The Roles of Hippocampal Atrophy, Cerebrovascular Burden, and Sleep Disturbance in Antidepressant Response Among Older Adults

Introduction: Late-life depression (LLD) causes considerable individual and public health burden. Prior studies have supported a role for cerebrovascular disease (white matter hyperintensity, WMH), hippocampal atrophy, and sleep in depression among older adults, and have demonstrated that these factors are all associated with poor treatment response. It remains unclear whether these brain changes lead to poor sleep, which interferes with treatment response, or the other way around. The current study aims to clarify these relationships between sleep and imaging markers, and treatment response. Methods: The study population consisted of individuals over the age of 60 with LLD using data from a previous 12-week openlabel treatment study funded by National Institute of Mental Health at the University of Pittsburgh. Participants were screened using Structured Clinical Interview for DSM IV Disorders for a current major depressive disorder. Depression was clinically assessed using the Hamilton Depression Rating Scale (HDRS) at baseline and week 12. The HDRS was further divided into scores representing core, sleep and anxiety symptoms. Medical comorbidity burden was measured with the Cumulative Illness Rating Scale for Geriatrics (CIRSG). Participants were treated open-label with venlafaxine or escitalopram and underwent MRI scans at baseline and at 12 weeks post-treatment. MRI data was processed using a standardized in-house pipeline. Treatment response was defined at an HDRS of less than 10 at week 12. Student’s t-test and nonparametric testing was used to determine prevs. post-treatment, demographic and clinical differences for the two groups. Binary logistic regression was used to predict treatment response using normalized hippocampal volumes, WMH volumes, and HDRS sleep subscores. Results: A total of 32 participants over the age of 60 with major depressive disorder were included in the study (Mean age 68 (5.9), 24 females). Treatment response was achieved for 18 participants. Median HDRS score at baseline for all participants was 18 and at week 12 was 8.5 (Z 1⁄4 4.58, p < .001). No significant differences in baseline HDRS and age were found between remitters and non-remitters. At week 12, non-remitters had greater core, anxiety, and sleep symptoms than remitters (U 1⁄4 18.5, 32, and 41, p < .001 for all subscores). Remitters had a 70% reduction in total HDRS score (Z 1⁄4 -3.73, p < .001) compared to 22.5% in non-remitters (Z 1⁄4 -2.38, p 1⁄4 .02). Subsequent analysis of subscores demonstrated decreased core, anxiety and sleep symptoms in remitters at week 12 compared to baseline (Z 1⁄4 -3.74, -3.74, -3.66, p < .001 for all subscores). However, nonremitters demonstrated no significant change in sleep symptoms (Z 1⁄4 -.081, p 1⁄4 .94) while core and anxiety symptoms improved at week 12 (Z 1⁄4 -2.84 and -2.17, p 1⁄4 .004 and .03). MRI analyses demonstrated greater global WMH burden for nonremitters than remitters at week 12 but this was not significant at an alpha level of .05. However, the mean change in global WMH burden from baseline to week 12 was significantly greater for non-remitters than remitters (t(30) 1⁄4 2.15, p 1⁄4 .04). The left hippocampus was found to have increased volume in remitters compared to non-remitters (t(30) 1⁄4 -2.00, p 1⁄4.05). Spearman’s correlation demonstrated a positive correlation between sleep symptoms and increased WMH burden from baseline to week 12 (r 1⁄4.393, p 1⁄4 .03). Logistic regression demonstrated that sleep symptoms increased the odds of treatment resistance (OR: 2.77; 95% CI: 1.38-5.56, p < .01). Decreased left hippocampal volumes and increased WMH burden increased the odds of treatment resistance however this was not significant at an alpha level of .05. After sleep score was added as a covariate, it was found that that these sleep symptoms continued to increase the odds of treatment resistance (OR: 2.53; 95% CI: 1.15-5.58, p 1⁄4 .02). Results were reported using two-tailed tests. Conclusions: Treatment resistant patients have a greater increase in white matter lesion burden over time and smaller hippocampal volumes than treatment responders. Greater sleep severity is associated with white matter lesion burden regardless of the treatment response. Sleep symptoms also predict poorer treatment response independent of white matter lesion burden and hippocampal volumes. These results will help guide further focused research into the role that these imaging markers have on treatment response.