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 findings from the current funding period where we observed higher 5- HT1A autoreceptor binding in both bipolar and MDD major depressive episodes, an effect that persists in long-term remitted MDD off medication and that is unaffected by a six week treatment period on SSRIs. This picture is consistent with a biochemical trait which may be due to genetic or enduring consequences of childhood adversity and explain the predisposition to recurrent episodes of mood disorders. We find that this elevation in autoreceptor binding is associated with greater frequency of the higher expressing G allele in a promotor polymorphism G (-1910) C in this gene. This allele is associated with higher expression in raphe and not hippocampal neuron cultures and we therefore hypothesize that higher autoreceptor binding that we have also shown to have G allele dose-dependent association, is part of the primary psychopathology of at least one type of hyposerotonergic depression where the firing rate of serotonin neurons is low due to more autoreceptors. Changes in post-synaptic terminal field 5- HT1A binding are thought to be secondary and may represent up-regulation or supersensitivity in response to less serotonin release. In the current funding period, we have developed a method for quantifying 5-HT1A agonist binding in vivo using positron emission tomography (PET) and a new ligand [11C]CUMI-101. We have acquired pilot data showing the tracer is an agonist, displaceable by full agonists, accounts for about half the binding level of an antagonist indicating that the ratio of high to low affinity binding sites is about 2:1, but varies across brain regions and cannot be predicted by the level of antagonist binding. We have completed toxicology, safety and dosimetry studies qualifying the tracer for human use. We now propose to systematically determine high and low affinity 5-HT1A binding in a major depressive episode in both MDD and bipolar disorders by sequential PET scans of [11C] CUMI-101and [11C] WAY-100635, where the injections are separated by 6 half-lives. The functional effects of more binding are to be found in the level of high affinity binding including supersensitivity due to low serotonin in terminal fields of depressed and the hypothesized desensitization of auto-receptors by SSRIs, to date only detected in animal studies.

Public Health Relevance

The proposed research seeks to define an abnormality in serotonin system regulation involving overexpression of the 5-HT1A autoreceptor that results in reduced serotonin release and post-synaptic supersensitivity in major depressive disorders and in bipolar disorder. This abnormality is a biochemical trait that is detectable in remitted patients and is linked to a promotor polymorphism. The project will use a novel PET agonist ligand and an established antagonist ligand to evaluate high and low affinity binding in depressed MDD and bipolar patients during depression, and remitted MDD to determine the state-trait status of high and low affinity binding.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH040695-20
Application #
8213591
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Meinecke, Douglas L
Project Start
1990-03-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
20
Fiscal Year
2012
Total Cost
$591,407
Indirect Cost
$221,245
Name
Columbia University (N.Y.)
Department
Psychiatry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Daray, Federico M; Mann, J John; Sublette, M Elizabeth (2018) How lipids may affect risk for suicidal behavior. J Psychiatr Res 104:16-23
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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
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
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

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