Antidepressant for the prevention of DEPression following first episode Psychosis trial (ADEPP)

Background. At least 40% of patients who have first-episode psychosis (FEP- defined as the first experience of significant hallucinations, delusions or disordered thinking with impact on functioning) develop depression in the months after starting treatment for their psychosis. Depression after FEP is related to poorer functional recovery, anxiety, increased risk of relapse, poorer quality of life and suicidal behaviour. Antidepressants work for treating depression in established psychotic disorders such as schizophrenia, however we do not know if antidepressants will prevent the onset of depression early in the course of psychosis. If we are able to prevent depression before it starts, this may improve outcomes for people in the months after FEP, and potentially also in the longer term. Aims and Objectives: To establish the effectiveness and cost effectiveness of an antidepressant medication (sertraline) for the prevention of a depressive episode following FEP. We will establish if, compared with placebo, the addition of sertraline to continuing antipsychotic medication following FEP reduces the likelihood of developing depression over a 6-month intervention period. We will investigate whether this intervention reduces the likelihood of developing anxiety or suicidal behaviour, reduces the risk of psychotic relapse, and improves the level of functional recovery achieved. We will additionally gather evidence as to whether the prescription of antidepressant medication after FEP is cost-effective and whether any clinical benefit and cost-effectiveness continue beyond the 6-month intervention, up to a year. Methods: 452 participants will be recruited to a multi-centre randomised, double-blind, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) sertraline at a dose of 50 mg once a day, for 6 months. We will include an internal pilot with clear stop-go criteria and an additional post-therapy un-blinded follow up. Participants will be recruited from Early Intervention in Psychosis Services in England and Wales, within 12 months of FEP treatment onset. Analysis: The analysis will be on an intention-to-treat basis. The primary outcome will be the proportion of participants assigned sertraline who become depressed compared with those assigned placebo. A chi-squared or Fisher’s exact test will be used to compare this outcome between the treatment arms, with a sample size powered to detect a significant reduction from 40 to 25%. Secondary analyses will compare the mean difference between patients in the sertraline and placebo arms on longitudinal measures of anxiety, positive symptoms, suicidal behaviour and functional recovery. We will include an economic evaluation based on the cost per case of depression avoided, and the cost per Quality-Adjusted Life Year gained. Impact: Should analysis of the ADEPP trial show that sertraline is effective, together with our health economic analyses we will have sufficient evidence to make clear recommendations to NICE and other international bodies providing guidance on the treatment of FEP. A reduction in post-psychotic depression will have the potential to reduce self-harm and suicide (the early phase of psychosis is a high-risk period), reduce relapse and raise functional outcome during a critical period. Given that over 21 million people in the world are living with a psychotic illness, there is the potential for very significant clinical impact.