Longitudinal hypothalamic-pituitary-adrenal axis trait and state effects in recurrent depression

Lok, A., Mocking, R. J. T., Ruhe, E., Visser, I., Koeter, M. W. J., Assies, J., Bockting, C. L. H., Olff, M. & Schene, A. H., Jul-2012, In : Psychoneuroendocrinology. 37, 7, p. 892-902 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Anja Lok
  • Roel J T Mocking
  • Eric Ruhe
  • Ieke Visser
  • Maarten W J Koeter
  • Johanna Assies
  • Claudi L H Bockting
  • Miranda Olff
  • Aart H Schene

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity has been observed in (recurrent) major depressive disorder (MDD), although inconsistently and mainly cross-sectional. Longitudinal studies clarifying state-trait issues are lacking. We aimed to determine whether HPA-axis (hyper)activity in recurrent MDD is: (I) reflecting a persistent trait; (II) influenced by depressive state; (III) associated with stress or previous episodes; (IV) associated with recurrence; and (V) influenced by cognitive therapy.

METHODS: We included 187 remitted highly recurrent MDD-patients (mean number of previous episodes: 6.3), participating in a randomized-controlled-trial investigating the preventive effect of additional cognitive therapy on recurrence. In an add-on two-staged patient-control and prospective-cohort design, we first cross-sectionally compared patients' salivary morning and evening cortisol concentrations with 72 age- and sex-matched controls, and subsequently longitudinally followed-up the patients with repeated measures after three months and two years.

RESULTS: Patients had higher cortisol concentrations than controls (p<.001), which did not change by MDD-episodes during follow-up. HPA-axis activity had no relation with daily hassles or childhood life events. Cortisol concentrations were lower in patients with more previous episodes (p=.047), but not associated with recurrence(s) during follow-up. Finally, randomly assigned cognitive therapy at study-entry enhanced cortisol declines over the day throughout the two-year follow-up (p=.052).

CONCLUSIONS: Our results indicate that remitted recurrent MDD-patients have a persistent trait of increased cortisol concentrations, irrespective of stress. In combination with our finding that patients' cortisol concentrations do not change during new MDD-episodes (and thus not represent epiphenomenal or state-effects), our results support that hypercortisolemia fulfills the state-independence criterion for an endophenotype for recurrent depression.

Original languageEnglish
Pages (from-to)892-902
Number of pages11
Issue number7
Publication statusPublished - Jul-2012


  • Depressive disorder, Major, Recurrence, Hypothalamo-hypophyseal system, Pituitary-adrenal system, Glucocorticoids, Saliva, Cohort studies, Case-control studies, Randomized controlled trial, Cognitive therapy, COMBINED DEXAMETHASONE/CRH TEST, WAKING SALIVARY CORTISOL, NEGATIVE LIFE EVENTS, HIGH FAMILIAL RISK, DEX-CRH TEST, MAJOR DEPRESSION, GLUCOCORTICOID-RECEPTORS, AFFECTIVE-DISORDERS, COGNITIVE THERAPY, OUTPATIENTS

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