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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Rumsey, Judith M
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Wade, Benjamin S C; Joshi, Shantanu H; Njau, Stephanie et al. (2016) Effect of Electroconvulsive Therapy on Striatal Morphometry in Major Depressive Disorder. Neuropsychopharmacology 41:2481-91
Eyre, Harris A; Yang, Hongyu; Leaver, Amber M et al. (2016) Altered resting-state functional connectivity in late-life depression: A cross-sectional study. J Affect Disord 189:126-33
Leaver, Amber M; Espinoza, Randall; Pirnia, Tara et al. (2016) Modulation of intrinsic brain activity by electroconvulsive therapy in major depression. Biol Psychiatry Cogn Neurosci Neuroimaging 1:77-86
Joshi, Shantanu H; Espinoza, Randall T; Pirnia, Tara et al. (2016) Structural Plasticity of the Hippocampus and Amygdala Induced by Electroconvulsive Therapy in Major Depression. Biol Psychiatry 79:282-92
Joshi, Shantanu H; Vizueta, Nathalie; Foland-Ross, Lara et al. (2016) Relationships Between Altered Functional Magnetic Resonance Imaging Activation and Cortical Thickness in Patients With Euthymic Bipolar I Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging 1:507-517
Njau, Stephanie; Joshi, Shantanu H; Leaver, Amber M et al. (2016) Variations in myo-inositol in fronto-limbic regions and clinical response to electroconvulsive therapy in major depression. J Psychiatr Res 80:45-51
Vasavada, Megha M; Leaver, Amber M; Espinoza, Randall T et al. (2016) Structural connectivity and response to ketamine therapy in major depression: A preliminary study. J Affect Disord 190:836-41
Pirnia, T; Joshi, S H; Leaver, A M et al. (2016) Electroconvulsive therapy and structural neuroplasticity in neocortical, limbic and paralimbic cortex. Transl Psychiatry 6:e832
Leaver, Amber M; Espinoza, Randall; Joshi, Shantanu H et al. (2015) Desynchronization and Plasticity of Striato-frontal Connectivity in Major Depressive Disorder. Cereb Cortex :
Wade, Benjamin S C; Joshi, Shantanu H; Pirnia, Tara et al. (2015) Random Forest Classification of Depression Status Based On Subcortical Brain Morphometry Following Electroconvulsive Therapy. Proc IEEE Int Symp Biomed Imaging 2015:92-96

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