Do Oral Contraceptives Increase Depression Risk?

Oral contraceptive (OC) use has been linked to increased depression risk, especially within the first 2 years following initiation, new research shows.

In addition, OC use in adolescence has been tied to an increased risk for depression later in life. However, some experts believe the study's methodology may be flawed.

Investigators tracked more than 250,000 women from birth to menopause, gathering information about their use of combined contraceptive pills (progesterone and estrogen), the timing of the initial depression diagnosis, and the onset of depressive symptoms that were not formally diagnosed.

Women who began using these OCs before or at the age of 20 experienced a 130% higher incidence of depressive symptoms, whereas adult users saw a 92% increase. But the higher occurrence of depression tended to decline after the first 2 years of use, except in teenagers, who maintained an increased incidence of depression even after discontinuation.

This effect remained, even after analysis of potential familial confounding.

"Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life," write Therese Johansson, of Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden, and colleagues.

The study was published online June 12 in Epidemiology and Psychiatric Sciences.

Inconsistent Findings

Previous studies suggest an association between adolescent use of hormonal contraceptives (HCs) and increased depression risk, but it's "less clear" whether these effects are similar in adults, the authors write. Randomized clinical trials have "shown little or no effect" of HCs on mood. However, most of these studies didn't consider previous use of HC.

The researchers wanted to estimate the incidence rate of depression associated with first initiation of OC use as well as the lifetime risk associated with use.

They studied 264,557 female participants in the UK Biobank (aged 37-71 years), collecting data from questionnaires, interviews, physical health measures, biological samples, imaging, and linked health records.

Most participants taking OCs had initiated use during the 1970s/early 1980s when second-generation OCs were predominantly used, consisting of levonorgestrel and ethinyl estradiol.

The researchers conducted a secondary outcome analysis on women who completed the UK Biobank Mental Health Questionnaire (MHQ) to evaluate depressive symptoms.

They estimated the associated risk for depression within 2 years after starting OCs in all women, as well as in groups stratified by age at initiation: before age 20 (adolescents) and age 20 and older (adults). In addition, the investigators estimated the lifetime risk for depression.

Time-dependent analysis compared the effect of OC use at initiation to the effect during the remaining years of use in recent and previous users.

They analyzed a subcohort of female siblings, utilizing "Inference about Causation from Examination of Familial Confounding," defined by the authors as a "regression-based approach for determining causality through the use of paired observational data collected form related individuals."

Adolescents at Highest Risk

Of the participants, 80.6% had used OCs at some point.

The first 2 years of use were associated with a higher rate of depression among users, compared to never-users (HR, 1.79; 95% CI, 1.63 - 1.96). Although the risk became less pronounced after that, ever-use was still associated with increased lifetime risk for depression (HR, 1.05; 95% CI, 1.01 - 1.09).

Adolescents and adult OC users both experienced higher rates of depression during the first 2 years, with a more marked effect in adolescents than in adults (HR, 1.95; 95% CI, 1.64 - 2.32; and HR, 1.74; 95% CI, 1.54 - 1.95, respectively).

Previous users of OCs had a higher lifetime risk for depression, compared to never-users (HR, 1.05; 95% CI, 1.01 - 1.09).

Of the subcohort of women who completed the MHQ (n = 82,232), about half reported experiencing at least one of the core depressive symptoms.

OC initiation was associated with an increased risk for depressive symptoms during the first 2 years in ever- vs never-users (HR, 2.00; 95% CI, 1.91 - 2.10).

Those who began using OCs during adolescence had a dramatically higher rate of depressive symptoms compared to never-users (HR, 2.30; 95% CI, 2.11 - 2.51], as did adult initiators (HR, 1.92; 95% CI, 2.11 - 2.51).

In the analysis of 7354 first-degree sister pairs, 81% had initiated OCs. A sibling's OC use was positively associated with a depression diagnosis, and the co-sibling's OC use was also associated with the sibling's depression diagnosis. "These results support the hypothesis of a causal relationship between OC use and depression, such that OC use increases the risk of depression," the authors write.

The main limitation is the potential for recall bias in the self-reported data, and that the UK Biobank sample consists of a healthier population than overall UK population, which "hampers the generalizability" of the findings, the authors state.

Flawed Study

Commenting for Medscape Medical News, Natalie Rasgon, MD, founder and director of the Stanford Center for Neuroscience in Women's Health, Stanford, California, said the study was "well-researched" and "well-written" but had "methodological issues."

She questioned the sibling component, "which the researchers regard as confirming causality." The effect may be "important but not causative." Causality in people who are recalling retrospectively "is highly questionable by any adept researcher because it's subject to memory. Different siblings may have different recall."

The authors also didn't study the indication for OC use. Several medical conditions are treated with OCs, including premenstrual dysphoric disorder, the "number one mood disorder among women of reproductive age." Including this "could have made a huge difference in outcome data," said Rasgon, who was not involved with the study.

Also commenting for Medscape Medical News, Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology, University of Washington School of Medicine, Seattle, noted participants were asked to recall depressive symptoms and OC use as far back as 20 to 30 years ago, which lends itself to inaccurate recall.

And the researchers didn't ascertain whether the contraceptives had been used continuously or had been started, stopped, and restarted. Nor did they look at different formulations and doses. And the observational nature of the study "limits the ability to infer causation," continued Oelschlager, chair of the American College of Obstetrics and Gynecology Clinical Consensus Gynecology Committee. She was not involved with the study.

"This study is too flawed to use meaningfully in clinical practice," Oelschlager concluded.

This work was primarily funded by the Swedish Research Council, the Swedish Brain Foundation, and the Uppsala University Center for Women 's Mental Health during the Reproductive Lifespan . The authors, Rasgon, and Oelschlager declare no relevant financial relationships.

Epidemiol Psychiatr Sci. Published online June 12, 2023. Full text

Batya Swift Yasgur, MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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