The overarching objective that has guided my research endeavors, collaborations and training opportunities has been to determine the mechanism by which sex hormones and neurosteroids interact with neurotransmitters to modulate behavior, mood, and cognition in women. With my previous two mentored K awards, I was able to develop a unique clinical research program that relied heavily on knowledge gained from molecular and basic neuroscience to inform our investigations of the pathogenesis of premenstrual dysphoric disorder (PMDD), postnatal depression (PPD), and perimenopausal mood and cognitive changes. To this end, I have employed an array of research paradigms and technologies with the goal of translating preclinical findings to the human laboratory. I have relied heavily on the use of proton magnetic resonance spectroscopy (1H-MRS) to explore the relationship between sex hormones, neurosteroids and gamma-aminobutyric acid (GABA) function in women across the menstrual cycle. In the past year, we have moved towards the use of hormonal and pharmacologic challenge paradigms to address changes in GABA concentrations and whether individual factors such as diagnosis, neurosteroid metabolism, and/or genetic polymorphisms, are responsible for observed variations in response. It is this paradigm that I propose to pursue during K24-funding. While 1H-MRS as a tool is excellent for exploring the interaction between progesterone (via allopregnanolone) and GABA, it is not the appropriate technology for questions related to estrogen and serotonin interactions, which may be critical to mood and cognition in aging women. Our previous work using the tryptophan depletion paradigm in menopausal women (Epperson et al., 2007b;Amin et al., 2006b) led me to become increasingly interested in the utility of functional magnetic resonance imaging (fMRI). My lab recently received funding from the National Institute on Aging to study the individual and interactive effects of estrogen and serotonin on cognition and brain activation in menopausal women. This grant will provide important opportunities for me to hone my skills with fMRI and to mentor new trainees. These are just two lines of investigations that I wish to pursue during K24 funding. I have described in this application several other areas of on-going work and how they will not only provide avenues for continued research, but fertile ground for the development of future investigators in patient-oriented research. It is my increasing focus on mentoring junior investigators that motivates me to apply for a K24 instead of submitting a competitive renewal for my K02. As my KO2 is drawing to an end (12/31/09), timely funding of this K24 grant will insure that I can focus on both the research career development plans and project outlined herein, as well as commit substantial effort to fostering the careers of junior researchers. Without K24 funding, I will have to assume additional, non-research related activities in my new Tenured Associate Professor position at the University of Pennsylvania, which is beginning September 1, 2009. My translational research and educational endeavors over the past 9 years have insured that I am uniquely poised to advance our understanding of neuroendocrine contribution to mood and behavior in women. With the full support of both the Departments of Psychiatry and Obstetrics/Gynecology at Penn, I am situated in an intellectually rich and supportive academic community that is certain to further my career development as well as that of individuals I mentor.

Public Health Relevance

Importance of Knowledge Gained: The primary importance of this study is its focus on the neuroendocrine basis for a reproductive endocrine related mood disorder known as Premenstrual Dysphoric Disorder (PMDD). Most previous studies have been limited to peripheral indicators of central abnormalities, and have been less than successful at furthering our knowledge of the pathogenesis of this disorder. In addition, we have the opportunity to understand how a known effective treatment interacts with the endocrine system via neurosteroidogenesis to modulate brain neurotransmitter systems. Furthermore, it is important to consider that mood disorders associated with the hormonal changes occurring in the context of reproductive processes are commonplace. While PMDD occurs in only 3-5% of women, a greater percentage of women experience relatively less severe (but still clinically meaningful) symptoms, while women with ongoing psychiatric disorders frequently experience exacerbation of their illness in the premenstruum. By further studying this specific population we will continue to develop supplementary rationales and methods for studying women with premenstrual exacerbations of ongoing psychiatric mood disorders. Thus far, we have been limited in our ability to study this population of women due to obvious difficulties of with holding medications for several months. Whereas, in PMDD it is part of the diagnostic assessment to prospectively screen women for two months.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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
Wetherington, Cora Lee
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University of Pennsylvania
Schools of Medicine
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Kim, Deborah R; Hantsoo, Liisa; Thase, Michael E et al. (2014) Computer-assisted cognitive behavioral therapy for pregnant women with major depressive disorder. J Womens Health (Larchmt) 23:842-8
Epperson, C Neill; Kim, Deborah R; Bale, Tracy L (2014) Estradiol modulation of monoamine metabolism: one possible mechanism underlying sex differences in risk for depression and dementia. JAMA Psychiatry 71:869-70
Hantsoo, Liisa; Czarkowski, Kathryn A; Child, Josiah et al. (2014) Selective serotonin reuptake inhibitors and endothelial function in women. J Womens Health (Larchmt) 23:613-8
Sockol, Laura E; Epperson, C Neill; Barber, Jacques P (2014) The relationship between maternal attitudes and symptoms of depression and anxiety among pregnant and postpartum first-time mothers. Arch Womens Ment Health 17:199-212
Comasco, Erika; Hahn, Andreas; Ganger, Sebastian et al. (2014) Emotional fronto-cingulate cortex activation and brain derived neurotrophic factor polymorphism in premenstrual dysphoric disorder. Hum Brain Mapp 35:4450-8
Yonkers, Kimberly Ann; Smith, Megan V; Forray, Ariadna et al. (2014) Pregnant women with posttraumatic stress disorder and risk of preterm birth. JAMA Psychiatry 71:897-904
Kim, Deborah R; Epperson, C Neill; Weiss, Amy R et al. (2014) Pharmacotherapy of postpartum depression: an update. Expert Opin Pharmacother 15:1223-34
Shanmugan, Sheila; Epperson, C Neill (2014) Estrogen and the prefrontal cortex: towards a new understanding of estrogen's effects on executive functions in the menopause transition. Hum Brain Mapp 35:847-65
Mathews, Sarah B; Arnold, Steven E; Epperson, C Neill (2014) Hospitalization and cognitive decline: Can the nature of the relationship be deciphered? Am J Geriatr Psychiatry 22:465-80
Nevatte, Tracy; O'Brien, Patrick Michael Shaughn; Backstrom, Torbjorn et al. (2013) ISPMD consensus on the management of premenstrual disorders. Arch Womens Ment Health 16:279-91

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