Serotonin, cerebral blood flow, and cerebral metabolic rate in geriatric major depression and normal aging

While there is substantial evidence for abnormalities in serotonin (5-HT) neurotransmission in major depressive disorder (MDD), almost all of the findings derive from studies of young adults. Moreover, relatively little research has assessed brain 5-HT transmission in vivo. Neuroendocrine studies do not permit evaluation of a range of brain regions, but only the limited circuitry associated with hormone release. Data from autopsy studies are limited by the difficulties of assessment of the acute clinical picture before death, and by post-mortem artifacts. In vivo neuroimaging techniques overcome many of the methodological limitations of both these approaches. There is a large body of imaging data indicating regional cerebral blood flow (rCBF) and cerebral metabolic rate (rCMR) decrements both with aging and in patients with MDD. While the physiological bases for these phenomena are largely unknown, changes in brain 5-HT function may be involved. Neuroanatomical studies have revealed an intricate network of 5-HT-containing neurons within the cerebral microvasculature, with physiological evidence for serotonergic control of both rCBF and rCMR. Acute pharmacological challenges are available to probe brain 5-HT function. Such paradigms, using neuroendocrine responses as endpoints, have been of some utility in predicting outcome with antidepressant treatment. The role of 5-HT dysregulation in geriatric MDD takes on more importance given concerns regarding putative reduced efficacy of serotonin-specific reuptake inhibitors (SSRIs) in this population. If this is due to diminished responsivity of 5-HT systems, then the ability to identify antidepressant nonresponders via 5-HT challenge in combination with neuroimaging measures may have important clinical utility.