Traumatic brain injury (TBI) comprises a clinically heterogeneous group of disorders caused by trauma inflicted on the brain by a mechanical force of external origin. Traumatic brain injury is one of the most common causes of death and disability worldwide. In the United States alone, there is an estimated 1.7 million cases of TBI annually,1 with an incidence of approximately 558 per 100,000 in the United States2 and 235 per 100,000 in Europe.3 People aged 15–24 years and over 64 years, males, those from low socioeconomic status backgrounds, and individuals with cognitive impairment are disproportionately affected by TBI.4,5 As the majority of TBI cases occur as a result of motor vehicle crashes, falls, assault and violence,4 the consequences of TBI can be severe. Although the majority (up to 90%) of TBIs are mild and physically recover within three to six months, a substantial proportion of TBI survivors report ongoing neurobehavioral and emotional difficulties which may include depressive symptomatology.6 Studies indicate that neurobehavioral and emotional disturbances impair quality of life the most for TBI survivors.7,8
Depression is one of the most common and disabling psychiatric diagnoses for individuals with TBI,9 with reports suggesting that between 12% and 60% of patients with TBI develop depression within 12 months of injury, irrespective of severity.10,11 Rates of depression in persons with TBI are up to 7.5 times higher than rates reported in the general population.12 Depressive symptoms can vary between persons post-TBI and may include: fatigue, sleep disturbances, irritability, loss of interest in social activities, poor concentration, memory problems and feelings of sadness.13-15 Moreover, anxiety symptoms co-morbid to depressive symptoms are common.11 Development of depressive symptoms post-TBI has been linked to increased post-concussive symptoms, poorer cognitive functioning, poor adherence with treatment plans, increased health service utilization, higher healthcare costs as well as poorer psychosocial outcomes.10,16-19 Depression can undermine the survivor's capacity for close relationships, social independence, activities of daily living including employment and community integration.9,20-22 Such symptomatology that leads to disabling outcomes highlights the importance of treating depression post-TBI.
The management of depressive symptomatology in a person's post-TBI requires a multimodal and multidisciplinary approach incorporating social, psychological and medical interventions.23 The aim of pharmacotherapy is to provide targeted treatment for discrete neurobehavioral symptoms and emotional disturbances on an individualized basis while managing the adverse effects of medications. To date, standard antidepressant pharmacological agents for major depressive disorder in the general population have been used to treat depression post-TBI.24 Although depression is common post-TBI and pharmacotherapies are often prescribed, there is a general lack of clinical consensus on their effectiveness and harms, and their place in multimodal management of depression post-TBI remains unclear.25 The extent to which the effectiveness and harms of available pharmacotherapies differs between people with TBI and the general population is unclear, with concerns that the TBI population may be more susceptible to toxicity and refractory to therapeutic effects.26,27 Given this, there is an urgent need to review the safety and effectiveness of pharmacotherapy for the management of depressive symptoms across the TBI severity spectrum.
Previous reviews in this area have focused on mild TBI,28 pharmacological and non-pharmacological interventions,28,29 clinical trials30 and neurological disorders, including TBI.31 A meta-analysis by Salter et al.30 included literature published up to October 2014, while a recently published clinical guideline on this topic included literature to 2012 but did not report a risk of bias assessment.32 Of concern is that none of the recent reviews have formally considered the adverse effects of pharmacotherapy for depression post-TBI.28-31 The Canadian clinical practice guidelines for concussion/mild TBI and persistent symptoms graded all evidence on pharmacotherapy as Grade C (expert opinion) except for the optimal duration of pharmacotherapy remaining as inconclusive which was graded A (based on at least one randomized controlled trial [RCT], systematic review or meta-analysis).33 The authors of a systematic review of drugs for behavior disorders after TBI leading to French recommendation for good practice published in 2016 concluded that there was insufficient evidence to standardize drug treatments for these disorders, (including depression).32 Since the most recent search (October 2014) to identify relevant literature for both guidelines and systematic reviews, additional relevant studies have been published.34,35
While recent systematic reviews and guidelines conclude that prescribing sertraline for depressive symptoms post-TBI may have merit, these conclusions are based on a small number of participants (n = 348), the majority of whom have sustained a mild TBI. Barker-Collo et al.28 conducted a meta-analysis of treatment for depression following mild TBI, reporting that the effectiveness of sertraline differed across the included studies. The authors’ overall finding was one of limited effective treatments for depression post-TBI. In a second meta-analysis, Salter et al.30 reported that based only on within group comparisons, pharmacotherapy post-TBI might be associated with a reduction in depressive symptoms but that these results should be treated with caution. The three RCTs included in the Salter et al.30 meta-analysis examined three different pharmacotherapies and were based on a very small number of participants (interventions n = 48, comparator n = 33). The consensus across systematic reviews is that more research is necessary to develop evidence-based practice guidelines. In the absence of available RCT data, carefully evaluating other study designs with an explicit acknowledgement of inherent biases may provide some data including data on safety that could inform practice.
The current review forms part of a larger project which aims to synthesize the evidence for pharmacotherapy in the treatment of neurobehavioral symptoms post-TBI, as a prelude to the development of a clinical practice guideline. The ultimate goal of the guideline is to increase the number of skilled prescribers with current knowledge of pharmacotherapy for adults experiencing neurobehavioral symptoms post-TBI.
As we are focusing on a range of study designs, the systematic review will include a large descriptive component. Risk of bias will be considered when interpreting the results, therefore, we have incorporated validated tools that will assess the methodological quality of a range of study designs including RCTs, controlled non-randomized clinical trials, analytical observational studies and case series. Our review will inform health providers, drug regulators, policy makers, researchers and consumers as end-users on the safety and efficacy of pharmacological management of depressive symptomatology in adults who have sustained a TBI. Gaps in the evidence together with weaknesses in study design will be highlighted, offering directions for future research. Recommendations for pharmacovigilance will be outlined.
A preliminary search (performed in December 2016) of PubMed, Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports, PROSPERO and Epistemonikos found that there are no recent systematic reviews that consider research published since October 2014 or systematic review protocols exploring the precise review objective and questions, with the inclusion criteria of interest for this review.
Types of participants
The review will include studies of persons post-TBI who present with depressive symptoms. The presence or absence of depressive symptoms must be determined using a standardized diagnostic interview procedure, a validated assessment tool or Diagnostic and Statistical Manual of Mental Disorders criteria (DSM). Studies that rely on self-reported depressive symptoms that have not used either an interview or valid rating scale will not be included.
The review will consider studies that include adults, both males and females, who have sustained a TBI of any severity. Studies where 80% of the baseline population are 16 years and over will be eligible for inclusion. Traumatic brain injury is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force. Studies will be included regardless of the mechanism of injury. Post-TBI patients in both the early stages of recovery and in rehabilitation will be included. Studies of participants with closed and open head injury, penetrating head injury and non-penetrating head injury will be eligible for inclusion. Participants must have definite medical evidence of TBI. For the purpose of this review, this means that TBI has been documented in medical records or other health-medical reports sighted by the research team associated with the published article. These record reports must provide unequivocal evidence of injury. Examples of unequivocal evidence include findings from brain imaging (e.g. computed tomography [CT] scan, magnetic resonance imaging), Glasgow Coma Scale score, post-traumatic amnesia, loss of consciousness. Self-report of TBI from either the individual or an informant in the absence of other medical evidence regarding the head injury as outlined above will not be deemed sufficient.
Studies of acquired brain injury populations will only be included if data for the TBI group are reported separately. The literature indicates variance in the criteria used to diagnose traumatic brain injuries and depressive symptoms.36 There will be no exclusion of studies based on their use of different diagnostic and assessment criteria.
The current review will exclude:
- Studies that include self-reported TBI in the absence of other medical evidence regarding the head injury.
- Studies that rely on self reports of depressive symptoms in the absence of a standardized diagnostic interview procedure, validated scale or DSM criteria.
- Studies that include mixed brain injury populations where the data on TBI are not able to be disaggregated.
- Studies that report on clusters of individuals rather than individuals themselves, for example, clinic attendees, families, people living in a defined geographical area.
Types of intervention(s)
The current review will consider studies that evaluate the use of pharmacotherapy interventions. All pharmacotherapy will be included. This will primarily include antidepressant medications including selective serotonin re-uptake inhibitors (SSRI), serotonin-norepinephrine (noradrenaline) reuptake inhibitors (SNRI), tricyclic antidepressants and monoamine oxidase inhibitors. It may also include benzodiazepines and neurostimulants. No restriction on dose, duration, frequency, timing of delivery or combination of pharmacotherapies drugs will be made.
Studies reporting mixed interventions (e.g. pharmacotherapy and psychological therapy) will be included if the data for the pharmacotherapeutic intervention is reported separately.
The current review will exclude studies of complementary medicines and over the counter medicine unless these are part of the intervention, as a co-intervention to pharmacotherapy.
The current review will include studies that compare the intervention to all types of comparators. There will be no restrictions on the type of comparator. Placebo (dummy or active), supportive or standard care or a non-pharmacological intervention will be accepted. Studies comparing drugs within a pharmacological class will also be included.
The current review will preferentially report on all and any validated disease specific and generic measurement tools used in each of the included studies for the measurement of the primary and secondary outcomes of interest. For some of the outcomes of interest, validated measurement scales may not be available. In this situation, information on outcomes will be reported as described in the included study.
The primary outcomes of interest for the review will be:
- Treatment efficacy as measured by an improvement in depressive symptoms and diagnoses. Severity of depression, response to treatment, remission following treatment and loss of depression diagnosis will be reported according to the criteria specified in individual papers. This will be measured using validated measurement instruments such as but not limited to the Hamilton Depression Rating Scale, Centre for Epidemiologic Studies Depression Inventory Hospital Anxiety and Depression Scale and the Beck Depression inventory.36
- Harms including adverse effects resulting from pharmacotherapy and study dropouts:
- - Adverse effects: General and specific (qualitatively documented or documented using Medical Dictionary for Regulatory Activities, World Health Organization Adverse Reaction Terminology or other classification systems) associated with pharmacotherapy. The need for medication to manage adverse effects as reported.
- - Study dropout: Loss to follow-up and leaving the study early due to adverse events, inefficacy of treatment, death, any reason.
The secondary outcomes of interest for the review will be:
- Functional independence in activities of daily living measured using validated measurement instruments such as but not limited to the Functional Independence Measure, Glasgow Outcome Scale-Extended, Community Integration Questionnaire.36
- Cognitive functioning using validated measurement instruments including but not limited to the Wechsler Adult intelligence scale and the Wechsler Memory Scale.36
- Health-related quality of life using validated measurement instruments such as the Medical Outcomes Short Form 36.
- Change in co-morbid anxiety symptoms measured using validated measurement scales such as the Hospital Anxiety and Depression Scale.36
Types of studies
The current review will consider the following study types:
- Randomized controlled trials
- Controlled non-randomized clinical trials
- Quasi-RCTs including, but not limited, to controlled before and after studies, interrupted time series with a control group, and interrupted time series without a parallel concurrent control group
- Analytical observational studies (including cohort and case control studies)
- Case series with pre-test/post-test outcomes
- Single arm studies.
The literature search will be limited to the English language and human subjects. If we identify potentially relevant titles in any other language, they will be provided as an appendix to the review. No date restriction will apply to the search for literature.
Published and unpublished studies will be identified using a seven-step approach. Initially the Cochrane Library and PubMed will be searched to identify key words used in the titles and abstracts and in the search strategies of relevant published systematic reviews. Second, a more extensive search in international electronic bibliographic databases will be undertaken to further identify articles. We will search the following databases with no date limitation:
- MEDLINE, OVID SP interface
- PubMed excluding MEDLINE
- CINAHL: Cumulative Index to Nursing and Allied Health Literature
- Embase: Excerpta Medica Database excluding MEDLINE, OVID SP interface
- PsycINFO, OVID SP interface
- Cochrane Library: CENTRAL.
An information specialist with extensive experience in conducting systematic reviews will develop and run the search strategy for each database. Third, reference lists of retrieved articles will be reviewed to identify research not located through other search strategies. Fourth, electronic searching of the following online journals: Brain Injury, Neuropsychology, Journal of Neurotrauma and Journal of Head Trauma Rehabilitation will be carried out. Fifth, clinical trial registries will be searched to identify ongoing studies. The trial registers to be searched include International Clinical Trials Registry Platform Search Portal and ClinicalTrials.gov. Sixth, we will search Research Gate and international drug regulators Food and Drug Administration and European Medicines Agency, and the Medicines and Healthcare products Regulatory Agency to identify unpublished studies. In addition, we will correspond with colleagues and collaborators for additional studies. Finally, to ensure as complete a search as possible, we will supplement formal database searches with additional citations from Google Scholar.
If the review takes more than six months to undertake from the date of the literature searches, we will re-run searches just before the final analyses to identify any recent studies that meet the inclusion criteria for this review. We will develop a search strategy that includes a range of Medical Subject Headings terms and keywords linked by Boolean operators. The search strategies for the other databases will be based on the PubMed strategy and modified in accordance with the specific requirements of other databases.
The current review is part of a large project that will review and update the current evidence on a range of neurobehavioral symptoms as the first stage in the development of a clinical guideline on pharmacotherapy for the management of neurobehavioral symptoms in adults post-TBI in Australia. The search strategy was developed based on the PICO (Population, Intervention, Comparator, Outcome) elements of relevance to this review (P = TBI with depressive symptoms, I = pharmacotherapy). Results from the database search will be downloaded into Endnote (Clarivate Analytics, PA, USA) and de-duplicated. A full search strategy for MEDLINE is provided in Appendix I.
Following the search, all identified citations will be collated and uploaded into Endnote and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion and exclusion criteria for the review. Where there is disagreement over whether a study is included, a third team member will review the article and adjudicate.
Studies that potentially meet the inclusion criteria at the title and abstract stage will be retrieved in full and independently assessed against the inclusion criteria by two review team members. We will seek additional information from study authors where necessary to resolve questions about eligibility. Any disagreement over the eligibility of particular studies will be resolved through discussion with a third reviewer. All discussions on eligibility will be documented including the reasons for excluding studies.
Full text studies that do not meet the inclusion criteria will be excluded and reasons for exclusion will be provided in an appendix in the final systematic review report. Included studies will then undergo a process of critical appraisal. The results of the search will be presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
Inter-rater reliability between the independent reviewers will be measured using percent agreement and Cohen's kappa at the full text screening stage, assessment of methodological quality and selection for meta-analysis. All decision making will be carefully documented, and all electronic searches will be saved on file where possible.
While we anticipate that there will be limited scope for a meta-analysis because of the range of study designs, diagnostic criteria and outcome measures across the included studies, should a meta-analysis become feasible, two review authors will independently review all included studies for inclusion in meta-analysis. Where there is disagreement over whether a study is included, a third team member will adjudicate.
Assessment of methodological quality
The current review forms part of a larger research project that will develop a clinical guideline notionally entitled, “Pharmacological management of neurobehavioral symptoms following TBI”. The guideline will be informed by a series of systematic reviews. These include:
- New Cochrane reviews of RCTs and updates of current Cochrane reviews.
- Systematic reviews of pharmacotherapy for depression and anxiety disorders post-TBI. These reviews will include both randomized and non-randomized study designs.
- Systematic reviews of pharmacotherapy for the management of agitation, aggression, irritability, psychosis, emotional lability and apathy that will only include non-randomized study designs. No relevant randomized study designs have been identified for some of these symptoms. Moreover, some of the available RCTs differ from other types of studies in regards to certain parameters including length of follow-up and sample size.
A number of these reviews are in process. For consistency purposes and to be able to easily compare across these reviews and previous reviews of the topic, we will use the standardized critical appraisal instruments from the Cochrane Collaboration37 and the Newcastle-Ottawa instruments38 to critically appraise studies. We will also assess and report methodological quality using the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument critical appraisal instruments.39 Independent critical appraisal will be conducted by two reviewers. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. The methodological quality assessments for each study will be presented in the results section. The assessment of methodological quality will contribute to an evaluation of the quality of the evidence and the impact of bias on the findings. No studies will be excluded based on methodological quality.
Where available, we will extract data from each of the included studies on design, analysis and results. Data will be extracted from included studies using a customized data extraction tool (Appendix II) based on the standardized data extraction tool from JBI-System for the Unified Management, Assessment and Review of Information.39 It will be piloted and refined early in the data extraction phase to accurately capture all of the data required for analysis. The specific data items that will be collected will be:
- Country where study carried out
- Study setting
- Study population – traumatic brain injuries (severity, assessment scales, other injuries, time post-injury)
- Neurobehavioral symptom – depression (assessment scales, severity, other symptoms, timing of onset, diagnostic criteria)
- Study design
- Main inclusion and exclusion criteria
- Details of the pharmacotherapy intervention/exposure and control conditions if used including type of pharmacological compound, treatment dose, frequency and duration, generic and trade names of pharmacotherapy, drug class
- Co-interventions and their details (dose, intensity, frequency, etc.)
- Outcomes, outcome measures and timing of measurement
- Type of financial support received to carry out the study
- Baseline sample size
- Statistical analysis methods
- Participant demographics and baseline characteristics
- Recruitment and study completion rates; compliance rates, extent of missing data
- Main results
- Treatment harms and adverse events.
Due to possible variation in the definition of TBI and depression over time, we will extract definitions of each as reported in individual studies.
We will provide a narrative descriptive synthesis of the findings structured around the type of pharmacotherapy, depressive symptoms, target population characteristics, study methodology, outcomes and intervention. This narrative synthesis will explain the relationships and findings within and between the included studies. Where data are available, we will provide summaries of pharmacotherapeutic effects for each study by calculating risk ratios (dichotomous outcomes) or standardized mean differences (continuous outcomes).
Suitability for meta-analysis will be determined by the degree of heterogeneity (clinical and statistical) observed between the studies.39 We will calculate the effect measures by obtaining the relative risks with their 95% confidence intervals and pooled according to study design (clinical trials and observational studies, respectively) using a random effects model. Statistical heterogeneity will be assessed using the I2 statistic and the chi-square (P < 0.1 will be considered statistically significant). We will interpret an I2 estimate ≥50% as evidence of substantial heterogeneity.37 We anticipate that there will be limited scope for meta-analysis because of the range of different study designs, diagnostic criteria and outcomes measured across the included studies. However, where at least five studies have used the same study design, type of intervention/exposure and comparator, and outcome measure, we will pool the results using a random-effects meta-analysis, with standardized mean differences for continuous outcomes and risk ratios for binary outcomes, and calculate 95% confidence intervals and two-sided P values for each outcome.39
We will contact authors where substantial outcomes of interest are not reported or to clarify uncertainty about study characteristics. For RCTs, controlled and quasi-randomized study design, missing data for dichotomous outcomes will be taken into account using an intention-to-treat analysis using imputation based on event rate observed in the control group. A funnel plot will be generated to assess publication bias if there are more 10 or more studies included in a meta-analysis. Statistical tests for funnel plot asymmetry (Egger and Begg tests) will be performed where appropriate.
In published reviews of this topic, subgroup analyses have been limited to the type of antidepressant used.28,30 If the necessary data are available, subgroup analyses will be done according to the following categories.
- Gender (male and female)
- Age (<20, 20–30, 30–40 and >40 years)
- Severity of TBI (mild, moderate and severe)
- Medication dosage
- Adverse effects (serious versus non-serious)
- Single or more than one pharmacological regimen
- Treatment of single neurobehavioral symptom (e.g. depression only) or multiple symptoms (e.g. depression and anxiety)
- Medication type (e.g. antidepressants and neurostimulants)
- Class of antidepressants (e.g. SSRI, SNRI and Tricyclics)
- Severity of depressive symptoms (mild, moderate and severe).
The current review will be reported in accordance with the PRISMA guidelines.40 As we expect to include many observational studies, these will be reported according to the strengthening the reporting of observational studies in epidemiology guidelines.41 Study characteristics and measured outcomes will be compiled into summary tables. If a meta-analysis is possible, results will be presented in a forest plot. In the event of protocol amendments, we will provide in the systematic review report the date of each amendment in a tabular form alongside an explicit description and justifications of all deviations from the approved peer reviewed systematic review protocol.
If we find sufficient information in the research literature for the different pharmacotherapy interventions, we will use the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach to define the quality of the evidence in terms of the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest. The quality of evidence will be assessed across the domains of risk of bias, consistency, directness, precision and publication bias. Quality will be adjudicated as:
- High (further research is very unlikely to change our confidence in the estimate of effect)
- Moderate (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate)
- Low (further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate)
- Very low (very uncertain about the estimate of effect).
We will use the GRADE profiler GRADEpro to import data from RevMan 5.3 (The Nordic Cochrane Centre, Cochrane, Copenhagen, Denmark) to create “Summary of findings” tables. Summary of findings tables provide outcome-specific information concerning the overall quality of evidence from each included study in the comparison, the magnitude of effect of the interventions examined and the sum of available data on all outcomes rated as important to patient care and decision making. All decisions will be recorded and provided as supplementary data. This will enable readers to appreciate the degree of any uncertainty as well as provide greater transparency.
If the data are sufficient, summary of findings tables will be prepared on the following outcomes: treatment efficacy, quality of life, cognitive functioning, functional independence in activities of daily living, study dropout and adverse events.
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 Amitriptyline/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 Clorazepate Dipotassium/OR Clozapine/OR Desipramine/OR Desvenlafaxine Succinate/OR Dextroamphetamine/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 Agomelatine 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 ApoAmitriptyline 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 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 Demethylimipramine 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 Propylpentanoic 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 Levopromazine 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 “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 Oxcarbazepine 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 Phenethylhydrazine OR Nardelzine OR Nardil OR Phenobarbital OR Phenobarbitone OR “Phenylethylbarbituric 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 Transamine 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” 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
Appendix II: Data extraction form
The authors acknowledge with thanks the input of our information specialist, Farhad Shokraneh, in the design of search strategies. The Institute for Safety, Compensation and Recovery Research (ISCRR), Monash University, provided funding for this review through the Neurotrauma strategy 2010–2015. The institute is a research-policy partnership established in 2009 via an agreement between WorkSafe Victoria, the Transport Accident Commission (TAC) and Monash University. The funder will not be involved in any other aspect of the project. This includes the preparation and submission of the protocol, all aspects of the proposed review method and the preparation of the review manuscript for submission.
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