Antiglucocorticoid augmentation of antiDepressants in Depression
What is the ADD study?
(Antiglucocorticoid augmentation of antiDepressants in Depression) The ADD study is a multicentre study funded by the National Institute of Health Research and the Medical Research Council through the Efficacy and Mechanism Evaluation (EME) programme. It is being conducted in three centres in the UK – The North East (Newcastle and Teesside), The North West (Manchester) and Leeds.
The ADD study is “translational” – it is a clinical trial based upon clinical and pre-clinical observations leading to rational treatment development:
• Stress has long been acknowledged as being aetiologically important in depression.
• Depression is associated with abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis stress response system with elevated cortisol levels.
• Studies in rats demonstrate that corticosteroids attenuate the 5-HT elevating effects of the SSRI fluoxetine (figure 1A).
• Conversely administering a glucocorticoid antagonist that blocks the effects of corticosteroids has been shown to enhance the effects of fluoxetine (figure 1B).
• A pilot study in Germany has shown that augmenting serotonergic antidepressants with metyrapone (which inhibits cortisol synthesis) enhances response (figure 2).
HAMD-21 scores for metyrapone vs placebo
augmentation of fluvoxamine or nefazadone (n = 63)
Jahn, H. et al. Arch Gen Psychiatry 2004;61:1235-1244
The ADD study builds on this data in two ways:
• It is a large study recruiting 190 patients with depression from primary and secondary care, randomised to metyrapone or placebo augmentation of standard (serotonergic) antidepressants, to assess the utility of this treatment in the NHS for patients with treatment refractory depression.
• It includes a number of mechanistic investigations (using fMRI, EEG and neuropsychological tests) to help understand through which biological mechanism(s) (or processes) metyrapone exerts its effect.
