Oral contraceptive use was not associated with depression in a recent double-blind, randomized, placebo-controlled trial. Out of 162 women randomized to using 150 micrograms levonorgestrel and 30 micrograms ethinyl estradiol and 167 randomized to placebo pills, 7% of women in each group were moderately to severely depressed after 3 months. This study, with a strong study design is a powerful response contradicting findings of an earlier and weaker study that had claimed a depression link (see the December LateBreaker “Make Me Cry: Depression Link (Again).”
The study sample comprised women willing to start OCs. They were randomized to OC or placebo use and asked to fill out the Beck Depression Inventory at baseline and at the end of the study period. The researchers verified compliance with OC use by measuring serum hormone content. In contrast, the earlier study that reported a depression link identified women through Danish public registries, identifying women who obtained antidepressants and those who obtained oral contraceptives or received a depression diagnosis from January 2000 to December 2013. Participants were not randomized to OC use; instead they were self-selecting, so users and non-users less likely to be similar to one another in the factors that could contribute to depression risk. The researchers did not verify OC use compliance or use a standard instrument to measure and verify the depression diagnoses. As with most studies exploring the issue, there was no placebo control.
An interesting aspect to the new randomized, placebo-controlled study showing no depression link is that the researchers had actually hypothesized that they would find an OC link to depression. They had anticipated that the reduced free testosterone associated with OC use, as well as a progestin-induced central nervous system effect, would cause depression. What they did find was a null hypothesis: no association between depression and OC use.
Although the researchers found no link to depression, they found that OC users reported a decrease general well-being when compared with women in the study arm taking placebo pills. Six percent of the women taking OCs were more likely to report reduced sense of positive well-being, self-control, and vitality than were the women taking the placebo pills. The researchers did not indicate whether they had explored any connection between reduced feelings and well-being and adverse effects of OC use, but the question of a connection may be important. Only 4 women taking placebo pills reported adverse effects (including 2 pregnancies and 1 ovarian cyst). In comparison, 14 OC users reported bleeding disturbances, 5 reported acne, and 3 reported appetite changes. There were also 12 reports of anxiety and mood changes among OC users, and it would be interesting to know whether these mood changes were reported by the same women who reported another adverse effect as well, such as bleeding disturbances. It is likely, too, that women who reported adverse effects suspected they were taking OCs and therefore were not blinded to the study arm in which they were placed. Before concluding that OCs may be associated with reduced well-being, it would be important to examine whether adverse effects, such as unscheduled bleeding, may be at the root of the mood changes, rather than the hormonal effect alone on mood.
The researchers primarily focused their conclusions on whether the reports of reduced well-being may contribute to the high percentage of women who discontinue pill use. The study ended at 3 months, however, so the researchers’ speculation was not examined. Most clinicians do counsel patients about bleeding changes, in anticipation of confusion or worry over the changes that does contribute to discontinuation. Until the issue is further examined, it may be premature to advise that clinicians counsel all OC users about a potential reduction in well-being associated with their method. In any event, the finding that depression was not associated with pill use is good news, and that finding joins the findings from several other studies that have reported the same, including the few other placebo-control trials.
 Zethraeus N, Dreber A, Ranehill E, et al. A first-choice combined oral contraceptive influences general well-being in healthy women: a double-blind, randomized, placebo-controlled trial. Fertil Steril doi.org/10.1016/j.fertnstert.2017.02.120
 Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Association of hormonal contraception with depression. JAMA Psychiatry. 2016;73(11):1154-1162.