Neurocognitive Mechanisms of Perimenstrual Estrogen Effects on Suicidality

NCT06191289 | Terminated Phase 2 DMC FDA Drug

• 1 other identifier: 2023-1560
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Suicide

Keywords

MENSTRUAL CYCLE; HORMONES; ESTROGEN; REWARD; EXECUTIVE FUNCTION

Outcome Measures

Primary Outcomes (3)

• Early-Luteal-to-Perimenstrual Worsening of Daily Passive Suicidal Ideation (PSI)

  Three daily survey questions assessing PSI will be administered each day (i.e., "I wished I were dead", "I wish I could go to sleep and not wake up", "I thought that life was not worth living"; scale from 1 (Not at All) to 5 (Extremely)). Composite mean scores for these 3 items are computed, providing a single number for each day, with higher daily values representing more severe PSI. Early-luteal-to-perimenstrual worsening of daily PSI is estimated for each person in each condition as the mean of scores in the perimenstrual phase (Days -3 to +1 relative to menses onset) minus the mean in the early luteal phase (Days +2 to +6 relative to the luteinizing hormone surge at day 0).

  Mean daily rating in the perimenstrual phase (Days -3, -2, -1, and +1 relative to menses onset where menses onset is day +1 and there is no 0 on the menses-onset timeline) minus the mean daily rating in the early luteal phase (Days +2, +3, +4, +5, and +6

• Early-Luteal-to-Perimenstrual Worsening of Daily Active Suicidal Ideation (ASI)

  Three daily survey questions assessing ASI will be administered each day (i.e., "I thought about killing myself", "I wanted to kill myself", "I had the urge to kill myself"; scale from 1 (Not at All) to 5 (Extremely)). Composite mean scores for these 3 items are computed, providing a single number for each day, with higher daily values representing more severe ASI. Early-luteal-to-perimenstrual worsening of daily ASI is estimated for each person in each condition as the mean of scores in the perimenstrual phase (Days -3 to +1 relative to menses onset) minus the mean in the early luteal phase (Days +2 to +6 relative to the luteinizing hormone surge at day 0).

  Mean daily rating in the perimenstrual phase (Days -3, -2, -1, and +1 relative to menses onset where menses onset is day +1 and there is no 0 on the menses-onset timeline) minus the mean daily rating in the early luteal phase (Days +2, +3, +4, +5, and +6

• Early-Luteal-to-Perimenstrual Increase in the Probability of Daily Suicidal Planning (SP)

  Two questions from the ASIQ assessing SP will be administered each day in an adapted daily format (i.e., "I thought about how I might kill myself", "I thought about when I might kill myself"; scale from 1 (Not at All) to 5 (Extremely)). Daily dichotomous scores will be derived such that if either of these two items are endorsed with a score higher than 1 (not at all) on a given day, the composite score will be 1 (otherwise the score will be 0) for that day. Early-luteal-to-perimenstrual increase in the probability of daily SP is estimated for each person in each condition as the mean of dichotomous daily scores in the perimenstrual phase (Days -3 to +1 relative to menses onset) minus the mean of dichotomous scores in the early luteal phase (Days +2 to +6 relative to the luteinizing hormone surge at day 0).

  Mean daily dichotomous outcome (ranging from 0-1) in the perimenstrual phase (Days -3, -2, -1, and +1 relative to menses onset where menses onset is day +1 and there is no 0 on the menses-onset timeline) minus the mean in the early luteal phase (Days +2,

Secondary Outcomes (4)

• Perimenstrual Reward Positivity (RewP)

  Mean RewP amplitude in the perimenstrual phase (Days -3, -2, -1, and +1 relative to menses onset where menses onset is day +1 and there is no 0 on the menses-onset timeline)

• Early-Luteal-to-Perimenstrual Worsening of daily self-reported anhedonia

  Mean daily rating in the perimenstrual phase (Days -3, -2, -1, and +1 relative to menses onset where menses onset is day +1 and there is no 0 on the menses-onset timeline) minus the mean daily rating in the early luteal phase (Days +2, +3, +4, +5, and +6

• Early-Luteal-to-Perimenstrual change (improvement) in daily N-Back performance

  Mean daily rating in the perimenstrual phase (Days -3, -2, -1, and +1 relative to menses onset where menses onset is day +1 and there is no 0 on the menses-onset timeline) minus the mean daily rating in the early luteal phase (Days +2, +3, +4, +5, and +6

• Early-Luteal-to-Perimenstrual Worsening of daily self-reported working memory failures (WMF)

  Mean daily rating in the perimenstrual phase (Days -3, -2, -1, and +1 relative to menses onset where menses onset is day +1 and there is no 0 on the menses-onset timeline) minus the mean daily rating in the early luteal phase (Days +2, +3, +4, +5, and +6

Study Arms (2)

Transdermal Estradiol

EXPERIMENTAL

.1mg per 24 hours transdermal estradiol applied to the skin weekly, for 14 days.

Drug: Transdermal Estradiol

Placebo

PLACEBO COMPARATOR

Clear patch manufactured to mimic the E2 patch applied to the skin weekly, for 14 days.

Other: Placebo

Interventions

Transdermal Estradiol DRUG

1mg/24hr transdermal estradiol for 14 days starting day 7 after positive urine luteinizing hormone test Other Names: Climara

Transdermal Estradiol

Placebo OTHER

Weekly application of a placebo patch for 14 days starting day 7 after positive urine luteinizing hormone test

Placebo

Eligibility Criteria

• Age: 20 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Ability to adhere to medication regimen
• Speaks English
• Assigned female at birth with intact ovaries
• Premenopausal
• Normal menstrual cycles between 24-32 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• University of Illinois at Chicago: lead

Study Sites (1)

University of Illinois Neuropsychiatric Institute

Chicago, Illinois, 60612, United States

Location

MeSH Terms

Conditions

Suicide

Condition Hierarchy (Ancestors)

Self-Injurious Behavior; Behavioral Symptoms; Behavior

Study Officials

• Tory A Eisenlohr-Moul, Ph.D.

  University of Illinois at Chicago

  PRINCIPAL INVESTIGATOR

• Elizabeth Mulligan, Ph.D.

  University of Illinois at Chicago

  PRINCIPAL INVESTIGATOR

• Katja M Schmalenberger, Ph.D.

  University of Illinois at Chicago

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: double-blind
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Psychiatry

Model Details: Crossover 2-condition placebo-controlled trial

Study Record Dates

• First Submitted: December 20, 2023
• First Posted: January 5, 2024
• Study Start: March 16, 2024
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: October 29, 2025

Record last verified: 2025-10

Locations

US (1)