Pharmacotherapeutic treatments are the most common intervention in the treatment of major depressive disorder (MDD). Response rates to the first antidepressant can be as low as 50-60%1 while clinically more meaningful remission rates are typically only between 20%2-35%1. Development of biological tests that would enable clinicians to select the correct class of antidepressant would significantly reduce morbidity and mortality associated with MDD by reducing the time to remission. We propose to evaluate potential biological tests that can predict remission from MDD when treated with a selective serotonin reuptake inhibitor (SSRI) and whether an individual patient is more likely to respond to a SSRI or a selective norepinephrine reuptake inhibitor (SNRI), the 2 most common classes of medication for MDD. We have shown that depressed patients have higher serotonin 1A (5-HT1A) binding potential than controls. Additionally, in a naturalistic treatment study we found MDD patients with higher 5-HT1A binding potential were less likely to remit to community based treatment. It has recently been shown that baseline serotonin transporter (5-HTT) availability in the midbrain, but not striatum3, predicts response to treatment with a SSRI.4 In our naturalistic study we show that remitters have higher 5-HTT binding potential in a regionally specific manner compared to non-remitters. The treatment protocol was not controlled in our pilot study and there were too few patients to determine if remission depended on the class of antidepressant. In this proposal, we propose to perform pretreatment positron emission tomography (PET) scans and have all patients receive a standardized treatment protocol of a SSRI followed by a SNRI in SSRI non-remitters. Escitalopram is the SSRI and desipramine the SNRI of choice because at the doses we will administer, they are highly selective for the respective transporters. We hypothesize that patients with high pre and postsynaptic 5-HT1A binding potential and low 5-HTT binding potential in the midbrain, amygdala, thalamus, and dorsal putamen will not remit to a SSRI and will remit to a SNRI. Finally, we will generate a predictive model of remission based on brain imaging outcome measures. Our overall goal is to reduce the trial and error associated with finding an effective antidepressant by using data from pre-treatment quantification of 5-HT1A receptors and 5-HTT to guide antidepressant treatment selection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH074813-05
Application #
7813862
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Rumsey, Judith M
Project Start
2006-05-01
Project End
2012-07-30
Budget Start
2010-05-04
Budget End
2012-07-30
Support Year
5
Fiscal Year
2010
Total Cost
$450,082
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
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
Kaufman, Joshua; DeLorenzo, Christine; Choudhury, Sunia et al. (2016) The 5-HT1A receptor in Major Depressive Disorder. Eur Neuropsychopharmacol 26:397-410
Schneck, Noam; Miller, Jeffrey M; Delorenzo, Christine et al. (2016) Relationship of the serotonin transporter gene promoter polymorphism (5-HTTLPR) genotype and serotonin transporter binding to neural processing of negative emotional stimuli. J Affect Disord 190:494-498
Kaufman, Joshua; Sullivan, Gregory M; Yang, Jie et al. (2015) Quantification of the Serotonin 1A Receptor Using PET: Identification of a Potential Biomarker of Major Depression in Males. Neuropsychopharmacology 40:1692-9
Sullivan, Gregory M; Oquendo, Maria A; Milak, Matthew et al. (2015) Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder. JAMA Psychiatry 72:169-78
Olvet, Doreen M; Peruzzo, Denis; Thapa-Chhetry, Binod et al. (2014) A diffusion tensor imaging study of suicide attempters. J Psychiatr Res 51:60-67
Lan, Martin J; Chhetry, Binod Thapa; Oquendo, Maria A et al. (2014) Cortical thickness differences between bipolar depression and major depressive disorder. Bipolar Disord 16:378-88
Lan, Martin J; Ogden, R Todd; Huang, Yung-Yu et al. (2014) Genetic variation in brain-derived neurotrophic factor val66met allele is associated with altered serotonin-1A receptor binding in human brain. Neuroimage 94:33-39
Delorenzo, Christine; Delaparte, Lauren; Thapa-Chhetry, Binod et al. (2013) Prediction of selective serotonin reuptake inhibitor response using diffusion-weighted MRI. Front Psychiatry 4:5
Miller, Jeffrey Morris; Schneck, Noam; Siegle, Greg J et al. (2013) fMRI response to negative words and SSRI treatment outcome in major depressive disorder: a preliminary study. Psychiatry Res 214:296-305

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