2016 — 2020 |
Eisenlohr-Moul, Tory Anne |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Ovarian Hormone Withdrawal and Suicide Risk: An Experimental Approach @ Univ of North Carolina Chapel Hill
PROJECT SUMMARY/ABSTRACT Recent calls from the President, Surgeon General, and the NIMH-sponsored Suicide Research Prioritization Agenda emphasize a dire need for the identification of biological predictors of acute suicide risk that are amenable to intervention. In response, the proposed experimental work investigates a causal role of perimenstrual (around menses) withdrawal from the hormones estradiol (E2) and progesterone (P4) in previously-documented acute perimenstrual increases in suicidality. The proposed project also fully prepares the candidate for a uniquely impactful research career in the pathophysiology of suicide. The aim of the proposed K99 research is to test the hypothesis that natural perimenstrual E2/P4 withdrawal acutely increases suicidality. Using a placebo-controlled, within-person design in a sample of 30 women with current suicidal ideation but minimal risk for suicide attempt, the experiment will test the hypothesis that suicidality will be heightened during natural perimenstrual E2/P4 withdrawal (under placebo), but that experimental prevention of this perimenstrual E2/P4 withdrawal will prevent these perimenstrual increases in suicidality. The aim of the R00 research will be to disentangle the roles of E2 and P4 withdrawal in perimenstrual worsening of suicidality using an expanded three-arm within-person experiment (perimenstrual E2/P4 withdrawal under placebo, E2 stabilization [with perimenstrual P4 withdrawal], and P4 stabilization [with perimenstrual E2 withdrawal]), also in 30 women with current suicidal ideation but minimal suicide attempt risk. It is predicted that only natural P4 withdrawal conditions will be associated with worsened suicidality, mediated by withdrawal from P4-derived neurosteroids. Both projects will utilize multi-modal measurement (tasks, interviews, phone assessments, and ecological momentary assessment [EMA]). Mentorship: Experts from UNC Chapel Hill and neighboring Duke University will mentor the candidate: Susan Girdler, Ph.D. (mentor) will provide mentorship in hormone manipulation. Mitch Prinstein, Ph.D. (co-mentor) will provide mentorship in suicide and risk management. David Rubinow, M.D. contributes expertise in the neurobiological effects of ovarian hormones. Steven Young, M.D., Ph.D. contributes expertise in manipulation of the menstrual cycle. Daniel Bauer, Ph.D. provides expertise in advanced statistics. M. Zachary Rosenthal, Ph.D. contributes expertise in suicidality and EMA. Career Goal: The candidate is committed to a research career focused on the role of hormone changes in impulsivity and suicidality. Her goal is to contribute knowledge through R01-funded projects while also translating findings into treatments. Career Development: Her previous work has established prospective associations between acute hormone changes and impulsivity (aggression, alcohol abuse); this award will allow her to develop skills to conduct safe experiments that will determine the causal role of hormone change in suicidality. Training Outcomes include skills in hormonal experiments, research-based suicide risk management, ecological momentary assessment, and multimodal measurement of suicide-related constructs.
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0.958 |
2019 |
Eisenlohr-Moul, Tory Anne |
RF1Activity Code Description: To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the R01 but can be used also for multi-year funding of other research project grants such as R03, R21 as appropriate. |
Cyclical Neuroactive Steroid Changes, Arousal, and Proximal Suicide Risk: An Experimental Approach @ University of Illinois At Chicago
Project Summary and Abstract Suicide is the second leading cause of death among women of reproductive age, and female suicide attempts occur most frequently around menses (perimenstrually), when estradiol (E2) and progesterone (P4) fall rapidly. A recent prospective study demonstrated that suicidal ideation (SI) and attempts peak perimenstrually in natural cycles, and that this perimenstrual worsening of SI can be prevented by administering stabilizing doses of E2+P4 (relative to placebo). Therefore, while E2+P4 withdrawal is a viable model of proximal suicide risk in females with SI, mechanisms are unclear. GABAergic neuroactive steroid metabolites of ovarian hormones (e.g., allopregnanolone), exert potent sedative and antidepressant effects; we hypothesize that acute perimenstrual withdrawal from these hormone metabolites may increase suicide risk by increasing hyperarousal and hopelessness. The long-term objectives of this research are to (1) use the menstrual cycle as a model to probe the proximal mechanisms of suicide, and (2) develop long-term treatments that eliminate hormonal contributions to suicide. The objective of the current work is to use a crossover placebo-controlled trial of E2+P4 stabilization (vs. natural E2+P4 withdrawal under placebo) in the perimenstrual weeks to probe behavioral (hopelessness, hyperarousal) and molecular/genetic (neuroactive steroid levels, mRNA expression for neurosteroidogenic enzymes) mediators of perimenstrual suicide risk. Design: In this mechanistic trial, 90 female outpatients with past-month SI will complete two counterbalanced conditions: (1) two weeks of placebo during natural perimenstrual E2+P4 withdrawal, and (2) two weeks of perimenstrual E2+P4 stabilization (.1mg/day transdermal estradiol + 200mg/day oral micronized progesterone) to prevent withdrawal. Five labs per condition will capture changes in GC-MS quantified neuroactive steroids, mRNA expression for neurosteroidogenic enzymes, and physiological arousal. Our app (BiAffect) will collect EMA (4x/day) of behavioral constructs and SI, and will passively track arousal via movement and typing speed instability. Specific Aims. Aim 1 is to evaluate hyperarousal and hopelessness as interacting mechanisms by which perimenstrual E2+P4 withdrawal (vs. experimental E2+P4 stabilization) increases proximal suicide risk. Aim 2 is to evaluate neuroactive steroid withdrawal as a mechanism by which perimenstrual E2+P4 withdrawal (vs. stabilization) increases proximal suicide risk. If appropriate, a multilevel path model will test a path in which E2+P4 withdrawal (vs. stabilization) causes neuroactive steroid withdrawal, which increases in hopelessness and hyperarousal, which in turn increases proximal suicide risk. Relevance. By conducting a mechanistic experiment to probe the mediators of a known cause of proximal suicide risk, the proposed research responds to public calls from the NIMH-sponsored Suicide Research Prioritization Agenda to identify modifiable causes of proximal suicide risk.
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0.958 |