Title: Antidepressant for the prevention of DEPression following first episode Psychosis trial (ADEPP)
Funder: Department of Health and Social Care

Abstract: Existing treatments for psychosis are only partially effective, with only 30% of people recovering to previous levels of role and work functioning. First episode of psychosis (FEP), which includes illnesses such as schizophrenia, typically begins in the late teens or early 20s and is diagnosed by the presence of hallucinations (such as hearing voices) and delusions (unusual beliefs held with conviction). Medication and cognitive behavioural therapy help to treat these symptoms, but people struggle to return to previous social and work roles, have suicidal thoughts and are at high risk of relapse. These are related to depression experienced after FEP. 40% of people who have experienced FEP will become depressed. _x000D_ _x000D_ Antidepressant medication is effective for treating depression in established schizophrenia, and robust evidence suggests that using antidepressants in people over the age of 18 along with medication for psychosis is safe. However, we want to know whether antidepressant medication can reduce the risk of depression happening at all after FEP, and whether by preventing depression we can improve recovery and reduce relapse._x000D_ _x000D_ Our Patient, Public Involvement and Engagement group (PPIE) co-designed and strongly support this clinical trial. We will compare two groups of people who have had FEP. One group will be given a highly effective antidepressant medication (sertraline) while the other will receive a placebo (‘sugar pill’), to take once a day for 6 months. In all other ways the two groups will receive the same types of treatment including antipsychotic medication and support from Early Intervention Services (EIS). _x000D_ _x000D_ We will monitor people in the study closely and they will receive sensitive testing as to whether they are showing signs of depression or psychosis monthly. If at any time a person is thought to have depression, their multi-disciplinary team will assess them and decide if they need to stop taking trial medication, and their illness be more actively managed_x000D_ _x000D_ We will measure the effectiveness of antidepressant medication by comparing the number of people who become depressed in the treatment versus the placebo groups. We will also measure other things such as recovery, suicidal thoughts or behaviour, anxiety and relapse using standardised assessments as well as monitoring for side-effects. We will also estimate the cost effectiveness of antidepressant medication after FEP to the NHS._x000D_ _x000D_ The study will recruit over 400 people from around the UK who have experienced FEP. This will improve the generalisability of the results, and give patients from many geographical areas the opportunity to join the study and impact the way future care is managed. _x000D_ _x000D_ We will also measure the acceptability of the intervention by peoples willingness to join the study, whether they take their study medication and whether they are happy to continue to be followed up._x000D_ _x000D_ If we find that sertraline is effective in preventing people becoming depressed after FEP, we (including our PPIE group) will be able to write guidelines for clinicians that will help patients achieve a better recovery, which will also result in considerable economic benefit for the NHS. We will engage with NHS decision makers to ensure the results are implemented. This information will also be made available to people experiencing FEP to enable them to make more informed choices about their care.

Lay abstract: 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._x000D_ _x000D_ Aims and Objectives: To establish the effectiveness and cost effectiveness of an antidepressant medication (sertraline) for the prevention of a depressive episode following FEP. _x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH