk for mood disorders. A primary aim of the project is to relate cognition to the 5-HTTLPR genoty pe. It is hypothesized that the S allele is associated with impaired performance on tasks reflecting basic cognitive control functions as compared to L allele homozygotes in patients with MDD. The possible interactive effects of serotonin polymorphisms an d sex on basic cognitive control in MDD will also be studied. Another research issue is related to the hypothesized prefrontal modulation of amygdala reactivity to threat; the aim being to investigate whether S allele carriers with MDD show less adequate activation of prefrontal cortex when performing a working memory fMRI task as compared to L allele homozygotes. The 5-HTTLPR genotype seems to represent a classic susceptibility factor for mood changes and affective disorders, however, no cognitive vulner ability markers or endophenotypes have been identified. The second main objective of the project is to investigate the relations between serotonin polymorphisms and cognitive control in healthy subjects; the hypothesis being that S allele carriers will sh ow subtle impairments in the basic cognitive control functions as compared to L allele homozygotes. A possible interactive effect with sex will also be studied.