Antiglucocorticoid augmentation of antiDepressants in Depression (The ADD study)

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Scientific Abstract|Design: Randomised, double blind, placebo controlled trial.|Setting: NHS primary care and specialist mental health secondary care out-patients.|Target population: Men and women aged 18-70 who have a DSM-IV confirmed diagnosis of a major depressive episode that has not responded adequately to at least two different antidepressant treatments.|Interventions being evaluated: The study is of augmentation of ongoing antidepressant treatment. Subjects will be randomised to receive either metyrapone 500mg, or placebo, twice a day for 3 weeks, in addition to their current antidepressant medication. |Measurement of outcomes and duration of follow up: The primary outcome is the degree of improvement in depressive symptoms, as rated using the Montgomery Esberg Depression Rating Scale (MADRS), 5 weeks after randomisation (2 weeks after treatment with metyrapone or placebo has ended). Secondary outcomes include MADRS at 3 weeks (i.e. the time metyprapone/placebo is discontinued) and 9 weeks after randomisation to assess the persistence of the effects. Quality of life will be assessed at weeks 3, 5 and 9 using the EQ-5D scale. Hypothalamic-pituitary-adrenal (HPA) axis function will be assessed from saliva samples on waking and every 15 minutes for one hour at weeks 0, 3 and 5. In a sub sample of patients, neuropsychological assessments, fMRI and EEG measures sensitive to serotonin and corticosteroid changes will be made at weeks 0 and 5 to study other outcome markers and the mechanism of the effects of metyrapone.|Sample size: The study is powered on the primary outcome measure - the change in MADRS between start of treatment and week 5. A pilot study found an effect size of 0.63. We have powered the proposed study around the more conservative effect size of 0.5 which is considered by NICE as the clinically meaningful effect size for antidepressant treatments. For a 90% power with alpha = 0.05, 85 subjects are required per group. Allowing for 10% attrition during the trial, we plan to randomise 95 per group, 190 in total. Sub-samples balanced on treatment will be studied to investigate the mechanism of metyrapones effect and the effect sizes predicted for these various measures suggest that the sample sizes will provide an 80-90% power at an alpha of 0.05.|Planned analyses: The primary outcome will be analysed using an independent sample t-test. Repeated measures ANOVA will be used to assess the changes in MADRS and EQ-5D at the secondary outcome time points. Correlational coefficients will examine the relationship between hypothalamic-pituitary-adrenal (HPA) axis function and clinical outcome. |Project timetables including recruitment rate: The study will last 24 months. Months 0-5 will involve staff recruitment and training and setting up of the study. First patient enrolement is planned for 6 months and last enrolement by 20 months, allowing 4 months for data analysis and writing of draft report and papers. Recruitment is anticipated at a rate of 13 patients per month from three Hubs (5 NHS Trusts). This rate is based on past experience of recruitment to similar studies and population sizes of the three Hubs. |Expertise in team: The team is multidisciplinary including psychiatrists with expertise in the research methodology and in working with this patient population, an endocrinologist providing advice regarding safety issues and assessment of HPA axis function, a psychologist and a medical physicist to support the neuropsychological and fMRI studies respectively, a statistician, a clinical trials expert and a service user and carer.|