The candidate for this K23 application is a psychiatrist who proposes to acquire expertise in pharmacogenomics. He intends to accomplish this goal through guided didactics and consultations and a research protocol designed to examine genetic polymorphisms that may affect vulnerability to interferon-alpha-induced depression (I-ID) in humans. Interferon-alpha can trigger depression in about 25% of patients and is the primary treatment for hepatitis C, which affects about 4 million individuals in the U.S. In addition to this being a significant mental health issue in its own right, I-ID offers the opportunity to feasibly examine a prospective human model of depression. Therefore, specific candidate polymorphisms will be examined in a well-characterized cohort of patients with hepatitis C who are assessed prior to interferon-a treatment and who are currently euthymic. The development of depression will be prospectively followed, along with pharmacokinetic assessments of interferon-a exposure. In conjunction with didactic training, this research will provide a platform for acquiring expertise in quantitative genetics and associational analyses in clinical pharmacology research, and designs using high throughput genetic polymorphism assays. The didactic training will involve specific classes in human genetics, supervised readings and software tutorials, and exposure to high throughput laboratory techniques. A small ancillary pilot study will also be included to ascertain, in parallel, potential candidate genes for further genetic association analyses of I-ID. This ancillary study will generate pilot micro-array data in an analogous murine model of interferon-alpha exposure, ascertaining the genome-wide set of frontal cortical genes affected by interferon-alpha. In conjunction with didactic training in the analysis and collaborative verification of micro-array data, this ancillary project will provide a training platform for incorporating the use of micro-arrays into psychiatric pharmacogenetic research. This developmental program will initiate the candidate's long-term interdisciplinary and integrative strategy for delineating genetic vulnerability to depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23MH074012-01
Application #
6913106
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chavez, Mark
Project Start
2005-06-01
Project End
2010-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$173,556
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lenze, Eric J; Dixon, David; Nowotny, Petra et al. (2013) Escitalopram reduces attentional performance in anxious older adults with high-expression genetic variants at serotonin 2A and 1B receptors. Int J Neuropsychopharmacol 16:279-88
Lotrich, Francis E (2011) Gene-environment interactions in geriatric depression. Psychiatr Clin North Am 34:357-76, viii
Franzen, Peter L; Buysse, Daniel J; Rabinovitz, Mordechai et al. (2010) Poor sleep quality predicts onset of either major depression or subsyndromal depression with irritability during interferon-alpha treatment. Psychiatry Res 177:240-5
Lotrich, Francis E; Ferrell, Robert E; Rabinovitz, Mordechai et al. (2010) Labile anger during interferon alfa treatment is associated with a polymorphism in tumor necrosis factor alpha. Clin Neuropharmacol 33:191-7
Lotrich, Francis (2010) Management of Psychiatric Disease in Hepatitis C Treatment Candidates. Curr Hepat Rep 9:113-118
Lotrich, Francis E (2009) Major depression during interferon-alpha treatment: vulnerability and prevention. Dialogues Clin Neurosci 11:417-25
Lotrich, Francis E; Ferrell, Robert E; Rabinovitz, Mordechai et al. (2009) Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism. Biol Psychiatry 65:344-8
Prather, Aric A; Rabinovitz, Mordechai; Pollock, Bruce G et al. (2009) Cytokine-induced depression during IFN-alpha treatment: the role of IL-6 and sleep quality. Brain Behav Immun 23:1109-16
DiMartini, Andrea; Fontes, Paulo; Dew, Mary Amanda et al. (2008) Age, model for end-stage liver disease score, and organ functioning predict posttransplant tacrolimus neurotoxicity. Liver Transpl 14:815-22
Lotrich, Francis E; Pollock, Bruce G; Kirshner, Margaret et al. (2008) Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients. J Psychiatry Neurosci 33:123-30

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