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Pharmacotherapy for the pseudobulbar affect in individuals who have sustained a traumatic brain injury: a systematic review protocol

Clay, Fiona J.1,2,3,∗; Hicks, Amelia J.4,∗; Perry, Luke A.1; Ponsford, Jennie L.4; Jayaram, Mahesh1; Hopwood, Malcolm1,5

Author Information
JBI Database of Systematic Reviews and Implementation Reports: September 2018 - Volume 16 - Issue 9 - p 1739-1757
doi: 10.11124/JBISRIR-2017-003648
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Traumatic brain injury (TBI) is estimated to affect 10 million people annually worldwide,1 and is a leading cause of disability and death.2,3 Traumatic brain injury can be defined as an alteration in brain function or other evidence of brain pathology, caused by an external force,4 and is most commonly categorized as mild (accounting for 80% of all injuries), moderate (10%), or severe (10%).5 In the United States, TBI occurs at a rate of approximately 538 per 100,000,6 in Europe it is estimated at 262 per 100,000,7 and in New Zealand, 790 per 100,000.8 Traumatic brain injury disproportionately affects the very young, adolescents, young adults, the elderly, males, people from low socioeconomic backgrounds, and individuals with pre-existing cognitive impairment.5,9

Traumatic brain injury is a complex and a heterogeneous disorder that is associated with significant, and often chronic, changes in cognition,10,11 functional ability,10 physical independence,10 mood12,13 and behavior.14,15 Neurobehavioral and emotional disturbances have a prominent and significant impact on quality of life for survivors, impairing their capacity for social independence, employment and community integration.16-18 Close relationships are at risk of breaking down, exacerbating the psychological burden felt by the survivor and their carers.16,17 One form of emotional disturbance, often under-recognized and misdiagnosed in individuals with TBI, is pseudobulbar affect (PBA).

The term “pseudobulbar affect” refers to sudden involuntary and uncontrollable emotional expression that is exaggerated, inappropriate and incongruent with the individuals underlying emotional state.19 Pseudobulbar affect is a common manifestation of brain pathology occurring secondary to a range of neurological conditions, including mild to severe TBI, amyotrophic lateral sclerosis, Alzheimer's disease, stroke, multiple sclerosis and Parkinson's disease.20,21 Epidemiology studies report that, depending on the measurement scale and threshold for symptoms, between 5.3% and 54.0% of people with TBI have symptoms consistent with or suggestive of PBA.22-24 These rates likely underrepresent the true prevalence of PBA as it is often overlooked, or misdiagnosed as depression or other mood disorders.20 As a consequence, PBA may be undertreated and persist for longer than it should. This is of significant concern, given that PBA has a negative impact on many aspects of health and quality of life, and can impair participation in activities of daily living including social and occupational roles.20 It is seen as a source of embarrassment for patients and caregivers, and is described by patients as extremely burdensome.20

Advancing knowledge in this area may have been slowed somewhat by inconsistencies regarding conceptualizations of PBA. Indeed, some studies have restricted the use of the term PBA to manifestations of pathological laughing and crying only, while others have interpreted PBA within the broader clinical construct of “emotional lability”. Pathological laughter and crying and emotional lability are related but nosologically distinct entities with important clinical differences. Emotional lability refers to an exaggerated affective response to a stimulus that is congruent with the subjective emotional state and that is partially controllable by the individual.25 By comparison, pathological laughter and crying refers to an effective response that is exaggerated both in relation to the stimulus and the subjective emotional state, and is uncontrollable.26 These conceptualizations are used to define a study sample, and as such may greatly impact the actual clinical construct being measured and the subsequent results produced. This has important implications for how research in this area is synthesized and understood.

The pathophysiology of PBA is complex and not well understood. Dysfunction of the cortico-pontine-cerebellar tracts, as well as disruption of serotonergic and glutamatergic neurotransmission are hallmarks of PBA, but much of the current understanding of the neurochemical basis of PBA is informed indirectly by differential efficacy of pharmacotherapies.27

Evidence for pharmacological intervention for PBA in TBI is drawn primarily from case reports using varied drugs. Since 2014, there have been a small number of higher quality studies published, mostly focused on the combination drug dextromethorphan hydrobromide and quinidine.28,29 Although there have been a number of narrative reviews of treatment for PBA in recent times, most have not been specific to TBI. Pioro30 reviewed the evidence for completed double-blind clinical trials of pharmacological interventions in PBA; however, none of these trials comprised TBI cohorts. Ahmed and Simmons31 reported on uncontrolled trials of selective serotonin reuptake inhibitors in PBA; two of the included studies were in TBI. Schoedel et al.32 summarized previous treatment studies in both PBA and pathological laughing and crying, reporting only on a single case series of TBI. No systematic reviews could be found that have identified and synthesized the evidence for pharmacological management of PBA specifically following TBI. Summarizing findings across conditions, or extrapolating findings from other neurological illnesses to TBI may be problematic, as individuals with TBI commonly exhibit unique medication response and tolerance, requiring extremely large or conversely small doses, long periods for titration and discontinuation.33

Treatment for PBA following TBI has been considered in a small number of clinical guidelines. The Colorado Division of Workers’ Compensation Traumatic Brain Injury Medical Treatment Guidelines published in 2012 reported that a combination of dextromethorphan and quinidine may be used for patients with the PBA.34 This drug combination has since been listed by both the Food and Drug Administration and Medicines Health Regulatory Agency. More recently, the French SOFMER (Société Française de Médecine Physique et de Réadaptation [French Society of Physical Medicine and Rehabilitation]) guidelines reported Level 3 (case-control) evidence based on a single study for the use of paroxetine and citalopram and a similar level of evidence based on a single study for the use of lamotrigine.35 The evidence for harms associated with pharmacotherapy were not formally examined.34,35 Since the publication of the French guidelines which included literature published to June 2015, a number of studies on the pharmacological management of PBA secondary to TBI have been published.28,29

For appropriate management of individuals who have sustained a TBI, clinicians need to have access to the most up-to-date research evidence. Given the distressing and socially isolating nature of PBA, together with the lack of current up to date recommendations for medication management, a synthesis of the current evidence for the pharmacological management of PBA post-TBI is needed.

This 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. Our review will inform clinicians, pharmacists, allied health providers, drug regulators, policy makers, researchers and consumers as end-users on the safety and efficacy of pharmacological management of neurobehavioral symptoms in individuals following a TBI. Gaps in the evidence will be highlighted and directions for future research and recommendations for pharmacovigilance outlined.

A preliminary search (performed in September 2017) of PubMed, Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports, PROSPERO and EPISTEMONIKOS found that there were no recent systematic reviews or systematic review protocols exploring the precise review objective and questions, with the inclusion criteria of interest for this review.

Inclusion criteria


The review will include studies that include participants who have sustained a TBI and present with PBA. The symptoms of PBA must be determined using a standardized diagnostic interview procedure or validated assessment tool (e.g. Diagnostic and Statistical Manual of Mental Disorders criteria [DSM], Pathological Laughter and Crying Scale, the Center for Neurological Studies Lability Scale). Due to the complexity around the definition of PBA, we will include studies that consider either pathological laughter and crying or emotional lability. Studies that only rely on self-reported symptoms and have not used either an interview or valid rating scale will not be included.

The following will be included:

  • Studies that include persons 16 years and over, 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.
  • Studies will be included regardless of the mechanism of injury, and both penetrating and non-penetrating injuries will be included.
  • Studies of acquired brain injury populations if data for TBI participants are reported separately.

Post-TBI patients in both the early stages of recovery and in rehabilitation will be included. 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 records must provide unequivocal evidence of injury. Examples of unequivocal evidence include findings from brain imaging, Glasgow Coma Scale (GCS) score, post traumatic amnesia (PTA); loss of consciousness.

This review will exclude:

  • Studies that include self-reported TBI from either the individual or an informant in the absence of other medical evidence regarding the head injury.
  • Studies that rely on self-report of PBA in the absence of a standardized diagnostic interview procedure, validated scale or DSM criteria.
  • Studies that include mixed brain injury populations where data on individuals with TBI cannot 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.


This review will consider studies that evaluate the use of pharmacotherapy interventions. All pharmacotherapy will be included. No restriction on dose, duration, frequency, timing of delivery, or combination of drug therapy will be made. Pharmacotherapy must be prescribed by a health provider and the names of the drugs must be specified. Studies reporting mixed interventions (e.g. pharmacotherapy and psychological therapy) will be included if the data for the pharmacological intervention is reported separately. This review will exclude studies of complementary medicines and over the counter medicine unless these are part of the intervention, that is, a co-intervention to pharmacotherapy.


This review will include studies that compare the pharmacological intervention to all types of comparators. There will be no restrictions on the type of comparator; placebo, active control (e.g. drugs within the same pharmacological class or another class or compound), supportive, standard care or a non-pharmacological intervention will be accepted. Complimentary therapies will also be included if they are used as a comparator either alone or as an adjuvant to a drug.


This 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 are:

  • Change in symptoms of PBA: this will be measured using validated measurement instruments such as the Pathological Laughter and Crying scale,36 and the Center for Neurological Studies Lability Scale.37 Given the variations in the conceptualization of PBA, we will include all studies that report on symptoms of PBA, regardless of how PBA has been defined in the study.
  • Harms including adverse effects resulting from pharmacotherapy:
    • Adverse effects general and specific (qualitatively documented or documented using Medical Dictionary for Regulatory Activities [MEDRA], WHO Adverse Reaction Terminology [WHO-ART] or other classification systems) associated with pharmacotherapy. The need for medication to manage adverse effects, as reported.

The secondary outcomes of interest are:

  • Participation in activities of daily living measured using validated measurement instruments such as the Community Integration Questionnaire and the Extended Activities of Daily Living Questionnaire.
  • Health-related quality of life using validated measurement instruments such as the Medical Outcomes Short Form 36 (SF-36).
  • Change in co-morbid depression symptoms measured using validated measurement scales such as the Hospital Anxiety and Depression Scale.

Types of studies

This review will consider the following study types

  • Randomized controlled trials (RCTs)
  • Controlled non-randomized clinical trials
  • Quasi-randomized controlled trials including for example but not limited to controlled before and after studies, interrupted time series with a control group, 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.

Relevant case reports will be included in the review but will be analyzed and reported separately from other study designs.

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. The following study types will be excluded from this review: editorials and opinion pieces, qualitative research, methodological papers, secondary studies including narrative reviews, systematic reviews and meta-analyses.


Search strategy

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:

  • CINAHL: Cumulative Index to Nursing and Allied Health Literature
  • Cochrane Library: CENTRAL
  • Embase: Excerpta Medica Database excluding MEDLINE (OVID SP)
  • PsycINFO (OVID SP)
  • PubMed excluding MEDLINE.

An information specialist with extensive experience in conducting systematic reviews will develop and run the search strategy for each database. The search strategy was developed based on the PICO (Population, Intervention, Comparator, Outcome) elements of relevance to this review (P = traumatic brain injury, I = pharmacotherapy for PBA). The search strategy will include a range of Medical Subject Headings (MeSH) terms and key words 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. A full search strategy for Medline is provided in Appendix I.

Third, electronic searching of the following online journals: Brain Injury, Neuropsychology, Journal of Neurotrauma and Journal of Head Trauma Rehabilitation will be carried out. Fourth, the following clinical trial registries will be searched to identify ongoing studies: International Clinical Trials Registry Platform Search Portal and Fifth, we will search Research Gate and the international drug regulators: Food and Drug Administration (FDA), European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) to identify unpublished studies. Sixth, we will correspond with colleagues and collaborators for additional studies. To ensure as complete a search as possible, we will supplement formal database searches by seeking additional citations from Google Scholar. Finally, reference lists of included articles will be reviewed to identify research not located through other search strategies. If the review takes more than six months to produce from the date the literature searches are carried out, we will re-run searches prior to the final analyses to identify any recent studies that meet the inclusion criteria for this review.

Study selection

Following the search, all identified citations will be collated and uploaded into Endnote (Clarivate Analytics, PA, USA) 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. Disagreements will be resolved through consensus; if required a third team member will review the article and adjudicate.

Studies that potentially meet the inclusion criteria at the title/abstract stage will be retrieved in full and independently assessed against the inclusion criteria by two review team members. Study authors will be contacted where necessary to resolve questions about eligibility. Disagreements over eligibility will be resolved through discussion with a third reviewer.

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 published systematic review. Included studies will then undergo a process of critical appraisal. The results of the search will be presented in a PRISMA flow diagram.38 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

Methodological quality will be reported using the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI) critical appraisal instruments.39 Independent critical appraisal will be conducted by two reviewers; disagreements 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. Throughout the study selection process and assessment of methodological quality, reviewers will not be blinded to the journal titles, study authors or their institutions.

Data extraction

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 SUMARI.39 It will be piloted and refined early in the data extraction phase in order to accurately capture all of the data required for analysis. The specific data items that will be collected are provided below.

  • Country where study carried out
  • Study setting
  • Study design
  • Study population – traumatic brain injuries (injury severity, assessment scales, other injuries, time post-injury)
  • Neurobehavioral symptom – pathological laughter and crying or emotional lability (assessment scales, severity, other symptoms, timing of onset, diagnostic criteria)
  • Main inclusion and exclusion criteria
  • Pharmacotherapy intervention/exposure and control conditions, if used, including type of pharmacological compound, treatment dose, frequency and duration, drug name and drug class
  • Co-interventions and their details (dose, intensity, frequency, etc.)
  • Outcomes, outcome measures and timing of measurement
  • Receipt of financial support for the study
  • Baseline sample size
  • Statistical analysis methods
  • Participant demographics and baseline characteristics
  • Study completion rates, compliance rates and extent of missing data
  • Main results
  • Treatment harms and adverse events.

Data synthesis

We will provide a narrative descriptive synthesis of the findings, with the aid of tables, structured around the pharmacological intervention, PBA symptoms, characteristics of the target population, study methodology, outcomes and intervention. This narrative synthesis will explain the relationships and findings within and between the included studies. We will report how PBA has been defined and measured. We will consider how differences in conceptualisations of PBA may influence the findings of individual studies, by comparing and contrasting the findings from studies based on the definition of PBA that has been used. Where data is available, we will provide summaries of pharmacotherapeutic effects for each study by calculating risk ratios (dichotomous outcomes) or standardized mean differences (continuous outcomes).

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. Suitability for meta-analysis will be determined by a qualitative assessment of the extent of clinical heterogeneity between studies. If a meta-analysis is possible, results will be presented in a forest plot. We will calculate the effect measures by obtaining the relative risks with their 95% confidence intervals and pooled according to type of study design using a random effects model. Heterogeneity will be assessed using prediction intervals (generated from the T statistic), and the I-squared statistic.39 No studies will be excluded based on the assessment of methodological quality.

For RCTs, controlled and quasi randomized study design, missing data for dichotomous outcomes will be considered using an intention-to-treat (ITT) 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 test, Begg test) will be performed where appropriate.

If the required data are available, the following subgroup analyses will be carried out.

  • Gender
  • Age (<20, 20–30, 30–40, >40 years)
  • Severity of TBI (mild, moderate, severe)
  • Severity of PBA (mild, moderate, severe)
  • Pathological laughter and crying versus emotional lability
  • Medication type and dose
  • Adverse effects (serious versus non-serious).

If sufficient studies are available, sensitivity analyses will be performed to examine whether the results of the meta-analysis are robust to changes in criteria used during the systematic review process. Specifically, we will repeat the meta-analysis substituting alternative decisions or ranges of values when we feel the original decision could be considered arbitrary or unclear. For example, excluding studies with “high” and “unclear” risk of bias. We will report sensitivity analyses by producing a summary table. Where sensitivity analyses suggest that the overall results may have been greatly influenced by certain decisions made during the review, we will attempt to address this by sourcing further information from authors and study coordinators.

This review will be reported in accordance with PRISMA guidelines.38,40,41 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.

Assessing certainty in the findings

If we identify sufficient research evidence for different pharmacological interventions, we will use the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE)42 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 GRADEpro43 to import data from RevMan 5.3 (Copenhagen: The Nordic Cochrane Centre, Cochrane) to create a Summary of Findings. Summaries of Findings 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. To enable readers to appreciate the degree of any uncertainty as well as provide greater transparency, all decisions will be recorded and provided as supplementary data. If the data are sufficient, a Summary of Findings will be prepared on the following outcomes: change in PBA symptoms, quality of life, activities of daily living and adverse events.


The authors acknowledge expert input from 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 ISCRR 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 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.

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: Draft Data Extraction Form – Pseudobulbar Affect


Basic study identifying information


Study methodology


Traumatic brain injury


Pseudobulbar symptoms


Pharmacotherapy intervention/exposure


Comparator conditions




Study methodology – outcomes


Treatment harms and adverse events


Study sample and findings – participant demographics


Study sample and findings - compliance rates


Study sample and findings – participant baseline characteristics


Study sample and findings – recruitment & study completion rates


Study sample and findings – extent of missing data


Study sample and findings – direct & indirect healthcare costs


Study sample and findings – main results: dichotomous data


Study sample and findings – main results: continuous data


Study sample and findings - treatment harms and adverse events



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Fiona J. Clay and Amelia J. Hicks are co-first authors.


Traumatic brain injury; pseudobulbar affect; pharmacotherapy; pathological laughter and crying; emotional lability