Hormone Withdrawal for Depression

(PEAR Trial)

Overseen By Lindsey Cunnane

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Exogenous hormones

Disqualifiers: Pregnancy, BMI <18 or >29, 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: 7

75 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that participants stop taking any form of hormonal medications at least one month before the study. If you are on other medications, the protocol does not specify, so it's best to discuss with the trial coordinators.

What data supports the effectiveness of the drug Progesterone and Estradiol Patch for treating depression?

Research suggests that hormonal changes can influence depression in women, and treatments like transdermal estrogens (Estradiol Patch) have been effective in managing depression related to hormonal fluctuations, such as premenstrual and postnatal depression. This indicates that the use of hormones like estradiol may help alleviate depression symptoms in women experiencing hormonal changes. ^{1 2 3 4 5}

Is hormone withdrawal treatment generally safe for humans?

Research on transdermal hormone patches, like those containing estradiol and norelgestromin, shows they are generally well tolerated, though some people may experience skin reactions or menstrual disturbances like breakthrough bleeding. In a tropical climate, one type of estradiol patch caused skin reactions due to its alcohol carrier, but another type was better tolerated. ^{6 7 8 9 10}

How does the drug Progesterone, Transdermal estradiol differ from other treatments for depression?

This drug is unique because it targets hormonal fluctuations that can lead to depression, particularly in women experiencing premenstrual, postnatal, or perimenopausal depression. Unlike standard antidepressants, it uses hormones like progesterone and estradiol to stabilize mood by addressing the underlying hormonal changes. ^{1 2 11 12 13}

What is the purpose of this trial?

The goal of this clinical trial is to learn how hormonal changes over the menstrual cycle affect mood symptoms in reproductive-aged women with depression that worsens during the premenstrual period. The main questions it aims to answer are: --How do fluctuations in estradiol and progesterone across the menstrual cycle affect the ability to experience pleasure and the neural sensitivity to reward in hormone-sensitive, depressed women? And consequently, how does stabilizing the luteal phase decline in estrogen and progesterone (using estradiol patches and progesterone pills) affect these changes? Participants will: * Receive hormones followed by placebo, or vice versa, for a total of four weeks across three menstrual cycles * Complete daily mood ratings * Collect home urine samples for hormone testing * Complete five biobehavioral testing sessions during which neural responses are recorded (via electroencephalography, or EEG) during an acute stress task and computer tasks

Research Team

Chris Sikes-Keilp, MD

Principal Investigator

University of North Carolina, Chapel Hill

Eligibility Criteria

This trial is for reproductive-aged women who experience depression that gets worse before their period. They should be generally healthy and not currently pregnant or breastfeeding. Participants must not be on hormonal treatments, have a history of hormone-sensitive cancers, or any serious psychiatric conditions other than depression.

Inclusion Criteria

A previous diagnosis of major depressive disorder, with self-reported premenstrual worsening of symptoms

My menstrual cycles are regularly between 25 and 35 days.

English-speaking

Exclusion Criteria

BMI less than 18 or greater than 29

Current cigarette smoking

A history of mania, psychosis, or substance use disorder

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phone screening and 1 in-person enrollment visit

Prospective Assessment

Participants complete daily mood ratings for one menstrual cycle using EMA to determine eligibility for the intervention phase

4 weeks

Daily virtual assessments

Lead-in Phase

Participants continue daily EMA and complete a single in-person visit for randomization and initial testing

4 weeks

1 in-person visit

Intervention Phase

Participants receive hormone treatment or placebo in a crossover design across three menstrual cycles, with biobehavioral testing sessions

12 weeks

5 biobehavioral testing sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Progesterone
• Transdermal estradiol

Trial Overview The study tests how stabilizing hormones during the menstrual cycle affects mood in depressed women. It compares the effects of estradiol patches and progesterone pills against placebos over three cycles, measuring pleasure response and brain activity related to reward.

Participant Groups

Group I: Placebo, then Estradiol+Progesterone Experimental Treatment 4 Interventions

Two weeks of luteal phase transdermal/oral placebo during the first intervention cycle, followed by a one cycle washout, followed by two weeks of luteal phase transdermal estradiol (0.1 mg/day)+oral progesterone (200 mg/day)

Group II: Estradiol+Progesterone, then Placebo Experimental Treatment 4 Interventions

Two weeks of luteal phase transdermal estradiol (0.1mg/day)+oral progesterone (200 mg/day) during the first intervention cycle, followed by a one cycle washout, followed by two weeks of luteal phase transdermal/oral placebo

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

Approved in United States as Progesterone for:

• Contraception
• Menstrual disorders
• Endometriosis
• Infertility

Approved in European Union as Progesterone for:

• Contraception
• Hormone replacement therapy
• Menstrual disorders
• Endometriosis

Approved in Canada as Progesterone for:

• Contraception
• Menstrual disorders
• Endometriosis
• Infertility

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

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]

Withdrawal from high levels of progesterone in female DBA/2J mice led to increased immobility in the forced swim test, indicating depressive-like behavior, particularly after 3 days of withdrawal.

Treatment with the 5alpha-reductase inhibitor finasteride, which reduces levels of the neurosteroid allopregnanolone, also resulted in increased immobility, suggesting that lower allopregnanolone levels may contribute to depressive symptoms associated with progesterone withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility. Beckley, EH., Finn, DA.[2018]

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 contraception, particularly older oral contraceptive pills containing ethinylestradiol, can trigger or worsen depression in some individuals due to the type and amount of progestogen they contain.

Newer oral contraceptive pills that use physiological forms of estrogen may have a lower risk of causing mood problems, suggesting that clinicians should carefully evaluate the relationship between hormonal contraception use and mood changes in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormonal contraception and mood disorders. Mu, E., Kulkarni, J.[2022]

In a study involving nine postmenopausal women, the combination of cyclical conjugated estrogen (CEE) with medroxyprogesterone acetate (MPA) resulted in significantly less vaginal bleeding and spotting compared to CEE with low dosage norgestrel (NG), with 97% of cycles free of bleeding in the MPA group versus 85% in the NG group.

All hormonal regimens, including CEE alone, significantly improved mood and reduced postmenopausal symptoms, indicating that while MPA is more effective in reducing bleeding, both treatments are beneficial for overall symptom relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact on postmenopausal symptoms of adding continuous C-21 versus C-19 progestin to estrogen. Wolfe, BM., Koval, JJ., Nisker, JA.[2019]

A clinical trial evaluated two different 50 microgram estradiol patches for estrogen replacement therapy, revealing that the first patch (patch A) was discontinued due to a high rate of skin reactions caused by its alcohol carrier in a humid climate.

The second patch (patch B) was tested on 21 female subjects and was found to be equally effective as patch A, but with fewer skin reactions and better adherence over a 6-month period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of two types of estradiol-releasing skin patches for menopausal patients in a tropical climate. McCarthy, T., Dramusic, V., Ratnam, S.[2019]

Transdermal ethinylestradiol/norelgestromin is an effective hormonal contraceptive that works primarily by inhibiting ovulation and altering the endometrium and cervical mucus, with efficacy comparable to oral contraceptives in large randomized studies.

Users of the transdermal patch demonstrated higher rates of perfect compliance compared to those using oral contraceptives, and the patch was generally well tolerated, with low discontinuation rates due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal ethinylestradiol/norelgestromin: a review of its use in hormonal contraception. Goa, KL., Warner, GT., Easthope, SE.[2019]

In a study of 392 Canadian women over 9 cycles, 60.6% preferred the transdermal contraceptive patch over their previous contraceptive method, with 91% expressing satisfaction with the patch.

The patch demonstrated high compliance rates (88%) and while 49% experienced mild application site reactions, overall satisfaction and preference for the patch were significantly high due to its convenience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preference for and satisfaction of Canadian women with the transdermal contraceptive patch versus previous contraceptive method: an open-label, multicentre study. Weisberg, F., Bouchard, C., Moreau, M., et al.[2019]

Both the estradiol-releasing vaginal ring combined with oral progestin and the transdermal patch with a levonorgestrel-releasing intrauterine device effectively relieved urogenital symptoms in postmenopausal women, based on a study of 56 participants over one year.

Neither treatment led to endometrial proliferation, indicating that both methods are safe for managing hormone replacement therapy without increasing the risk of abnormal endometrial changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative study of the effects of an estradiol-releasing vaginal ring combined with an oral gestagen versus transdermal estrogen combined with a levonorgestrel-releasing IUD: clinical findings and endometrial response. Kalogirou, D., Antoniou, G., Karakitsos, P., et al.[2016]

The novel transdermal contraceptive patch containing norelgestromin and ethinylestradiol maintains effective hormone levels without the peaks associated with oral contraceptives, ensuring consistent efficacy and cycle control.

User compliance is significantly higher with the weekly patch compared to daily oral contraceptives, and the patch adheres reliably under various conditions such as heat and humidity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A transdermal form of combined hormonal contraceptives (EVRA)]. Fanta, M.[2019]

Neurosteroids DHEAS and pregnenolone sulfate significantly reduced immobility time in the forced swim test in mice, indicating potential antidepressant-like effects without affecting general activity levels.

The antidepressant effects of DHEAS and pregnenolone sulfate appear to involve delta receptors, as their effects were blocked by a delta receptor antagonist, suggesting a specific mechanism of action for these neurosteroids in treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sigma (sigma1) receptor mediated anti-depressant-like effects of neurosteroids in the Porsolt forced swim test. Reddy, DS., Kaur, G., Kulkarni, SK.[2019]

In a study using mice, the administration of progesterone receptor antagonists mifepristone and CDB-4124 after progesterone priming led to increased depression-like behavior, as measured by immobility in the forced swim test, indicating a link between decreased progesterone receptor activity and depression.

These results support the idea that progesterone withdrawal may play a role in premenstrual syndrome and postpartum depression, highlighting the importance of progesterone receptors in mood regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability. Beckley, EH., Scibelli, AC., Finn, DA.[2021]

Brexanolone (ZULRESSO™) is an intravenously administered treatment specifically designed for postpartum depression (PPD), acting as a positive allosteric modulator of GABAA receptors, which helps enhance inhibitory neurotransmission in the brain.

Approved in March 2019, brexanolone is a formulation that combines allopregnanolone, a natural neurosteroid, with a solubilizing agent, marking a significant advancement in the treatment options available for adult women suffering from PPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brexanolone: First Global Approval. Scott, LJ.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility. [2018]

3. England pubmed.ncbi.nlm.nih.gov

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

4. Australia pubmed.ncbi.nlm.nih.gov

Hormonal contraception and mood disorders. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

Impact on postmenopausal symptoms of adding continuous C-21 versus C-19 progestin to estrogen. [2019]

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

Use of two types of estradiol-releasing skin patches for menopausal patients in a tropical climate. [2019]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Transdermal ethinylestradiol/norelgestromin: a review of its use in hormonal contraception. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Preference for and satisfaction of Canadian women with the transdermal contraceptive patch versus previous contraceptive method: an open-label, multicentre study. [2019]

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

A comparative study of the effects of an estradiol-releasing vaginal ring combined with an oral gestagen versus transdermal estrogen combined with a levonorgestrel-releasing IUD: clinical findings and endometrial response. [2016]

10. Czech Republic pubmed.ncbi.nlm.nih.gov

[A transdermal form of combined hormonal contraceptives (EVRA)]. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Sigma (sigma1) receptor mediated anti-depressant-like effects of neurosteroids in the Porsolt forced swim test. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability. [2021]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Brexanolone: First Global Approval. [2020]