A Phase 4 interventional study of Transdermal Estradiol + Placebo and Oral Micronized Progesterone + Placebo in Suicidal Ideation, sponsored by University of Illinois at Chicago. Completed at 1 site in United States. Open to female participants aged 18 Years to 45 Years. Per ClinicalTrials.gov, last updated 2022-09-14.
Sponsored by University of Illinois at Chicago · Phase 4, Interventional, and Basic science
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.
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.
Exclusion Criteria:
.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
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
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
.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.
Also known as: Climara, sugar pill
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.
Also known as: Prometrium, placebo patch
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.
Also known as: sugar pill, placebo patch
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.
Time frame: Days 1 to 17 following positive LH test
| Milestone | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E |
|---|---|---|---|---|---|---|
| Started | 9 | 8 | 9 | 5 | 9 | 6 |
| Completed | 8 | 7 | 9 | 4 | 9 | 6 |
| Not completed | 1 | 1 | 0 | 1 | 0 | 0 |
| Withdrew: Adverse event | 1 | 0 | 0 | 1 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Milestone | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E |
|---|---|---|---|---|---|---|
| Started | 8 | 7 | 9 | 4 | 9 | 6 |
| Completed | 7 | 4 | 9 | 3 | 9 | 5 |
| Not completed | 1 | 3 | 0 | 1 | 0 | 1 |
| Withdrew: Anovulation | 1 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 3 | 0 | 1 | 0 | 1 |
| Milestone | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E |
|---|---|---|---|---|---|---|
| Started | 7 | 4 | 9 | 3 | 9 | 5 |
| Completed | 7 | 4 | 9 | 3 | 8 | 3 |
| Not completed | 0 | 0 | 0 | 0 | 1 | 2 |
| Withdrew: Adverse event | 0 | 0 | 0 | 0 | 1 | 2 |
| Milestone | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E |
|---|---|---|---|---|---|---|
| Started | 7 | 4 | 9 | 3 | 8 | 3 |
| Completed | 3 | 2 | 9 | 2 | 6 | 1 |
| Not completed | 4 | 2 | 0 | 1 | 2 | 2 |
| Withdrew: Physician decision | 1 | 0 | 0 | 1 | 0 | 1 |
| Withdrew: Withdrawal by subject | 3 | 2 | 0 | 0 | 2 | 0 |
| Withdrew: Anovulation | 0 | 0 | 0 | 0 | 0 | 1 |
| Milestone | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E |
|---|---|---|---|---|---|---|
| Started | 3 | 2 | 9 | 2 | 6 | 1 |
| Completed | 3 | 2 | 9 | 2 | 6 | 1 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 |
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.
| units on a scale | Transdermal Estradiol + Placebo | Oral Micronized Progesterone + Placebo | Placebos |
|---|---|---|---|
| Cyclical Change in Suicidal Ideation (SI) Severity | -.22 ± .05 | -.05 ± .07 | .25 ± .11 |
Collected over Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total).. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Transdermal Estradiol + Placebo | 0/38 (0%) | 0/38 (0%) | 15/38 (39.5%) |
| Oral Micronized Progesterone + Placebo | 0/35 (0%) | 2/35 (5.7%) | 10/35 (28.6%) |
| Placebos | 0/35 (0%) | 0/35 (0%) | 15/35 (42.9%) |
| Event | Transdermal Estradiol + Placebo | Oral Micronized Progesterone + Placebo | Placebos |
|---|---|---|---|
| Hospitalization for Respiratory InfectionRespiratory, thoracic and mediastinal disorders | 0/38 | 1/35 | 0/35 |
| Hospitalization for Worsening Suicidal IdeationPsychiatric disorders | 0/38 | 1/35 | 0/35 |
| Event | Transdermal Estradiol + Placebo | Oral Micronized Progesterone + Placebo | Placebos |
|---|---|---|---|
| HeadacheGeneral disorders | 4/38 | 5/35 | 6/35 |
| Breast DiscomfortReproductive system and breast disorders | 4/38 | 1/35 | 4/35 |
| NauseaGeneral disorders | 2/38 | 2/35 | 3/35 |
| Skin IrritationSkin and subcutaneous tissue disorders | 3/38 | 0/35 | 0/35 |
| Muscle PainMusculoskeletal and connective tissue disorders | 0/38 | 0/35 | 2/35 |
| Self-Report of Adverse Mood ChangesPsychiatric disorders | 0/38 | 2/35 | 0/35 |
| DizzinessGeneral disorders | 1/38 | 0/35 | 0/35 |
| Vision ChangesEye disorders | 1/38 | 0/35 | 0/35 |
| Age, Categorical(Participants) | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E | Total |
|---|---|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 9 | 8 | 9 | 5 | 9 | 6 | 46 |
| >=65 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Sex: Female, Male(Participants) | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E | Total |
|---|---|---|---|---|---|---|---|
| Female | 9 | 8 | 9 | 5 | 9 | 6 | 46 |
| Male | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E | Total |
|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| Asian | 2 | 2 | 1 | 0 | 1 | 2 | 8 |
| Native Hawaiian or Other Pacific Islander | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| Black or African American | 0 | 0 | 4 | 0 | 2 | 2 | 8 |
| White | 6 | 6 | 4 | 4 | 6 | 1 | 27 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Region of Enrollment(participants) | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E | Total |
|---|---|---|---|---|---|---|---|
| United States | 9 | 8 | 9 | 5 | 9 | 6 | 46 |
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University of Illinois at Chicago