Differential effects of estradiol on neural and emotional stress response in postmenopausal women with remitted Major Depressive Disorder

Introduction Ovarian hormones can influence neural systems involved in mood regulation, suggesting a pathway explaining why women have a greater incidence of Major Depressive Disorder (MDD) than men primarily beginning at puberty. Estrogen fluctuations may contribute to MDD risk through effects on brain networks important in emotion processing, stress responding, and mood regulation. Although there is evidence to support the use of ovarian hormone treatment for peri-menopausal depression, postmenopausal use has not been as well examined. As the neural systems involved in emotional processing and stress response are altered in MDD, it is possible that the effect of estrogen treatment on these systems may differ between postmenopausal women with and without a history of MDD. The objective of this study was to investigate whether estrogen modulation of the neural and emotional cognitive responses to stress differs between postmenopausal women with and without MDD vulnerability. Methods 60 postmenopausal women completed this fMRI study including a psychosocial stress task, the Montreal Imaging Stress Task (MIST), after receiving no drug or 3 months of daily 2mg 17β estradiol (E2). Participants included women with no personal history of MDD by SCID interview and women with remitted MDD with at least one episode in the last ten years and no depressive episodes within the last year. There were 4 participant groups: 1) MDD+/E2+ (n=10), 2) MDD+/E2- (n=12), 3) MDD-/E2= (n=20), 4) MDD-/E2- (n=18). All groups were euthymic at the time of study with non-clinical scores on the Beck Depression and Anxiety Inventories. Subjective mood response to the MIST was assessed as change score on the Stress-Arousal Checklist (SACL stress) before and after the MIST. fMRI analyses examined activity differences between the “stress and “control” conditions of the MIST using SPM 12. Second level analyses included 2 × 2 interactions (MDD history X E2 administration), whole-brain (gray matter masked), and cluster threshold corrected for multiple comparisons (p 102, FDR Results E2 administration was associated with different effects in post-menopausal women with or without a history of MDD. In accordance with our previous work, the MDD-/E2+ group had a more negative mood response (higher SACL stress score) to the stress task than the MDD-/E2- group. In contrast, this effect was reversed in women with a history of MDD, where the MDD+/E2+ group had a less negative mood response than the MDD+/E2- group. Additionally, both groups who exhibited more negative mood responses also showed greater activity in emotional perception areas (left inferior frontal and left angular gyri) during the stress condition of the task than the groups which showed less negative mood responses. Group differences were also observed on fMRI. Women who did not receive E2 showed a positive correlation between greater right inferior frontal activity and higher SACL stress score, while the MDD+/E2- group additionally showed a positive correlation between right insula activity and SACL score. The MDD+/E2+ group showed negative correlations between activity in each area and SACL stress score in both the "stress" and "control" conditions of the MIST, while the MDD-/E2+ did not show significant correlations between activity in any area and SACL stress Score. Conclusions These results support a differential effect of estrogen administration on emotional and neural responses to psychosocial stress in postmenopausal women with and without a history of MDD. We had previously show that in women without a history of MDD, E2 is associated with a more negative mood response to stress than placebo. The results of this study replicated those findings in women without a history of MDD and show that E2 is also associated with increased activity in brain areas involved in emotion perception and response. Additionally, the result of this study support that the effect of E2 is reversed in women with a history of MDD, such that E2 is associated with a less negative mood response to stress and a differential relationship between activity in brain areas involved in emotion response. This suggests that women with a history of MDD, even while currently euthymic, have both a different mood and neural response to psychosocial stress and may show a beneficial mood effect E2 that is not seen in women without a history of MDD. These results may provide a neurological basis for recurrence risk and the beneficial mood effects of post-menopausal hormone treatment in women with a history of MDD. Funding This work was supported by the National Institutes of Aging R01AG021476, the National Institutes of Mental Health H110598, and Vanderbilt CTSA grant UL1 TR002243 from National Center for Advancing Translational Sciences.