title: Study protocol for the randomised controlled trial: antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study).
abstract: BACKGROUND
  Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service.
  
  
  METHODS
  Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone.
  
  
  CONCLUSIONS
  Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments.
  
  
  BACKGROUND
  Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.
authors.forename: R Hamish
authors.initials: RH
authors.lastname: McAllister-Williams
authors.forename: Eleanor
authors.initials: E
authors.lastname: Smith
authors.forename: Ian M
authors.initials: IM
authors.lastname: Anderson
authors.forename: Jane
authors.initials: J
authors.lastname: Barnes
authors.forename: Peter
authors.initials: P
authors.lastname: Gallagher
authors.forename: Heinz C R
authors.initials: HC
authors.lastname: Grunze
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haddad
authors.forename: Allan O
authors.initials: AO
authors.lastname: House
authors.forename: Tom
authors.initials: T
authors.lastname: Hughes
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Lloyd
authors.forename: Elaine M M
authors.initials: EM
authors.lastname: McColl
authors.forename: Simon H S
authors.initials: SH
authors.lastname: Pearce
authors.forename: Najma
authors.initials: N
authors.lastname: Siddiqi
authors.forename: Baxi
authors.initials: B
authors.lastname: Sinha
authors.forename: Chris
authors.initials: C
authors.lastname: Speed
authors.forename: I Nick
authors.initials: IN
authors.lastname: Steen
authors.forename: June
authors.initials: J
authors.lastname: Wainright
authors.forename: Stuart
authors.initials: S
authors.lastname: Watson
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Winter
authors.forename: I Nicol
authors.initials: IN
authors.lastname: Ferrier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000627:therapeutic use*; D002985:Clinical Protocols; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000523:psychology; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000523:psychology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008797:Metyrapone / Q000627:therapeutic use*; D008875:Middle Aged; D010865:Pilot Projects; D011788:Quality of Life; D012107:Research Design; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D008797:Metyrapone; D017367:Selective Serotonin Reuptake Inhibitors
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