Depressive episodes occurring at times of reproductive hormone change—including the peripartum period, the premenstrual phase, and menopause—are thought to reflect sensitivity to hormone fluctuation rather than differences in absolute hormone levels. Oral contraceptive pills (OCPs) introduce exogenous hormones that stabilize this fluctuation, which may benefit some women while triggering mood deterioration in others. Prior research has been inconsistent, partly due to healthy user bias and the grouping of heterogeneous OCP formulations. This study sought to characterize women at elevated risk for OCP-related adverse mood effect, and to determine whether such women share genetic and clinical features that distinguish them from those who experience neutral or positive mood effects.
This retrospective study drew from the Australian Genetics of Depression Study (AGDS), a large case-cohort study of individuals with lifetime depression. A total of 3,547 female OCP users completed a follow-up questionnaire and were asked how OCP use affected their mood (no effect, improves it, or makes it worse). Outcomes of interest included peripartum depression (PPD), premenstrual dysphoric disorder (PMDD), perimenopausal depression, depression onset prior to first OCP use (prior depression), and depression onset before age 20 (child/teen depression onset).
Of the 3,547 participants, 38% reported adverse mood effect, 51% reported no effect, and 11% reported improved mood. PPD, PMDD, prior depression, and child/teen depression onset were each significantly associated with adverse mood effect. Women with a history of PPD were 66% more likely to report adverse mood effect than neutral mood effect (RR = 1.66; 95% CI, 1.35–2.04; P = 2.0 × 10−6). Women with PMDD showed the strongest association, with nearly a fourfold increased relative risk of adverse mood effect (RR = 3.78; 95% CI, 2.37–6.03; P = 2.2 × 10−8). Prior depression (RR = 1.32; P = 5.9 × 10−4) and child/teen depression onset (RR = 1.56; P = 1.1 × 10−7) were also independently associated with adverse mood effect.
Notably, the association between PPD and adverse mood effect remained significant even among women with no prior or child/teen depression history (RR = 1.77; P = 4.6 × 10−4), suggesting a distinct hormone-sensitive subgroup. Women reporting adverse mood effect also carried a significantly higher polygenic burden for MD compared with those reporting neutral mood effect (RR = 1.18 per SD increase in PGS; P = 3.6 × 10−5), and this genetic signal persisted even when restricting the analysis to women with no prior or child/teen depression onset.
This study identifies a clinically meaningful pattern: women who experience poor mood on the OCP tend to have higher genetic liability for depression, earlier depression onset, and greater likelihood of reproductive mood episodes such as PPD and PMDD. The persistence of the PPD–adverse mood effect association in women without prior depression suggests a hormone-sensitive phenotype that is not fully explained by general depression vulnerability. Importantly, both adverse and positive mood responses to the OCP were associated with PPD, suggesting heightened hormonal sensitivity (i.e., a propensity for non-neutral mood responses) rather than a purely negative mood effect.
These findings underscore the value of a detailed reproductive and psychiatric history when counseling patients about OCP initiation and raise the possibility that adverse OCP mood response could serve as a clinical marker for elevated risk of future reproductive depressive episodes. However, findings should be interpreted in the context of key limitations, including that the sample consisted entirely of women with lifetime depression, the retrospective self-report design, and the lack of information on specific OCP formulations.
Reference:
Kiewa, J et al. Arch Womens Ment Health 29, 71 (2026). Abstract