<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (<jats:italic toggle="yes">P</jats:italic> = 0.34) or Beck Depression Inventory (<jats:italic toggle="yes">P</jats:italic> = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (<jats:italic toggle="yes">P</jats:italic> = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (<jats:italic toggle="yes">P</jats:italic> = 0.0005), and less consistently with placebo (<jats:italic toggle="yes">P</jats:italic> = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE—15.3 (4.5), raloxifene—16.0 (3.7), Rimostil—14.0 (2.7), and placebo—15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE—5.2(1.1), raloxifene—5.8(1.2), Rimostil—11.2(1.4), and placebo—7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (<jats:italic toggle="yes">P</jats:italic> values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).</jats:p> </jats:sec>