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Effectiveness of pharmacotherapy for depression after traumatic brain injury in adults: an umbrella review protocol

Hicks, Amelia J.1; Clay, Fiona J.2,3,4; James, Amelia C.1; Hopwood, Malcolm2,4; Ponsford, Jennie L.1

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doi: 10.11124/JBIES-20-00363
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Traumatic brain injury (TBI) is recognized as a significant global health problem, with approximately 69 million individuals sustaining TBI worldwide annually.1 Traumatic brain injury can be defined as an alteration in brain function or other evidence of brain pathology caused by an external force,2 and is most commonly categorized as mild (80% of all injuries), moderate (10%), or severe (10%).3 TBI is associated with a myriad of significant and often chronic sequalae, including physical, cognitive, and behavioral changes, as well as debilitating changes to mood and mental health. Symptoms of depression are among the most commonly reported mood changes.4 Pooled prevelance rates from meta-analyses suggest a 17% prevalence for depressive disorders in the first year post-TBI, with long-term pooled prevalence estimates of 27% to 43% depending on diagnostic method.5,6 There are multiple trajectories of symptom evolution and resolution over time, with evidence of depression symptoms improving over time,7,8 remaining stable,9 and worsening.8

Post-TBI depression can have a considerable impact on the lives of the individuals with TBI, their family members, and the broader health care system. Post-TBI depression is associated with significant health care costs, with the estimated cost for military veterans with comorbid TBI and depression recently estimated at more than USD$1 billion annually.10 Post-TBI depression is associated with lower return to employment; less engagement in leisure, recreation, and community life; and difficulties with social relationships.11

Depression may develop directly or indirectly as a result of biological changes in the brain after injury, genetic factors, pre-injury and comorbid personal factors, post-injury changes to functional ability, independence, and participation, as well as psychological adjustment factors, or a combination of these factors.12 Post-TBI mood disorders have been associated with the disruption of neural circuits involving the prefrontal cortex, amygdala, hippocampus, insula, basal ganglia, and thalamus.13,14 Abnormalities in neurotransmitter systems, including the dopaminergic system,14 have also been implicated. The most consistent predictor of post-TBI depression is the presence of pre-injury depression or other psychiatric condition.6,15,16 Other factors associated with increased risk of post-TBI depression include post-injury employment issues6,15 and lack of social support.17 The association between TBI severity and risk of depression is unclear. Increasing TBI severity can increase,5,15 decrease,8 or have no association with the risk of depression.7

There is no gold standard treatment for post-TBI depression.12 The best evidence broadly is for serotonergic medications and cognitive behavioral approaches.12 In line with this, US data show that selective serotonin reuptake inhibitors are the most commonly prescribed medications for post-TBI depression, with the most common drugs being citalopram, escitalopram, and sertraline, with mirtazapine (a tetracyclic antidepressant) also commonly used.18 Several large retrospective cohort studies have reported that approximately one-half (44% to 56%) of individuals with depression post-TBI are prescribed at least one antidepressant.18,19

Pharmacological treatment for depression following TBI has been considered in at least seven clinical guidelines since 2006. The guidelines have been broadly consistent in recommending selective serotonin reuptake inhibitors as first-line treatment, with tricyclic and tetracyclic antidepressants, stimulants, and serotonin-norepinephrine reuptake inhibitors also suggested as options.20-26 However, it was not always clear upon which research evidence the conclusions were drawn.20,26 It was acknowledged in two guidelines that there was insufficient evidence to draw strong conclusions.24,25

There have been many recent systematic reviews examining pharmacotherapy for post-TBI depression.27-31 The conclusions of these reviews are mixed, with only some reporting pharmacological interventions as having greater efficacy than placebo. Given that these reviews differ in their conduct, quality, and reporting, and often have discordant conclusions, it is important to provide prescribers with a summary of this review evidence. This umbrella review will highlight evidence from the best-quality reviews in a single document, providing definitive summaries that may be used to inform clinical practice. A preliminary search in May 2020 of PubMed, Cochrane Database of Systematic Reviews, CINAHL, JBI Evidence Synthesis, PROSPERO, and Epistemonikos found that there are no recent umbrella reviews or protocols exploring the precise review objective and questions, with the inclusion criteria of interest for this review.

The objective of this review is to synthesize systematic reviews of the effectiveness of pharmacotherapy compared with any other comparator for the management of post-TBI depression in adults 16 years and older.

Review question

What is the current evidence for the effectiveness of pharmacotherapy for the management of depression in adults 16 years and older with mild to severe TBI?

Inclusion criteria


The umbrella review will consider systematic reviews that include studies of adults (16 years and older) who have sustained a TBI of any cause and severity. Both penetrating and non-penetrating injuries will be included. There will be no restrictions on age at injury or time since injury. If reviews include participants with TBI and non-TBI (ie, other acquired brain injury), these reviews will be included only if the findings from the TBI samples are presented separately or if greater than 80% of the sample is TBI. Both medically confirmed and self-reported TBI will be accepted.

Participants in the systematic reviews must have presented with depression of any severity. Depression must have been diagnosed using a standardized diagnostic interview procedure (eg, Diagnostic and Statistical Manual of Mental Disorders criteria) or valid rating scale (eg, Hospital Anxiety and Depression Scale). Depression symptoms may be reported by the individual with TBI, by their clinician, or by another informant (eg, family member, carer).


Only systematic reviews with pharmacotherapeutic interventions will be considered for inclusion. The primary focus of the intervention must be to treat depression. All pharmacotherapy interventions will be eligible for inclusion, and there will be no restriction on dosage, frequency, duration, or follow-up of intervention. Mixed interventions (eg, pharmacotherapy and psychological therapy) will be included if the data for the pharmacological intervention are reported separately. Systematic reviews of prophylactic (ie, preventive) pharmacotherapy will be excluded.


There will be no restrictions on the type of comparator.


This review will consider studies that include the following outcomes: change in symptoms of depression and occurrence of harms. No secondary outcomes will be included in the review.

Changes in symptoms of depression must be measured using a standardized diagnostic interview procedure or valid rating scale. Harms may be qualitatively documented or documented using Medical Dictionary for Regulatory Activities, WHO Adverse Reaction Terminology, or other classification systems.

Types of studies

This umbrella review will consider any systematic reviews of the effectiveness of pharmacotherapy for post-TBI depression in adults. Systematic reviews with and without meta-analyses will be considered. We will consider a paper to be a systematic review if it includes i) a PICO statement (population, intervention, comparator, outcome) expressed as a study objective or a research question, ii) a search strategy, and iii) clear study inclusion criteria. Systematic reviews including RCTs and non-RCTs (eg, case-control studies) will be included. We will also include meta-analyses that were not part of a systematic review. The following study types will be excluded: systematic reviews of qualitative studies or case reports, narrative reviews, or primary research. Reviews focusing more broadly on psychopathology or neurobehavioral symptoms following TBI will be included if the outcomes for depression are presented separately.


The proposed umbrella review will be conducted in accordance with JBI methodology.32 This umbrella review protocol has been registered in PROSPERO CRD42020184915.

Search strategy

The search strategy will be designed to identify both published and unpublished systematic reviews. An information specialist will develop and run the search strategy for each database. An initial limited search of the Cochrane Library and PubMed was undertaken to identify key words used in the titles and abstracts and in the search strategies of relevant published systematic reviews. The search strategy included a range of Medical Subject Headings (MeSH) terms and keywords linked by Boolean operators. The search strategy was developed based on elements of the PICO (population = brain injury and depression; intervention = pharmacotherapy) and study type. The MEDLINE search strategy was peer-reviewed by the independent information specialist using the Peer-Review of Electronic Search Strategies (PRESS)33 checklist. The search strategy will be adapted for each database. A full search strategy for MEDLINE (Ovid) is provided in Appendix I.

If the review takes more than 12 months to produce from the date the literature searches were carried out, we will re-run searches prior to the final analyses.

Only studies published in English will be included. Any potentially eligible studies not available in English will be provided in an appendix. No date restrictions will be applied to the search to maximize the likelihood that all available evidence is screened.

The databases to be searched include MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Cochrane Database of Systematic Reviews (Cochrane Library), Epistemonikos, and PROSPERO. Where a protocol is found with no accompanying published systematic review, the authors will be contacted on up to two occasions over three months to confirm the publication status of the systematic review. All published protocols without an accompanying systematic review will be listed in an appendix. We will also search reference lists of included systematic reviews, hand search key journals (Neuropsychology Review, Brain Impairment, Journal of Neurotrauma), and search ResearchGate, Google Scholar and the TRIP Medical Database.

Study selection

Following the search, all identified citations will be collated and uploaded into EndNote V8 (Clarivate Analytics, PA, USA) and duplicates removed. Titles and abstracts will be screened by two independent reviewers against the inclusion and exclusion criteria. Potentially relevant reviews will be retrieved in full and their citation details imported into the JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; JBI, Adelaide, Australia). Full-text reviews will be independently assessed against the inclusion criteria by two review team members. Reviews that do not meet the inclusion criteria will be excluded and reasons for exclusion will be provided in an appendix. Included studies will then undergo a process of critical appraisal and data extraction. Any disagreements that arise between the reviewers at each stage of the study selection process will be resolved through discussion or with a third reviewer. The results of the search will be presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.34

Given the purpose of this umbrella review is to present and describe the current body of systematic review evidence on a topic, where systematic reviews containing the same primary studies are identified, we will include both reviews. A citation matrix will be included in the review to depict the primary study overlap within the systematic reviews, and the corrected covered area index will be calculated.35

Throughout the review process, reviewers will not be blinded to the journal titles, study authors, or their institutions.

Assessment of methodological quality

Eligible studies will be critically appraised by two independent reviewers. Overall methodological quality will be appraised using the JBI critical appraisal tool for research synthesis.36 We will provide the overall methodological quality score for each systematic review in the Characteristics of Included Systematic Reviews table. An additional table will be provided as an appendix that includes a breakdown of how each systematic review was rated on each item of the tool and the rationale for the rating. Authors of reviews will be contacted to request missing or additional data where required.

All studies, regardless of methodological quality, will undergo data extraction and synthesis. We will use the results of the quality assessments to help contextualize the umbrella review's evidence base and discuss to what extent the quality of the included systematic reviews may have affected the umbrella review's evidence comprehensiveness and results.

Data extraction

Data extraction will be conducted by two reviewers using a customized version of the JBI data extraction tools (Appendix II). The customized tool will be piloted prior to use. Two independent reviewers will complete data extraction for one review and provide feedback on the ease of use of the tool and whether it captured sufficient information from the review. A third author will examine the completed extracted forms against the list of information (see below) to ensure all desired information is being captured, and revise the form as needed. This process will be repeated throughout the review process, with new versions of the data extraction form developed as required. Only findings relevant to the two primary outcomes (changes in depression; occurrence of harms) will be extracted from the systematic reviews.

Guided by the data extraction tool, the following information will collected:

  • Citation details
  • Financial support
  • Objectives of the review
  • Inclusion/exclusion criteria for study selection
  • Search strategy
    • ∘ Number and names of databases searched
    • ∘ Search for unpublished literature
    • ∘ Date range of searching
    • ∘ Date last assessed as up-to-date
  • Number of studies included
  • Methodological quality assessments
    • ∘ Appraisal/risk of bias instruments
      • Outcome of methodological assessment
    • ∘ Evidence quality assessment instruments
      • Outcome of quality assessment
  • Primary studies in the systematic review
    • ∘ Citation details
    • ∘ Study type/design
    • ∘ Number of participants that inform each outcome for the umbrella review
    • ∘ Type of research synthesis
  • Participants
  • Interventions
  • Comparators
  • Outcomes relevant to the umbrella review question
  • Results/findings relevant to the umbrella review question (regardless of statistical significance of the outcomes)
  • Conclusions relevant to the umbrella review question

Data synthesis

The aims of this umbrella review are to provide a comprehensive map of the available evidence from systematic reviews and to highlight key differences in the methodology and conclusions of reviews. We will rely on the analyses presented in the systematic reviews, and not undertake any re-analysis of the outcome data provided in systematic reviews. We will provide a brief narrative summary of the included systematic reviews, and the details of each review will be presented in a Characteristics of Included Systematic Reviews table. A Summary of Evidence will be provided. We will provide a narrative discussion of the outcomes (ie, changes in depression and harms) with respect to the interventions used, participants’ characteristics (including injury severity, time post-injury), and methodological quality of reviews, including consideration of study design.

Assessing certainty in the findings

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE)37 approach for grading the certainty of evidence will be followed, and a Summary of Findings (SoF) will be created using GRADEpro (McMaster University, ON, Canada). The SoF will present the following information where appropriate: absolute risks for the treatment and control, estimates of relative risk, and a ranking of the quality of the evidence based on the risk of bias, directness, heterogeneity, precision, and risk of publication bias of the review results. The outcomes reported in the SoF will be change in depression symptoms and harms.


Information specialist Farhad Shokraneh for input into the design of the search strategies.


The project was funded by the Transport Accident Commission (TAC) through the Institute for Safety, Compensation and Recovery Research (ISCRR) in Victoria, Australia. The funder will not be involved in any aspect of the project, including the preparation and submission of the protocol, all aspects of the proposed review method, and the preparation of the review manuscript for submission.

Appendix I: Search strategy


Search conducted: May 2020


Appendix II: Draft data extraction instrument


Review details


Search strategy




Participants – traumatic brain injury


Appraisal and quality





Provide details of the analysis of heterogeneity or record “N/A” if this was not done.


Findings – depression


Findings – harms


Final comments

Please document any final comments such as the congruence between the systematic review results and conclusions, limitations of the systematic review, and methodological differences between the included systematic reviews.



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depression; pharmacotherapy; traumatic brain injury; umbrella review

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