This revised application requests a Scientist Development Award for Clinicians to study the neurophysiological correlates of clinical response in patients with major depression treated with electroconvulsive therapy (ECT) or with nortriptyline. There is evidence that subgroups of patients suffering from depression have abnormalities in cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMR). ECT and nortriptyline are effective forms of somatic therapy for depression, yet relatively little is known about their impact on neuroimaging measures. The major goal of this work is to better define neurophysiological indices that are related to successful treatment with ECT or with medications, as well as abnormalities that remain constant despite antidepressant response. I have collected substantial preliminary data that suggest that acute reductions in global CBF and in specific topographic patterns are predictive of positive clinical response to ECT. These acute reductions are superimposed on abnormal baseline values. other preliminary findings suggest that 'deepened' hypofrontality is also associated with clinical response to antidepressant medications. I propose to be trained in the radiopharmacology and clinical applications of neuroimaging with positron emission tomography (PET), single photon emission computerized tomography (SPECT) and magnetic resonance imaging (MRI), biostatistics, advanced approaches to image analysis, and the theoretical and practical aspects of psychopharmacology and ECT. There is evidence that relatively elderly and severely depressed patients may have both state and trait abnormalities in cortical CBF. Little is known about the impact of ECT or medications on these abnormalities. Under this award, I would extend preliminary evidence from planar xenon rCBF studies, and use 150-water and FDG PET to assess acute and short-term changes in cortical and subcortical CBF and CMR that are associated with response to ECT. Concurrently, I will use SPECT to examine changes in CBF following treatment with nortriptyline. Future studies may use PET to assess change in CMR with nortriptyline. I hypothesize that, with both ECT and nortriptyline, decreased manifestation of an anterior/posterior gradient, or deepened hypofrontality, is associated with positive clinical outcome. Exploratory analyses will examine the relations of CBF and CMR changes to the amnestic side effects of ECT, as well as covariance with other behavioral and physiological measures that may predict treatment outcome. Ultimately, I hope to determine the extent to which alterations in discrete functional brain systems provide necessary and/or sufficient conditions for the antidepressant effects of somatic treatment and extend this research by exploring the neurochemical bases for these alterations.
