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?

Purpose of this study: The purpose of this study is to learn more about how hormonal oral contraceptives affect brain processes and emotional wellbeing. Procedures: If participants agree to participate, the following will happen: 1. Eligibility visit (remote screening session) 2. If participants are eligible to participate in the study, they will be placed in one of two groups. If they are in the first group, they will be asked to take an oral contraception pill ("study drug") every day for 21 days. If they are in the second, they will take a placebo every day for 21 days. A placebo is a pill that looks like medicine but is not real and will have no medical effect on participants. Participants will not get to choose which group they are in, nor will they be told which group they are in. 3. During the three-week period in which participants will take either the study drug or placebo, they will be asked to complete daily check-in surveys on their computer or mobile device. 4. Participants will be asked to attend two additional visits over the course of about three weeks. At these visits, participants will be asked to undergo a urine drug screen, a blood draw, and a magnetic resonance imaging (MRI). They will also be asked to complete behavioral questionnaires.

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.

Is hormonal contraception generally safe for humans?

Hormonal contraceptives are widely used, but they can cause mood changes, including depression, in some people. Some studies suggest a link between contraceptive use and increased risk of depression and suicide, especially in adolescents, but the evidence is not conclusive. It's important to monitor mood changes when using these contraceptives. ^{1 2 3 4 5}

How does the drug Levonorgestrel/ethinyl estradiol differ from other treatments for depression?

Levonorgestrel/ethinyl estradiol is primarily a hormonal contraceptive, and its use for depression is unique because it involves hormones that can affect mood. Unlike traditional antidepressants, this drug's impact on depression may be linked to its hormonal components, which can sometimes worsen mood in some users, highlighting the need for careful consideration of its effects on mental health. ^{1 4 6 7 8}

What data supports the effectiveness of the drug Levonorgestrel/ethinyl estradiol for depression?

The research suggests that hormonal contraceptives, including those containing ethinyl estradiol, may be linked to mood changes and depression in some women. However, there is no clear consensus or strong evidence supporting their effectiveness for treating depression, and more research is needed to understand their impact on mood disorders. ^{1 4 7 9 10}

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

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]

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]

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]

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]

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]

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]

Citations

1. Australia pubmed.ncbi.nlm.nih.gov

Hormonal contraception and mood disorders. [2022]

2. England pubmed.ncbi.nlm.nih.gov

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

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

Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression. [2019]

4. Poland pubmed.ncbi.nlm.nih.gov

EFFECT OF HORMONAL CONTRACEPTION ON DEPRESSION IN WOMEN. [2023]

5. England pubmed.ncbi.nlm.nih.gov

A double-blind randomised placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones. [2022]

6. England 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. [2019]

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

New hormonal contraceptives: a comprehensive review of the literature. [2019]

8. Denmark pubmed.ncbi.nlm.nih.gov

[Hormonal contraceptive use, depression and suicide]. [2021]

9. France pubmed.ncbi.nlm.nih.gov

[New forms of hormonal contraception]. [2014]

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

Hormonal Contraception Use and Depression Among Women in Saudi Arabia. [2022]