In vivo brain pet responses and neuroendocrine alterations following serotonin release in depressed patients versus healthy controls

The indoleamine hypothesis of depression proposes that major depression is due to a deficiency of available serotonin or subsensitivity of key serotonin receptors in relevant brain regions. We and others have reported results from the serotonin-releasing fenfluramine challenge test which demonstrate a blunted serotonin-mediated prolactin (PRL) response to d-1 fenfluramine (FEN) in depressed patients compared with normal controls. The limitations of such results are that these studies only assess hypothalamic neural pathways and do not inform us about where in the brain such serotonin changes occur. We have recently described a methodology for visualizing in vivo regional brain responses to serotonin release with positron emission tomography (PET) by comparing regional brain glucose metabolism after administration of FEN, relative to placebo. We now report on differences between the neuroendocrine responses to FEN and regional brain metabolic responses (rCMRglu) following FEN in 11 patients with an untreated major depressive episode versus 6 healthy controls. The PRL response to FEN did not distinguish between groups. However, several statistically highly significant prefrontal cortical areas of increase in rCMRglu were seen in healthy controls, whereas no significant increases or decreases in regional glucose metabolism were seen in patients. No overlap was seen in degree of response in patients compared to controls. These results provide direct in vivo support for the indoleamine hypothesis of depression, and are a further step towards visualization of brain regions associated with neurotransmitter alterations that may underlie major depression.