HISTORY OF PERIPARTUM DEPRESSION MODERATES THE ASSOCIATION BETWEEN ESTRADIOL PRS AND BASAL GANGLIA VOLUMES IN MAJOR DEPRESSIVE DISORDER

Abstract Background Past studies have identified associations among brain structural alterations in major depressive disorder patients (MDD) and cases of peripartum depression (PPD) [1,2]. Furthermore, previous findings have identified an effect of sex hormones on the brain and in PPD with emerging evidence for the involvement of genes related to hormonal levels [3,4]. However, the long-term neurobiological correlates of a peripartum depressive episode are unknown. In addition, it is unclear whether brain structural differences exist between females who have experienced a peripartum episode and those who have only experienced episodes outside of the peripartum period. Aims and Objectives In this study we investigated the structural grey matter correlates of a positive history of peripartum depression using a whole brain approach and the associations of the polygenic risk score (PRS) for estradiol in a sample of MDD patients. Methods MDD female patients with (n=29) and without (n=34) a history of peripartum depression were recruited from the psychiatric ward at IRCCS San Raffaele Hospital in Milan, Italy. T1-weighted images were acquired on two 3.0 Tesla scanners and processed using Computational Anatomy Toolbox (CAT12) for SPM12 in Matlab R2016b. An independent two-sample t-test comparing patients with a history of peripartum depression to patients without a history was performed using voxel-based morphometry analysis (VBM) in the Statistical Parametric Mapping 12 (SPM12) software package. In the analysis, whole-brain grey matter volumes were used as dependent variables, and age, total intracranial volume, scanner, duration of illness, menopause status, and antidepressant dose equivalents were used as covariates. Additionally, in a subsample of patients with a history (n=21) and without (n=18) with available genetic data, PRS for estradiol were calculated and a moderation analysis was conducted with extracted cluster volumes as the dependent variable, estradiol PRS as independent variable, and PPD history as a moderator using IBM SPSS PROCESS macro. Results The VBM analysis t-test identified larger grey matter volumes in a cluster encompassing the right putamen, right pallidum, and right caudate (pFWE= 0.037) in female patients with a history of peripartum depression compared to patients without a history. The moderation analysis identified a significant interaction of estradiol PRS and PPD history on grey matter cluster volumes (t= 2.128, p= 0.041) with no effect in the no PPD group (b= -0.011, t= -1.293, p= 0.205) and a positive significant effect in the PPD group (b= 0.010, t= 2.498, p= 0.018). Discussion and Conclusion We identified a cluster within the basal ganglia, an area important for reward and decision making [5], that was significantly larger in MDD females who have experienced a peripartum episode. Furthermore, we demonstrated that the genetic load for estradiol levels affects basal ganglia volumes differently based on history of peripartum episodes. This brain area is thought to be rich in sex hormone receptors and thus may be particularly sensitive to hormonal fluctuations and hormonally sensitive events [6], yet further study is needed to confirm these results and untangle the mechanisms behind them. References [1]Gray, J.P., Mü ller, V.I., Eickhoff, S.B. and Fox, P.T., 2020. Multimodal abnormalities of brain structure and function in major depressive disorder: a meta-analysis of neuroimaging studies. American Journal of Psychiatry, 177(5), 422-434. [2]Cheng, B., Hu, X., Roberts, N., Zhao, Y., Xu, X., Zhou, Y., Tan, X., Chen, S., Meng, Y., Wang, S. and Xing, H., 2022. Prolactin mediates the relationship between regional gray matter volume and postpartum depression symptoms. Journal of Affective Disorders, 301, 253-259. [3]Rehbein, E., Hornung, J., Sundströ m Poromaa, I. and Derntl, B., 2021. Shaping of the female human brain by sex hormones: a review. Neuroendocrinology, 111(3), 183-206. [4]Smeeth, D.M., Dima, D., Jones, L., Jones, I., Craddock, N., Owen, M.J., Rietschel, M., Maier, W., Korszun, A., Rice, J.P. and Mors, O., 2019. Polygenic risk for circulating reproductive hormone levels and their influence on hippocampal volume and depression susceptibility. Psychoneuroendocrinology, 106, 284-292. [5]Balleine, B.W., Delgado, M.R. and Hikosaka, O., 2007. The role of the dorsal striatum in reward and decision-making. Journal of Neuroscience, 27(31), 8161-8165. [6]Pletzer, B., Harris, T. and Hidalgo-Lopez, E., 2018. Subcortical structural changes along the menstrual cycle: beyond the hippocampus. Scientific reports, 8(1), 16042.