Study protocol for the randomised controlled trial: Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study)

R Hamish Mcallister-Williams ,Eleanor Smith,Najma Siddiqi,Peter Gallagher,Tom Hughes,Fiona H Winter,Chris Speed,Stuart Watson,June Wainright,Allan House ,Baxi Neeraj Prasad Sinha ,Elaine Mccoll ,Adrian J Lloyd ,Heinz Grunze ,James L Barnes ,Ian M Anderson ,In Steen ,Simon H S Pearce ,Peter M Haddad ,I Nicol Ferrier

doi:10.1186/1471-244x-13-205

Abstract

BackgroundSome 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/designPatients 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.DiscussionStrengths 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.Trial registrationCurrent Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.

Highlights

Some patients with depression do not respond to first and second line conventional antidepressants and are characterised as suffering from treatment refractory depression (TRD)
Strengths of the anti-Depressants in Depression” (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

Summary

Introduction

Some patients with depression do not respond to first and second line conventional antidepressants and are characterised as suffering from treatment refractory depression (TRD). 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. Depression is a common disorder, affecting some 10% of the population [1] It is rated by the Disease Control Priorities Project as one of the leading medical contributors to the global burden of disease [2]. The large pragmatic STAR*D study conducted in the USA showed that even with protocol driven treatment, first line therapy with a selective serotonin reuptake inhibitor (SSRI: citalopram) in over 2500 patients was associated with remission in only 28%, and response (defined as a 50% decrease in symptom scores) in less than 50% of patients [6]. Much of the burden is consequent upon this treatment refractory depression (TRD)

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