Transdermal estradiol for postpartum depression: results from a pilot randomized, double-blind, placebo-controlled study

Abstract

Postpartum depression (PPD) is a common complication following delivery, though evidence-based treatment options are limited. This study explores the feasibility and efficacy of outpatient PPD treatment with transdermal estradiol (TE). In a pilot, double-blind, placebo-controlled trial, women with PPD were randomized to receive transdermal 17β-estradiol (100 mcg/day) or placebo patch. Over 6 weeks, women completed weekly ratings on the Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS), and Hamilton Depression Scale (HAM-D). Primary outcome measures were treatment response (> 50% decrease from baseline BDI) and remission (BDI < 10) at 6 weeks, and secondary outcome measures included severity on all scales at weeks 3 and 6. Of 12 recruited women, 6 received TE and 6 received placebo. By week 6, 5 women receiving TE responded to treatment and 4 showed symptom remission, compared to 2 responders and 1 remitter in the placebo group. This difference was not significant (p = 0.24). In a mixed-model of BDI ratings, TE was associated with a 9.2 point decrease at 3 weeks (95%CI - 19.5 to + 1.0, p = 0.074) and a 10.5 point decrease at 6 weeks (95%CI - 21.0-0.0, p = 0.049) compared to placebo, though these differences did not survive multiple comparisons correction. Analogous effects were found for HAM-D but not EPDS scores. Interestingly, no significant difference in plasma estradiol levels existed between groups. We were unable to demonstrate a significant therapeutic benefit of TE compared with placebo in PPD. Although limited by under-recruitment and loss to follow-up, our results suggest TE is a feasible option for outpatient PPD management, with preliminary evidence (based on secondary outcomes) for efficacy. Therapeutic effects may be seen as early as 3 weeks and may not directly depend on peripheral measures of estradiol.

Keywords: Postpartum depression; Randomized controlled trial; Transdermal estradiol.

Fig. 1

Flow of participants through the study. Fourteen women were recruited to the study Two women (1 TE, 1 placebo) dropped out prior to the first follow-up visit and were not included in the analysis. An additional three women in the placebo group dropped out after weeks 3, 4, and 5 due to severity of depressive symptoms requiring referral to a community provider

Fig. 2

Modeled BDI, HAM-D, and EPDS scores overtime. Fitted values from LME models of BDI, HAM-D, and EPDS scores. Adjusted means and standard error are plotted for each treatment group. BDI scores were significantly reduced by week 6 (95%CI − 21.04 to − 0.04, p = 0.05). HAM-D scores were significantly reduced by week 3 (95%CI − 16.55 to − 0.43, p = 0.04) and week 6 (95%CI − 17.98 to − 1.22, p = 0.03)

Fig. 3

Modeled mean estradiol levels over the 6-week study period, stratified by ovulatory status. Mean estradiol levels are plotted with standard error. Stratification by ovulatory status shows that TE may possibly increase estradiol levels in anovulatory patients only, though this difference was not significant with our limited sample size