Do Oral Contraceptives Increase the Risk of Depression?

Use of oral contraceptives (OC) has been associated with an increased risk of depression, especially in the first 2 years after initiation, new research shows.

Additionally, OC use in adolescence has been associated with an increased risk of depression later in life. However, some experts believe the research methodology may be flawed.

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

Women who started using this OC before or at the age of 20 experienced a 130% higher rate of depressive symptoms, while adult users experienced a 92% increase. But the higher incidence of depression tended to decrease after the first 2 years of use, except in adolescents, who maintained the increased incidence of depression even after discontinuation.

This effect persisted, even after analysis of potential family confounders.

“Our findings suggest that use of oral contraceptives, especially during the first 2 years, increases the risk of depression. In addition, use of oral contraceptives during adolescence may increase the risk of depression later in life,” wrote Therese Johansson, Department of Immunology, Genetics. and Pathology, Science for Life Laboratory, Uppsala University, Sweden, and colleagues.

The study was published online on June 12 Epidemiology and Psychiatry.

Inconsistent findings

Previous studies have shown an association between adolescent use of hormonal contraceptives (HCs) and an increased risk of depression, but it was “less clear” whether these effects were similar in adults, the authors wrote. Randomized clinical trials have “showed little or no effect” of HCs on mood. However, most of these studies did not consider prior use of HC.

The researchers wanted to estimate the depressive event rate 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), gathering data from questionnaires, interviews, physical health measures, biological samples, imaging and related health records.

Most of the participants taking oral contraceptives started using oral contraceptives during the 1970s/early 1980s when second-generation oral contraceptives, consisting of levonorgestrel and ethinyl estradiol, were widely used.

The researchers performed 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 of starting OC 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 researchers estimated a lifetime risk of depression.

Time-dependent analysis compared the effect of OC use at initiation with the effect over the remaining years of use in new and previous users.

They analyzed a subcohort of sisters, making use of “Inference about Cause from Examining Family Disorders,” which the authors define as “a regression-based approach to determining causality through the use of paired observational data collected from related individuals.”

Adolescents at Highest Risk

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

The first 2 years of use were associated with higher rates of depression among users, compared with never use (HR, 1.79; 95% CI, 1.63 – 1.96). Although the risk became less clear afterward, continued use was still associated with an increased lifetime risk for depression (HR, 1.05; 95% CI, 1.01 – 1.09).

Adolescents and adult OC users alike experienced higher rates of depression during the first 2 years, with the effect being more pronounced 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 OC users had a higher lifetime risk of depression, compared to those who had never used OC (HR, 1.05; 95% CI, 1.01 – 1.09).

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

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

Those who started taking oral contraceptives during adolescence had significantly higher rates of depressive symptoms than those who had never used oral contraceptives (HR, 2.30; 95% CI, 2.11 – 2.51], as did adult initiators (HR, 1.92; 95% CI, 2.11 – 2.51 ).

In an analysis of 7354 pairs of first-degree relatives, 81% had started OC. Sibling OC use was positively associated with a diagnosis of depression, and sibling OC use was also associated with a sibling diagnosis of depression. “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 wrote.

The main limitations are the potential for recall bias in the self-reported data, and that the UK Biobank sample consisted of a healthier population than the UK population as a whole, which “inhibits generalizability” of the findings, the authors said.

Disability Studies

Comment for Medscape Medical NewsNatalie 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 problems.”

He questioned the sibling component, “which the researchers considered as justifying causality.” The effect may be “important but not causal”. Causality in retrospective recall “is highly questioned by any skilled researcher because memory is subject to. Different relatives may have different memories.”

The author also did not study the indications for using OC. Several medical conditions are treated with oral contraceptives, including premenstrual dysphoric disorder, “the number one mood disorder among women of reproductive age.” Including these “could make a big difference in the outcome data,” said Rasgon, who was not involved in the study.

Also comment for Medscape Medical NewsAnne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology, University of Washington School of Medicine, Seattle, noted participants were asked to recall symptoms of depression and use of OC as far back as 20 to 30 years, which tends to be inaccurate. remember.

And the researchers couldn’t confirm whether the contraceptives had been used continuously or had been started, stopped, and restarted. They also didn’t look at the different formulations and dosages. 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. He was not involved in research.

“This study is too flawed to be used meaningfully in clinical practice,” concluded Oelschlager.

This work was primarily funded by the Swedish Research Council, the Swedish Brain Foundation, and the Uppsala University Women’s Center ‘S Soul Health during That Reproduction Lifetime . The authors, Rasgon, and exposed to oil declared no relevant financial relationship.

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. He is a regular contributor to various medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books and Behind the Burqa: Our Life in Afghanistan and How We Flee to Freedom (memories of two brave Afghan sisters telling their stories).

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