Effects of estradiol administration on brain activation and anhedonia in perimenopausal women: A pharmaco-fMRI study

Background: Half of perimenopausal women experience depressive symptoms, including anhedonia. Anhedonia is associated with dysregulation of the frontostriatal circuit. Both the frontrostriatal circuit and depression may be regulated by the reproductive hormone estradiol (E2). Here, we present data from a pharmaco-fMRI trial investigating E2 effects on brain activation and anhedonia in those with perimenopause-onset major depression (PO-MDD). Methods: Participants with PO-MDD (n = 16) and those without depression (i.e., Controls; n = 19) received transdermal E2 for three weeks and completed two fMRI sessions (Pre- and Post-E2), and weekly anhedonia assessments. During each fMRI session, neural responses to anticipation and outcomes of monetary rewards were measured. Results: The PO-MDD group exhibited steeper declines in anhedonia following E2 administration (t(101.95) = -8.7, pFDR < 0.001). Contrary to a priori hypotheses, there were no group differences in striatal activation at baseline nor did striatal activation significantly change with E2 administration in either group. However, exploratory whole-brain analyses revealed a significant Group*Time interaction in a cluster spanning the right inferior, middle, and precentral gyri during reward anticipation (Z = 2.58 and pFWE < 0.05). From Pre-E2 to Post-E2, PO-MDD showed decreased activation within this cluster (t = 3.0, p < 0.009), whereas the Controls did not (t = 1.89, p = 0.08). Further, following E2 administration, both PO-MDD and Control groups exhibited reduced activation in the cerebellum, inferior and medial frontal gyri, and occipital pole during reward anticipation (Z = 2.58, pFWE < 0.05). Conclusions: While both anhedonia and right prefrontal activation during anticipatory reward processing were reduced in PO-MDD after three weeks of E2 administration, further research investigating the antidepressant effects of E2 is needed.