Transdermal Estradiol for Mental Illness

(PEEPS Trial)

Overseen by Gabriel Dichter, PhD

Age: 18 - 65

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

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

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This proposal will examine the effects of estradiol administration on perimenopausal-onset (PO) anhedonia and psychosis symptoms as well as on brain function using simultaneous positron emission tomography and functional magnetic resonance imaging (PET-MR).

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 data supports the effectiveness of the drug Transdermal Estradiol for Mental Illness?

The research highlights that micronized progesterone, a component of the treatment, is effective in hormone replacement therapy and is well-tolerated, suggesting it may have beneficial effects when combined with other components like estradiol. ^{1 2 3 4 5}

Is transdermal estradiol generally safe for humans?

Micronized progesterone, often used with estradiol, is considered safe and well-tolerated, with mild side effects like drowsiness. It has been used widely in Europe and is recommended for hormone therapy, showing no adverse effects on blood pressure or cholesterol. ^{1 2 3 4 6}

How does the drug Transdermal Estradiol with Micronized Progesterone differ from other treatments for mental illness?

This drug is unique because it uses hormones applied through the skin to address mental health issues related to hormonal changes, such as premenstrual and postnatal depression, which are not typically treated with hormones. It offers an alternative to traditional antidepressants by targeting the hormonal causes of depression, providing a novel approach for women whose depression is linked to hormonal fluctuations. ^{1 7 8 9 10}

Research Team

Crystal E Schiller, PhD

Principal Investigator

UNC School of Medicine - Department of Psychiatry

Gabriel Dichter, PhD

Principal Investigator

UNC School of Medicine - CIDD

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Matching Placebo Patch (Drug)
• Micronized Progesterone (Hormone Therapy)
• Raclopride C11 (Drug)
• Transdermal Estradiol (Hormone Therapy)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Oral micronized progesterone. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Micronized progesterone: clinical indications and comparison with current treatments. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Micronized progesterone: a new therapeutic option. [2013]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Systematic review of the clinical efficacy of vaginal progesterone for luteal phase support in assisted reproductive technology cycles. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. United States 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. [2023]

8. England pubmed.ncbi.nlm.nih.gov

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

9. United States pubmed.ncbi.nlm.nih.gov

Hormone therapy for reproductive depression in women. [2022]

10. England pubmed.ncbi.nlm.nih.gov

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