22,104,107,108 These observations have led some investigators to postulate an MRI-defined vascular or atherosclerotic form of depression,107,109 which supports a strong link between aging and biological factors in depression occurring in the elderly. Also, evidence for serotonergic control of the regulation of CBF110,111 and the potential influence of age on this regulatory mechanism112 suggest an interaction – although as yet, illdefined – between disturbances in serotonergic function and risk of cerebral ischemic injury. Depression has been widely attributed

to deficient 5-HT neurotransmission. In the unique setting of geriatric depression, age-related alterations Inhibitors,research,lifescience,medical in the 5-HT system may perturb its functional integrity and thus potentially contribute to the high prevalence and distinct, character of depression Inhibitors,research,lifescience,medical in late life. Postmortem studies have reported

conflicting findings of 5-HT receptor status in suicide victims.113-119 In a small group of elderly nonsuicide depressed patients, reductions in binding to 5HT2A, but not to 5-HT1A, sites in temporal, frontal, and parietal cortex were reported using membranes.120 Using autoradiographic techniques, the density (Bmax) for the 5-HT1A Inhibitors,research,lifescience,medical receptor was reduced by approximately 40% in the superficial layers of frontal cortex (Brodmann area 9) from patients undergoing surgery for intractable depression.71 It is also worth noting that there was a 30% to 40% reduction in the concentration of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in the ventricular Inhibitors,research,lifescience,medical CSF of these depressed patients, underlining the possible relationship between disturbances of serotonergic neurotransmission and depressive symptoms. Evaluation of serotonergic function Inhibitors,research,lifescience,medical through imaging techniques has offered a unique approach to evaluating the heterogeneity of depression in the elderly. In an attempt, to assign neurochemical specificity to the blood flow and metabolic disturbances reported in depression,121-123 fluorodeoxyglucose (FDG) PET coupled with the 5-HT-releasing agent, dl-fenfluramine provided indirect yet in vivo evidence of serotonergic

Org 27569 dysfunction in the prefrontal cortex in depressed patients, who exhibited a blunted response relative to healthy controls.124,125 With the subsequent development, of selective imaging agents for serotonergic receptor sites, it became possible to quantify central 5-HT binding in depressed patients. Of particular interest are the 5-HT2A and 5-HT1A receptors and the 5-HT transporter, which are all heavily implicated in the antidepressant, response (Figure 2). There are few published studies to date of serotonergic PET imaging in mood disorders and fewer conducted in elderly patients. Biver et al126 demonstrated a Akt inhibitor significant, reduction in the binding of [18F]altanserin to right, orbitofrontai 5-HT2A receptors in a group of mid-life depressed subjects.