Archival Report| Volume 70, ISSUE 4, P373-380, August 15, 2011

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Depression, Hypothalamic Pituitary Adrenal Axis, and Hippocampal and Entorhinal Cortex Volumes—The SMART Medea Study

  • Lotte Gerritsen
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, the Netherlands

    Department of Psychiatry, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
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  • Hannie C. Comijs
    Department of Psychiatry, Extramuraal Geneeskundig Onderzoek (EMGO+) Institute for Health and Care Research, Vrije University Medical Center, Amsterdam, the Netherlands
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  • Yolanda van der Graaf
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands
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  • Arnoud J.G. Knoops
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands

    Department of Radiology, University Medical Center Utrecht, the Netherlands
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  • Brenda W.J.H. Penninx
    Department of Psychiatry, Extramuraal Geneeskundig Onderzoek (EMGO+) Institute for Health and Care Research, Vrije University Medical Center, Amsterdam, the Netherlands
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  • Mirjam I. Geerlings
    Address correspondence to Mirjam Geerlings, Ph.D., Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands
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      Structural brain changes have often been found in major depressive disorder (MDD), and it is thought that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity may explain this relation. We investigated the association of MDD and history of depression with hippocampal and entorhinal cortex volumes and whether HPA axis activity explained this association.


      In 636 participants with a history of atherosclerotic disease (mean age 62 ± 9 years, 81% male) from the second Manifestation of ARTerial disease-Memory depression and aging (SMART-Medea) study, a 12-month diagnosis of MDD and history of depression were assessed. Age of first depressive episode was classified into early-onset depression (< 50 years) and late-onset depression (≥ 50 years). HPA axis regulation was assessed by four morning saliva samples, two evening samples, and one awakening sample after .5 mg dexamethasone. Hippocampus and entorhinal cortex volume were manually outlined on three-dimensional T1-weighted magnetic resonance images.


      General linear models adjusted for demographics, vascular risk, antidepressant use, and white matter lesions showed that ever having had MDD was associated with smaller hippocampal volumes but not with entorhinal cortex volumes. Remitted MDD was related to smaller entorhinal cortex volumes (p < .05). Participants with early-onset depression had smaller hippocampal volumes than those who were never depressed (p < .05), whereas participants with late-onset depression had smaller entorhinal cortex volumes (p < .05). HPA axis activity did not explain these differences.


      We found differential associations of age of onset of depression on hippocampal and entorhinal cortex volumes, which could not be explained by alterations in HPA axis regulation.

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      Linked Article

      • Depression and the Hippocampus: Cause or Effect?
        Biological PsychiatryVol. 70Issue 4
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          Research examining the relationship between major depressive disorder (MDD) and hippocampal volume has long wrestled with the chicken and egg question. From the time the first report was published finding smaller hippocampal volumes in patients with MDD compared with healthy control subjects (1), there have been hundreds of studies in the literature, with the majority, but not all, finding smaller hippocampal volumes in MDD (2). The direction of a potential causal arrow, however, remains unresolved.
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