Examination of Brain Serotonin Receptors in Patients With Mood Disorders

Multiple lines of evidence suggest that serotonin1A (5-HT1A) receptor and serotonin transporter (5-HTT) function is abnormal in major depressive disorder (MDD) and that somatic antidepressant treatments effect changes in the function of these systems that are relevant to their therapeutic mechanisms. The data supporting these hypotheses have been obtained by assessing neuroendocrine and temperature responses to 5-HT1A agonists in MDD subjects, measuring 5-HT1A receptor and 5-HTT binding in brain tissue acquired post mortem from small samples of MDD subjects, and examining effects on 5-HT1A receptor function in rats following antidepressant drug (AD) administration. The recent development of highly selective 5-HT1A receptor and 5-HTT radioligands for positron emission tomography (PET) imaging made direct, noninvasive exploration of the central serotonin sites binding possible. Two studies conducted using one of these, \[carbonyl-11C\]-WAY-100635, found reduced 5-HT1A receptor binding potential (BP) in the mesiotemporal cortex, the raphe, and the prefrontal cortex (PFC). Pilot data from these studies suggested that the abnormal reduction in 5-HT1A receptor BP is more prominent in bipolar disorder (BD) than MDD subjects (i.e., unipolar depressives) who did not have bipolar relatives, and that it exists independently of mood state. However, these data have the limitations that the subject samples studied in these preliminary post mortem and PET series have been small, and that \[carbonyl-11C\]WAY-100635 uptake is difficult to quantitate in PET images. Therefore, these observations require replication in subject samples large enough to establish main effects of diagnostic subtype using a 5-HT1A receptor radioligand that can be validly quantitated. A selective 5-HT1A receptor radioligand suitable for this purpose, \[18F\]FC-WAY100635 (\[18F\]FCWAY), has recently been developed at the NIH. In addition, a recently developed selective 5-HTT ligand, \[11C\] DASB provides a unique opportunity to image the 5-HTT in the same depressed sample. The proposed study will advance knowledge regarding the neurobiology of mood disorders by employing PET and \[18F\]FCWAY and \[11C\] DASB to compare 5-HT1A receptor BP between mood disordered and healthy control subjects in the mesiotemporal cortex, raphe, anterior cingulate gyrus, and left orbital cortex. The following hypotheses, based upon pilot data acquired using \[carbonyl-11C\]-WAY-100636, will be tested: 1) Depressives have reduced 5-HT1A receptor binding relative to healthy controls. 2) Bipolar depressives will have significantly greater reductions in 5-HT1A receptor binding than unipolar depressives with only unipolar relatives. A pilot study in which bipolar depressives are treated with lithium or divalproex and then re-imaged will test the third hypothesis, that 5-HT1A receptor binding will increase in bipolar subjects during mood stabilizer therapy. Finally, because central 5-HT1A receptor density is down-regulated in rodents by corticosterone administration and by stress-mediated corticosterone secretion, assessments of hypothalamic-pituitary-adrenal (HPA) axis activity (which is commonly elevated in MDD and BD), will be assessed to determine whether down-regulation of 5-HT1A receptors correlates with cortisol hypersecretion in mood disorders. Because this down-regulation may play a compensatory role to reduce cortisol secretion, neuroendocrine assessments of long-standing rather than acute hypercortisolism and of the pathophysiological diathesis to hypersecrete cortisol will be emphasized as providing the most sensitive correlates of reduced 5-HT1A receptor binding. A medical control group with Cushing's Disease will also be imaged to determine whether pathological elevation of glucocorticoid levels down-regulates 5-HT1A receptor expression in humans, as it does in rats.