Abstract
Background:
Traumatic brain injury (TBI) is an increasingly common cause of behavioral and emotional dysregulation among hospitalized patients. While consultation-liaison psychiatrists are often called to help manage these behaviors, acute pharmacological management guidelines are limited.
Objective:
Conduct a systematic review to determine which pharmacological measures are supported by the literature for targeting agitation and aggression in the acute time period following a TBI.
Methods:
In a systematic review of MEDLINE, Embase, PsycInfo, ClinicalTrials.gov and the Cochrane Library, we identified and then analyzed publications that investigated the pharmacological management of behavioral and emotional dysregulation following a TBI during the acute time period following injury.
Results:
There were a limited number of high quality studies that met our inclusion criteria, including only five randomized controlled trials. The majority of the literature identified consisted of case reports or case series. Trends identified in the literature reviewed suggested that amantadine, propranolol, and anti-epileptics were the best supported medications to consider. For many medication classes, the time of medication initiation and duration of treatment, relative to the time of injury, may impact the effect observed.
Conclusions:
The pharmacological management of agitated patients immediately following a TBI is still an area of much-needed research, as there is limited data-driven guidance in the literature.
Keywords: Traumatic Brain Injury, Behavioral Dysregulation, Agitation, Aggression, Disinhibition
INTRODUCTION
Traumatic Brain Injury (TBI) is a major cause of morbidity and mortality worldwide (1, 2). It is defined by the Centers for Disease Control and Prevention (CDC) and National Institute of Neurological Disorders and Stroke (NINDS) as a change in brain function caused by an external force (1, 2). An estimated 50 million TBIs occur globally each year, with approximately 3.5 million in the United States (US) (1). Both in the US and internationally, the incidence of TBI is increasing, along with its financial implications. Currently, global costs already exceed 400 billion US dollars per year, when considering direct healthcare costs along with indirect costs associated with loss of productivity (1). In the US, the age-adjusted rate of health care encounters for TBI increased by almost 50% from 2007 to 2010 (2). In the United States, children and elderly adults are at the highest risk for TBI. The most common causes of TBI are falls, motor vehicle-related injuries and strikes against the head (3). However, as car travel in high income countries becomes safer, other etiologies are becoming increasingly prevalent and the ratio of non-fatal TBI to fatal TBI has been increasing (2). These less severe injuries can go unaccounted for, as individuals do not necessarily seek medical care. As a result, the true incidence and prevalence of TBI, both in the US and elsewhere, is likely underestimated (1).
Once thought of as a discrete event, TBI is widely accepted and best conceptualized as an acute injury with possible lifelong implications (4–7). Neurological sequelae from TBI can include increased risk of seizures, stroke, and persistent cognitive impairment (1). While these neurological sequelae can be devastating, individuals often suffer from behavioral and emotional dysregulation and personality changes as well (2, 8, 9). This dysregulation is often manifested as agitation, irritability, or aggression, which can be both distressing and challenging for patients, caregivers, and medical staff. Estimates of the frequency of agitation and/or aggression following TBI range from 10–70% (10, 11).
As the incidence and prevalence of TBI increases, health care providers are increasingly likely to encounter patients in the emergency department or inpatient hospital setting following a TBI (2). At our institution (the University of North Carolina Hospitals), the consultation-liaison (CL) psychiatry service is receiving a growing number of consult requests to manage behavioral and emotional dysregulation following a TBI. However, much of the literature on TBI and TBI management is geared towards medical specialties other than psychiatry, and the available guidelines regarding acute management of behavioral and emotional dysregulation following TBI are limited (8). Therefore, an updated summary of the pharmacological management of dysregulation during the acute time period following a TBI for the CL psychiatrist is warranted.
METHODS
We conducted a systematic review of the literature based upon guidelines established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Search Strategy
Five literature databases were searched for publications which met the following inclusion criteria: 1) an experimental study design (including case reports and series), 2) involving adult human subjects, documenting or investigating 3) the pharmacological management of 4) behavioral and emotional dysregulation following a 5) TBI during 6) the acute time period following injury.
The medical librarian developed search strategies for each of the inclusion criteria. These strategies were created using a combination of subject headings and keywords and were used to search MEDLINE via PubMed, Embase via Elsevier, PsycInfo via EBSCO, ClinicalTrials.gov and the Cochrane Library from date of database inception to December 20, 2017, when all searches were completed. The full list of the search terms can be found in the Supplemental Methods. A wide range of keywords were searched in order to capture the multifaceted concept of behavioral and emotional dysregulation; these included “aggression”, “psychomotor agitation”, “violence”, “disinhibition”, “impulsivity”, and “irritability”. For the purpose of simplicity, we will use the terms “behavioral/emotional dysregulation”, “agitation” or “aggression” when describing and discussing results from the literature identified by our search.
Literature Review
All abstracts and titles were initially examined by two independent reviewers (RN, SL, JG, MW). The full texts of publications that met initial inclusion criteria were then read and evaluated by two independent reviewers (RN, MW, JB). During both steps, if a conflict arose between reviewers, the publication in question was re-considered in order to reach a consensus regarding whether or not it met the defined criteria. Case reports, case series, retrospective studies and prospective studies, including randomized controlled trials (RCTs), were considered for analysis, while all literature reviews were excluded.
Based on the consensus clinical experience of several senior psychiatric consult physicians, we defined the acute time period following TBI as a three-month window following injury, as this the time frame most commonly associated with consultation requests. If a publication lacked information regarding time since injury, the decision to consider the publication for further analysis was based on study location. In particular, if the primary location was an acute care hospital or associated inpatient rehabilitation hospital, then the publication was considered for further analysis; however, if the primary location was a free-standing rehabilitation center, the publication was not considered.
All publications that met the defined criteria after full text review were included in the data abstraction. Data abstracted from the full text included patient or participant characteristics, mechanism of injury, interventions employed, location of treatment, and all outcomes measured. If a text did not meet inclusion criteria at this stage, it was excluded from analysis. Publications included in the data abstraction step were then sorted and analyzed based on study type (RCTs, prospective and retrospective trials, cases series, and case reports).
RESULTS
Search Results
The searches in MEDLINE, Embase, PsycInfo, and the Cochrane Library yielded a total of 1,297 citations. An additional 59 citations were found through non-database searching, 44 citations by searching ClinicalTrials.gov, and 15 citations through hand searching of literature, as detailed in the next paragraph. The 1,356 total citations were exported to Endnote and 89 duplicates were removed using the Endnote deduplication feature. This left a total of 1,267 unique citations found in all searches (Figure 1).
Figure 1.
PRISMA Diagram.
The initial abstract and title review reduced the total number of citations to 129 of interest, and the full text review resulted in 28 publications for data analysis and abstraction. After the full text review stage, with the goal of identifying any additional citations of interest, the references cited by several literature reviews identified by the original search strategy were compared to the list of citations generated by our full text review. Fifteen citations of potential interest were identified from these references. The titles, abstracts, and then full texts of these citations were reviewed, and nine were included in the data abstraction step. The entire process resulted in a total of 37 publications for data review and abstraction. During data review and abstraction, an additional six publications were excluded due to failing to meet inclusion criteria on closer evaluation. As a result, data were abstracted from a total of 31 publications (Figure 1). A full list of reasons for exclusion during the full text review can be found in Figure 1.
Publication Characteristics
The 31 publications included in the data abstraction step were published in 17 different peer-reviewed journals, and occurred in a variety of settings. Seventy percent (22/31) were based in the United States (see Table 1A–C for additional details). Pharmacological classes represented in the publications included antidepressants, anti-epileptics, antipsychotics, benzodiazepines, beta-blockers, alpha-agonists, NMDA antagonists, dopamine agonists, and several investigational and herbal medications (Table 1D).
Table 1.
Publication Characteristics
| Journal Name | Number |
|---|---|
| Brain Injury | 11 |
| Archives of Physical Medicine and Rehabilitation | 3 |
| American Journal of Physical Medicine and Rehabilitation | 2 |
| Journal of Neuropsychiatry and Clinical Neurosciences | 2 |
| Neurocritical Care Journal | 1 |
| CNS Spectrums | 1 |
| American Journal of Psychiatry | 1 |
| International Journal of Preventive Medicine | 1 |
| Annals of the New York Academy of Sciences | 1 |
| Journal of Head Trauma Rehabilitation | 1 |
| Journal of Clinical Psychiatry | 1 |
| Acute Medicine and Surgery | 1 |
| NeuroRehabilitation | 1 |
| Journal of Neuroscience Nursing | 1 |
| Clinical Neuropharmacology | 1 |
| Behavioral Neurology | 1 |
| American Journal of Emergency Medicine | 1 |
| Total | 31 |
| Country | Number |
| United States | 22 |
| Canada | 4 |
| Iran | 2 |
| Spain | 2 |
| China | 1 |
| Total | 31 |
| Setting | Number |
| Rehabilitation setting (inpatient) | 11 |
| ICU/MedSurg/Brain Injury Floor | 9 |
| Inpatient Hospital, not otherwise defined | 8 |
| Long Term Acute Care (LTAC) | 1 |
| Psychiatric Emergency Service | 1 |
| Emergency Department | 1 |
| Total | 31 |
| Medication Class | Number |
| Alpha 2-Agonist | 2 |
| Anesthetic | 2 |
| Antidepressant | 8 |
| SSRI | 3 |
| TCA | 2 |
| NDRI | 1 |
| Other | 2 |
| Anti-epileptic | 4 |
| Antipsychotic | 8 |
| Benzodiazepine | 3 |
| Beta-Blocker | 1 |
| Dopamine Agonist, NMDA Antagonist | 1 |
| H-1 Blocker, Dopamine Antagonist | 1 |
| Herbal | 2 |
| Mood Stabilizer | 1 |
| Narcotic | 2 |
| NDMA Antagonist | 1 |
| Stimulant | 1 |
| Total | 37 |
SSRI, selective seroton in reuptake inhibitor; TCA, tricyclic antidepressant; NDRI, norepinephrine dopamine reuptake inhibitor
Publication Quality
The majority of publications were case reports (11 total) and case series (9 total). There were five randomized, placebo-controlled trials, and of these, three had a cross-over design (Table 2). Due to the large number of case reports and case series and limited number of RCTs, our data analyses were primarily descriptive in nature, as the publications identified during literature review were not amendable to analysis by traditional meta-analytical techniques or other standardized quality assessment tools. Thus, the decision to use a primarily descriptive approach was made based upon the results of our search, and was not defined a priori. Publications were first divided into four categories based on quality of study design: high-quality study design (RCTs); moderate-quality study design (prospective open label trials or retrospective case-control trials); low-quality study design (retrospective studies with three or more subjects) (Table 3); and case reports and small case series (Table 4). Each category was then examined separately.
Table 2.
Publication Quality
| Type of Litterature | Number |
|---|---|
| Case Report | 11 |
| Case Series | 9 |
| n<3 | 4 |
| n=/>3 | 5 |
| Retrospective Cohort with Control Cohort | 1 |
| Prospective Open Label Trial | 5 |
| Randomized Placebo Controlled Double Blinded Cross Over Study | 3 |
| Randomized Placebo Controlled Double Blinded Study | 2 |
| Total | 31 |
Table 3A.
High Quality Study Design.
| Class | Medication | Author | Study Design | Timeframe | Number of Subjects | Mechanism of Injury | Outcome |
|---|---|---|---|---|---|---|---|
| Dopamine Agonist | Amantadine (200mg) | Meythaler, 2002 | RCT (Cross over design) | S: 4 d - 6 w; D: 6 w | 35 (26M, 9F) | MVC | Increased rate of recovery on MMSE, DRS, GOS, FIM-cog (not stastically significant); no difference with GOAT or ABS |
| NMDA-Antagonist | CP-101606 (0.37 −0.75mg/kg/hr) | Merchant, 1999 | RCT (4:1 randomization) | S: 12 h; D: up to 72 h | 53 (45 w TBI) (39M, 14F) | TBI (45: MVC, 31; Fall, 11; Assault, 3), Stroke (8) | No difference: GCS, NRS, Kurtzke Neurological Status Evaluation, or 3 mo outcomes |
| Herbal | Boswellia Serrata (1080mg) | Moein, 2013 | RCT (Cross over design) | S: 7 d (SD 3); D: 6 w | 38 (35M,3F) | MVC | No difference in total DRS, but trend towards improvement in ‘cognitive ability for self care’ subscore |
| Beta-Blocker | Propranolol (60mg – 420mg titration) | Brooke, 1992 | RCT | S: during initial inpatient admission D: 6 w | 21 (10 placebo, 11 treatment) | “closed head injury” | Reduced intesity of agitation, number of physical restraints, but NOT in number of agitated episodes or use of medications for agitation |
| SSRI | Sertraline (100mg) | Meythaler, 2001 | RCT (Cross over design) | S: </= 2–4 w; D: 2w | 9 (6 drug, 3 placebo) | MVC | No difference in the 3 measures used (ABS, GOAT, Orientation Log) |
MVC = motor vehicle collision; RCT = randomized control trial; SSRI = selective serotonin reuptake inhibitor; TBI = traumatic brain injury
S = start date relative to initial injury; D = duration of treatment; h = hours; d = days; w = weeks; M = male; F = female
ABS = Agitated Behavior Scale; DRS = Disability Rating Scale; FIM-cog = Functional Independence Measure-cognitive subscale; GCS = Glascow Coma Score; GOAT = Galveston Orientation and Amnesia Test; GOS = Glascow Outcome Scale; MMSE = Mini-Mental State Exam; NRS = Neurobehavioral Rating Scale; OAS = Overt agitation scale
Table 4.
Case Reports and Small Case Series
| Medication | Number of Case Reports/Series | Number of Subjects | Daily Dose Range/Duration (if provided) | Net Outcome | |
|---|---|---|---|---|---|
| Amantadine | 3 | 3 | 200mg × days -weeks | − | Concern for increased irritability raised in 2/3 cases (Silver 1996, Wroblowski 1997), improvement in symptoms in 1/3 cases when started in combination with sertraline, propranolol (Wilkinson 1999) |
| Bupropion | 1 | 1 | 150mg | Decrease in restlessness, agitation when started in combination with haloperidol and propranolol (Teng 2001) | |
| Buspirone | 2 | 2 | 30mg × weeks | + | Effective in 2/2 cases (Levine 1988, Pourcher 1994), in one, subject simultaneously treated with carbamazepine (Pourcher 1994) |
| Carbamazepine | 4 | 4 | 400mg – 1000mg × weeks | − | Effective in 2/4 cases when in combination with other agents (Iruela 1992, Pourcher 1994); not effective in 2/4 cases when used as monotherapy (Slaughter 1999, Wroblowski 1997) |
| Chloral hydrate | 1 | 1 | 1g × weeks | − | Not effective in the 1 case report available (Haas 1985) |
| Clonidine | 1 | 1 | 0.3mg × 2+ weeks | − | Not effective in the 1 case report available (Oster 2007) |
| Dexmedetomidine | 1 | 1 | 0.5mcg/kg/hr -> 1.5mcg/kg/hr × 8 days | Effective in combination with lorazepam, phenytoin (Tang 2011) | |
| Diazepam | 3 | 3 | 2.5mg – 40mg × several days | − − |
Not effective in 3/3 case reports (Haas 1985, Krieger 2003, Teng 2001) |
| Fentanyl | 1 | 1 | 25ug/hr – 100ug/hr × 2+ weeks | − | Not effective in the 1 case report available (Oster 2007) |
| Fluoxetine | 1 | 1 | 60mg × days | + | Effective in the 1 case report available (Slaughter 1999) |
| Gabapentin | 1 | 1 | 1600mg, then tapered × 3+ weeks | − | Not effective in the one case report available (Oster 2007) |
| Haloperidol | 8 | 8 | 2mg – 20mg × days - months | − | Some positive effect reported in combination with other agents in 3/8 cases (Fowler 1995, Mousavi 2013, Teng 2001), concern for akathesia in 1/8 cases (Silver 1996), concern for NMS in 2/8 cases (Slaughter 1999, Wilkinson 1999), not effetive in 2/8 cases (Haas 1985, Oster 2007) |
| Lithium | 1 | 1 | 900mg × 20 days | + | Effective in the 1 case report available (Haas 1985) |
| Lorazepam | 4 | 4 | 1mg – 2mg × days - weeks | − | Not effective in 3/4 cases (Hufford 2012, Slaughter 1999, Oster 2007); Effective in case reported by Fowler, et al. (1995) |
| Loxapine | 2 | 2 | 20mg – 60mg × weeks - months | Effective in 1/2 cases (Krieger 2003), not effective in other case (Teng 2001) | |
| Methylphenidate | 3 | 3 | 20mg – 80mg × days - weeks | − − |
Not effective or worsened behaviors in 3/3 cases (Haas 1985, Teng 2001, Wroblowski 1997) |
| Midazolam | 1 | 1 | continuous infusion with 10mg IV push | − | Not effective in the 1 case report available (Fowler 1995) |
| Morphine | 2 | 2 | 24mg - continuous infusion | − − |
Not effective in 2/2 case reports (Fowler 1995, Oster 2007) |
| Nortriptyline | 1 | 1 | 50mg – 100mg | Concern for seizure activity but improved behavior in the one case report available (Wroblowski 1997) | |
| Olanzepine | 4 | 4 | 5mg – 20mg × days | Not effective in 2/4 case reports (Krieger 2003, Slaughter 1999), Effective in combination with behavioral plan or other agents in 2/4 case reports (Mousavi 2013, Hufford 2012) | |
| Paroxetine | 1 | 1 | 5mg – 10mg × 3 days | − | Not effective in the one case report available (Teng 2001) |
| Phenytoin | 2 | 2 | 300mg × 2+ weeks | − − |
Not effective or concern for side effective in 2/2 case reports (Oster 2007, Wroblowski 1997) |
| Pimozide | 1 | 1 | 12mg × 3 months | Effective in combo with carbamazepi ne in the one case report available (Iruela 1992) | |
| Promethazine | 1 | 1 | 100mg × 2+ weeks | − | Not effective in the one case report available (Oster 2007) |
| Propofol | 1 | 1 | continuous infusion × days | Effective in the one case report available (Fowler 1995) | |
| Propranolol | 5 | 5 | 30mg – 320mg × days - months | − | Not effective in 3/5 case reports (Haas 1985, Krieger 2003, Slaughter 1999), effective per 1/5 case reports in combination with other agents (Wilkinson 1999), and effective after initation of additional agent in 1/5 case reports (Teng 2001) |
| Quetiapine | 1 | 1 | Up to 900mg × 18 days | + | Effective in the one case report available (Oster 2007) |
| Sertraline | 3 | 4 | 50mg – 150mg × mulitiple days | Effective in 1 case report in combination with other agents (Wilkinson 1999), effective in 2 cases in 1 case series, though one case complicated by GI distress (Slaughter 1999); not effective in 1 case report (Krieger 2003) | |
| Temazepam | 1 | 1 | 30mg × 8 days | − | Not effective in the one case report available (Haas 1985) |
| Thiothixine | 1 | 1 | 10mg – 20mg | Effective in combination with sertraline in the one case report available (Slaughter 1999) | |
| Trazodone | 1 | 1 | − | Not effective in the one case report available (Slaughter 1999) | |
| Valproic Acid | 3 | 3 | 600mg – 2250mg × 10 days and longer | Effective in combination with other agents in 2/3 case reports (Mousavi 2013, Wroblowski 1997), not effective in 1/3 case reports (Slaughter 1999) | |
NMS = neuroleptic malignancy syndrome
++ Effective in all cases (and case # >1)
+ Effective in most cases
Mixture of results OR Impact only reported in the context of other medications
− Not effective/harmful in most casese
−− Not effective/harmful in all cases (and case # >1)
Case Series
Results by Study Design
Five publications met criteria for high quality study design, all of which were RCTs. The five medications included in these studies were amantadine, propranolol, sertraline, an investigation drug CP-101606 and Boswellia Serrata (an anti-inflammatory herbal medicine, also called frankincense) (12–16) (Table 3A). Only three of these five medications are currently commercially available (amantadine, propranolol, and sertraline), and only one, propranolol, was associated with statistically significant improvement in agitation. Specifically, propranolol was shown to be associated with reduced intensity of agitation and use of physical restraints, but not number of agitated behaviors or use of additional medications to target agitation (12). In contrast, amantadine was associated with a trend towards improvement on a variety of cognitive measures, but not agitation (16). Sertraline had no effect (positive or negative) on Agitated Behavioral Scale (ABS) scores, Galveston Orientation and Amnesia Test (GOAT) results, or Orientation Log (O-Log) performance, relative to placebo (13).
Six publications met criteria for moderate quality study design, with five of the six being prospective open label trials (Table 3B). Two analyzed the impact of amantadine on agitation (17, 18). In particular, Gramish et al. (17) noted an increase in agitation when amantadine was initiated an average of three days after injury and continued for one week. However, Rosati et al. (18) reported an improvement in Rancho Los Amigos (RLA) scale scores and a reduction in antipsychotic and benzodiazepine use when a multi-drug regimen of amantadine, trazodone, and either methylphenidate or dextroamphetamine were given, starting an average of 14 days post injury (Table 3B).
Table 3B.
Moderate Quality Study Design
| Class | Medication | Author | Study Design | Timeframe | Number of Subjects | Mechanism of Injury | Outcome |
|---|---|---|---|---|---|---|---|
| Dopamine Agonist | Amantadine, 200mg | Gramish, 2017 | Retrospective Cohort (with Control Cohort) | S: 3 d (avg); D: 7 d | 139 (70 Cohort, 69 Control) (110 M, 29 F) | MVC (23, 19), motorcycle/bicycle /all-terain (13, 16), fall (12, 15), Assault (11, 6), other (5, 5) (intervention, cntrl)* | Amantadine associated with increased agitation, opioid use, hospital LOS; no difference in haloperidol, benzodiazepine use |
| Amantadine, 100mg | Rosati, 2002 | Prospective Open Label | S: 14.5 d (range 4–23) | 11 (11 M) | MVC (10), GSW (1) | Improvement in RLA scores seen with change in treatment (amantadine + trazodone + stimulant) and allowed for discontinuation of haloperidol, taper of lorazepam | |
| TCA | Amitriptyline, 75mg (avg), 150mg (max) | Mysiw, 1988 | Prospective Open Label | S: 10.5 w (+/− 5.5 w); D: 7–14 d | 20 (18M, 2F) | MVC (18), Trauma/Fall (2) | 13/20 treated patients demonstrated improvement in Orientation Group Monitoring Scale as well as in the frequency, severity, type of agitation; 1/20 had increased agitation, after amtriptyline initiation; No difference in cognitive scores relative to less agitated, non-treated patients observed |
| Anti-epileptic | Carbamazepine, 800–900mg | Chatham-Showalter, 1996 | Prospective Open Label | S: hospital day 12.5 (avg; range: 5–21) D: 4–24 d | 7 (6M, 1F) | MVC(4), motorcycle (1), pedestrian hit by car (1), skier (1) | all subjects improved to at least RLA = 5, and fewer other meds were required for agitation after CBZ started (though patients still discharged on combination of carbamazepine and haloperidol (4), thiothixene (1), buspirone (1) |
| Stimulant | Methylphenidate/Dextroampheta mine | Rosati, 2002 | Prospective Open Label | S: 14.5 d (range 4–23) | 11 (11 M) | MVC (10), GSW (1) | Improvement in RLA scores seen with change in treatment (amantadine + trazodone + stimulant) and allowed for discontinuation of haloperidol, taper of lorazepam |
| Anesthetic | Propofol | Holger, 1999 | Prospective Open Label | S: hours; D: minutes | 3 (2F, 1M) | Fall (1), Asault (2) | Propofol safe, effective sedation method for imaging after head injury; Side effects: 1 case of mild hypotension, 1 episode of brief apnea |
| Serotonergic Agent | Trazodone | Rosati, 2002 | Prospective Open Label | S: 14.5 d (range 4–23) | 11 (11 M) | MVC (10), GSW (1) | Improvement in RLA scores seen with change in treatment (amantadine + trazodone + stimulant) and allowed for discontinuation of haloperidol, taper of lorazepam |
| Herbal | Yokukansan**, 7.5g | Kan’o, 2014 | Prospective Open Label | S: 4–20 d; D: 2 w |
6 (4M, 2F) | MVC (2), Fall (3), Fight (1) | improvement in GCS, MMSE, BI, VI, NPI |
total of all etiologies do not add up to totals reported by study for unknown reason
Yokukansan: a Japanese Kampo medicine reported to be safe and useful in treating behavioral and pyschological symptoms in dementia patients
CBZ = carbamazepine; GSW = gun shot wound; LOS = length of stay; MVC = motor vehicle collision; TBI = traumatic brain injury; TCA = tricyclic antidepressant
S = start date relative to initial injury; D = duration of treatment; h = hours; d = days; w = weeks; M = male; F = female
BI = Barthell Index; GCS = Glascow Coma Score; MMSE = Mini-Mental State Exam; NPI = Neuropsychiatric Inventory; RLA = Rachos Los Amigos Scale; VI = Vitality Index
The remaining four publications meeting criteria for moderate quality design demonstrated at least partial improvement in agitation in the context of starting amitriptyline (19), carbamazepine (CBZ) (20), propofol (21), or a Japanese Kampo medication, yokukansan (22). However, in the case of amitriptyline, the study size was small (20 total participants), six participants did not demonstrate any improvement with treatment, and one suffered increased agitation (19). In the case of CBZ, five of the seven subjects still required treatment with an antipsychotic in addition to CBZ (20). In the case of propofol, the authors noted that it was challenging to limit the depth of sedation, though no adverse effects from treatment were reported (21). Yokukansan was associated with promising results on a wide variety of neuropsychiatric batteries; however, it is not currently commercially available in the United States (22).
Five publications met criteria for low quality study design. These analyzed amantadine, haloperidol, methotrimeprazine (MTZ), valproic acid (VPA), and ziprasidone (Table 3C). Amantadine, when initiated several weeks post injury, was associated with improved alertness, concentration, and agitation in all four subjects (23). Haloperidol and MTZ were used by Rao et al. (24) and Maryniak et al. (25), respectively, to target agitation not responsive to other behavioral interventions. Both reported improvement in agitation after drug initiation. Neither of these two studies had a true comparator group; however, despite being used in patients with more severe agitation, haloperidol use was associated with functional outcomes and levels of independence similar to less agitated and untreated patients (24). In a related publication, ziprasidone was also associated with reduced agitation in five severely brain injured patients after two weeks of treatment (26). Finally, VPA, a mood stabilizer, was associated with reduced agitation in nearly 90% (26/29) of subjects suffering from various types of head trauma (27).
Table 3C -.
Low Quality Study Design
| Class | Medication | Author | Study Design | Timeframe | Number of Subjects | Mechanism of Injury | Outcome |
|---|---|---|---|---|---|---|---|
| Dopamine Agonist | Amantadine, 100–400mg | Nickels, 1994 | Retrospective Case Series | S: 55–80 d | 4 (3M, 1F) | MVC | Amantadine late in recovery can help alertness, concentration, agitation; Side effects: For entire cohort: Pedal edema, hypomania, seizure, visual hallucinations (unknown if these applied to four subjects meeting this study’s inclusion criteria) |
| Antipsychotic | Haloperidol, 2–15mg | Rao, 1985 | Retrospective Case Series | S: median 5 d (range 2–80 d); D: median 35 d (range 14–61 d) | 11 | Despite use in more severly injured patients, haloperidol-treated patients recovered to comparable functional extent, with no significant difference in recovery of Independent function at discharge, when compared to an untreated (and less agitated) group | |
| Methotrimeprazine | Maryniak, 2001 | Retrospective Case Series | S: <3 mo; D: 42 d (avg; SD 24.4; range 1–124) | 56 | Only combined etiology provided for both agitated (and treated group) as well as non-agitated (and un-treated group)? | 96% who received drug responded to it (with less agitation); those receiving drug also with longer LOS, PTA, coma compared to less agitated and untreated group, but this likely because treated group more severely injured; Side effects: drowsiness (dose dependent), EPS (1), Akathesia (1) | |
| Ziprasidone, 52.8mg (avg) +/− 27.11mg, range 20–80mg | Noe, 2007 | Retrospective Case Series | S: mean = 54.6 d (+/− 11.5, range 40–72 d); D: mean = 48.2 d (+/− 14.8, range 35–68 d) | 5 (3M, 2F) | “severe TBI” | reduction in ABS and all ABS subscales (disinhibition, aggressiveness, lability) at two weeks of treatment; resolution of PTA by conclusion of treatment | |
| Anti-epileptic | Valproic Acid, 250–2000mg | Chatham-Showalter, 2000 | Retrospective Case Series | S: 4– 180d; D: variable** | 22 | MVC (14), fall (7), blunt trauma(1), gun shot (1), intracranial hemorrhage (5), vasculititis (1), anoxia (1)** | 26/29 demonstrated improvement on valproicacid with less agitation, fewer additional medicaitons required; side effects: two patients: increased lethargy |
Methotrimeprazine (MTZ): an aliphatic phenothiazine low potency neuroleptic with strong antihistamine activity
a portion of subjects started study medication after our criteria for acute time period after TBI (90d); however, unclear how many started after 90d; 7 subject suffered non-traditional TBI mechanism, but information not provided to remove these from the results; however, publication does indicate that no mechanism of injury corrrelated with a specific response pattern to treatment
EPS = extra-pyramidal symptoms; LOS = length of stay; MVC = motor vehicle collision; PTA = post-traumatic amnesia; TBI = traumatic brain injury
S = start date relative to initial injury; D = duration of treatment; h = hours; d = days; w = weeks; M = male; F = female
ABS = Agitated Behavior Scale
In addition to publications classified as high, moderate, or low quality, 11 case reports and four small cases series (n < 3) met our inclusion criteria. When considering the results of all 16 studies, four medications [(buspirone (28, 29), fluoxetine (30), lithium (31), and quetiapine (32)] were consistently associated with an improvement in symptoms, with no adverse events reported. In contrast, diazepam (31, 33, 34), methylphenidate (31, 34, 35), morphine (32, 36), and phenytoin (32, 35) were associated with a worsening of symptoms or significant adverse effects, with no report of improvement in symptoms. The majority of medications were associated with inconsistent effects on behavior. Individual study results and overall conclusions are further detailed in Table 4.
DISCUSSION
This systematic review revealed a paucity of high quality primary research available to guide the CL psychiatrist during the pharmacological management of the agitated patient in the acute time period following a TBI. While there were numerous case studies and small case series addressing this question, only five RCTs were identified. Of the five RCTs, only two demonstrated measurable improvement in agitation with drug administration, and one of the two reportedly effective drugs is not currently commercially available (12, 15).
However, several interesting trends did emerge from the literature as a whole. First, the time of treatment initiation, and duration of treatment, relative to time of head injury, may impact whether or not a particular agent will be effective in the TBI population. For example, four publications, including one RCT, investigated the impact of amantadine on behavioral dysregulation. The results of these publications initially appeared contradictory, with some reporting improvement in agitation with amantadine administration, some reporting no change in behaviors, and others reporting increased agitation (16, 17, 23, 37). However, when the time of initial amantadine administration was compared to time of head injury, the impact of amantadine on level of agitation appeared to demonstrate a time-dependent effect. An improvement in agitation was more likely to occur when the drug was initially prescribed several weeks post-injury (16, 23, 37), but when amantadine was initiated only days post-injury, agitation was more likely to increase (17). In addition, in one RCT, sertraline was not associated with an improvement in agitation relative to placebo (13); however, due the timeframe of the study (subjects were followed a maximum of six weeks post injury), the duration of treatment may have been insufficient to see an effect. Indeed, other trials have suggested that SSRIs are most beneficial outside of the acute period following a TBI (38). Future research investigating the impact of drug initiation vs. placebo, given at specified time points and durations post-injury, will be necessary to determine if these effects persist.
Second, certain drug classes appeared to be more consistently beneficial when targeting agitation, as compared to others. For example, six of nine publications that described the impact of anti-epileptics on agitation demonstrated an improvement in agitation. VPA was associated with improvement in agitation in 26/29 subjects in a retrospective case series (27) and two out of three case reports (30, 35, 39); CBZ similarly was associated with improvement in a prospective open label study (20) and two out of four case reports (29, 30, 35, 40). In contrast, three of the four publications involving psychostimulants demonstrated increased agitation with drug initiation. Three case reports described increased agitation in the context of starting methylphenidate at a month (31, 35) or two months (34) post injury. One prospective open label trial demonstrated improvement in agitation with methylphenidate or dextroamphetamine, but these stimulants were prescribed in combination with amantadine and trazodone (37).
Third, there were some medications and classes of medications, that were only associated with negative outcomes or side effects across multiple publications, regardless of study quality. These included diazepam (31, 33, 34), phenytoin (32, 35), and opiates (32, 36). Lorazepam was associated with negative side effects in three of four case reports (30, 32, 36, 41).
Of note, while antipsychotics are often used to target agitation due to a wide variety of etiologies, our search only identified three retrospective case series (24–26) involving antipsychotics, along with 11 case studies and small case series (30–34, 36, 39–43). The case studies demonstrated mixed results regarding efficacy, as well as risk of side effects. The retrospective case series demonstrated an overall reduction in agitation; however, without a comparator group, it was difficult to assess what improvement was due to treatment, as opposed to improvement that would have occurred over time without intervention. Therefore, while this class may reduce agitation, it is advisable to consider if other classes such as beta-blockers or anti-epileptics might provide a similar effect.
The limited number of high-quality studies identified by our work likely reflects the challenges faced by researchers when designing and implementing randomized and placebo-controlled trials in the TBI population. These challenges include obtaining proper informed consent from the subject or appropriate surrogate in a timely fashion, the need to provide medications emergently or urgently to reduce the risk of harm to the patient or others, and the heterogeneous nature of TBI. Indeed, each TBI is the unique result of etiology, brain region affected, and baseline neurological function. The broader concept of post-traumatic encephalopathy (PTE) encompasses several hierarchical stages of post-traumatic cognitive, emotional, and behavioral disturbances that are linked to the occurrence of a TBI, and provides a conceptual framework for understanding some of the complexity of TBI (44). Unfortunately, a detailed review of PTE is outside the scope of this manuscript.
In summary, a treatment regimen for the management of agitation in the context of an acute TBI is difficult to construct solely from high quality primary literature. There are significant challenges when interpreting the current literature, as large trials are not available, and the results that are available are at high risk for bias due to small population size and an inability to account for confounders and other variables, such as time of drug initiation relative to time of head injury. However, while additional work is greatly needed in this area, it appears that a regimen including propranolol, amantadine (when started several weeks post injury), and an anti-epileptic such as VPA is reasonably supported by the limited data available, and it appears prudent to avoid benzodiazepines, opiates, and phenytoin when clinically feasible.
Acknowledgements:
We would like to acknowledge the contributions of Jonathan Gerkin, MD, and Gary Gala, MD, during the planning and initial stages of this work.
Funding Sources:
For James Bateman: This research is supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the W.G. (Bill) Hefner Veterans Affairs Medical Center, and the Department of Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC).
Footnotes
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Contributor Information
Rebekah Nash, University of North Carolina at Chapel Hill School of Medicine, Psychiatry.
Marc Weinberg, University of North Carolina at Chapel Hill School of Medicine.
Sarah Laughon, University of North Carolina at Chapel Hill, Psychiatry.
Rebecca McCall, University of North Carolina at Chapel Hill, Health Sciences Library.
James Bateman, VISN 6 Mental Illness Research, Education, and Clinical Center (MIRECC); Salisbury VA Medical Center; Wake Forest University School of Medicine, Neurology.
Donald Rosenstein, University of North Carolina, Psychiatry.
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