Suicidal Ideation
Conditions
Keywords
steroid hormones, estradiol, estrogen, progesterone, depression, suicide
Brief summary
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.
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.
Interventions
DRUGTransdermal 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.
DRUGOral 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.
DRUGPlacebos
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.
Sponsors
National Institute of Mental Health (NIMH)
University of Illinois at Chicago
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Masking description
double-blind
Intervention model description
Crossover 3-condition placebo-controlled trial
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cyclical Change in Suicidal Ideation (SI) Severity | Days 1 to 17 following positive LH test | 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. |
Countries
United States
Participant flow
Pre-assignment details
60 participants were enrolled (consented) in the study. Following a baseline phase in which participants completed daily symptom ratings and prepared to begin urinary LH testing as part of the lead-up to the first experimental period, 46 participants remained in the study and were randomized to one of six sequences of the three experimental conditions.
Participants by arm
| Arm | Count |
|---|---|
| E-P-PBO Estrogen First, then Progesterone, then Placebo | 9 |
| E-PBO-P Estrogen, Placebo, Progesterone | 8 |
| P-E-PBO Progesterone, Estrogen, Placebo | 9 |
| P-PBO-E Progesterone, Placebo, Estrogen | 5 |
| PBO-E-P Placebo, Estrogen, Progesterone | 9 |
| PBO-P-E Placebo, Progesterone, Estrogen | 6 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Experimental Period 1 | Adverse Event | 1 | 0 | 0 | 1 | 0 | 0 |
| Experimental Period 1 | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Experimental Period 2 | Adverse Event | 0 | 0 | 0 | 0 | 1 | 2 |
| Washout Period 1 | Anovulation | 1 | 0 | 0 | 0 | 0 | 0 |
| Washout Period 1 | Withdrawal by Subject | 0 | 3 | 0 | 1 | 0 | 1 |
| Washout Period 2 | Anovulation | 0 | 0 | 0 | 0 | 0 | 1 |
| Washout Period 2 | Physician Decision | 1 | 0 | 0 | 1 | 0 | 1 |
| Washout Period 2 | Withdrawal by Subject | 3 | 2 | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | E-P-PBO | E-PBO-P | P-E-PBO | P-PBO-E | PBO-E-P | PBO-P-E | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 8 Participants | 9 Participants | 5 Participants | 9 Participants | 6 Participants | 46 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 2 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 6 Participants | 4 Participants | 4 Participants | 6 Participants | 1 Participants | 27 Participants |
| Region of Enrollment United States | 9 participants | 8 participants | 9 participants | 5 participants | 9 participants | 6 participants | 46 participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 9 Participants | 5 Participants | 9 Participants | 6 Participants | 46 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 35 | 0 / 35 |
| other Total, other adverse events | 15 / 38 | 10 / 35 | 15 / 35 |
| serious Total, serious adverse events | 0 / 38 | 2 / 35 | 0 / 35 |
Outcome results
Primary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Estradiol + Placebo | Cyclical Change in Suicidal Ideation (SI) Severity | -.22 units on a scale | Standard Error 0.05 |
| Oral Micronized Progesterone + Placebo | Cyclical Change in Suicidal Ideation (SI) Severity | -.05 units on a scale | Standard Error 0.07 |
| Placebos | Cyclical Change in Suicidal Ideation (SI) Severity | .25 units on a scale | Standard Error 0.11 |
Comparison: Fixed interaction effect of treatment (0=Placebo, 1=E2) by cycle phase (0=Lower-Risk Early Luteal Baseline, 1=Higher-Risk Perimenstrual Phase) predicting SI severity in a multilevel model (with daily observations nested within conditions nested within participants over time).p-value: 0.00295% CI: [-0.41, -0.08]Mixed Models Analysis
Comparison: Fixed interaction effect of treatment (0=Placebo, 1=P4) by cycle phase (0=Lower-Risk Early Luteal Baseline, 1=Higher-Risk Perimenstrual Phase) predicting SI severity in a multilevel model (with daily observations nested within conditions nested within participants over time).p-value: 0.4695% CI: [-0.22, 0.1]Mixed Models Analysis