Hormone withdrawal during combined oral contraceptives (COCs) pill pause is associated with adverse mental health outcomes among long-term users, according to findings published in JAMA Network Open. This worsening in mood changes was comparable to endogenous hormone withdrawal during menses, supporting the notion that COCs appear to have a mood-stabilizing effect.

The mental health outcomes associated with long-term COC use are controversial, as some studies have related COC use to increased risk for depression and suicide attempts whereas other studies have not replicated these findings. Given this diversity in findings, researchers conducted a case-control study to evaluate the relationship between long-term COC use and mental health outcomes, taking into account mental health at baseline, progestin type, and estrogen dose.

Between 2021 and 2022, the researchers recruited long-term (6 months or greater) COC users aged 18 to 35 years. Individuals with psychiatric, neurologic, or endocrinologic disease and those taking other medication besides COC were excluded from analyses. Additionally, control participants with natural menstrual cycles (no COC use) were selected from a previous study.

Investigators assessed trait measures of mental health over the 4 weeks prior to study participation using the Premenstrual Symptom Screening Tool (PSST), Beck Anxiety Inventory (BAI), and the Beck Depression Inventory (BDI-II). In addition, the researchers assessed mood states during active pill intake, pill pause, or during natural menstrual cycle. These mood state assessments included the Positive and Negative Affect Schedule (PANAS), Daily Rating of Severity of Problems (DRSP), and State-Trait Anxiety Inventory (STAI) questionnaires.

The participants (N=180) were categorized by nonusers (n=60), androgen COC users (COC-A; n=61), and antiandrogenic COC users (COC-AA; n=59). The 3 groups comprised women aged median 21 (interquartile range [IQR], 3), 23 (IQR, 5), and 21 (IQR, 3.5) years (P =.002), respectively. The median length of COC use was 47.00 (IQR, 49.00) months for the COC-A users and 53.00 (IQR, 48.00) months for the COC-AA users.

At baseline, comparisons revealed no significant group differences in the trait measures of mental health prior to enrollment. However, the researchers observed a 23.61% (95% CI, 16.49%-30.73%; P <.001) increase in mental health symptoms, a 12.67% (95% CI, 6.94%-18.39%; P =.009) increase in negative affect, and a 7.42% (95% CI, 3.43%-11.40%; P =.003) increase in anxiety among COC users during pill pause compared with active pill intake. These values were comparable to the changes in negative affect (12.93%), anxiety (6.83%), and mental health symptoms (33.08%) experienced during natural phase changes in the control group. Furthermore, analyses revealed a significant interaction between BDI scores and pill pause (F_[1,117], 7.14; P =.008), as individuals with depression scores greater than 8 had a 17.95% (95% CI, 7.80%-28.10%) increase in negative affect during COC withdrawal.

Study authors concluded, “These results question the usefulness of pill pauses from a mental health perspective, and it should be explored whether long-term COC users benefit more from the mood-stabilizing effects of COCs in cases of continuous intake.”

These findings may not be generalizable for women with a mental health history, as this population was excluded from present analyses.

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.