SYSTEMATIC REVIEW PROTOCOL Safety and effectiveness of pharmacotherapy for depression in adults who have sustained a traumatic brain injury: a systematic review protocol 1,2 1 3 1 2 4 Fiona J. Clay Luke A. Perry Amelia J. Hicks Rachel Batty Catalin Tufanaru Mahesh Jayaram 3,5 6 Jennie Ponsford Malcolm Hopwood 1Department of Psychiatry, Melbourne Neuropsychiatric Centre, The University of Melbourne, Melbourne, Australia, 2The Joanna Briggs Institute, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia, 3Monash-Epworth Rehabilitation Research Centre, Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia, 4Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia, 5School of Psychological Sciences, Monash University, Melbourne, Australia, and 6Professorial Psychiatry Unit, Department of Psychiatry, University of Melbourne, Melbourne, Australia Review objective/question: The objective of this systematic review is to synthesize the current evidence on the effectiveness and harms of pharmacotherapy in the management of depression in adults who have sustained a traumatic brain injury. Keywords Depression; depressive symptomatology; pharmacotherapy; traumatic brain injury JBI Database System Rev Implement Rep 2017; 15(9):2270–2286. Background of TBI survivors report ongoing neurobehavioral and emotional difficulties which may include depres- raumatic brain injury (TBI) comprises a clini- 6 cally heterogeneous group of disorders caused sive symptomatology. Studies indicate that neuro- T behavioral and emotional disturbances impair by trauma inflicted on the brain by a mechanical 7,8 force of external origin. Traumatic brain injury is quality of life the most for TBI survivors. one of the most common causes of death and dis- Depression is one of the most common and dis- abling psychiatric diagnoses for individuals with ability worldwide. In the United States alone, there is 9 an estimated 1.7 million cases of TBI annually,1 with TBI, with reports suggesting that between 12% an incidence of approximately 558 per 100,000 in and 60% of patients with TBI develop depres- 2 3 sion within 12 months of injury, irrespective of the United States and 235 per 100,000 in Europe. 10,11 People aged 15–24 years and over 64 years, males, severity. Rates of depression in persons with TBI are up to 7.5 times higher than rates reported those from low socioeconomic status backgrounds, 12 and individuals with cognitive impairment are dis- in the general population. Depressive symptoms can proportionately affected by TBI.4,5 As the majority vary between persons post-TBI and may include: of TBI cases occur as a result of motor vehicle fatigue, sleep disturbances, irritability, loss of interest 4 in social activities, poor concentration, memory prob- crashes, falls, assault and violence, the consequen- 13-15 ces of TBI can be severe. Although the majority (up lems and feelings of sadness. Moreover, anxiety symptoms co-morbid to depressive symptoms are to 90%) of TBIs are mild and physically recover 11 within three to six months, a substantial proportion common. Development of depressive symptoms post-TBI has been linked to increased post-concussive symptoms, poorer cognitive functioning, poor adher- ence with treatment plans, increased health service Correspondence: Fiona J. Clay, [email protected] utilization, higher healthcare costs as well as poorer Conflict of interest: The chief investigator (MH) has given talks on this psychosocial outcomes.10,16-19 Depression can under- topic for which travel and accommodation have been paid by the organizers. In addition, he has accepted fees for consulting and mine the survivor’s capacity for close relationships, research from the following pharmaceutical companies: Servier, Bio- social independence, activities of daily living includ- 9,20-22 nomics, Novartis, Eli Lilly and Lundbeck. ing employment and community integration. DOI: 10.11124/JBISRIR-2016-003326 Such symptomatology that leads to disabling JBI Database of Systematic Reviews and Implementation Reports ß 2017 THE JOANNA BRIGGS INSTITUTE 2270 ©2017 Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited. SYSTEMATIC REVIEW PROTOCOL F.J. Clay et al. outcomes highlights the importance of treating most recent search (October 2014) to identify rele- depression post-TBI. vant literature for both guidelines and systematic The management of depressive symptomatology reviews, additional relevant studies have been pub- in a person’s post-TBI requires a multimodal and lished.34,35 multidisciplinary approach incorporating social, While recent systematic reviews and guidelines psychological and medical interventions.23 The conclude that prescribing sertraline for depressive aim of pharmacotherapy is to provide targeted treat- symptoms post-TBI may have merit, these conclu- ment for discrete neurobehavioral symptoms and sions are based on a small number of participants emotional disturbances on an individualized basis (n ¼ 348), the majority of whom have sustained a while managing the adverse effects of medications. mild TBI. Barker-Collo et al.28 conducted a meta- To date, standard antidepressant pharmacological analysis of treatment for depression following mild agents for major depressive disorder in the general TBI, reporting that the effectiveness of sertraline population have been used to treat depression post- differed across the included studies. The authors’ TBI.24 Although depression is common post-TBI and overall finding was one of limited effective treat- pharmacotherapies are often prescribed, there is a ments for depression post-TBI. In a second meta- general lack of clinical consensus on their effective- analysis, Salter et al.30 reported that based only on ness and harms, and their place in multimodal man- within group comparisons, pharmacotherapy post- agement of depression post-TBI remains unclear.25 TBI might be associated with a reduction in depres- The extent to which the effectiveness and harms of sive symptoms but that these results should be available pharmacotherapies differs between people treated with caution. The three RCTs included in with TBI and the general population is unclear, with the Salter et al.30 meta-analysis examined three concerns that the TBI population may be more different pharmacotherapies and were based on susceptible to toxicity and refractory to therapeutic a very small number of participants (interventions effects.26,27 Given this, there is an urgent need to n ¼ 48, comparator n ¼ 33). The consensus across review the safety and effectiveness of pharmacother- systematic reviews is that more research is necessary apy for the management of depressive symptoms to develop evidence-based practice guidelines. In the across the TBI severity spectrum. absence of available RCT data, carefully evaluating Previous reviews in this area have focused on mild other study designs with an explicit acknowledge- TBI,28 pharmacological and non-pharmacological ment of inherent biases may provide some data interventions,28,29 clinical trials30 and neurological including data on safety that could inform practice. disorders, including TBI.31 A meta-analysis by Salter The current review forms part of a larger project et al.30 included literature published up to October which aims to synthesize the evidence for pharma- 2014, while a recently published clinical guideline on cotherapy in the treatment of neurobehavioral symp- this topic included literature to 2012 but did not toms post-TBI, as a prelude to the development of a report a risk of bias assessment.32 Of concern is that clinical practice guideline. The ultimate goal of none of the recent reviews have formally considered the guideline is to increase the number of skilled the adverse effects of pharmacotherapy for depres- prescribers with current knowledge of pharmaco- sion post-TBI.28-31 The Canadian clinical practice therapy for adults experiencing neurobehavioral guidelines for concussion/mild TBI and persistent symptoms post-TBI. symptoms graded all evidence on pharmacotherapy As we are focusing on a range of study designs, the as Grade C (expert opinion) except for the optimal systematic review will include a large descriptive duration of pharmacotherapy remaining as incon- component. Risk of bias will be considered when clusive which was graded A (based on at least interpreting the results, therefore, we have incorpo- one randomized controlled trial [RCT], systematic rated validated tools that will assess the methodo- review or meta-analysis).33 The authors of a system- logical quality of a range of study designs including atic review of drugs for behavior disorders after TBI RCTs, controlled non-randomized clinical trials, leading to French recommendation for good practice analytical observational studies and case series. published in 2016 concluded that there was insuffi- Our review will inform health providers, drug cient evidence to standardize drug treatments for regulators, policy makers, researchers and consum- these disorders, (including depression).32 Since the ers as end-users on the safety and efficacy of JBI Database of Systematic Reviews and Implementation Reports ß 2017 THE JOANNA BRIGGS INSTITUTE 2271 ©2017 Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited. SYSTEMATIC REVIEW PROTOCOL F.J. Clay et al. pharmacological management of depressive symp- resonance imaging), Glasgow Coma