Major depressive disorder (MDD) is a serious and recurrent illness and a leading cause of disability. Though treatments are available, these often take weeks to months to exert their effect, and some people only respond partially or do not respond at all. To guide more effective, faster acting and personalized treatment strategies in the clinical setting, there is thus an important need to identify biological markers predictive of rapid therapeutic response. To advance discovery in this area, this K24 proposal includes mentorship, career development and research aims that build onto the goals of our NIH-funded R01 (MH092301), which is focused on using advanced neuroimaging methods to detect different aspects of treatment-related brain plasticity in MDD. Electroconvulsive therapy (ECT), which is currently the most effective acute treatment for severe MDD and which involves direct action on the central nervous system, is used as the R01 treatment modality. Since a combination of biological markers may better characterize the mechanisms and predictors of treatment response, as a recent adjunct to our R01, we are also examining peripheral lymphocyte gene expression to more comprehensively address the biological bases of rapid therapeutic response to ECT. Producing a clinical response within hours, the NMDA receptor antagonist, ketamine, has recently emerged as a novel pharmacologic agent for depression treatment with a response rate comparable only to ECT. To obtain a greater understanding of the biological processes underlying fast-acting therapies and to confirm basic science findings implicating glutamatergic pathways, the candidate's K24 Research Plan is to identify imaging and gene expression markers of therapeutic response to ketamine treatment. To target overlapping rapid response mechanisms, by leveraging data from our R01 project, candidate markers of response to ketamine and ECT will be compared. Novel imaging methods applied in a subsample of ketamine patients will provide further opportunity to explore treatment-related neuroplasticity localized to dorsal and/or ventral fronto-limbic networks. To allow the candidate to better design and lead clinical studies incorporating interdisciplinary approaches to investigate and compare mechanisms of rapid antidepressant action, the candidate's Career Development Plan is to develop knowledge and/or new skills in the field of genomics and in the pharmacological basis of antidepressant treatments for MDD as well as also hone existing skills in neuroimaging. In line with the candidate's area of expertise in imaging and clinical neuroscience, the Mentoring Plan will provide theoretical and hands-on training to mentees in clinical imaging applications directed towards the longitudinal investigation of treatment mechanisms in MDD and potentially in other psychiatric conditions, and the skills to successfully incorporate imaging methods into patient-oriented research (POR) programs that will lead to future independent funding. The candidate's research and career development aims, which are both complementary and unique to our funded R01, will provide a rich basis for training while furthering POR in a critical area.

Public Health Relevance

to Public Health Though depression may be treated, for many people these treatments take a long time or are ultimately unsuccessful. This application for a K24 Mid-career Development Award will foster the development of knowledge and skills in neuroimaging and functional genomics that will help the candidate and clinical trainees identify biological markers to predict who will respond to treatment in the future. Research outcomes might also lead to more effective and faster treatments or cures for depression in the future that will improve the lives of patients and their families and lower healt care costs to society.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24MH102743-04
Application #
9320917
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Rumsey, Judith M
Project Start
2014-09-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Leaver, Amber M; Vasavada, Megha; Joshi, Shantanu H et al. (2018) Mechanisms of Antidepressant Response to Electroconvulsive Therapy Studied With Perfusion Magnetic Resonance Imaging. Biol Psychiatry :
Kruse, Jennifer L; Congdon, Eliza; Olmstead, Richard et al. (2018) Inflammation and Improvement of Depression Following Electroconvulsive Therapy in Treatment-Resistant Depression. J Clin Psychiatry 79:
Leaver, Amber M; Yang, Hongyu; Siddarth, Prabha et al. (2018) Resilience and amygdala function in older healthy and depressed adults. J Affect Disord 237:27-34
Leaver, Amber M; Wade, Benjamin; Vasavada, Megha et al. (2018) Fronto-Temporal Connectivity Predicts ECT Outcome in Major Depression. Front Psychiatry 9:92
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Njau, Stephanie; Joshi, Shantanu H; Espinoza, Randall et al. (2017) Neurochemical correlates of rapid treatment response to electroconvulsive therapy in patients with major depression. J Psychiatry Neurosci 42:6-16
Oltedal, Leif; Bartsch, Hauke; Sørhaug, Ole Johan Evjenth et al. (2017) The Global ECT-MRI Research Collaboration (GEMRIC): Establishing a multi-site investigation of the neural mechanisms underlying response to electroconvulsive therapy. Neuroimage Clin 14:422-432

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