Feeling depressed? Check your birth control pills!Ruslan Dorfman, PhD, MBA
Updated September 13, 2022
Changes in mood have been reported for decades by women on hormonal birth control. A large-scale study now confirms a link between hormonal birth control and depression.
Health data collected from over one million Danish women aged 15 to 34 for a period of 14 years was analyzed by researchers at the University of Copenhagen. The study utilized Denmark’s nationalized health information system and is the first of its kind.
Key findings include:
- Women on birth control pills were 23 percent more at risk of developing depression than women not taking the pill.
- The risk associated with progestin-only pills was even higher at 34 percent.
- Women using progestin-releasing IUDs had a 40 percent greater risk.
- Women using the patch had double the risk.
- Other methods, such as the vaginal ring, had a 60 percent higher risk than non-users.
The most at-risk group was adolescents aged 15 to 19. In addition, the first six months of starting hormonal birth control had the highest incidence of depression overall.
Why some women become depressed and others do not remains unknown.
Are there genetic reasons why hormonal birth control affects women differently?
Hormonal birth control contains either a combination of synthetic estrogen and progesterone (different pills vary in the type of synthetic progesterone used) or a progestin-only formulation. Once inside the body, the liver changes the chemical structure of these synthetic hormones to make them easier to excrete. Because of this process, a daily dose is required for the pill to continue to tip the hormonal balance enough to prevent ovulation.
The liver enzyme that works to remove synthetic estrogen is called Cytochrome P450 3A4 or CYP3A4. Due to genetic differences, some individuals have a fast-acting CYP3A4, and others have a version that works much more slowly. People with slow CYP3A4 are called poor metabolizers, people with fast CYP3A4 are called ultra-rapid metabolizers, and people with normal functioning CYP3A4 are intermediate metabolizers.
These differences in liver enzyme function mean that some women taking birth control may have higher circulating levels of hormones than others. High hormone levels in the body can cause bloating, fatigue, weight gain, insomnia, and mood changes.
Removing progestin-releasing IUDs or switching continuous hormone-delivery contraceptives to non-hormonal IUDs was noted to reverse depression symptoms and fatigue.
Genetics can cause some women to develop serious side effects
All hormonal birth control carries the risk of developing life-threatening side effects, such as blood clots. And some women are more susceptible to developing blood clots than others. These women often have a super-clotting gene mutation called Factor V Leiden. One in five Caucasian women carry Factor V Leiden, and most don’t know they have it. Carriers of Factor V Leiden are 35 times more likely to develop a blood clot from using hormonal birth control. In addition, birth control pills based on the drospirenone formulation (the progesterone component), such as Yasmin and Yaz, have an even higher risk. A study led by Dr. Ojvind Lidegaard of Copenhagen University found that women taking Yaz or Yasmin had a 64 percent higher risk of blood clots than women taking other types.
These findings demonstrate that hormonal birth control – drugs so ubiquitous they are often referred to only as “The Pill” – are not a one-size-fits-all prescription.
Genetic testing can help women considering hormonal birth control make a more informed decision
Doctors use family history, age, and whether or not someone smokes to screen for women who may develop serious complications from hormonal birth control. However, rarely is a simple genetic test administered to identify Factor V Leiden carriers.
Genetic testing can also determine how rapidly liver enzymes work to remove synthetic hormones. The Pillcheck pharmacogenetic test looks for genetic variations in CYP3A4 and can help predict side effects to your prescription medications.
Women carrying Factor V variations or slow metabolizers of synthetic steroid hormones may choose non-hormonal contraceptives such as copper intrauterine devices (IUD).
- See how Pillcheck helps you and your healthcare provider choose the right mental health medications (video)
- Pillcheck for mental health
- Reimbursement for pharmacogenetic testing
- How accurate is pharmacogenetic testing?
Charlotte Wessel Skovlund, Lina Steinrud Mørch, Lars Vedel Kessing, and Øjvind Lidegaard, Association of Hormonal Contraception with Depression JAMA Psychiatry 2016;73(11):1154-1162.
Øjvind Lidegaard, Ellen Løkkegaard, Anne Louise Svendsen, and Carsten Agger, Hormonal contraception and risk of venous thromboembolism: national follow-up study BMJ. 2009;339:b2890.
Judy L Kujovich, Factor V Leiden Thrombophilia Gene Reviews. Oregon Health and Science University. March 9, 2010.
Roland N et al., Association Between Doses of Levonorgestrel Intrauterine Systems and Subsequent Use of Psychotropic Drugs in France JAMA. Published online December 22, 2022. doi:10.1001/jama.2022.21471.
Elin Stenhammar E et al., Levonorgestrel intrauterine device and depression: A Swedish register-based cohort study Int J Psychophysiol. 2023 Aug 21;193:112230.