Transdermal Estradiol for Suicide

(CLEAR-4 Trial)

Overseen By Gabriela Guzman, M.S.

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: University of Illinois at Chicago

Must not be taking: Exogenous hormones

Disqualifiers: Pregnancy, Chronic conditions, Smoking, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 14 days per condition, with a washout cycle in between

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a skin patch that releases estradiol, a form of estrogen, to determine if it reduces suicidal thoughts in women who experience them around their menstrual cycle. The study compares two scenarios: using the estradiol patch during the perimenstrual phase and using a placebo patch. Women with regular menstrual cycles, who are premenopausal, and have recently experienced suicidal thoughts might be suitable candidates. The goal is to assess whether the estradiol patch affects the severity of these thoughts. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop taking any form of hormonal medications at least one month before starting. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

Is there any evidence suggesting that transdermal estradiol is likely to be safe for humans?

Research has shown that transdermal estradiol, a type of estrogen applied to the skin, has been studied for its effects around menstruation. Some studies suggest that changes in hormone levels, such as those from estradiol, might affect mood and thoughts of self-harm. However, these studies focus more on hormone changes rather than the safety of estradiol itself.

Transdermal estradiol is generally considered safe and well-tolerated. The FDA has approved it for other uses, indicating its safety. Most people using it for hormone therapy experience mild side effects, like skin irritation where the patch is applied, and serious issues are rare.

It is important to note that this study is in the early stages of exploring its use for people with suicidal symptoms. Much remains to be learned about its effects in this specific area. However, estradiol has been safe for many people in other treatments. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for suicide?

Most treatments for suicidal ideation focus on psychological therapy or medications like antidepressants and antipsychotics, which can take weeks to show effectiveness. However, transdermal estradiol offers a unique approach by using a hormone treatment applied through a skin patch. Researchers are excited about this method because it delivers estradiol directly into the bloodstream, potentially offering faster relief. Unlike traditional treatments, which may not address underlying hormonal imbalances, estradiol could provide a novel mechanism by regulating mood through hormonal pathways, possibly offering quicker results in just days.

What evidence suggests that transdermal estradiol might be an effective treatment for suicidality?

This trial will compare Transdermal Estradiol with a placebo to evaluate its effects on suicidal thoughts and related symptoms. Research has shown that transdermal estradiol, a hormone therapy applied to the skin, can improve symptoms around menstruation. One study found that estradiol helped prevent memory and speech problems in people with suicidal thoughts. Another study showed that estradiol reduced the worsening of suicidal thoughts, plans, depression, and feelings of hopelessness during this time. These findings suggest that estradiol might help manage these severe symptoms. While more research is needed, the results are promising for those experiencing these challenges. ^{2 6 7 8 9}

Who Is on the Research Team?

Tory A Eisenlohr-Moul, Ph.D.

Principal Investigator

University of Illinois at Chicago

Elizabeth Mulligan, Ph.D.

Principal Investigator

University of Illinois at Chicago

Katja M Schmalenberger, Ph.D.

Principal Investigator

University of Illinois at Chicago

Are You a Good Fit for This Trial?

This trial is for premenopausal females who were assigned female at birth, have intact ovaries, and a normal weight. Participants must have had suicidal thoughts in the past month but are not at immediate risk of suicide. They should speak English, have regular menstrual cycles, be under mental health care with quarterly visits minimum, and agree to use barrier contraception during the study.

Inclusion Criteria

Speaks English

Ability to adhere to medication regimen

Willing to use a barrier method of birth control during the study

Exclusion Criteria

Must not be pregnant, breastfeeding, or trying to become pregnant

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)

Any current cigarette smoking is exclusionary

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a crossover trial with two perimenstrual conditions: estradiol administration and placebo, each lasting 14 days, separated by a washout cycle.

14 days per condition, with a washout cycle in between

Washout

A washout cycle separates the two treatment conditions to prevent carryover effects.

1 menstrual cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Transdermal Estradiol

Trial Overview The study tests how perimenstrual estradiol affects suicidality by comparing two conditions: applying transdermal estradiol patches or using a placebo during the natural drop in estrogen before menstruation. It's designed as a crossover trial where participants experience both conditions.

How Is the Trial Designed?

Group I: Transdermal Estradiol Experimental Treatment 1 Intervention

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

Group II: Placebo Placebo Group 1 Intervention

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

Who Is Running the Clinical Trial?

University of Illinois at Chicago

Lead Sponsor

Trials

653

Recruited

1,574,000+

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0165178124004736

Effects of acute estradiol administration on perimenstrual ... We find perimenstrual declines in working memory and verbal fluency in patients with SI, which can be prevented by administering E2.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05282277

Examining the Effects of Estradiol on Neural and Molecular ... This project will examine the effects of estradiol administration on perimenopausal-onset (PO) anhedonia and psychosis using simultaneous positron emission ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11888058/

Mental Health Changes in US Transgender Adults ... This study evaluated the relationship between initiating GAHT via a telehealth clinic and changes in depression, anxiety, and suicide ideation over a 3-month ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36585408/

Effects of acute estradiol and progesterone on perimenstrual ... Experimental administration of E2 and P4 (relative to PBO) reduced perimenstrual exacerbation of SI, suicide planning, depression, hopelessness, perceived ...

5. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.20250862

Adolescent Suicidality and Depression, Premenstrual ... The total sample includes self-report data on suicidal ideation and attempts collected from 1) 16,784 individuals from 9–12th grade from the ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9803670/

Effects of acute estradiol and progesterone on ... At least 15 cross-sectional studies have reported a higher risk of suicidal ideation (SI), behavior, or death in the perimenstrual phase ( ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12247532/

a real-world study of the FDA adverse event reporting system Notably, in this study, combined estrogen and progestogen therapy was significantly associated with suicidal ideation, which is the only PT in ...

8. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.2017.17060616

Association of Hormonal Contraception With Suicide ... Use of hormonal contraception was positively associated with subsequent suicide attempt and suicide. Adolescent women experienced the highest relative risk.

9. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.20250862

Adolescent Suicidality and Depression, Premenstrual ... The total sample includes self-report data on suicidal ideation and attempts collected from 1) 16,784 individuals from 9–12th grade from the ...