Hormonal Contraceptives for Depression

(CHARM Trial)

Overseen By Andrew M Novick, MD PhD

Age: 18+

Sex: Female

Trial Phase: Phase 4

Sponsor: University of Colorado, Denver

Must not be taking: Hormonal contraceptives, Psychotropic medications

Disqualifiers: Psychotic disorders, Hypertension, Malignancy, others

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 3 weeks

144 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how hormonal birth control pills, specifically Levonorgestrel/ethinyl estradiol, might affect brain processes and emotional well-being. Participants will take either the actual birth control pill or a placebo (a pill that looks real but isn’t) for 21 days, without knowing which one they receive. They will complete daily check-ins and attend study visits for tests like MRIs and questionnaires. The trial seeks individuals assigned female at birth who have regular menstrual cycles, are in good health, and are willing to use non-hormonal birth control during the study. As a Phase 4 trial, this research aims to understand how this FDA-approved and effective treatment benefits more patients.

Will I have to stop taking my current medications?

The trial requires that participants do not currently use hormonal contraceptives or medications that affect sex hormones. Additionally, participants cannot be on psychotropic medications. If you are taking these types of medications, you may need to stop them to participate.

What is the safety track record for Levonorgestrel/ethinyl estradiol?

Research shows that the combination of levonorgestrel and ethinyl estradiol, found in many birth control pills, is generally safe for most people. The FDA has approved this treatment to prevent pregnancy, indicating its safety when used as directed.

However, some people might experience side effects. Common ones include nausea, headaches, and mood changes. There is also a chance of increased blood pressure, so monitoring is important for those taking the medication. Serious side effects are rare but can include blood clots, especially in smokers or those with a history of clotting problems.

Overall, many people worldwide have used this treatment, and extensive research supports its safety for approved uses. Prospective trial participants should discuss any personal health concerns with a healthcare provider. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about using levonorgestrel/ethinyl estradiol for depression because it offers a unique hormonal approach to managing mood disorders. Unlike typical antidepressants that target neurotransmitters like serotonin or dopamine, this treatment combines a progestin (levonorgestrel) and an estrogen (ethinyl estradiol) to potentially influence mood through hormonal regulation. This mechanism could provide an alternative for those who don't respond well to traditional antidepressants, offering new hope for managing depressive symptoms.

What evidence suggests that this treatment might be an effective treatment for depression?

In this trial, participants will receive either a birth control pill containing levonorgestrel and ethinyl estradiol or a placebo. Research has shown that birth control pills with these ingredients might improve mood for some women. These pills can reduce premenstrual symptoms, such as mood swings and feelings of sadness. However, some individuals might experience worsened mood or increased depression as a side effect. While primarily used to prevent pregnancy, the pills' effect on mood is under study. Overall, evidence suggests mixed results, with some women experiencing improvement and others not. ^{1 6 7 8 9}

Who Is on the Research Team?

Andrew M Novick, MD PhD

Principal Investigator

University of Colorado Denver Anschutz Medical Campus

Are You a Good Fit for This Trial?

The CHARM Study is for right-handed females aged 18+, with regular menstrual cycles and good health. Participants must not smoke, have a history of severe disorders, or use hormonal contraceptives recently. They should be willing to avoid intercourse or use non-hormonal contraception during the study.

Inclusion Criteria

In generally good health per self-report. Those with a chronic medical condition may participate at the discretion of the principal investigator if the condition is stable

For those wishing to complete study screening session remotely: access to a reliable internet connection, computer to complete electronic consent and a private space to complete the session

Access to a reliable internet connection or cell phone data to complete daily questionnaires

Exclusion Criteria

Metal in body unsafe for magnetic resonance imaging

I have irregular menstrual cycles.

Presence or history of severe or unstable physical, neurological (per health history interview) or psychiatric disorders (assessed by Miniature International Neuropsychiatric Interview (MINI) but per Diagnostic and Statistical Manual of Mental Disorders - fifth edition (DSM-V) criteria, and the discretion of the principal investigator)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (remote)

Treatment

Participants take either an oral contraceptive or placebo daily for 21 days and complete daily check-in surveys

3 weeks

2 visits (in-person)

Follow-up

Participants are monitored for changes in sexual function, anhedonia, and neural activity after treatment

3 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Levonorgestrel/ethinyl estradiol
• Placebo

Trial Overview This trial tests how oral contraceptives affect brain activity and mood. Participants will take either an oral contraceptive pill or a placebo daily for three weeks while completing surveys and undergoing MRI scans, urine tests, blood draws, and questionnaires.

How Is the Trial Designed?

Group I: Levonorgestrel/ethinyl estradiol Experimental Treatment 1 Intervention

Levonorgestrel 0.15mg/ethinyl estradiol 0.03mg - once a day for 21 days

Group II: Placebo Placebo Group 1 Intervention

Placebo once a day for 21 days

Levonorgestrel/ethinyl estradiol is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Levonorgestrel/ethinyl estradiol for:

• Contraception
• Menstrual regulation
• Premenstrual dysphoric disorder

Approved in United States as Levonorgestrel/ethinyl estradiol for:

• Contraception
• Premenstrual dysphoric disorder
• Acne vulgaris

Approved in Canada as Levonorgestrel/ethinyl estradiol for:

• Contraception
• Menstrual regulation
• Premenstrual dysphoric disorder

Approved in Japan as Levonorgestrel/ethinyl estradiol for:

• Contraception
• Menstrual regulation

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Published Research Related to This Trial

New hormonal contraceptive methods, such as the norelgestromin-ethinyl estradiol patch and etonogestrel-ethinyl estradiol vaginal ring, aim to improve compliance and reduce side effects compared to traditional oral contraceptives, which are taken daily.

Despite their different administration methods, these new contraceptives maintain similar efficacy and adverse effect profiles to oral contraceptives, making them viable alternatives for women who may struggle with daily pill adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New hormonal contraceptives: a comprehensive review of the literature. Forinash, AB., Evans, SL.[2019]

Hormonal contraception is linked to serious mood disorders, including depression and increased risk of suicide attempts, particularly among adolescents, highlighting a need for caution in prescribing these methods.

All types of hormonal contraceptives appear to affect women's mood, suggesting that healthcare providers should pay closer attention to the psychological side effects when recommending these products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hormonal contraceptive use, depression and suicide]. Bchtawi, AK., Issa, BSM., Jørgensen, EF., et al.[2021]

Three new hormonal contraceptives have been identified that offer high effectiveness with lower dosages, improving safety and tolerance: a low-dose combination of ethinylestradiol and gestodene, a progestogen-only subcutaneous implant with etonogestrel, and a levonorgestrel-releasing intrauterine system.

These contraceptive options allow for better personalization of therapy, catering to individual needs and preferences in contraception.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New forms of hormonal contraception]. Gaspard, U., Buicu, C., van den Brûle, F.[2014]

Postnatal administration of norethisterone enanthate is linked to higher depression scores in new mothers compared to a placebo, indicating a potential risk for postnatal depression.

The use of norethisterone enanthate also leads to lower levels of key hormones like 17beta-oestradiol and progesterone, suggesting that hormonal suppression may contribute to the increased risk of depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind randomised placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones. Lawrie, TA., Hofmeyr, GJ., De Jager, M., et al.[2022]

In a study involving 784 menstrual cycles from healthy women, the monophasic oral contraceptive regimen (LNG/EE) resulted in significantly better menstrual cycle control compared to the triphasic regimen (NET/EE), with 69.9% of cycles classified as normal in the LNG/EE group versus 54.4% in the NET/EE group by cycle 4.

Both contraceptive regimens had similar rates of treatment-emergent adverse events, indicating that the monophasic LNG/EE is not only more effective in cycle control but also maintains a comparable safety profile to the multiphasic NET/EE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of cycle control with monophasic levonorgestrel/ethinylestradiol 100 micrograms/20 micrograms versus triphasic norethindrone/ethinylestradiol 500-750-1000 micrograms/35 micrograms: a multicenter, randomized, open-label study. Chavez, A., DelConte, A.[2019]

Oral contraceptives are the most popular method of pregnancy prevention in Poland, but mood changes, including depression, are common reasons for discontinuation among young women.

There is ongoing debate in the scientific community regarding the relationship between hormonal contraceptives and the risk of depression and antidepressant use, highlighting the need for large-scale studies to clarify these potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EFFECT OF HORMONAL CONTRACEPTION ON DEPRESSION IN WOMEN. Ból, K., Brudzińska, A., Wybrańczyk, Ł., et al.[2023]

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 of 4853 women in Saudi Arabia, 29% reported moderate to severe depression, with higher rates observed among those using hormonal contraceptives compared to non-hormonal methods.

Factors such as psychiatric disorders, medical illnesses, substance use, and the use of depressogenic medications were linked to increased depression risk in both groups of contraceptive users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormonal Contraception Use and Depression Among Women in Saudi Arabia. Albawardi, I., Alqahtani, AH., Aljamea, DA., et al.[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]

Women with major depressive disorder (MDD) using combined estrogen-progestin contraceptives reported significantly lower depression severity and better physical functioning compared to those not using hormonal treatment, based on data from the STAR*D study involving 1,338 female outpatients.

In contrast, women using progestin-only contraceptives experienced more general medical comorbidities and worse physical functioning, highlighting the differing impacts of hormonal contraceptives on mood and health in women with MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression. Young, EA., Kornstein, SG., Harvey, AT., et al.[2019]

Citations

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Hormonal contraception and mood disorders - PMC Hormonal contraception is known to precipitate or perpetuate depression in some patients. The link between oral contraceptive pills and ...

2. mayoclinic.org mayoclinic.org/drugs-supplements/levonorgestrel-and-ethinyl-estradiol-oral-route/description/drg-20406441

Levonorgestrel and ethinyl estradiol (oral route) Levonorgestrel and ethinyl estradiol combination is used to prevent pregnancy. It works by stopping a woman's egg from fully developing each month.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0002937821007742

Efficacy of combined oral contraceptives for depressive ... Combined oral contraceptives may improve overall premenstrual symptomatology in women with premenstrual syndrome or premenstrual dysphoric disorder, but not ...

4. goodrx.com goodrx.com/portia/what-is?srsltid=AfmBOopFrS51rgrHcEZLs7Qn8uRrP2pakGH5_G8gv98L8WCKANoLGEfB

Portia: Uses, Side Effects, Dosage & Reviews Portia is a combined contraceptive that contains two hormones: ethinyl estradiol (an estrogen) and levonorgestrel (a progestin). Both hormones work together to ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2971737/

New low-dose, extended-cycle pills with levonorgestrel ... This is a review of trends in the development of various birth controls pills and includes data from phase III clinical trials for this new ...

6. goodrx.com goodrx.com/vienva/what-is?srsltid=AfmBOoox44E4FwxqQYnEpwSVwMTIhMEalO3oqxstsx3n118ewFQPSFCW

Vienva: Uses, Side Effects, Dosage & Reviews Learn about Vienva usage and dosing. Read the latest news and reviews about the drug as well as potential side effects and popular alternatives.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/020683s016lbl.pdf

1 ALESSE® 28 Tablets (levonorgestrel and ethinyl estradiol ... The FDA has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ...

8. healthy.kaiserpermanente.org healthy.kaiserpermanente.org/health-wellness/drug-encyclopedia/drug.levonorgestrel-ethinyl-estradiol-0-1-mg-20-mcg-tablet.176156

levonorgestrel-ethinyl estradiol 0.1 mg-20 mcg tablet This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high. Tell your doctor right away if ...

9. goodrx.com goodrx.com/portia/what-is?srsltid=AfmBOoo7csBpUo-PC3FhJkh7_uw6UWjE0b4be8NMKS56GHlVSigztpKJ

Portia: Uses, Side Effects, Dosage & Reviews Learn about Portia usage and dosing. Read the latest news and reviews about the drug as well as potential side effects and popular alternatives.