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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH001244-04
Application #
2889830
Study Section
Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
Program Officer
Light, Enid
Project Start
1996-05-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Psychiatry
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Nobler, Mitchell S; Olvet, Kristian R; Sackeim, Harold A (2002) Effects of medications on cerebral blood flow in late-life depression. Curr Psychiatry Rep 4:51-8
Parker, V; Nobler, M S; Pedley, T A et al. (2001) A unilateral, prolonged, nonconvulsive seizure in a patient treated with bilateral ECT. J ECT 17:141-5
Nobler, M S; Teneback, C C; Nahas, Z et al. (2000) Structural and functional neuroimaging of electroconvulsive therapy and transcranial magnetic stimulation. Depress Anxiety 12:144-56
Luber, B; Nobler, M S; Moeller, J R et al. (2000) Quantitative EEG during seizures induced by electroconvulsive therapy: relations to treatment modality and clinical features. II. Topographic analyses. J ECT 16:229-43
Nobler, M S; Luber, B; Moeller, J R et al. (2000) Quantitative EEG during seizures induced by electroconvulsive therapy: relations to treatment modality and clinical features. I. Global analyses. J ECT 16:211-28
Nobler, M S; Roose, S P; Prohovnik, I et al. (2000) Regional cerebral blood flow in mood disorders, V.: Effects of antidepressant medication in late-life depression. Am J Geriatr Psychiatry 8:289-96
Nobler, M S; Mann, J J; Sackeim, H A (1999) Serotonin, cerebral blood flow, and cerebral metabolic rate in geriatric major depression and normal aging. Brain Res Brain Res Rev 30:250-63
Nobler, M S; Sackeim, H A; Moeller, J R et al. (1997) Quantifying the speed of symptomatic improvement with electroconvulsive therapy: comparison of alternative statistical methods. Convuls Ther 13:208-21