Safety and Effectiveness of Pharmacotherapy for Depression in Adults Who Have Sustained a Traumatic Brain Injury: a Systematic Review Protocol

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 disabling 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

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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

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pharmacological management of depressive symp- resonance imaging), Glasgow Coma Scale score, tomatology in adults who have sustained a TBI. post-traumatic amnesia, loss of consciousness. Gaps in the evidence together with weaknesses in Self-report of TBI from either the individual or an study design will be highlighted, offering directions informant in the absence of other medical evidence for future research. Recommendations for pharma- regarding the head injury as outlined above will not covigilance will be outlined. be deemed sufficient. A preliminary search (performed in December Studies of acquired brain injury populations will 2016) of PubMed, Cochrane Library, JBI Database only be included if data for the TBI group are of Systematic Reviews and Implementation Reports, reported separately. The literature indicates variance PROSPERO and Epistemonikos found that there are in the criteria used to diagnose traumatic brain no recent systematic reviews that consider research injuries and depressive symptoms.36 There will be published since October 2014 or systematic review no exclusion of studies based on their use of different protocols exploring the precise review objective and diagnostic and assessment criteria. questions, with the inclusion criteria of interest for The current review will exclude: this review. Studies that include self-reported TBI in the absence of other medical evidence regarding the Inclusion criteria head injury. Types of participants Studies that rely on self reports of depressive The review will include studies of persons post-TBI symptoms in the absence of a standardized diag- who present with depressive symptoms. The pres- nostic interview procedure, validated scale or ence or absence of depressive symptoms must be DSM criteria. determined using a standardized diagnostic inter- Studies that include mixed brain injury popula- view procedure, a validated assessment tool or tions where the data on TBI are not able to Diagnostic and StatisticalManualofMentalDis- be disaggregated. orders criteria (DSM). Studies that rely on self- Studies that report on clusters of individuals reported depressive symptoms that have not used rather than individuals themselves, for example, either an interview or valid rating scale will not clinic attendees, families, people living in a be included. defined geographical area. The review will consider studies that include adults, both males and females, who have sustained Types of intervention(s) a TBI of any severity. Studies where 80% of the The current review will consider studies that evalu- baseline population are 16 years and over will ate the use of pharmacotherapy interventions. All be eligible for inclusion. Traumatic brain injury is pharmacotherapy will be included. This will primar- defined as an alteration in brain function, or other ily include antidepressant medications including evidence of brain pathology, caused by an external selective serotonin re-uptake inhibitors (SSRI), sero- force. Studies will be included regardless of the tonin-norepinephrine (noradrenaline) reuptake mechanism of injury. Post-TBI patients in both the inhibitors (SNRI), tricyclic antidepressants and early stages of recovery and in rehabilitation will monoamine oxidase inhibitors. It may also include be included. Studies of participants with closed and benzodiazepines and neurostimulants. No restric- open head injury, penetrating head injury and non- tion on dose, duration, frequency, timing of delivery penetrating head injury will be eligible for inclusion. or combination of pharmacotherapies drugs will Participants must have definite medical evidence of be made. TBI. For the purpose of this review, this means that Studies reporting mixed interventions (e.g. phar- TBI has been documented in medical records macotherapy and psychological therapy) will be or other health-medical reports sighted by the included if the data for the pharmacotherapeutic research team associated with the published article. intervention is reported separately. These record reports must provide unequivocal The current review will exclude studies of com- evidence of injury. Examples of unequivocal evi- plementary medicines and over the counter medicine dence include findings from brain imaging unless these are part of the intervention, as a (e.g. computed tomography [CT] scan, magnetic co-intervention to pharmacotherapy.

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Comparator(s) Functional Independence Measure, Glasgow The current review will include studies that compare Outcome Scale-Extended, Community Integra- the intervention to all types of comparators. There tion Questionnaire.36 will be no restrictions on the type of comparator. Cognitive functioning using validated measure- Placebo (dummy or active), supportive or standard ment instruments including but not limited to the care or a non-pharmacological intervention will be Wechsler Adult intelligence scale and the Wechs- accepted. Studies comparing drugs within a pharma- ler Memory Scale.36 cological class will also be included. Health-related quality of life using validated measurement instruments such as the Medical Outcomes Outcomes Short Form 36. The current review will preferentially report on all Change in co-morbid anxiety symptoms mea- and any validated disease specific and generic measured using validated measurement scales such surement tools used in each of the included studies as the Hospital Anxiety and Depression Scale.36 for the measurement of the primary and secondary outcomes of interest. For some of the outcomes of Types of studies interest, validated measurement scales may not be The current review will consider the following study available. In this situation, information on outcomes types: will be reported as described in the included study. Randomized controlled trials The primary outcomes of interest for the review Controlled non-randomized clinical trials will be: Quasi-RCTs including, but not limited, to con- Treatment efficacy as measured by an improve- trolled before and after studies, interrupted time ment in depressive symptoms and diagnoses. series with a control group, and interrupted time Severity of depression, response to treatment, series without a parallel concurrent control remission following treatment and loss of depres- group sion diagnosis will be reported according to the Analytical observational studies (including co- criteria specified in individual papers. This will hort and case control studies) be measured using validated measurement instru- Case series with pre-test/post-test outcomes ments such as but not limited to the Hamilton Single arm studies. Depression Rating Scale, Centre for Epidemio- The literature search will be limited to the English logic Studies Depression Inventory Hospital Anx- language and human subjects. If we identify poten- iety and Depression Scale and the Beck tially relevant titles in any other language, they will Depression inventory.36 be provided as an appendix to the review. No date Harms including adverse effects resulting from restriction will apply to the search for literature. pharmacotherapy and study dropouts: - Adverse effects: General and specific (qualita- Search strategy tively documented or documented using Med- Published and unpublished studies will be identified ical Dictionary for Regulatory Activities, using a seven-step approach. Initially the Cochrane World Health Organization Adverse Reaction Library and PubMed will be searched to identify key Terminology or other classification systems) words used in the titles and abstracts and in the search associated with pharmacotherapy. The need strategies of relevant published systematic reviews. for medication to manage adverse effects as Second, a more extensive search in international reported. electronic bibliographic databases will be undertaken - Study dropout: Loss to follow-up and leaving to further identify articles. We will search the follow- the study early due to adverse events, ineffi- ing databases with no date limitation: cacy of treatment, death, any reason. MEDLINE, OVID SP interface The secondary outcomes of interest for the review PubMed excluding MEDLINE will be: CINAHL: Cumulative Index to Nursing and Functional independence in activities of daily Allied Health Literature living measured using validated measurement Embase: Excerpta Medica Database excluding instruments such as but not limited to the MEDLINE, OVID SP interface

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PsycINFO, OVID SP interface Study selection Cochrane Library: CENTRAL. Following the search, all identified citations will be An information specialist with extensive experi- collated and uploaded into Endnote and duplicates ence in conducting systematic reviews will develop removed. Titles and abstracts will then be screened and run the search strategy for each database. Third, by two independent reviewers for assessment against reference lists of retrieved articles will be reviewed to the inclusion and exclusion criteria for the review. identify research not located through other search Where there is disagreement over whether a study is strategies. Fourth, electronic searching of the follow- included, a third team member will review the article ing online journals: Brain Injury, Neuropsychology, and adjudicate. Journal of Neurotrauma and Journal of Head Studies that potentially meet the inclusion criteria Trauma Rehabilitation will be carried out. Fifth, at the title and abstract stage will be retrieved in full clinical trial registries will be searched to identify and independently assessed against the inclusion ongoing studies. The trial registers to be searched criteria by two review team members. We will seek include International Clinical Trials Registry Plat- additional information from study authors where form Search Portal and ClinicalTrials.gov. Sixth, we necessary to resolve questions about eligibility. will search Research Gate and international drug Any disagreement over the eligibility of particular regulators Food and Drug Administration and Eu- studies will be resolved through discussion with a ropean Medicines Agency, and the Medicines and third reviewer. All discussions on eligibility will be Healthcare products Regulatory Agency to identify documented including the reasons for excluding unpublished studies. In addition, we will correspond studies. with colleagues and collaborators for additional Full text studies that do not meet the inclusion studies. Finally, to ensure as complete a search as criteria will be excluded and reasons for exclusion possible, we will supplement formal database will be provided in an appendix in the final system- searches with additional citations from Google atic review report. Included studies will then under- Scholar. go a process of critical appraisal. The results of the If the review takes more than six months to search will be presented in a Preferred Reporting undertake from the date of the literature searches, Items for Systematic Reviews and Meta-Analyses we will re-run searches just before the final analyses (PRISMA) flow diagram. to identify any recent studies that meet the inclusion Inter-rater reliability between the independent criteria for this review. We will develop a search reviewers will be measured using percent agreement strategy that includes a range of Medical Subject and Cohen’s kappa at the full text screening stage, Headings terms and keywords linked by Boolean assessment of methodological quality and selection operators. The search strategies for the other data- for meta-analysis. All decision making will be care- bases will be based on the PubMed strategy and fully documented, and all electronic searches will be modified in accordance with the specific require- saved on file where possible. ments of other databases. While we anticipate that there will be limited The current review is part of a large project that scope for a meta-analysis because of the range of will review and update the current evidence on a study designs, diagnostic criteria and outcome mea- range of neurobehavioral symptoms as the first stage sures across the included studies, should a meta- in the development of a clinical guideline on phar- analysis become feasible, two review authors will macotherapy for the management of neurobehavio- independently review all included studies for inclu- ral symptoms in adults post-TBI in Australia. The sion in meta-analysis. Where there is disagreement search strategy was developed based on the PICO over whether a study is included, a third team (Population, Intervention, Comparator, Outcome) member will adjudicate. elements of relevance to this review (P ¼ TBI with depressive symptoms, I ¼ pharmacotherapy). Assessment of methodological quality Results from the database search will be downloaded The current review forms part of a larger research into Endnote (Clarivate Analytics, PA, USA) and de- project that will develop a clinical guideline notion- duplicated. A full search strategy for MEDLINE is ally entitled, ‘‘Pharmacological management of provided in Appendix I. neurobehavioral symptoms following TBI’’. The

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guideline will be informed by a series of systematic analysis. The specific data items that will be collected reviews. These include: will be: New Cochrane reviews of RCTs and updates of Country where study carried out current Cochrane reviews. Study setting Systematic reviews of pharmacotherapy for Study population – traumatic brain injuries depression and anxiety disorders post-TBI. These (severity, assessment scales, other injuries, time reviews will include both randomized and non- post-injury) randomized study designs. Neurobehavioral symptom – depression (assess- Systematic reviews of pharmacotherapy for the ment scales, severity, other symptoms, timing of management of agitation, aggression, irritability, onset, diagnostic criteria) psychosis, emotional lability and apathy that will Study design only include non-randomized study designs. No Main inclusion and exclusion criteria relevant randomized study designs have been Details of the pharmacotherapy intervention/ex- identified for some of these symptoms. More- posure and control conditions if used including over, some of the available RCTs differ from type of pharmacological compound, treatment other types of studies in regards to certain pa- dose, frequency and duration, generic and trade rameters including length of follow-up and names of pharmacotherapy, drug class sample size. Co-interventions and their details (dose, intensi- A number of these reviews are in process. For ty, frequency, etc.) consistency purposes and to be able to easily com- Outcomes, outcome measures and timing of pare across these reviews and previous reviews of measurement the topic, we will use the standardized critical Type of financial support received to carry out appraisal instruments from the Cochrane Collabo- the study ration37 and the Newcastle-Ottawa instruments38 Baseline sample size to critically appraise studies. We will also assess and Statistical analysis methods report methodological quality using the Joanna Participant demographics and baseline character- Briggs Institute Meta Analysis of Statistics Assess- istics ment and Review Instrument critical appraisal Recruitment and study completion rates; compli- instruments.39 Independent critical appraisal will ance rates, extent of missing data be conducted by two reviewers. Any disagreements Main results that arise between the reviewers will be resolved Treatment harms and adverse events. throughdiscussionorwithathirdreviewer.The Due to possible variation in the definition of TBI methodological quality assessments for each study and depression over time, we will extract definitions will be presented in the results section. The of each as reported in individual studies. assessment of methodological quality will con- tribute to an evaluation of the quality of the Data synthesis evidence and the impact of bias on the find- We will provide a narrative descriptive synthesis of ings. No studies will be excluded based on method- the findings structured around the type of pharma- ological quality. cotherapy, depressive symptoms, target population characteristics, study methodology, outcomes and Data extraction intervention. This narrative synthesis will explain Where available, we will extract data from each of the relationships and findings within and between the included studies on design, analysis and results. the included studies. Where data are available, we Data will be extracted from included studies using a will provide summaries of pharmacotherapeutic customized data extraction tool (Appendix II) based effects for each study by calculating risk ratios on the standardized data extraction tool from JBI- (dichotomous outcomes) or standardized mean dif- System for the Unified Management, Assessment ferences (continuous outcomes). and Review of Information.39 It will be piloted Suitability for meta-analysis will be determined and refined early in the data extraction phase to by the degree of heterogeneity (clinical and statisti- accurately capture all of the data required for cal) observed between the studies.39 We will

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calculate the effect measures by obtaining the rela- Severity of depressive symptoms (mild, moderate tive risks with their 95% confidence intervals and and severe). pooled according to study design (clinical trials and The current review will be reported in accordance observational studies, respectively) using a random with the PRISMA guidelines.40 As we expect to effects model. Statistical heterogeneity will be include many observational studies, these will be assessed using the I2 statistic and the chi-square reported according to the strengthening the (P < 0.1 will be considered statistically significant). reporting of observational studies in epidemiology We will interpret an I2 estimate 50% as evidence of guidelines.41 Study characteristics and measured substantial heterogeneity.37 We anticipate that there outcomes will be compiled into summary tables. If will be limited scope for meta-analysis because of the a meta-analysis is possible, results will be presented range of different study designs, diagnostic criteria in a forest plot. In the event of protocol amendments, and outcomes measured across the included studies. we will provide in the systematic review report the However, where at least five studies have used the date of each amendment in a tabular form alongside same study design, type of intervention/exposure an explicit description and justifications of all devi- and comparator, and outcome measure, we will pool ations from the approved peer reviewed systematic the results using a random-effects meta-analysis, review protocol. with standardized mean differences for continuous outcomes and risk ratios for binary outcomes, and Assessing confidence calculate 95% confidence intervals and two-sided If we find sufficient information in the research P values for each outcome.39 literature for the different pharmacotherapy inter- We will contact authors where substantial out- ventions, we will use the Grades of Recommenda- comes of interest are not reported or to clarify tion, Assessment, Development and Evaluation uncertainty about study characteristics. For RCTs, (GRADE) approach to define the quality of the controlled and quasi-randomized study design, miss- evidence in terms of the extent to which one can ing data for dichotomous outcomes will be taken be confident that an estimate of effect or association into account using an intention-to-treat analysis is close to the quantity of specific interest. The using imputation based on event rate observed in quality of evidence will be assessed across the the control group. A funnel plot will be generated to domains of risk of bias, consistency, directness, assess publication bias if there are more 10 or more precision and publication bias. Quality will be ad- studies included in a meta-analysis. Statistical tests judicated as: for funnel plot asymmetry (Egger and Begg tests) will High (further research is very unlikely to change be performed where appropriate. our confidence in the estimate of effect) In published reviews of this topic, subgroup anal- Moderate (further research is likely to have an yses have been limited to the type of antidepressant important impact on our confidence in the esti- used.28,30 If the necessary data are available, sub- mate of effect and may change the estimate) group analyses will be done according to the follow- Low (further research is very likely to have an ing categories. important impact on our confidence in the esti- Gender (male and female) mate of effect and is likely to change the estimate) Age (<20, 20–30, 30–40 and >40 years) Very low (very uncertain about the estimate of Severity of TBI (mild, moderate and severe) effect). Medication dosage We will use the GRADE profiler GRADEpro to Adverse effects (serious versus non-serious) import data from RevMan 5.3 (The Nordic Cochrane Single or more than one pharmacological regimen Centre, Cochrane, Copenhagen, Denmark) to create Treatment of single neurobehavioral symptom ‘‘Summary of findings’’ tables. Summary of findings (e.g. depression only) or multiple symptoms tables provide outcome-specific information con- (e.g. depression and anxiety) cerning the overall quality of evidence from each Medication type (e.g. antidepressants and neuro- included study in the comparison, the magnitude of stimulants) effect of the interventions examined and the sum of Class of antidepressants (e.g. SSRI, SNRI and available data on all outcomes rated as important to Tricyclics) patient care and decision making. All decisions will be

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recorded and provided as supplementary data. This 7. Koskinen S. Quality of life 10 years after a very severe will enable readers to appreciate the degree of any traumatic brain injury (TBI): the perspective of the injured uncertainty as well as provide greater transparency. and the closest relative. Brain Inj 1998;12(8):631–48. If the data are sufficient, summary of findings 8. Zgaljardic DJ, Seale GS, Schaefer LA, Temple RO, Foreman J, tables will be prepared on the following outcomes: Elliott TR. Psychiatric disease and post-acute traumatic brain injury. J Neurotrauma 2015;32(23):1911–25. treatment efficacy, quality of life, cognitive function- 9. Hibbard MR, Uysal S, Kepler K, Bogdany J, Silver J. Axis I ing, functional independence in activities of daily psychopathology in individuals with traumatic brain injury. living, study dropout and adverse events. J Head Trauma Rehabil 1998;13(4):24–39. 10. Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Acknowledgements Dikmen SS. Rates of major depressive disorder and The authors acknowledge with thanks the input of clinical outcomes following traumatic brain injury. JAMA 2010;303(19):1938–45. our information specialist, Farhad Shokraneh, in the 11. Ste´fan A, Mathe´ JF. SOFMER Group. What are the disruptive design of search strategies. The Institute for Safety, symptoms of behavioral disorders after traumatic brain Compensation and Recovery Research (ISCRR), injury? A systematic review leading to recommenda- Monash University, provided funding for this review tions for good practices. Ann Phys Rehabil Med 2016;59(1): through the Neurotrauma strategy 2010–2015. 5–17. The institute is a research-policy partnership estab- 12. van Reekum R, Cohen T, Wong J. Can traumatic brain injury lished in 2009 via an agreement between WorkSafe cause psychiatric disorders? J Neuropsychiatry Clin Neurosci Victoria, the Transport Accident Commission (TAC) 2000;12(3):316–27. and Monash University. The funder will not be 13. Rosenthal M, Christensen BK, Ross TP. Depression following involved in any other aspect of the project. This traumatic brain injury. Arch Phys Med Rehabil 1998;79(1): includes the preparation and submission of the pro- 90–103. 14. Seel RT, Kreutzer JS, Rosenthal M, Hammond FM, Corrigan tocol, all aspects of the proposed review method JD, Black K. Depression after traumatic brain injury: a and the preparation of the review manuscript for National Institute on Disability and Rehabilitation Research submission. Model Systems multicenter investigation. Arch Phys Med Rehabil 2003;84(2):177–84. References 15. Masel BE, DeWitt DS. Traumatic brain injury: a disease 1. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology process, not an event. J Neurotrauma 2010;27(8): and impact of traumatic brain injury: a brief overview. 1529–40. 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Jorge RE, Robinson RG, Arndt S. Are there symptoms that Frencham et al. (2005), and Pertab et al. (2009). Clin Neuro- are specific for depressed mood in patients with traumatic psychol 2011;25(4):608–23. brain injury? J Nerv Ment Dis 1993;181(2):91–9.

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22. Jorge RE, Robinson RG, Arndt SV, Starkstein SE, Forrester 32. Plantier D, Luaute´ J. SOFMER Group. Drugs for behavior AW, Geisler F. Depression following traumatic brain injury: disorders after traumatic brain injury: systematic review and a 1 year longitudinal study. J Affect Disord 1993;27(4): expert consensus leading to French recommendations for 233–43. good practice. Ann Phys Rehabil Med 2016;59(1):42–57. 23. Wiart L, Luaute´ J, Stefan A, Plantier D, Hamonet J. Non 33. Marshall S, Bayley M, McCullagh S, Velikonja D, Berrigan L, pharmacological treatments for psychological and behav- Ouchterlony D, et al. Updated clinical practice guidelines for ioural disorders following traumatic brain injury (TBI). A concussion/mild traumatic brain injury and persistent systematic literature review and expert opinion leading symptoms. Brain Inj 2015;29(6):688–700. to recommendations. Ann Phys Rehabil Med 2016;59(1): 34. Ansari A, Jain A, Sharma A, Mittal RS, Gupta ID. Role of 31–41. sertraline in posttraumatic brain injury depression and 24. Chew E, Zafonte RD. Pharmacological management of quality-of-life in TBI. Asian J Neurosurg 2014;9(4):182–8. neurobehavioral disorders following traumatic brain 35. Failla MD, Juengst SB, Graham KM, Arenth PM, Wagner AK. injury – a state-of-the-art review. J Rehabil Res Dev Effects of depression and antidepressant use on cognitive 2009;46(6):851–79. deficits and functional cognition following severe traumatic 25. Albrecht JS, Kiptanui Z, Tsang Y, Khokhar B, Smith brain injury. J Head Trauma Rehabil 2016;31(6):E62–73. GS, Zuckerman IH, et al. Patterns of depression treat- 36. Zaninotto AL, Vicentini JE, Fregni F, Rodrigues PA, Botelho C, ment in Medicare beneficiaries with depression after de Lucia MC, et al. Updates and current perspectives traumatic brain injury. J Neurotrauma 2015;32(16): of psychiatric assessments after traumatic brain injury: a 1223–9. systematic review. Front Psychiatry 2016;14(7):95. 26. Arciniegas DB, Topkoff J, Silver JM. Neuropsychiatric aspects 37. Higgins JPT, Green S (editors). Cochrane Handbook for of traumatic brain injury. Curr Treat Options Neurol Systematic Reviews of Interventions Version 5.1.0 [updated 2000;2(2):169–86. March 2011]. The Cochrane Collaboration, 2011. Available 27. Warden DL, Gordon B, McAllister TW, Silver JM, Barth JT, from: www.handbook.cochrane.org. [Accessed November Bruns J, et al. Neurobehavioral Guidelines Working Group. 5, 2016]. Guidelines for the pharmacologic treatment of neurobeha- 38. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, vioral sequelae of traumatic brain injury. J Neurotrauma et al. The Newcastle–Ottawa Scale (NOS) for assessing the 2006;23(10):1468–501. quality of nonrandomised studies in meta-analyses. Pub- 28. Barker-Collo S, Starkey N, Theadom A. Treatment for de- lished 2008. Available from: http://www.ohri.ca/programs/ pression following mild traumatic brain injury in adults: a clinical_epidemiology/oxford.htm. [Accessed November 12, meta-analysis. Brain Inj 2013;27(10):1124–33. 2016]. 29. Fann JR, Hart T, Schomer KG. Treatment for depression after 39. The Joanna Briggs Institute. Joanna Briggs Institute traumatic brain injury: a systematic review. J Neurotrauma reviewers’ manual: 2014 edition. The Joanna Briggs Insti- 2009;26(12):2383–402. tute. Published 2014. 30. Salter KL, McClure JA, Foley NC, Sequeira K, Teasell RW. 40. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Pharmacotherapy for depression posttraumatic brain Group. Preferred reporting items for systematic reviews and injury: a meta-analysis. J Head Trauma Rehabil 2016;31(4): meta-analyses: the PRISMA Statement. PLoS Med 2009;6(7): E21–32. e1000097. 31. Price A, Rayner L, Okon-Rocha E, Evans A, Valsraj K, 41. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Higginson IJ, et al. Antidepressants for the treatment Vandenbroucke JP. The Strengthening the Reporting of of depression in neurological disorders: a systematic Observational Studies in Epidemiology (STROBE) State- review and meta-analysis of randomised controlled trials. ment: guidelines for reporting observational studies. Ann J Neurol Neurosurg Psychiatry 2011;82(8):914–23. Intern Med 2007;147(8):573–7.

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Appendix I: MEDLINE search strategy

1. Exp Brain Hemorrhage, Traumatic/ OR Brain Injuries/ OR Brain Injury, Chronic/ OR Cerebral Hemorrhage, Traumatic/ OR Cerebrovascular Trauma/ OR Craniocerebral Trauma/ OR Diffuse Axonal Injury/ OR Exp Head Injuries, Closed/ OR Head Injuries, Penetrating/ OR Exp Intracranial Hemorrhage, Traumatic/ OR Exp Pneumocephalus/ OR (((Brain OR Cerebr$ OR Crani$ OR Crushing Skull OR Diffuse Axonal OR Head OR Hemisphere?) adj1 (Injur$ OR Trauma$)) OR ((Cerebr$ OR Crani$ OR Head) adj (Lesion? OR Wound?)) OR ((Posttraumatic OR Traumatic) adj Encephalopath$) OR (Traumatic adj (Brain OR Cerebr$)) OR Concuss$ OR DAI OR DAIs OR Pneumocephalus OR TBI OR TBIs).ti,ab. 2. ‘‘Anti-Anxiety Agents’’/ OR ‘‘Anticonvulsants’’/ OR ‘‘Antidepressive Agents’’/ OR ‘‘Antipsychotic Agents’’/ OR ‘‘Benzodiazepines’’/ OR ‘‘Adrenergic Beta-Antagonists’’/ OR Alprazolam/ OR Amitripty- line/ OR Amoxapine/ OR Aripiprazole/ OR Atenolol/ OR Atomoxetine Hydrochloride/ OR Benztropine/ OR Bromazepam/ OR Bupropion/ OR Buspirone/ OR Carbamazepine/ OR Chlordiazepoxide/ OR Chlorpromazine/ OR Citalopram/ OR Clomipramine/ OR Clonazepam/ OR Clopenthixol/ OR Clor- azepate Dipotassium/ OR Clozapine/ OR Desipramine/ OR Desvenlafaxine Succinate/ OR Dextroam- phetamine/ OR Diazepam/ OR Valproic Acid/ OR Domperidone/ OR Dothiepin/ OR Doxepin/ OR Droperidol/ OR Duloxetine Hydrochloride/ OR Estazolam/ OR Eszopiclone/ OR Flunitrazepam/ OR Fluoxetine/ OR Flupenthixol/ OR Fluphenazine/ OR Fluvoxamine/ OR Guanfacine/ OR Haloperidol/ OR Imipramine/ OR Isocarboxazid/ OR Methotrimeprazine/ OR Lithium/ OR Lithium Carbonate/ OR Lorazepam/ OR Loxapine/ OR Lurasidone Hydrochloride/ OR Methylphenidate/ OR Mianserin/ OR Midazolam/ OR Moclobemide/ OR Molindone/ OR Nitrazepam/ OR Nortriptyline/ OR Oxazepam/ OR Paliperidone Palmitate/ OR Paroxetine/ OR Phenelzine/ OR Phenobarbital/ OR Pindolol/ OR Prazepam/ OR Pregabalin/ OR Prochlorperazine/ OR Promazine/ OR Promethazine/ OR Propranolol/ OR Protriptyline/ OR Quetiapine Fumarate/ OR Remoxipride/ OR Risperidone/ OR Selegiline/ OR Sertraline/ OR Sulpiride/ OR Temazepam/ OR Thioridazine/ OR Thiothixene/ OR Tranylcypromine/ OR Trazodone/ OR Triazolam/ OR Trifluoperazine/ OR Trimipramine/ OR Venlafaxine Hydrochloride/ OR Vigabatrin/ OR ((Adrenergic adj Beta adj2 (Antagonist OR Block$)) OR Anti Anxiety OR Anti Convuls$ OR Anti Depress$ OR Anti Epilep$ OR Anti Psychotic? OR Antianxiety OR Anticonvuls$ OR Antidepress$ OR Antiepilep$ OR Antipsychotic$ OR Anxiolytic$ OR Benzodiazepine$ OR (Beta adj Block$) OR (Beta adj1 Adrenergic adj2 Block$) OR Thymoanaleptic$ OR Thymoleptic$ OR Agome- latine OR ‘‘S 20098’’ OR S20098 OR Thymanax OR Valdoxan OR ‘‘AGO 178’’ OR AGO178 OR Alprazolam OR Alprazolan OR ‘‘Apo Alpraz’’ OR ApoAlpraz OR Cassadan OR ‘‘D 65MT’’ OR D65MT OR Xanax OR Tafil OR Trankimazin OR ‘‘Novo Alprazol’’ OR NovoAlprazol OR ‘‘Nu Alpraz’’ OR NuAlpraz OR Ralozam OR ‘‘U-31,889’’ OR ‘‘U31,889’’ OR Alprox OR Esparon OR Kalma OR Amisulpride OR Sultopride OR Barnetil OR ‘‘DAN 2163’’ OR Solian OR ‘‘LIN 1418’’ OR Amitriptyline OR Amineurin OR Amitrip OR Amitriptylin OR Amitrol OR Tryptine OR ApoAmitripty- line OR Damilen OR Domical OR Laroxyl OR Endep OR Lentizol OR Novoprotect OR Saroten OR Sarotex OR Syneudon OR Triptafen OR Tryptizol OR Tryptanol OR Elavil OR Anapsique OR Amoxapine OR Desmethylloxapine OR ‘‘CL 67,772’’ OR ‘‘CL67,772’’ OR Demolox OR Asendin OR Defanyl OR Asendis OR Aripiprazole OR Aripiprazol OR ‘‘OPC 14597’’ OR Abilify OR Asenapine OR Saphris OR ‘‘ OR G 5222’’ OR Atenolol OR Tenormine OR Tenormin OR ‘‘ICI 66082’’ OR ICI66082 OR Atomoxetine OR Tomoxetine OR Strattera OR ‘‘LY 139603’’ OR Benztropine OR Benzatropine OR Bensylate OR PMSBenztropine OR Cogentin OR Cogentinol OR Methylbenztropine OR ApoBenztropine OR Brexpiprazole OR Bromazepam OR BromaLich OR ‘‘Bromaz 1A Pharma’’ OR Bromazanil OR ‘‘Bromazep von CT’’ OR Durazanil OR Lexotan OR Lexotanil OR Lexatin OR Lexomil OR ‘‘Ro 5–3350’’ OR ‘‘Ro 53350’’ OR Anxyrex OR Bupropion OR Amfebutamone OR Zyntabac OR Quomen OR Wellbutrin OR Zyban OR Buspirone OR ‘‘MJ 9022 1’’ OR MJ90221 OR Neurosine OR Busp OR Anxut OR Buspar OR Bespar OR Carbamazepine OR Tegretol OR Carbazepin OR Epitol OR Finlepsin OR Neurotol OR Amizepine OR Cariprazine OR ‘‘RGH 188’’ OR Chlordiazepoxide OR

JBI Database of Systematic Reviews and Implementation Reports ß 2017 THE JOANNA BRIGGS INSTITUTE 2279

Methaminodiazepoxide OR Librium OR Chlozepid OR Elenium OR Chlorpromazine OR Thorazine OR Aminazine OR Largactil OR Chlordelazine OR Contomin OR Fenactil OR Propaphenin OR Chlorazine OR Citalopram OR Cytalopram OR ‘‘Lu 10 171’’ OR Lu10171 OR Escitalopram OR Lexapro OR Clobazam OR ‘‘HR 376’’ OR Onfi OR ‘‘LM 2717’’ OR Frisium OR Urbanyl OR Clomipramine OR Chlomipramine OR Chlorimipramine OR Hydiphen OR Anafranil OR Clonazepam OR ‘‘Ro 5 4023’’ OR ‘‘Ro 54023’’ OR Antelepsin OR Rivotril OR Clopenthixol OR Zuclopenthixol OR Cisordinol OR Clorazepate OR Chlorazepate OR Tranxene OR Tranxilium OR ‘‘4306 CB’’ OR Clozapine OR Clozaril OR Leponex OR Desipramine OR Desmethylimipramine OR Demethylimipr- amine OR Norpramin OR Pertofrane OR Pertrofran OR Pertofran OR Petylyl OR Desvenlafaxine OR ‘‘O Desmethylvenlafaxine’’ OR ‘‘WY 45,233’’ OR ‘‘WY 45,233’’ OR ‘‘WY45,233’’ OR ‘‘WY 45233’’ OR WY45233 OR Pristiq OR Dextroamphetamine OR Dexamphetamine OR Dexamfetamine OR ‘‘Dextro Amphetamine’’ OR ‘‘D Amphetamine’’ OR Dexedrine OR DextroStat OR Oxydess OR Diazepam OR Diazemuls OR Faustan OR Valium OR Seduxen OR Sibazon OR Stesolid OR Apaurin OR Relanium OR ‘‘Valproic Acid’’ OR Divalproex OR ‘‘Propylisopropylacetic Acid’’ OR ‘‘2 Propyl- pentanoic Acid’’ OR Convulsofin OR Depakene OR Depakine OR Depakote OR Vupral OR Valproate OR Ergenyl OR ‘‘Dipropyl Acetate’’ OR Domperidone OR Domperidon OR Domidon OR Gastrocure OR Motilium OR Nauzelin OR Peridys OR ‘‘R 33,812’’ OR ‘‘R33,812’’ OR ‘‘R 33812’’ OR R33812 OR Dothiepin OR Dosulepin OR Prothiaden OR Doxepin OR Deptran OR Desidox OR Doneurin OR Doxepia OR Espadox OR Mareen OR Prudoxin OR Quitaxon OR Sinequan OR Sinquan OR Zonalon OR Xepin OR Aponal OR ApoDoxepin OR Droperidol OR Inapsine OR Dehidrobenzperidol OR Dehydrobenzperidol OR Droleptan OR Duloxetine OR ‘‘LY 248686’’ OR LY248686 OR ‘‘LY 227942’’ OR LY227942 OR Cymbalta OR Estazolam OR Tasedan OR ProSom OR ‘‘D 40TA’’ OR D40TA OR Nuctalon OR Eszopiclone OR Lunesta OR Estorra OR Flunitrazepam OR Fluridrazepam OR Flunibeta OR Flunimerck OR Fluninoc OR Rohypnol OR Rohipnol OR Narcozep OR ‘‘Flunizep von CT’’ OR ‘‘RO 5 4200’’ OR RO54200 OR Fluoxetine OR Fluoxetin OR ‘‘Lilly 110140’’ OR Lilly110140 OR Sarafem OR Prozac OR Flupenthixol OR Flupentixol OR Emergil OR Fluanxol OR Fluphenazine OR Flufenazin OR Lyogen OR Prolixin OR Fluvoxamine OR Fluvoxadura OR Fluvoxamin OR Fluvoxamina OR Luvox OR Fevarin OR Floxyfral OR Dumirox OR Faverin OR Desiflu OR ‘‘DU 23000’’ OR DU23000 OR Guanfacine OR Tenex OR Lon798 OR ‘‘BS 100 141’’ OR BS100141 OR Estulic OR Haloperidol OR Haldol OR Iloperidone OR Zomaril OR Fanapt OR ‘‘HP 873’’ OR Imipramine OR Imizin OR Norchlorimipramine OR Imidobenzyle OR Tofranil OR Melipramine OR Pryleugan OR Janimine OR Isocarboxazid OR Lamotrigine OR Crisomet OR Lamictal OR Lamiktal OR ‘‘BW 430C’’ OR Labileno OR Methotrimeprazine OR Levomepromazine OR Levopro- mazine OR Levomeprazin OR Tisercin OR Tizercine OR Tizertsin OR Lithium OR Dilithium OR Lithane OR Lithobid OR Lithonate OR ‘‘CP-15,467 61’’ OR ‘‘CP15,46761’’ OR Micalith OR ‘‘NSC 16895’’ OR NSC16895 OR Priadel OR ‘‘Quilinorm Retard’’ OR Quilinormretard OR Eskalith OR Lithotabs OR Lorazepam OR Ativan OR Temesta OR ‘‘Orfidal Wyeth’’ OR Donix OR Duralozam OR Durazolam OR Idalprem OR Laubeel OR ‘‘Lorazep von CT’’ OR ‘‘Novo Lorazem’’ OR NovoLorazem OR ‘‘Nu Loraz’’ OR NuLoraz OR Sedicepan OR Sinestron OR Somagerol OR Tolid OR ‘‘WY 4036’’ OR WY4036 OR ApoLorazepam OR Loxapine OR Cloxazepine OR Oxilapine OR Loxitane OR Loxipine OR Loxapinsuccinate OR ‘‘CL 71,563’’ OR ‘‘CL71,563’’ OR Lurasidone OR ‘‘SM 13496’’ OR SM13496 OR ‘‘SM-13,496’’ OR ‘‘SM13,496’’ OR Latuda OR Methylphenidate OR Metadate OR Equasym OR Methylin OR Concerta OR Phenidylate OR Ritalin OR Ritaline OR Tsentedrin OR Centedrin OR Daytrana OR Mianserin OR Tolvon OR Lerivon OR Org GB 94 OR Midazolam OR Dormicum OR Versed OR ‘‘Ro 21 3981’’ OR ‘‘Ro 213981’’ OR Milnacipran OR Midalcipran OR Levomilnacipran OR Savella OR ‘‘F 2207’’ OR Ixel OR Mirtazapine OR ‘‘6 Azamianserin’’ OR Esmirtazapine OR Remeron OR Remergil OR Zispin OR Norset OR Rexer OR ‘‘Org 50081’’ OR ‘‘ OR G 3770’’ OR Moclobemide OR Moclobamide OR Arima OR Aurorix OR Manerix OR Moclamine OR Aurorex OR Deprenorm OR Feraken OR Moclobemid OR Moclobeta OR Moclodura OR Moclonorm OR Rimoc OR ‘‘Ro 11 1163’’ OR Modafinil OR Benzhydrylsulfinylacetamide OR

JBI Database of Systematic Reviews and Implementation Reports ß 2017 THE JOANNA BRIGGS INSTITUTE 2280

‘‘CRL 40476’’ OR Vigil OR Provigil OR Sparlon OR Alertec OR Modiodal OR Molindone OR Moban OR Nefazodone OR Rulivan OR Serzone OR Dutonin OR Nefadar OR Menfazona OR Nitrazepam OR Nitrodiazepam OR ‘‘Dormo Puren’’ OR Eatan OR Imadorm OR Imeson OR Mogadon OR Nitrazadon OR Nitrazep OR Novanox OR Radedorm OR Remnos OR Serenade OR Somnite OR Alodorm OR Dormalon OR Nortriptyline OR Desmethylamitriptylin OR Desitriptyline OR Aventyl OR Paxtibi OR Allegron OR Norfenazin OR Pamelor OR Nortrilen OR Olanzapine OR Zolafren OR ‘‘LY 170052’’ OR Zyprexa OR ‘‘LY 170053’’ OR Oxazepam OR Serax OR Tazepam OR Adumbran OR Oxcarba- zepine OR Timox OR Trileptal OR ‘‘GP 47680’’ OR Paliperidone OR ‘‘9 OH Risperidone’’ OR ‘‘9 Hydroxy Risperidone’’ OR ‘‘9 Hydroxyrisperidone’’ OR Invega OR ‘‘R 76477’’ OR R76477 OR Paroxetine OR ‘‘BRL 29060’’ OR BRL29060 OR ‘‘FG 7051’’ OR FG7051 OR Seroxat OR Paxil OR Aropax OR Periciazine OR Propericiazine OR Pericyazine OR Neuleptil OR Neuleptyl OR Aolept OR Phenelzine OR ‘‘Beta Phenylethylhydrazine’’ OR ‘‘2 Phenethylhydrazine’’ OR Fenelzin OR Phene- thylhydrazine OR Nardelzine OR Nardil OR Phenobarbital OR Phenobarbitone OR ‘‘Phenylethylbar- bituric Acid’’ OR Phenemal OR Phenylbarbital OR Hysteps OR Luminal OR Gardenal OR Pindolol OR Prindolol OR Visken OR ‘‘LB 46’’ OR LB46 OR Prazepam OR Lysanxia OR Reapam OR Centrax OR Demetrin OR Pregabalin OR ‘‘3 Isobutyl GABA’’ OR Lyrica OR ‘‘CI 1008’’ OR CI1008 OR Prochlorperazine OR Compazine OR Promazine OR Sparine OR Sinophenin OR Protactyl OR Promethazine OR Prometazin OR Proazamine OR Rumergan OR Diprazin OR Phenergan OR Phenargan OR Phensedyl OR Pipolfen OR Pipolphen OR Promet OR Prothazin OR Pyrethia OR Remsed OR Atosil OR Diphergan OR Propranolol OR Propanolol OR Inderal OR Avlocardyl OR ‘‘AY 20694’’ OR AY20694 OR Rexigen OR Dexpropranolol OR Dociton OR Obsidan OR Obzidan OR Anaprilin OR Anapriline OR Betadren OR Protriptyline OR Vivactil OR Quetiapine OR ‘‘ICI 204,636’’ OR ‘‘ICI 204636’’ OR ICI204636 OR Seroquel OR Reboxetine OR Vestra OR Remoxipride OR ‘‘FLA 731’’ OR FLA731 OR Risperidone OR Risperdal OR Risperidal OR ‘‘R 64,766’’ OR ‘‘R64,766’’ OR ‘‘R 64766’’ OR R64766 OR Selegiline OR Selegyline OR ‘‘L Deprenyl’’ OR ‘‘E 250’’ OR E250 OR Eldepryl OR Emsam OR Zelapar OR Deprenil OR Deprenalin OR Yumex OR Jumex OR Humex OR Deprenyl OR Sertindole OR Serlect OR ‘‘Lu 23 174’’ OR Serdolect OR Sertraline OR Zoloft OR Altruline OR Lustral OR Aremis OR Besitran OR Sealdin OR Gladem OR Sulpiride OR Sulperide OR Arminol OR Deponerton OR Meresa OR Desisulpid OR Digton OR Dogmatil OR Dolmatil OR Eglonyl OR Ekilid OR Guastil OR Lebopride OR Neogama OR Pontiride OR Psicocen OR Sulp OR Sulpitil OR Sulpivert OR Sulpor OR Synedil OR Tepavil OR Aiglonyl OR Temazepam OR Hydroxydiazepam OR Methyloxazepam OR Signopam OR Tenox OR ‘‘WY 3917’’ OR WY3917 OR Dasuen OR Euhypnos OR Levanxol OR ‘‘Norkotral Tema’’ OR Normison OR Nocturne OR Temtabs OR Normitab OR Nortem OR Planum OR ‘‘Pronervon T’’ OR Remestan OR Restoril OR ‘‘Ro 5 5345’’ OR Ro55345 OR ‘‘SaH 47 603’’ OR ‘‘SaH 47603’’ OR Temaze OR ‘‘Temazep von CT’’ OR Thioridazine OR ApoThioridazine OR Meleril OR Melleril OR Melleryl OR Mellaril OR Melleretten OR Melzine OR Thiozine OR Sonapax OR Thioridazineneurazpharm OR Aldazine OR Rideril OR Thiothixene OR Tiotixene OR Navane OR Topiramate OR USL255 OR ‘‘McN 4853’’ OR Topamax OR Epitomax OR Tranylcypromine OR ‘‘Trans 2 Phenylcyclopropylamine’’ OR Jatrosom OR Trans- amine OR Parnate OR Trazodone OR Tradozone OR ‘‘AF 1161’’ OR AF1161 OR Deprax OR Desyrel OR Molipaxin OR Trittico OR Thombran OR ‘‘Trazodon Hexal’’ OR ‘‘Trazodon Neuraxpharm’’ OR Trazon OR Triazolam OR ‘‘U 33,030’’ OR ‘‘U33,030’’ OR Halcion OR Trilam OR ‘‘Apo Triazo’’ OR Trifluoperazine OR Trifluoroperazine OR Trifluperazine OR Eskazine OR Flupazine OR Terfluzine OR Triftazin OR Stelazine OR Trimipramine OR Trimeprimine OR Herphonal OR Trimineurin OR NovoTripramine OR Rhotrimine OR Stangyl OR Surmontil OR Trimidura OR Trimineurin OR Trimipramin OR ‘‘Apo Trimip’’ OR ApoTrimip OR Eldoral OR Venlafaxine OR ‘‘Wy 45030’’ OR Wy45030 OR ‘‘Wy 45,030’’ OR ‘‘Wy45,030’’ OR Effexor OR Trevilor OR Vandral OR Efexor OR Dobupal OR Vigabatrin OR ‘‘Gamma Vinyl GABA’’ OR ‘‘Gamma Vinyl Gamma Aminobutyric Acid’’ OR Sabril OR Sabrilex OR Vortioxetine OR Brintellix OR ‘‘Lu AA21004’’ OR LuAA21004 OR Zaleplon OR ‘‘SKP 1041’’ OR Sonata OR Zelepion OR Starnoc OR ‘‘CL 284,846’’ OR ‘‘CL284,846’’

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OR ‘‘CL 284846’’ OR ‘‘L 846’’ OR Ziprasidone OR Ziprazidone OR ‘‘CP 88,059’’ OR ‘‘CP 88059’’ OR Zolpidem OR Amsic OR Bikalm OR Dalparan OR ‘‘SL 80.0750’’ OR ‘‘SL 800750 23 N’’ OR Stilnoct OR Stilnox OR Zodormdura OR Zoldem OR Zolirin OR ‘‘Zolpi Lich’’ OR Zolpinox OR Zolpimist OR Ambien OR Zopiclone OR Zop OR Zopicalma OR Zopiclodura OR Zopiclon OR Zopitan OR Zorclone OR Imovane OR Ximovan OR Zimovane OR Limovan OR Optidorm OR Rhovane OR ‘‘RP 27 267’’ OR Siaten OR Somnosan OR Zileze OR Zimoclone OR ‘‘Zopi Puren’’ OR Zopicalm OR Zotepine OR Zoleptil OR Nipolept OR Zuclopenthixol OR Zuclopentixol OR Clopixol OR Zuclopenthixole OR Acuphase).ti,ab. 3. (1 AND 2) NOT (Animals NOT (Humans NOT Animals)).sh.

Limit 3 to English

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Appendix II: Data extraction form

Draft Data Extraction Form for ExperimentalI Observational Studies

Reviewer Date _

Author Year

Journal _ _ Record Number _

Financial support received for the study Support indicated Yes/No Source of financial support

Study Method RCT Quasi-RCT Longitudinal

Retrospective Observational Other

Participants Country where study was carried out

Setting

Participant baseline characteristics Age • Range, mean: Group A • Range, mean: Group B Gender • Proportion of Males: Group A • Proportion of Males: Group B Study population – 1. diagnostic criteria 2. severity 3. assessment scales 4. other injuries 5. time post-injury

Neurobehavioural symptom - Depression

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1. diagnostic criteria 2. severity 3. assessment scales 4. other neurobehavioural symptoms 5. timing of onset Main inclusion and exclusion criteria; 1. Inclusion 2. Exclusion

Outcomes

Outcomes included in article

Outcome measures used

Timing of Outcome measurement

Baseline Sample size

Group A Group B

Length of Follow-up

Group A Group B

Interventions Details of Pharmacotherapy Interventions and any control conditions used 1. type of pharmacological compound, 2. generic and trade names of pharmacotherapy 3. treatment dose 4. frequency of dose 5. duration of treatment 6. drug class Intervention A

Intervention B

Co-interventions allowed Details of Co-interventions

Statistical analysis methods

• Descriptive

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• Univariate

• Multivariate

Treatment harms and adverse events

Method of measurement of harms and adverse events

Specific harms and adverse events

Rates

1. Recruitment into the study

2. Loss to Follow-up

3. Compliance With Treatment Interventions

4. Extent Of Missing Data

5. Acceptability

Authors Conclusions:

Reviewers Conclusions:

JBI Database of Systematic Reviews and Implementation Reports ß 2017 THE JOANNA BRIGGS INSTITUTE 2285

Study results

Dichotomous data

Intervention ( ) Intervention ( ) number I total numberI total Outcome number number

Continuous data

Intervention ( ) Intervention ( ) Outcome number I total numberI total number number

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