HPA axis and aging in depression: systematic review and meta-analysis

Psychoneuroendocrinology. 2014 Mar;41:46-62. doi: 10.1016/j.psyneuen.2013.12.004. Epub 2013 Dec 17.


One of the most consistent findings in the biology of depression is an altered activity of the hypothalamic-pituitary-adrenal (HPA) axis. However, data concerning this issue have never been examined with a focus on the older population. Here we present a systematic review and meta-analysis, based on studies investigating levels of cortisol, adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) in depressed participants older than 60 and compared with healthy controls. We found 20 studies, for a total of 43 comparisons on different indices of HPA axis functioning. Depression had a significant effect (Hedges' g) on basal cortisol levels measured in the morning (0.89), afternoon (0.83) and night (1.39), but a smaller effect on cortisol measured continuously (0.51). The effect of depression was even higher on post-dexamethasone cortisol levels (3.22), whereas it was non-significant on morning ACTH and CRH levels. Subgroup analyses indicated that various methodological and clinical factors can influence the study results. Overall, older participants suffering from depression show a high degree of dysregulation of HPA axis activity, with differences compared with younger adults. This might depend on several mechanisms, including physical illnesses, alterations in the CNS and immune-endocrinological alterations. Further studies are needed to clarify the implications of altered HPA axis activity in older patients suffering from depression. Novel pharmacological approaches might be effective in targeting this pathophysiological feature, thus improving the clinical outcomes.

Keywords: ACTH; Antidepressant; CRH; Cortisol; Depression; Depressive symptoms; Dexamethasone; Elderly; HPA axis; Older adults.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adrenocorticotropic Hormone / metabolism
  • Aging / physiology*
  • Aging / psychology*
  • Corticotropin-Releasing Hormone / metabolism
  • Depression / metabolism
  • Depression / physiopathology*
  • Dexamethasone
  • Humans
  • Hydrocortisone / metabolism
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Pituitary-Adrenal Function Tests
  • Pituitary-Adrenal System / physiopathology*


  • Dexamethasone
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Hydrocortisone