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Cyclical Neuroactive Steroid Changes, Arousal, and Proximal Suicide Risk: An Experimental Approach (CLEAR-3)

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ClinicalTrials.gov Identifier: NCT04112368
Recruitment Status : Recruiting
First Posted : October 2, 2019
Last Update Posted : December 2, 2020
Sponsor:
Information provided by (Responsible Party):
Tory Anne Eisenlohr-Moul, University of Illinois at Chicago

Brief Summary:
Female suicide attempts occur more often in the weeks before and after menses onset, and have been linked to ovarian hormone withdrawal. The proposed project will use a two-week intervention to stabilize hormones in females with recent suicidal thoughts; this paradigm is a safe way to learn how cyclical changes in hormones and their metabolites influence short-term risk of suicide. The data acquired will contribute to our understanding of the biology of acute suicide risk and advance efforts to develop safe and effective treatments that eliminate predictable monthly worsening of suicide risk in reproductive-age females.

Condition or disease Intervention/treatment Phase
Suicidal Ideation Drug: Estradiol Transdermal Patch 0.1 mg/24 hrs Drug: Oral Micronized Progesterone 200mg Drug: Inactive Clear Patch Drug: Placebo capsule Phase 4

Detailed Description:
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 enzymes critical for synthesizing neuroactive steroids) 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 gas chromatography mass spectrometry (GC-MS) quantified neuroactive steroids, messenger ribonucleic acid (mRNA) expression for enzymes critical for synthesizing neuroactive steroids, and physiological arousal. Our app (BiAffect) will collect ecological momentary assessments (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 National Institute of Mental Health (NIMH)-sponsored Suicide Research Prioritization Agenda to identify modifiable causes of proximal suicide risk.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Crossover 2-Condition Placebo-Controlled Trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Identical placebos provided by the University of Illinois at Chicago investigational drug service.
Primary Purpose: Basic Science
Official Title: Cyclical Neuroactive Steroid Changes, Arousal, and Proximal Suicide Risk: An Experimental Approach
Actual Study Start Date : November 5, 2020
Estimated Primary Completion Date : July 1, 2023
Estimated Study Completion Date : July 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Suicide

Arm Intervention/treatment
Experimental: Active condition, then Inactive condition
Beginning 7 days after ovulation, active treatment begins 7 days after ovulation with an estradiol transdermal patch (0.1 mg/24 hrs) applied to the skin weekly (spanning 14 days of treatment) along with (active) 100 mg oral micronized progesterone capsules taken twice daily by mouth for 14 days. A 1-month washout is observed. Then, beginning 7 days after ovulation, inactive placebo capsules will be taken twice daily by mouth along with the application of inactive clear patches applied to the skin weekly for 14 days.
Drug: Estradiol Transdermal Patch 0.1 mg/24 hrs
Estradiol transdermal patch delivering 0.1 mg/24 hour administered by affixing to skin for 14 days starting on day 7 after ovulation
Other Name: Climara

Drug: Oral Micronized Progesterone 200mg
100 mg oral micronized progesterone taken orally twice daily for 14 days starting day 7 after ovulation (200mg total per day)
Other Name: Prometrium

Drug: Inactive Clear Patch
Matching placebo patch administered by affixing to skin for 14 days starting on day 7 after ovulation
Other Name: Placebo transdermal patch

Drug: Placebo capsule
Matching placebo capsules administered twice daily for 14 days starting day 7 after ovulation
Other Name: Sugar pill

Placebo Comparator: Inactive condition, then active condition
Beginning 7 days after ovulation, inactive placebo capsules will be taken twice daily by mouth along with the application of inactive clear patches applied to the skin weekly for 14 days. After completing a 1-month washout, active treatment begins 7 days after ovulation with an (active) estradiol transdermal patch applied to the skin weekly (spanning 14 days of treatment) along with (active) 100 mg oral micronized progesterone capsules taken twice daily by mouth for 14 days.
Drug: Estradiol Transdermal Patch 0.1 mg/24 hrs
Estradiol transdermal patch delivering 0.1 mg/24 hour administered by affixing to skin for 14 days starting on day 7 after ovulation
Other Name: Climara

Drug: Oral Micronized Progesterone 200mg
100 mg oral micronized progesterone taken orally twice daily for 14 days starting day 7 after ovulation (200mg total per day)
Other Name: Prometrium

Drug: Inactive Clear Patch
Matching placebo patch administered by affixing to skin for 14 days starting on day 7 after ovulation
Other Name: Placebo transdermal patch

Drug: Placebo capsule
Matching placebo capsules administered twice daily for 14 days starting day 7 after ovulation
Other Name: Sugar pill




Primary Outcome Measures :
  1. Perimenstrual Change in Daily Adult Suicidal Ideation Questionnaire (ASIQ) Scores [ Time Frame: Mean daily rating in the perimenstrual phase (days +12 to +17 following a positive luteinizing hormone surge in urine on day=0) minus the mean daily rating in the midluteal phase (days +0 to +5) ]

    The Adult Suicidal Ideation Questionnaire (ASIQ) is a 25-item self-report questionnaire assessing suicidality. Each day, individuals rate each of 25 items on a scale from 1 (Not at All) to 6 (Extreme). Mean scores are computed, providing a single number for each day that represents the participant's mean suicidal ideation (1 to 6), with higher daily values representing more severe suicidal ideation.

    Perimenstrual change scores are calculated for each person in each condition as the mean of scores in the perimenstrual phase (days +12 to +17 following a positive luteinizing hormone surge in urine on day=0) minus the mean in the midluteal phase (days +0 to +5). Therefore, positive values represent a perimenstrual increase in suicidal ideation, and negative values represent a perimenstrual decrease.


  2. Perimenstrual Change in Daily Columbia Suicide Severity Rating Scale (C-SSRS) Screening Interview Planning Item Scores [ Time Frame: Mean daily rating in the perimenstrual phase (days +12 to +17 following a positive luteinizing hormone surge in urine on day=0) minus the mean daily rating in the midluteal phase (days +0 to +5) ]

    The Columbia Suicide Severity Rating Scale is an interview designed to assess various aspects of suicide risk. In the present study, this questionnaire is administered daily via phone interview as part of a risk screening process. Here, we utilize a single dichotomous outcome from a single item representing suicidal planning from the C-SSRS interview: "Today, have you thought about how or when you might kill yourself?". Each day, individuals chose either "Yes" (coded as 1) or "No" (coded as 0).

    Perimenstrual change scores are calculated for each person in each condition as the mean of scores in the perimenstrual phase (days +12 to +17 following a positive luteinizing hormone surge in urine on day=0) minus the mean in the midluteal phase (days +0 to +5). Therefore, positive values represent a perimenstrual increase in suicidal planning, and negative values represent a perimenstrual decrease.



Secondary Outcome Measures :
  1. Perimenstrual Change in Daily Beck Hopelessness Scale (BHS) Short Form Scores [ Time Frame: Mean daily rating in the perimenstrual phase (days +12 to +17 following a positive luteinizing hormone surge in urine on day=0) minus the mean daily rating in the midluteal phase (days +0 to +5) ]

    Hopelessness is assessed with a daily Beck Hopelessness Scale (short form), a 10-item self-report measure with true-false items that assess hopelessness and the extent of positive and negative beliefs about the future. Summed scores range from 0 to 10. Scores provide a measure of the severity of self-reported hopelessness, with higher scores representing greater hopelessness.

    Perimenstrual change scores are calculated for each person in each condition as the mean of scores in the perimenstrual phase (days +12 to +17 following a positive luteinizing hormone surge in urine on day=0) minus the mean in the midluteal phase (days +0 to +5). Therefore, positive values represent a perimenstrual increase in hopelessness, and negative values represent a perimenstrual decrease.


  2. Perimenstrual Change in Daily Brief Agitation Measure (BAM) Scores [ Time Frame: Mean daily rating in the perimenstrual phase (days +12 to +17 following a positive luteinizing hormone surge in urine on day=0) minus the mean daily rating in the midluteal phase (days +0 to +5) ]

    Agitation is assessed with a daily Brief Agitation Measure (BAM), a 3-item self-report measure in which participants rate their symptoms of agitation ranging from 0 (Strongly Disagree) to 6 (Strongly Agree). Mean daily scores (ranging from 0 to 6) provide a measure of the severity of self-reported agitation, with higher scores representing greater agitation.

    Perimenstrual change scores are calculated for each person in each condition as the mean of scores in the perimenstrual phase (days +12 to +17 following a positive luteinizing hormone surge in urine on day=0) minus the mean in the midluteal phase (days +0 to +5). Therefore, positive values represent a perimenstrual increase in agitation, and negative values represent a perimenstrual decrease.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Since the study is focused on the menstrual cycle, the study includes only those assigned female sex at birth
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ability to adhere to medication regimen
  • Speaks English
  • Assigned female at birth with intact ovaries
  • Premenopausal
  • Normal menstrual cycles between 25-35 days
  • Under current care of an outpatient mental health provider with visits occurring at least once every 3 months.
  • At least 1 year postpartum.
  • Willing to use a barrier method of birth control during the study.
  • Normal weight (BMI between 18-29)
  • Must report at least some recent suicidal ideation (in the past month) at the time of recruitment.
  • Must be categorized as having acceptably low imminent risk for suicidal crisis/attempt by a licensed clinical psychologist utilizing evidence-based clinical and research guidelines for imminent suicide risk management.

Exclusion Criteria:

  • Must not be pregnant, breastfeeding, or trying to become pregnant.
  • Must not be taking any form of exogenous hormones or hormonal intrauterine device, and must have ended previous use of hormonal preparations at least one month prior to the study.
  • Must not have a personal history of any chronic medical condition, including but not limited to metabolic or autoimmune disease, epilepsy, endometriosis, cancer, diabetes, cardiovascular, gastrointestinal, hepatic, renal, or pulmonary disease, and no personal or first degree family history of thromboembolic events.
  • Any current cigarette smoking is exclusionary.
  • Must not report a history of clinical diagnosis or treatment for postpartum depression or premenstrual dysphoric disorder (Note: Premenstrual Dysphoric - - - Disorder diagnosis must have been made based on prospective daily ratings).
  • Must not report any history of manic episode, any history of psychotic symptoms, or current substance use disorder.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04112368


Contacts
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Contact: Tory A Eisenlohr-Moul, Ph.D. 859-317-0503 temo@uic.edu
Contact: Sekine Ozturk, B.A. (312) 355-2659 sozturk2@uic.edu

Locations
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United States, Illinois
University of Illinois Neuropsychiatric Institute Recruiting
Chicago, Illinois, United States, 60612
Contact: Tory A Eisenlohr-Moul, Ph.D.    859-317-0503    temo@uic.edu   
Sponsors and Collaborators
University of Illinois at Chicago
Investigators
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Principal Investigator: Tory A Eisenlohr-Moul, Ph.D University of Illinois at Chicago
  Study Documents (Full-Text)

Documents provided by Tory Anne Eisenlohr-Moul, University of Illinois at Chicago:
Statistical Analysis Plan  [PDF] September 24, 2019

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Responsible Party: Tory Anne Eisenlohr-Moul, Assistant Professor, University of Illinois at Chicago
ClinicalTrials.gov Identifier: NCT04112368    
Other Study ID Numbers: 2019-0624
First Posted: October 2, 2019    Key Record Dates
Last Update Posted: December 2, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Suicide
Suicidal Ideation
Self-Injurious Behavior
Behavioral Symptoms
Estradiol
Progesterone
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Progestins