Title: A multi-centre randomised controlled trial of the clinical and cost-effectiveness of sertraline in preventing depression in adults following a traumatic brain injury
Funder: Department of Health and Social Care

Abstract: Depression is very common following a traumatic brain injury, also called a head injury. Around 50% of people with a head injury will have some form of depression over the next 10 years. This is almost 10 times more common than the general public. There are two main symptoms of depression, a constant low mood and a loss of enjoyment in everyday life. Depression can affect relationships, jobs, education, financial hardship and unhealthy lifestyles like smoking and poor diets. People with depression following a traumatic brain injury tend to die earlier than the rest of the population and they are more likely to commit suicide. _x000D_ _x000D_ Our patient and public involvement group (PPI) recognised the symptoms of depression and also mentioned others such as irritability, confusion, being very sensitive to noises and light. They agree that trying to prevent depression occurring in the first place is very important. The idea that antidepressants given early could stop depression in the first place after a traumatic brain injury was appealing. They said they would want to be given everything for the best chance of recovery. In this study, we want to find out if a commonly used antidepressant called sertraline, is better at preventing depression than a placebo (also called a dummy or ‘fake’ pill). We will also want to study if sertraline improves quality of life, improve other symptoms like headaches, irritability, memory loss, and reduces stress for carers._x000D_ _x000D_ Participants will be recruited from 9 Major Trauma Centres across England and from all walks of life. Patients attending A&E with a traumatic brain injury will be given information about this study. We will wait for any immediate effects of the head injury, such as memory loss, to settle. Those patients who are suitable will be invited to consent to join the study. They will be randomised, that is, they will have an equal chance of receiving sertraline or a placebo. We will start the sertraline at the lowest dose which is 50mg and after 2 weeks increase to 100mg. In the older patient, we will increase the dose more slowly. We will then see participants again at 6 weeks and 3,6, 9 and 12 months. At 12 months the sertraline will be slowly reduced and stopped. We will meet the participants once more at 18 months. We will also seek their consent to link the research data with their GP and hospital records to see how they are getting over the next 10 years._x000D_ _x000D_ We asked some patients attending a typical outpatient clinic for head injury at St George’s Hospital if they would consider participating in this study if it was funded. The vast majority said they were interested in participating in research to prevent depression. _x000D_ _x000D_ We have brought together a unique team of senior doctors and researchers for this study. At each hospital a psychiatrist will lead the research supported by either a neurologist or neurosurgeon, so that patients are safely managed in terms of mental health and physical health. We also have patient groups working with us, such as the charity, Headway. They have already given feedback on the study which helped us to improve our methods. After the study finishes, we will share our results in medical journals, in social media and to leaders of the NHS so that the prevention of depression can be included for this group of patients.

Lay abstract: RESEARCH QUESTION_x000D_ What is the clinical and cost-effectiveness of a selective serotonin reuptake inhibitor (SSRI) for preventing depression following traumatic brain injury?_x000D_ _x000D_ BACKGROUND_x000D_ Traumatic brain injury (TBI) is a disruption in the normal function of the brain caused by an external force. It is one of the most common presentations in Accident and Emergency (A&E) departments, especially in young males and older people. The prevalence rates of post TBI depression (PTD) is on average 10 times higher than the general population, and this risk emerges very soon after the injury. PTD is associated with higher rates of disability, unemployment and premature mortality, including suicide. Those most at risk of PTD are more likely to be older, to be diagnosed with a mild TBI, and have a history of depression. Yet depression is not routinely screened for at TBI presentation, and rarely treated optimally. Our patient participation group have highlighted the lack of medical attention paid to mental health issues and that many neuropsychiatric symptoms are overlooked. Preliminary findings from 2 small randomised controlled trials (RCT) suggest that initiation of a selective serotonin reuptake inhibitor (SSRI) within a few weeks of the TBI could significantly reduce the incidence of PTD. _x000D_ _x000D_ AIMS_x000D_ We aim to build on this evidence by testing the primary hypothesis that in patients with TBI, sertraline 100mg once a day (od) prescribed for 12 months is more effective, and more cost effective, than placebo in reducing i) depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) and ii) incident rate of major depressive disorder (MDD) as measured by the Mini International Neuropsychiatric Interview (MINI), at 12 months from baseline, with interim measures at 6 and 18 months. We will also measure secondary outcomes of quality of life, employment and productivity, carer burden, other neuropsychiatric symptoms and cognitive functioning. We will seek consent for follow up over 10 years and for hospital episodes statistics (HES) data. _x000D_ _x000D_ METHODS_x000D_ The design is a placebo controlled double blind multi-centre RCT stratified by severity of TBI (mild versus moderate/severe) and by site. It is set in 9 Major Trauma Centres (MTC) across England which broadly represent the socioeconomic, geographical and ethnic diversity in TBI. The study population is adults (>=18 years) with mild, moderate or severe TBI who do not have PTD. Patients will be invited to participate as soon as they present and within 4 weeks of the incident. Those without capacity will also be included if they otherwise meet the study criteria. The intervention will consist of sertraline at 50mg once a day (od), and increased to 100mg od after 2 weeks (except in the older adult if it will not be tolerated) for 12 months and then stopped. The control group will receive a matched placebo using the same regimen. Patients will be seen at 2, 6, 12, 24, 52 and 78 weeks for patient monitoring and safety. A sample of n=514 are needed to observe a clinically significant 5 point difference in the PHQ-9 score taking into account 25% attrition. _x000D_ _x000D_ TIMELINE_x000D_ There will a 6 month set up phase, 12 months of recruitment and deliver the intervention, 18 months of follow up and 6 months analysis and dissemination. The total duration is 42 months._x000D_ _x000D_ IMPACT_x000D_ Our findings will inform whether, and how to integrate the screening and management for depression within MTC pathways.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INJURIES AND ACCIDENTS;MENTAL HEALTH