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

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

[1]  Nikolaos Koutsouleris,et al.  Childhood Stress, Serotonin Transporter Gene and Brain Structures in Major Depression , 2010, Neuropsychopharmacology.

[2]  Reinhard Heun,et al.  Depression in Alzheimer’s disease: is there a temporal relationship between the onset of depression and the onset of dementia? , 2002, European Psychiatry.

[3]  Robert Barber,et al.  Hippocampal volume change in depression: Late- and early-onset illness compared , 2004, British Journal of Psychiatry.

[4]  R. Sapolsky,et al.  The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. , 1991, Endocrine reviews.

[5]  F. Zitman,et al.  Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. , 2009, Archives of general psychiatry.

[6]  H. Möller,et al.  Depression-related variation in brain morphology over 3 years: effects of stress? , 2008, Archives of general psychiatry.

[7]  Lotte Gerritsen,et al.  Basal Hypothalamic Pituitary Adrenal Axis Activity and Hippocampal Volumes: The SMART-Medea Study , 2010, Biological Psychiatry.

[8]  C. Kirschbaum,et al.  Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change , 2003, Psychoneuroendocrinology.

[9]  P. Björntorp,et al.  The hypothalamic–pituitary–adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke , 2000, Journal of internal medicine.

[10]  Nicole A. Lazar,et al.  Statistical Analysis With Missing Data , 2003, Technometrics.

[11]  A. Farmer,et al.  The Composite International Diagnostic Interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures. , 1988, Archives of general psychiatry.

[12]  Michael Marriott,et al.  Lower hippocampal volume in patients suffering from depression: a meta-analysis. , 2004, The American journal of psychiatry.

[13]  Hans-Jürgen Möller,et al.  Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up. , 2004, The Journal of clinical psychiatry.

[14]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[15]  J. P. Hamilton,et al.  Decreased hippocampal volume in healthy girls at risk of depression. , 2010, Archives of general psychiatry.

[16]  R. Sapolsky,et al.  Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. , 2000, Archives of general psychiatry.

[17]  Koen L. Vincken,et al.  White Matter Lesions and Lacunar Infarcts Are Independently and Differently Associated with Brain Atrophy: The SMART-MR Study , 2009, Cerebrovascular Diseases.

[18]  Eric Vermetten,et al.  Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment , 2004, Biological Psychiatry.

[19]  D. Altman,et al.  STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT , 1986, The Lancet.

[20]  B. Thombs,et al.  Optimizing Detection of Major Depression Among Patients with Coronary Artery Disease Using the Patient Health Questionnaire: Data from the Heart and Soul Study , 2008, Journal of General Internal Medicine.

[21]  G. MacQueen,et al.  The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? , 2011, Molecular Psychiatry.

[22]  L. Ferrucci,et al.  Late-life depressive symptoms are associated with both hyperactivity and hypoactivity of the hypothalamo-pituitary-adrenal axis. , 2007, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[23]  W. Mali,et al.  American Journal of Epidemiology Original Contribution Association of White Matter Lesions and Lacunar Infarcts with Executive Functioning the Smart-mr Study , 2022 .

[24]  A. Hofman,et al.  CASCADE: A European Collaborative Study on Vascular Determinants of Brain Lesions , 2000, Neuroepidemiology.

[25]  James T Becker,et al.  Brain morphometric abnormalities in geriatric depression: long-term neurobiological effects of illness duration. , 2002, The American journal of psychiatry.

[26]  S. Kennedy,et al.  Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. , 2008, Bipolar disorders.

[27]  Dick J. Veltman,et al.  Intrapair Differences in Hippocampal Volume in Monozygotic Twins Discordant for the Risk for Anxiety and Depression , 2007, Biological Psychiatry.

[28]  R. Kahn,et al.  Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression , 2007, Journal of Neurology, Neurosurgery & Psychiatry.

[29]  R A Bryant,et al.  Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety , 2009, Molecular Psychiatry.

[30]  V. Kusumakar,et al.  Hippocampal volume in early onset depression , 2004, BMC medicine.

[31]  C. Nemeroff,et al.  Epidemiology of comorbid coronary artery disease and depression , 2003, Biological Psychiatry.

[32]  A. Beckett,et al.  AKUFO AND IBARAPA. , 1965, Lancet.

[33]  B. McEwen,et al.  The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. , 1986, Endocrine reviews.

[34]  S. Lupien,et al.  The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition , 2007, Brain and Cognition.

[35]  R. Spitzer,et al.  The PHQ-9: validity of a brief depression severity measure. , 2001, Journal of general internal medicine.

[36]  I. Hickie,et al.  Early and late onset depression in old age: different aetiologies, same phenomenology. , 2001, Journal of affective disorders.

[37]  Anil Gholkar,et al.  A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. , 2004, The American journal of psychiatry.

[38]  A. Stone,et al.  Several daily measurements are necessary to reliably assess the cortisol rise after awakening: State- and trait components , 2007, Psychoneuroendocrinology.

[39]  L. Squire,et al.  The medial temporal lobe memory system , 1991, Science.

[40]  M. Shenton,et al.  Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma , 2002, Nature Neuroscience.

[41]  Vincent A Magnotta,et al.  Hippocampal volume and 2-year outcome in depression. , 2008, The British journal of psychiatry : the journal of mental science.

[42]  N. Schuff,et al.  Age effects on atrophy rates of entorhinal cortex and hippocampus , 2006, Neurobiology of Aging.

[43]  T. Stijnen,et al.  Review: a gentle introduction to imputation of missing values. , 2006, Journal of clinical epidemiology.

[44]  Paul B. Fitzgerald,et al.  A magnetic resonance imaging study of the entorhinal cortex in treatment-resistant depression , 2008, Psychiatry Research: Neuroimaging.

[45]  Klaus P. Ebmeier,et al.  White matter hyperintensities in late life depression: a systematic review , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[46]  Philip B. Ward,et al.  Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression , 2005, British Journal of Psychiatry.