Oral Contraceptives and Risk of Depression: A Review of Research

By: Savannah Whitney

Director’s Note: This week we feature a summary of research that assessed the relationship between oral contraceptive pills (OCPs) and depression. It was summarized by Savannah Whitney, a former FACTS elective participant. The population-based cohort study by Johansson et al [4] was published in 2023 in Epidemiology and Psychiatric Sciences. Their findings revealed notable differences between adolescent and adult users, women who took OCPs at any point (ever users) and those never treated with OCPs (never users). Key takeaways for elective student Whitney included the value of offering women the full spectrum of options for family planning, including fertility awareness-based methods (FABMs), which pose no risk of side effects.

Introduction

Over 150 million women worldwide use oral contraceptive pills. Women choose to discontinue oral contraceptive use for many reasons, including headaches, moodiness, weight changes, and sexual side effects. [1] Although depression is one of the reported side effects of OCPs, clinical studies have been unclear about degree of risk as well as differences in age groups.

“Women choose to discontinue oral contraceptive use for many reasons, including headaches, moodiness, weight changes, and sexual side effects.”

An observational study by Skovlund et al found an association between hormonal contraception and a higher risk of depression among all age groups, with the highest risk seen among adolescents. [2] In 2012, a Swedish study found adolescents on any type of hormonal contraception were at higher risk of depression. [3] Although randomized controlled trials (RCTs) have concluded OCP use has little to no effect on mood, many published RCTs did not consider previous OCP use as a confounding factor, disregarding the potential influence of healthy user bias. Women who experience mood disturbances while taking OCPs may discontinue use and are not as likely to resume use.

The 2023 study by Johansson et al titled, “Population-based cohort study of oral contraceptive use and risk of depression: a research review,” is summarized below. [4] Like many studies about this topic, the one reviewed here is observational, but it also aims to provide supporting evidence of a causal relationship between OCP use and depression by examining familial confounding in sister pairs.

Methodology

This study used medical information from the UK Biobank (UKB), a cohort of 500,000 residents of the United Kingdom aged 37-71 years. All female participants in the UKB were included in this study, for a total of 264,557 participants. Pertinent data included history of OCP use, age at first initiation and last discontinuation, and history of depression with age at depression diagnosis. The study also included analysis of the UKB mental health questionnaire to assess for lifetime depressive disorder in patients who experienced depressive symptoms but never sought treatment or received a diagnosis.

Researchers followed women from birth until the onset of depressive symptoms or age at the initial UKB assessment, whichever came first. Through statistical analysis, they estimated the risk of depression within 2 years of OCP initiation among all women and in age-stratified groups: “adolescent” if OCPs were initiated before age 20, and “adult” if started at age 20 or older. They also determined the lifetime risk of depression.

Potential confounding variables were explored, including postpartum depression, population stratification, medical indications for OCP use, and other known psychiatric disorders. Finally, a subcohort comprising 7,354 female sibling pairs was analyzed to detect evidence of a causal relationship between OCP use and depression versus familial confounding.

Results

Of the 264,557 women included in the UKB, 80.6% were ever users of OCPs. During follow-up, a total of 24,750 women received a diagnosis of depression.

Within the first 2 years of OCP use, women had a 79% increased rate of depression compared to never users. In adolescents, this rate was even higher, at 95%, whereas the adult cohort had a 74% increased rate. Lifetime risk of depression was slightly higher, at 5%, but not as pronounced as the risk close to initiation of OCPs.

“Within the first 2 years of OCP use, women had a 79% increased rate of depression compared to never users. In adolescents, this rate was even higher, at 95%.”

In the mental health questionnaire, 44,605 women endorsed one or more core depressive symptoms. In this cohort, OCP initiation was associated with a 100% increased rate of depressive symptoms within the first 2 years after initiation; adolescent initiators had a 130% increased rate, and adult initiators had a 92% increased rate. Ever users had a 27% increased rate in this cohort compared to never users.

OCP use longer than 2 years did not correlate with an increased rate of depression. However, recent and previous OCP users had increased rates of depression compared to never users (17% and 7%, respectively). Exclusions of all previously mentioned potential confounding factors revealed hazard ratios similar to analysis of the general population. Sibling analysis showed a sibling’s OCP use was positively associated with a depression diagnosis; adjusting for co-sibling’s OCP use showed the same association, indicating OCP use does increase the risk of depression.

Discussion

This research is relevant to women’s health and family planning, as it pertains to side effects of one of the most used methods of family planning. Fertility awareness-based methods (FABMs) are a safe and effective family planning option for women, especially those who wish to avoid potential side effects like depression. Many women are prescribed OCPs to address conditions such as dysmenorrhea, menstrual irregularity, and abnormal uterine bleeding, all of which can be investigated and treated with the help of FABMs. [5]

“Fertility awareness-based methods are a safe and effective family planning option for women, especially those who wish to avoid potential side effects like depression.”

One limitation of this study was its inability to evaluate types of OCP use (combined versus progestin-only) due to lack of information. It could be helpful to compare results with the 2012 Swedish study in which progestin-only forms of oral contraception were associated with increased antidepressant use in adults, while combined forms exhibited a protective effect. [3] Also, most UKB participants identified as White Europeans with higher socioeconomic status, which raises questions of the generalizability of results to a more ethnically diverse population. Furthermore, UKB participants were described as healthy women compared to the general UK population. Given these limitations, a similar study conducted on a more diverse population in both ethnicity and overall health would be beneficial.

Although this study was published in 2023, the data analyzed was collected from 2006 to 2010; further study is needed with a present-day population. It would also be advantageous to compare different forms of hormonal contraception, including pills, patches, rings, injections, implants, and intrauterine devices (IUDs), to determine if route and location of administration affect the risk of depression.

References

[1] Westhoff CL, Heartwell S, Edwards S, et al. Oral contraceptive discontinuation: Do side effects matter? Am J Obstet Gynecol. 2007 Apr; 196(4):412.e1-412.e7.
[2] Skovlund CW, Mørch LS, Kessing LV, et al. Association of hormonal contraception with depression. JAMA Psychiatry 2016; 73(11), 1154-1162.
[3] Lindberg M, Foldemo A, Josefsson A, et al. Differences in prescription rates and odds ratios of antidepressant drugs in relation to individual hormonal contraceptives: A nationwide population-based study with age-specific analyses. The European Journal of Contraception & Reproductive Health Care 2012; 17(2), 106-118.
[4] Johansson T, Vinther Larsen S, Bui M, et al. Population-based cohort study of oral contraceptive use and risk of depression. Epidemiol Psychiatr Sci 2023; 32: e39.
[5] Duane M, Stanford JB, Porucznik CA, et al. Fertility awareness-based methods for women’s health and family planning. Front Med (Lausanne) 2022; 9:858977.

ABOUT THE AUTHOR

Savannah Whitney

Savannah Whitney is a fourth-year medical student at Liberty University College of Osteopathic Medicine in Lynchburg, VA. She completed her undergraduate education at Liberty University in Lynchburg, VA. She will soon begin family medicine residency at Cahaba FMR in Centreville, AL. She is interested in family medicine with a focus on women’s health, breastfeeding medicine, and mental health. She enrolled in the FACTS elective to learn more about FABMs to use them as tools for her future patients, giving them options for both family planning and general women’s health.