title: Longitudinal hypothalamic-pituitary-adrenal axis trait and state effects in recurrent depression.
abstract: 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.
authors.affiliation: Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. a.lok@amc.uva.nl
authors.forename: Anja
authors.initials: A
authors.lastname: Lok
authors.forename: Roel J T
authors.initials: RJ
authors.lastname: Mocking
authors.forename: Henricus G
authors.initials: HG
authors.lastname: Ruhé
authors.forename: Ieke
authors.initials: I
authors.lastname: Visser
authors.forename: Maarten W J
authors.initials: MW
authors.lastname: Koeter
authors.forename: Johanna
authors.initials: J
authors.lastname: Assies
authors.forename: Claudi L H
authors.initials: CL
authors.lastname: Bockting
authors.forename: Miranda
authors.initials: M
authors.lastname: Olff
authors.forename: Aart H
authors.initials: AH
authors.lastname: Schene
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015928:Cognitive Behavioral Therapy; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003866:Depressive Disorder / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism / Q000628:therapy*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000502:physiology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000502:physiology*; D012008:Recurrence; D055815:Young Adult
chemical_list: D006854:Hydrocortisone