Unique Effects of Perimenstrual Estradiol or Progesterone Supplementation on Perimenstrual Suicidality (CLEAR-2)

This within-person, crossover, 3-condition, placebo-controlled study compares the impact of three perimenstrual conditions on severity of suicidal symptoms in females with past-month suicidality but minimal risk of imminent suicide attempt. The three conditions are (1) perimenstrual withdrawal from estradiol only (during progesterone stabilization), (2) perimenstrual withdrawal from progesterone only (during estradiol stabilization), and (3) perimenstrual withdrawal from both estradiol and progesterone during placebo.

Study Overview

• Status: Completed
• Conditions: Suicidal Ideation
• Intervention / Treatment: Drug: Transdermal Estradiol + Placebo; Drug: Oral Micronized Progesterone + Placebo; Drug: Placebos

Detailed Description

Previous work from our group demonstrates that perimenstrual worsening of suicidal thoughts in females is caused by normal perimenstrual withdrawal from the ovarian steroids estradiol (E2) and progesterone (P4), since perimenstrual stabilization of E2+P4 prevented the perimenstrual worsening of suicidal ideation observed under placebo. In the present study, we follow up on that work with an additional mechanistic trial in which E2 and P4 will be stabilized in separate arms of the study.

60 (30 completers) female outpatients, with past-month suicidal ideation but minimal imminent risk for attempt, will complete self-reports and clinical interviews measuring presence and severity of suicidal ideation in each of three conditions (A, B, C: order randomized across three menstrual cycles): (A) perimenstrual E2/P4 withdrawal (under placebo), (B) perimenstrual P4 withdrawal (exogenous stabilization of E2 only), and (C) perimenstrual E2 withdrawal (exogenous stabilization of P4 only). A washout cycle will separate conditions. Analyses will compare the perimenstrual trajectories of symptoms and suicidality across the three conditions.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Neuropsychiatric Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 18.00-29.99)
• 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 that may interfere with the aims of the study or make the experimental protocol unsafe, 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 current diagnosis of major depressive episode with peripartum onset (current episode), and must not be currently receiving treatment for 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.
• Must not test positive for (unprescribed) opioid use, methamphetamine use, or cocaine use at the start of an experimental condition.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Transdermal Estradiol + Placebo; .1mg per 24 hours transdermal estradiol applied to the skin weekly, and sugar pill manufactured to mimic the progesterone pills taken twice daily by mouth, for 14 days.	Drug: Transdermal Estradiol + Placebo; .1mg/24hr transdermal estradiol for 14 days starting day 7 after positive urine luteinizing hormone test, plus twice daily placebo pills during the same time frame.; Other Names: Climara; sugar pill
Experimental: Oral Micronized Progesterone + Placebo; 100 mg oral micronized progesterone pill taken twice daily by mouth, and clear patch manufactured to mimic the E2 patch applied to the skin weekly, for 14 days.	Drug: Oral Micronized Progesterone + Placebo; 100mg oral micronized progesterone twice daily for 14 days starting day 7 after positive urine luteinizing hormone test, plus weekly application of a placebo patch during the same time frame.; Other Names: Prometrium; placebo patch
Placebo Comparator: Placebos; Sugar pill designed to mimic the P4 pills taken twice daily by mouth, and clear patch manufactured to mimic the E2 patch applied to the skin weekly, for 14 days.	Drug: Placebos; Twice daily placebo pills for 14 days starting day 7 after positive urine luteinizing hormone test, plus weekly application of a placebo patch during the same time frame.; Other Names: sugar pill; placebo patch

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cyclical Change in Suicidal Ideation (SI) Severity	Each day, participants completed five items from the Adult Suicidal Ideation Questionnaire (ASIQ; items 1,2,9,17,19). Response options ranged from 1 (no suicidal ideation) to 6 (extreme severity of suicidal ideation). For each participant on each day, "mean daily SI" was calculated as the mean of these five items. Our outcome, Cyclical Change in SI Severity, is calculated for each person, in each condition, as the DIFFERENCE between mean daily SI during the low-risk early luteal phase days (days LH surge +1,2,3,4,5,6,7) and the high-risk perimenstrual phase days (days LH surge +11,12,13,14,15,16,17), with the subtraction carried out as Perimenstrual mean minus Early Luteal mean. Therefore, this single value represents the degree to which an individual showed perimenstrual worsening of SI within a condition.	Days 1 to 17 following positive LH test

Collaborators and Investigators

• Sponsor: University of Illinois at Chicago
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Tory A Eisenlohr-Moul, PhD, University of Illinois at Chicago

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2018
• Primary Completion (Actual): May 9, 2021
• Study Completion (Actual): May 9, 2021

Study Registration Dates

• First Submitted: April 6, 2018
• First Submitted That Met QC Criteria: April 6, 2018
• First Posted (Actual): April 13, 2018

Study Record Updates

• Last Update Posted (Actual): September 14, 2022
• Last Update Submitted That Met QC Criteria: August 18, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: estrogen; depression; suicide; estradiol; progesterone; steroid hormones
• Additional Relevant MeSH Terms: Behavioral Symptoms; Self-Injurious Behavior; Suicide; Suicidal Ideation; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Progestins; Estradiol; Progesterone
• Other Study ID Numbers: 2018-0189; R00MH109667 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• 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.: Yes