Depression, depressive symptoms, and rate of hippocampal atrophy in a longitudinal cohort of older men and women M. Elbejjani 1 , R. Fuhrer 1 *, M. Abrahamowicz 1 , B. Mazoyer 2,3,4 , F. Crivello 2,3,4 , C. Tzourio 4,5 and C. Dufouil 4,5 1 Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, 1020 Pine Avenue West, Montreal, Quebec, Canada 2 CNRS, GIN UMR5296, Bordeaux, France 3 CEA, GIN UMR5296, Bordeaux, France 4 University of Bordeaux, Bordeaux, France 5 INSERM, Centre INSERM U897 and CIC-1401, Bordeaux School of Public Health, Bordeaux, France Background. Several studies have reported smaller hippocampal volume (HcV) in depression patients; however, the temporality of the association remains unknown. One proposed hypothesis is that depression may cause HcV loss. This study evaluates whether previous depression and recent depressive symptoms are associated with HcV and HcV loss. Method. We used a prospective cohort of older adults (n = 1328; age = 65–80 years) with two cerebral magnetic resonance imaging examinations at baseline and 4-year follow-up. Using multivariable linear regression models, we estimated, in stratified analyses by gender, the association between indicators of history of depression and its severity (age at onset, recurrence, hospitalization for depression), proximal depressive symptoms [Center for Epidemiologic Studies-Depression (CES-D) scale], baseline antidepressant use, and the outcomes: baseline HcV and annual percentage change in HcV. Results. At baseline, women with more depressive symptoms had smaller HcV [-0.05 cm 3 , 95% confidence interval (CI) -0.1 to -0.01 cm 3 per 10-unit increase in CES-D scores]. History of depression was associated with a 0.2% faster annual HcV loss in women (95% CI 0.01–0.36%). More baseline depressive symptoms and worsening of these symptoms were also associated with accelerated HcV loss in women. No associations were observed in men. Treatment for depression was associated with slower HcV loss in women and men. Conclusions. While only concomitant depressive symptoms were associated with HcV, both previous depression and more proximal depressive symptoms were associated with faster HcV loss in women. Received 4 November 2013; Revised 23 November 2014; Accepted 26 November 2014 Key words: Aging, atrophy, cohort studies, depression, hippocampus, imaging. Introduction Magnetic resonance imaging (MRI) studies have identified structural brain alterations associated with depression. Several reviews and meta-analyses sum- marizing these studies have reported a reduced hippo- campal volume (HcV) in depressed patients (Campbell et al. 2004; Videbech & Ravnkilde, 2004; Koolschijn et al. 2009; Lorenzetti et al. 2009; Kempton et al. 2011). However, the direction of this association remains unre- solved. Some studies have found that HcV is smaller in first-episode depression patients, suggesting that a reduced HcV is already present at the first manifestation of the illness and could therefore be a susceptibility fac- tor for depression (Frodl et al. 2002; Kronmüller et al. 2009; Dedovic et al. 2010). Other studies in clinical settings favor the converse, i.e. that smaller HcV can be the consequence of depression as they have found links between recurrence and duration of depression and HcV reductions (Bell-McGinty et al. 2002; MacQueen et al. 2003; Sheline et al. 2003). One proposed explanation for the relationship between depression and smaller HcV is the neurotoxi- city hypothesis, which implies that biological alterations that accompany depression tax the hippocampus, its morphology, and its functionality (Sapolsky et al. 1986; McEwen & Gianaros, 2010). It is derived from observa- tions that depression is accompanied by deregulations of key neural pathways such as the glucocorticoids and glutamate networks, which eventually cause neuro- nal damages and losses (Sapolsky et al. 1986; Bremner, 1999; Sapolsky, 2000; McEwen & Gianaros, 2010). * Address for correspondence: R. Fuhrer, Ph.D., Department of Epidemiology, Biostatistics, and Occupational Health, McGill University Faculty of Medicine, 1020 Pine Avenue West, Montreal, Quebec H3A 1A2, Canada. (Email: rebecca.fuhrer@mcgill.ca) Psychological Medicine (2015), 45, 1931–1944. © Cambridge University Press 2015 doi:10.1017/S0033291714003055 ORIGINAL ARTICLE