Transdermal Estradiol for Mental Illness

(PEEPS Trial)

Overseen By Laura C Lundegard, BA

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Psychotropics, Hormonal preparations, Statins, others

Disqualifiers: Pregnancy, Neurological conditions, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

103 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effects of transdermal estradiol (a skin patch that delivers hormones) and micronized progesterone (a hormone treatment) on mental health symptoms in perimenopausal women. It focuses on reducing symptoms like anhedonia (loss of interest or pleasure) and mild to moderate psychosis (difficulty distinguishing reality) that begin during menopause-related menstrual changes. Participants will receive either the hormone treatment or a placebo to determine if the treatment improves these symptoms and brain function. Women who have experienced menstrual irregularities, along with symptoms of anhedonia or psychosis that began during this time, might be suitable for this trial. As a Phase 4 trial, the treatment is already FDA-approved and proven effective, and this research aims to understand how it benefits more patients.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications. The trial excludes participants who are currently using psychotropics, anti-hypertensives, statins, hormonal preparations, or frequently using anti-inflammatory agents. However, medications without known mood effects, like stable thyroid hormone replacement, may be allowed.

What is the safety track record for these treatments?

Studies have shown that transdermal estradiol is generally well-tolerated. Previous safety data indicates it has been tested successfully in other human trials. Although hormone replacement therapy (HRT) in menopausal women carries some mental health risks, proper monitoring can manage these.

Research has shown that micronized progesterone is safe to use and is often chosen for its lower risks, particularly regarding breast cancer. However, some individuals might experience mood changes, such as depression or anxiety. These side effects are known and can be monitored.

Both transdermal estradiol and micronized progesterone are generally safe, but awareness of potential mood-related side effects is important. Participants should discuss any concerns with the clinical trial team. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike typical treatments for mental health conditions that often rely on oral medications like SSRIs or antipsychotics, transdermal estradiol and micronized progesterone offer a hormone-based approach. This treatment is unique because it targets hormonal imbalances during perimenopause, which could be a root cause of mood disturbances and psychosis in this group. Researchers are excited about the transdermal delivery method, as it allows for a steady release of hormones directly through the skin, potentially minimizing side effects associated with oral hormone therapies. Additionally, this approach could offer quicker relief by directly addressing hormone fluctuations, providing a novel option for those who may not respond well to traditional psychiatric medications.

What evidence suggests that this trial's treatments could be effective for perimenopausal-onset anhedonia and psychosis?

Research has shown that a skin patch called transdermal estradiol, which delivers estrogen, can help reduce depression and psychosis symptoms in women going through perimenopause. In this trial, some participants will receive transdermal estradiol, which studies have found reduces severe symptoms, especially after stressful events, and improves psychosis symptoms. Additionally, micronized progesterone, also part of the active treatment in this trial, has effectively eased depression during menopause. Both treatments show promise in boosting mood and mental health for women experiencing hormonal changes. ^{2 4 5 6 7}

Who Is on the Research Team?

Gabriel Dichter, PhD

Principal Investigator

UNC School of Medicine - CIDD

Crystal E Schiller, PhD

Principal Investigator

UNC School of Medicine - Department of Psychiatry

Are You a Good Fit for This Trial?

This trial is for unmedicated perimenopausal women aged 44-55 with anhedonia or psychosis symptoms that started during menstrual irregularity. They must have a CGI-S score >3 and SHAPS scores >20, indicating significant symptoms, and be willing to follow the study procedures. Exclusions include psychiatric illness history before perimenopause, certain physical health conditions, current nicotine use, claustrophobia, BMI <18 or >35 kg/m^2.

Inclusion Criteria

You have experienced a loss of interest or pleasure, or symptoms of being out of touch with reality, during a time when your menstrual cycle was not regular.

Your doctor has rated your overall mental health as moderately to severely impaired.

I am a woman aged 44-55, in late menopause transition, with irregular periods.

Exclusion Criteria

My parent, sibling, or child has had ovarian cancer.

PET contradictions: participation in >1 research study in the past 12 months that included ionizing radiation exceeding 3 rem to the whole body (e.g., PET, CT). Standard of care imaging is not exclusionary

I am currently taking medication for my mental health or hormones.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either transdermal estradiol or placebo for 3 weeks, followed by 1 week of combined estradiol and progesterone for the active group

4 weeks

Follow-up

Participants are monitored for changes in striatal activation and DA release using PET-MR, and changes in PO anhedonia and psychosis symptoms

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Matching Placebo Patch
• Micronized Progesterone
• Raclopride C11
• Transdermal Estradiol

Trial Overview The trial tests if estradiol affects brain function related to reward in women who developed anhedonia or psychosis during perimenopause. It involves PET-MR imaging to observe changes in brain activity after administering transdermal estradiol versus a placebo patch. Micronized progesterone and Raclopride C11 are also part of the interventions.

How Is the Trial Designed?

Group I: Perimenopausal women with mild-to-moderate anhedonia + moderate psychosis, placebo group Experimental Treatment 2 Interventions

Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.

Group II: Perimenopausal women with mild-to-moderate anhedonia + moderate psychosis, active group Experimental Treatment 3 Interventions

Participants will be randomly assigned to take 100 μg/day of transdermal estradiol for 3 weeks followed by 1 week of combined 100 μg/day of transdermal estradiol and 200 mg/day progesterone.

Group III: Perimenopausal women with mild-to-moderate anhedonia + absent-to-mild psychosis, placebo group Experimental Treatment 2 Interventions

Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.

Group IV: Perimenopausal women with mild-to-moderate anhedonia + absent-to-mild psychosis, active group Experimental Treatment 3 Interventions

Participants will be randomly assigned to take 100 μg/day of transdermal estradiol for 3 weeks followed by 1 week of combined 100 μg/day of transdermal estradiol and 200 mg/day progesterone.

Group V: Perimenopausal women with high anhedonia + moderate psychosis, placebo group Experimental Treatment 2 Interventions

Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.

Group VI: Perimenopausal women with high anhedonia + moderate psychosis, active group Experimental Treatment 3 Interventions

Participants will be randomly assigned to take 100 μg/day of transdermal estradiol for 3 weeks followed by 1 week of combined 100 μg/day of transdermal estradiol and 200 mg/day progesterone.

Group VII: Perimenopausal women with high anhedonia + absent-to-mild psychosis, placebo group Experimental Treatment 2 Interventions

Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.

Group VIII: Perimenopausal women with high anhedonia + absent-to-mild psychosis, active group Experimental Treatment 3 Interventions

Participants will be randomly assigned to take 100 μg/day of transdermal estradiol for 3 weeks followed by 1 week of combined 100 μg/day of transdermal estradiol and 200 mg/day progesterone.

Micronized Progesterone is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Micronized Progesterone for:

• Endometrial protection in hormone replacement therapy
• Menstrual disorders
• Infertility

Approved in United States as Prometrium for:

• Endometrial hyperplasia prevention
• Secondary amenorrhea

Approved in Canada as Utrogestan for:

• Hormone replacement therapy
• Menstrual disorders

Approved in Japan as Crinone for:

• Infertility
• Recurrent miscarriage

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

Oral micronized progesterone is recommended over synthetic progestins for women using estrogen therapy, as it minimizes the risk of endometrial hyperplasia and cancer while avoiding the metabolic and vascular side effects associated with synthetic options.

This formulation has been widely used in Europe since 1980, is well tolerated with minimal side effects, and has established long-term endometrial protection, making it a preferred choice for nonhysterectomized postmenopausal women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral micronized progesterone. de Lignières, B.[2022]

Hormonal treatments, particularly transdermal estrogens, can effectively manage premenstrual, postnatal, and climacteric depression by stabilizing hormonal fluctuations and enhancing mood, yet this approach is often overlooked by psychiatrists.

The treatment may also include testosterone for improved mood and energy, but caution is needed with progestogen due to potential intolerance; careful patient history is essential to avoid misdiagnosis of hormone-responsive depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A guide to the treatment of depression in women by estrogens. Studd, JW.[2022]

A systematic review of 18 randomized controlled trials found that different vaginal progesterone products (Crinone, Cyclogest, Lutigest, and Utrogestan Vaginal) are equally safe and effective for luteal phase support in assisted reproductive technology cycles.

No significant differences were observed in clinical pregnancy rates or ongoing pregnancy rates among the various progesterone preparations, indicating that patients can choose any of these options without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review of the clinical efficacy of vaginal progesterone for luteal phase support in assisted reproductive technology cycles. Child, T., Leonard, SA., Evans, JS., et al.[2022]

Oral micronized progesterone (MP) is a newly FDA-approved treatment that offers a safer and more effective alternative to traditional synthetic progestational agents, which often have adverse effects.

The article highlights the importance of individualized treatment plans and patient compliance, as demonstrated through five case studies, to achieve the best therapeutic outcomes with MP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Micronized progesterone: a new option for women's health care. Wetzel, W.[2013]

Transdermal estradiol plus intermittent progesterone (EPT) significantly improved self-reported sleep in perimenopausal women, reducing the time it took to fall asleep and the number of awakenings over a 12-month period.

The benefits of EPT on sleep were observed even after controlling for vasomotor symptoms and depressive symptoms, suggesting that hormone therapy's effects on sleep are independent of these factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of perimenopausal transdermal estradiol on self-reported sleep, independent of its effect on vasomotor symptom bother and depressive symptoms. Geiger, PJ., Eisenlohr-Moul, T., Gordon, JL., et al.[2023]

Oral micronized progesterone effectively reproduces the natural hormone's anti-estrogenic and anti-mineralocorticoid effects at a daily dose of 200 mg, making it a viable option for various hormonal therapies.

This preparation has shown no adverse effects on lipid profiles, coagulation factors, or blood pressure, indicating its safety for use in postmenopausal therapy, premenstrual syndrome, and pregnancy maintenance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review. Sitruk-Ware, R., Bricaire, C., De Lignieres, B., et al.[2019]

In a survey of 238 patients with depression attending a PMS and Menopause Centre, 71% had received antidepressants, and 55% reported considerable improvement with transdermal estrogen therapy, indicating its efficacy in treating hormone-related depression.

The study suggests that women experiencing premenstrual and postnatal depression are often the same individuals, and their symptoms can significantly improve with hormone therapy, highlighting the role of hormonal changes in these types of depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormone therapy for reproductive depression in women. Studd, J.[2022]

Oral micronized progesterone has enhanced bioavailability, making it effective for various therapeutic uses, including treating secondary amenorrhea and as part of hormone replacement therapy for postmenopausal women.

Research supports its potential benefits for premenopausal bleeding disorders and luteal phase dysfunction, indicating a broad clinical application for this formulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Micronized progesterone: clinical indications and comparison with current treatments. Fitzpatrick, LA., Good, A.[2019]

Micronized progesterone provides a new oral option for hormone therapy in pre- and postmenopausal women, effectively overcoming absorption issues associated with traditional progesterone.

It is functionally equivalent to synthetic progestogens for treating conditions like secondary amenorrhea, but offers a more natural metabolic profile, making it potentially safer for long-term use in hormone replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Micronized progesterone: a new therapeutic option. Langer, RD.[2013]

Hormonal fluctuations in women can lead to specific types of depression, such as premenstrual, postnatal, and perimenopausal depression, which may be misdiagnosed as bipolar disorder, leading to inappropriate treatments.

Effective treatments for severe premenstrual syndrome include hormonal therapies like transdermal estrogens and GnRH analogs, which help suppress ovulation and hormonal changes, highlighting the importance of understanding hormonal influences on women's mental health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personal view: Hormones and depression in women. Studd, J.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8011861/

Progesterone, reproduction, and psychiatric illness - PMC Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0091302224000402

Progestagens and progesterone receptor modulation This review highlights the effects of progestagens, including progesterone and synthetic progestins, on the brain, mood, stress, and cognition in females.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05282277

Examining the Effects of Estradiol on Neural and Molecular ... This proposal will examine the effects of estradiol administration on perimenopausal-onset (PO) anhedonia and psychosis symptoms as well as on brain function ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4330961/

Effects of Hormone Therapy on Cognition and Mood - PMC Results showed that all three preparations improved depressive symptoms in menopausal women relative to placebo. In a randomized, placebo-controlled, cross-over ...

5. frontiersin.org frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2025.1614087/full

a real-world study of the FDA adverse event reporting system This study aimed to systemically investigate the psychiatric risks associated with HRT in menopausal women using real-world data.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11294403/

Diagnostic and therapeutic use of oral micronized ... Micronized progesterone appears as a good therapeutic option because of its favorable safety profile, especially with regard to breast cancer ...

7. goodrx.com goodrx.com/prometrium/prometrium-side-effects?srsltid=AfmBOopn_DUEqB1hhFsiFzcm2Ca0SKgWyh0U6XG35fLLaNwylAwf6kho

7 Prometrium Side Effects You Should Know About These changes may include depression, anxiety, or irritability. You may also feel more sensitive or have more trouble controlling your emotions ...