Effects of acute estradiol administration on perimenstrual worsening of working memory, verbal fluency, and inhibition in patients with suicidal ideation: A randomized, crossover clinical trial

Accumulating evidence indicates that most female patients with suicidal ideation (SI) experience a dimensional worsening of depressive symptoms and SI in the perimenstrual phase of the menstrual cycle. Experimental trials demonstrate that acute perimenstrual administration of estradiol (E2; with or without progesterone/P4), can prevent these recurring episodes of increased risk. In this archival sample drawn from one of these clinical trials, we examined whether these beneficial E2 effects extend to specific types of cognition. For a double-blind, placebo-controlled experiment, we recruited transdiagnostic psychiatric outpatients with natural menstrual cycles who experienced past-month SI (N(per-protocol sample)=23; N(intent-to-treat sample)=44). In each of two counterbalanced conditions (perimenstrual administration of 0.1mg/d transdermal E2 vs. placebo), participants completed three cognitive tasks in three menstrual cycle phases (mid-luteal, perimenstrual, mid-follicular). Multilevel models revealed a significant interaction of condition and phase: E2 administration prevented mid-luteal-to-perimenstrual drops in working memory (p=.006) and verbal fluency (p=.005) observed under placebo. No effects were found for inhibitory control. In conclusion, we find perimenstrual declines in working memory and verbal fluency in patients with SI, which can be prevented by administering E2. This study contributes to our understanding of the hormone-brain pathways involved in the cyclical worsening of suicidality.