This competing continuation application proposes a set of patient studies of the serotonergic system in major depression and the effects of somatic antidepressants on the serotonergic system that builds on recent findings from patient studies of the biology of depression and from animal studies of the action of antidepressants. Recently, PET and SPECT studies have begun to provide more direct evidence in both bipolar and unipolar disorders that major depressive episodes are associated with serotonergic system abnormalities. In the current two plus years of funding, we have developed a method for quantifying 5- HT1A binding in human subjects in vivo using positron emission tomography (PET) and the ligand [11C]WAY-100635. We have acquired pilot data indicating lower regional brain 5-HT1A binding in depressed patients. We now propose to systematically investigate the neurobiology of a major depressive episode in both unipolar and bipolar disorders. To determine whether the biological changes associated with depression are reversible, we propose to study the short-term effects of antidepressant treatment, and also to examine a cohort of long-term, remitted and medication-free unipolar patients. In studying the action of antidepressants, we will compare depressed, unipolar patients from the baseline study above, after a six week course of an SSRI, paroxetine. The study of long-term recovered, drug-free patients will help distinguish the effects of recovery from the effects of treatment. The delayed therapeutic benefit of antidepressant medications such as SSRIs has been linked to delayed enhancement of intra-synaptic serotonin levels resulting from 5-HT1A autoreceptor downregulation found in animal studies. SSRIs (or serotonin transporter gene knockout) do not change post-synaptic terminal field 5-HT1A receptors, but downregulate the raphe autoreceptor. These observations have not been adequately tested in man because antidepressant actions on the 5-HT1A receptors may, at least partly, involve the same receptor population that is implicated in the pathogenesis of major depression, such effects need to be evaluated in patients. We propose to test these hypotheses directly in vivo using PET and the ligand [11C]WAY-100635, and to quantify the 5- HT1A receptor in healthy volunteers and patients with a major depressive episode.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH040695-17
Application #
7197348
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Brady, Linda S
Project Start
1990-03-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2009-01-31
Support Year
17
Fiscal Year
2007
Total Cost
$593,301
Indirect Cost
Name
Columbia University (N.Y.)
Department
Psychiatry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Rizk, Mina M; Rubin-Falcone, Harry; Lin, Xuejing et al. (2018) Gray matter volumetric study of major depression and suicidal behavior. Psychiatry Res Neuroimaging 283:16-23
Daray, Federico M; Mann, J John; Sublette, M Elizabeth (2018) How lipids may affect risk for suicidal behavior. J Psychiatr Res 104:16-23
Pillai, Rajapillai L I; Zhang, Mengru; Yang, Jie et al. (2018) Will imaging individual raphe nuclei in males with major depressive disorder enhance diagnostic sensitivity and specificity? Depress Anxiety 35:411-420
Rubin-Falcone, Harry; Zanderigo, Francesca; Thapa-Chhetry, Binod et al. (2018) Pattern recognition of magnetic resonance imaging-based gray matter volume measurements classifies bipolar disorder and major depressive disorder. J Affect Disord 227:498-505
Coplan, Jeremy D; Gupta, Nishant K; Flynn, Sarah K et al. (2018) Maternal Cerebrospinal Fluid Glutamate in Response to Variable Foraging Demand: Relationship to Cerebrospinal Fluid Serotonin Metabolites in Grown Offspring. Chronic Stress (Thousand Oaks) 2:
Milak, Matthew S; Pantazatos, Spiro; Rashid, Rain et al. (2018) Higher 5-HT1A autoreceptor binding as an endophenotype for major depressive disorder identified in high risk offspring - A pilot study. Psychiatry Res Neuroimaging 276:15-23
Pillai, Rajapillai L I; Malhotra, Ashwin; Rupert, Deborah D et al. (2018) Relations between cortical thickness, serotonin 1A receptor binding, and structural connectivity: A multimodal imaging study. Hum Brain Mapp 39:1043-1055
Rizk, Mina M; Rubin-Falcone, Harry; Keilp, John et al. (2017) White matter correlates of impaired attention control in major depressive disorder and healthy volunteers. J Affect Disord 222:103-111
Iscan, Zafer; Rakesh, Gopalkumar; Rossano, Samantha et al. (2017) A positron emission tomography study of the serotonergic system in relation to anxiety in depression. Eur Neuropsychopharmacol 27:1011-1021
CeƱido, Joshua F; Itin, Boris; Stark, Ruth E et al. (2017) Characterization of lipid rafts in human platelets using nuclear magnetic resonance: A pilot study. Biochem Biophys Rep 10:132-136

Showing the most recent 10 out of 107 publications