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Pharmacological management for agitation and aggression in people with acquired brain injury

Pharmacological management for agitation and aggression in
people with acquired brain injury (Review)
Fleminger S, Greenwood RRJ, Oliver DL
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2008, Issue 3 Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

PLAIN LANGUAGE SUMMARY AUTHORS' CONCLUSIONS CHARACTERISTICS OF STUDIES CONTRIBUTIONS OF AUTHORS Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pharmacological management for agitation and aggression in
people with acquired brain injury

Simon Fleminger1, Richard RJ Greenwood2, Donna L Oliver1 1Lishman Brain Injury Unit, Maudsley Hospital, London, UK. 2Regional Neurological Rehabilitation Unit, Homerton UniversityHospital, London, UK Contact address: Simon Fleminger, Lishman Brain Injury Unit, Maudsley Hospital, Denmark Hill, London, SE5 8AZ, UK.
.
Editorial group: Cochrane Injuries Group.
Publication status and date: Edited (no change to conclusions), published in Issue 3, 2008.
Review content assessed as up-to-date: 21 August 2006.
Citation: Fleminger S, Greenwood RRJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired
brain injury. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003299. DOI: 10.1002/14651858.CD003299.pub2.
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Of the many psychiatric symptoms that may result from brain injury, agitation and/or aggression are often the most troublesome. It istherefore important to evaluate the efficacy of psychotropic medication used in its management.
To evaluate the effects of drugs for agitation and/or aggression following acquired brain injury (ABI).
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and other electronic databases. We also searchedthe reference lists of included studies and recent reviews. In addition we handsearched the journals Brain Injury and the Journal of HeadTrauma Rehabilitation. There were no language restrictions. The searches were last updated in June 2006.
Randomised controlled trials (RCTs) that evaluated the efficacy of drugs acting on the central nervous system for agitation and/oraggression, secondary to ABI, in participants over 10 years of age.
Data collection and analysis
We independently extracted data and assessed trial quality. Studies of patients within six months after brain injury and/or in a confusionalstate, were distinguished from those of patients more than six months post-injury, or who were not confused.
Main results
Six RCTs were identified and included in this review. Four of theses evaluated the beta-blockers, propranolol and pindolol, one evaluatedthe central nervous system stimulant, methylphenidate and one evaluated amantadine, a drug normally used in parkinsonism and relateddisorders. The best evidence of effectiveness in the management of agitation and/or aggression following ABI was for beta-blockers.
Two RCTs found propranolol to be effective (one study early and one late after injury). However, these studies used relatively smallnumbers, have not been replicated, used large doses, and did not use a global outcome measure or long-term follow-up. Comparingearly agitation to late aggression, there was no evidence for a differential drug response. Firm evidence that carbamazepine or valproateis effective in the management of agitation and/or aggression following ABI is lacking.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Numerous drugs have been tried in the management of aggression in ABI but without firm evidence of their efficacy. It is thereforeimportant to choose drugs with few side effects and to monitor their effect. Beta-blockers have the best evidence for efficacy and deservemore attention. The lack of evidence highlights the need for better evaluations of drugs for this important problem.
Prescription drug use for managing agitation and aggression in people with acquired brain injury
This review found no firm evidence that drug management of agitation and aggression in adults with acquired brain injury is effective.
There was weak evidence, based on a few small randomized controlled trials, that beta-blockers can improve aggression after acquiredbrain injury, but very large doses were used which would have been likely to produce significant adverse effects. For other classes ofmedication, reasonable size randomized controlled trials have not been published.
Based on the lack of evidence, the review comes to no conclusion on the effectiveness of drugs. There is reasonable anecdotal evidence,for example in published cases series, that antipsychotics, mood stabilizers and antidepressants may be effective in the management ofthis situation.
B A C K G R O U N D
tient rehabilitation unit displayed aggressive behaviour In light of this it is surprising that clinicians are yet to agree ondefinitions of agitation and aggression (). A variety of Description of the condition
terms are used to refer to agitation and aggression and often the Psychological and psychiatric problems exceed physical problems two terms are treated as interchangeable. Although the concept of as causes of morbidity and disability following acquired brain in- agitation and aggression are closely intertwined it is useful, both jury (ABI) (). Of the many psychiatric symptoms that theoretically and practically, to draw a distinction between them.
may result from ABI, agitation and aggression are often the most Agitation, defined as disturbed behaviour as a result of overactivity, troublesome for carers and patients. Agitation and aggression on occurs frequently in the acute phase of recovery, where it is usually medical or surgical wards immediately following the injury occur related to post-traumatic amnesia (PTA). Post-traumatic amne- in about 11% of patients (They can cause disrup- sia is a transient period characterised by disorientation, confusion tion to the normal running of the ward and, when a patient re- and cognitive impairment. As improvements in cognition tend turns home, the family may suffer considerable distress ( to precede improvements in agitated behaviour ), resulting from the difficulties of looking after somebody environmental intervention rather than drug therapy is often the who may now be irritable ; and preferred means of managing agitation in the acute phase. Medi- occasionally violent (There is good evidence that pa- cation that adversely affects cognitive function may exacerbate the tients with a head injury have an increased risk of aggression and problem. However, people suffering from agitation related to PTA agitation. For example when compared with patients with mul- are generally, certainly in the UK, still on acute surgical or medical tiple trauma but without head injury, three times as many head wards that are least able to offer environmental interventions. On injured patients showed significant aggression during the first 6 the other hand, aggression in the later stages of recovery, which months post injury as did the control group (33.7% versus 11.5%) may be more responsive to pharmacological treatment, tends to (And problems with aggression continue for many occur when the patient is in a rehabilitation unit, by which time years in a proportion of cases. For example a quarter of patients environmental manipulation is more realistic.
at follow-up six, 24 and 60 months after discharge from an in-pa- The definition of aggression encompasses both verbal and physical Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
aggression against self, objects and other people ).
A further rationale for the use of antidepressants is the observa- It may also include severe irritability, violent, hostile, or assaulta- tion that metabolites of noradrenaline and serotonin have been tive behaviour and "episodic dyscontrol". A distinction is often found to be reduced in cerebrospinal fluid from agitated patients made between instrumental and goal directed aggression and hos- with ABI (). Most antidepressants potentiate tile and/or explosive aggression (). It is the latter noradrenaline and/or serotonin in the brain. Lithium potentiates type that is generally observed after brain injury, usually during serotonin pathways as does buspirone, an anxiolytic.
the later stages of recovery, when the patient is no longer suffer-ing from PTA and has regained cognitive awareness ).
Although a distinction can be made between types of aggression Adverse consequences of drug treatment
there is no empirical evidence, to the authors' knowledge, that There are many potential problems associated with prescribing they differ in their pharmacological response.
psychotropic medication in people with ABI. Perhaps the mostimportant is that sedating medications can cause confusion andmay, therefore, exacerbate agitation occurring during the confu- Description of the intervention
sional state of PTA.
Patients with brain injury may be particularly vulnerable to de-veloping neuroleptic malignant syndrome (; ). Another side effect of neuroleptics is akathisia, Rationale for drug treatment of agitation and
which may increase agitation. Benzodiazepines may occasionally cause an increase in aggressive behaviour ( Various classes of medications have been used to treat agitation Recent concerns about the possible in- and aggression following ABI (these creased risk of stroke in older patients taking atypical antipsy- chotics also need to be considered ).
There is some evidence from human studies that anticonvulsants • antipsychotics, including haloperidol; can have adverse effects on cognitive function when prescribed • benzodiazepines; to prevent post-traumatic seizures • anticonvulsants particularly carbamazepine; Furthermore, studies in animals have demonstrated the potential • buspirone (a non-benzodiazepine anxiolytic); for neuroleptics (), benzodiazepines ( • antidepressants including trycyclic antidepressants (TCAs) and anticonvulsants ) to impair recovery from brain injury. Yet these potentially harmful drugs are being pre- scribed to the majority of patients admitted to hospital after head • beta-blockers; • lithium.
The rationale for the use of the various psychotropics in the man-agement of agitation and/or aggression is poorly defined. Often Why it is important to do this review
medication is used to sedate the patient, rather than to treat a Given the possible harmful effects of treating agitation and aggres- specific mental illness or organic brain syndrome, which may be sion with drugs it is important to evaluate the evidence that psy- causing the aggressive behaviour.
chotropic drugs are effective in managing agitation and aggression Antipsychotics (synonymous with major tranquillisers or neu- following ABI.
roleptics) are commonly used to manage aggression. In the shortterm they may be used to quieten disturbed patients whatever theunderlying psychopathology. However, the only well establishedlong-term indication is the management of schizophrenia ().
O B J E C T I V E S
Patients with ABI are likely to be at risk of sub-clinical epileptic To determine the evidence that psychotropic medication is effec- activity which has been proposed as a cause of ag- tive for the management of agitation and/or aggression in patients gression (In patients without ABI carbamazepine with ABI. We have also looked at evidence for unwanted side ef- has been found to reduce aggression ), fects of medication to enable us to determine whether unwanted which could be related to its anticonvulsant or mood stabilising effects out weigh beneficial effects. All psychotropic medication was included in the review.
Depression and anxiety may cause irritability and aggravate aggres-sive behaviour. In this case sedative antidepressants might be ex- As there is no good evidence for a differential drug response for ag- pected to help. Mood stabilisers, such as lithium, could also work.
itation, as opposed to aggression, this review considered any form Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
of agitation or aggression secondary to brain injury. To enable a Types of interventions
study of differential treatment effects, papers were classified ac- Any drug acting on the central nervous system (see chapter 4 of cording to the type of agitation and/or aggression and the stage of the British National Formulary): • 4.1 hypnotics and anxiolytics; • 4.2 drugs used in psychoses and related disorders; • 4.3 antidepressant drugs; • 4.4 central nervous system stimulants; • 4.5 drugs used in the treatment of obesity; Criteria for considering studies for this review
• 4.6 drugs used in nausea and vertigo; • 4.7 analgesics; • 4.8 antiepileptics; • 4.9 drugs used in parkinsonism and related disorders; Types of studies
• 4.10 drugs used in substance dependence; Randomised controlled trials.
• 4.11 drugs for dementia; • Other (beta-adrenoceptor blocking drugs: bupropion).
Types of participants
The review identified studies of patients suffering from acquired Types of outcome measures
brain injuries that were single incidents, that is, not progressive,and were acquired in adult life. Therefore, it included anoxic braininjury, encephalitis and other forms of brain injury. Non-progres- sive brain injury due to alcohol or other drug abuse were also in- The primary outcome measure was agitation and/or aggression.
cluded. Cerebrovascular events (stroke) were excluded.
Where possible changes in the severity, frequency, or type of agi- Agitated and/or aggressive behaviour must have been described tation and/or aggression were recorded.
as a presenting symptom although a formal diagnosis of organicpersonality syndrome with recurrent outbursts of aggression orrage personality change due to a general medical condition, F07.0; aggressive type) was not required.
Additional outcome measures, if available, were as follows: Agitation and/or aggression must have been measured using anexplicit measurement tool that allowed a quantitative score of ag- • independent living itation and/or aggression.
• participation in rehabilitation Aggression against property or others, whether physical or verbal, • adverse events (increased cognitive impairment, side effects, was included. Aggression, which was only sexual or only against the self, was not included. Shouting behaviour that was not threat- • health service utilisation (in particular length of stay).
ening was not included.
Age at injury greater than 10 years (to exclude patients usuallyclassified as suffering from learning disabilities or mental impair- Search methods for identification of studies
ment).
Studies in which the major problem was post-traumatic epilepsywere excluded.
There was no restriction on time between injury and treatment, We searched the following electronic databases: severity of injury or setting of study.
Patients were classified according to the stage of recovery follow- • Cochrane Injuries Group specialised register ing the brain injury. We have attempted to distinguish agitation • Cochrane Central Register of Controlled Trials and/or aggression occurring earlier, during the confusional state, from aggressive behaviour occurring later. To do this we classified papers according to whether the patient was in a confused state, and/or Rancho level IV, and/or described as being in PTA, as op- • National Research Register posed to patients who were no longer confused. In the absence of adequate information in the paper for this assignment to be made we classified papers according to cohorts less than six months and greater than six months post-injury.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Description of studies
The search strategy is described in .
Searching other resources
Results of the search
The journals Brain Injury and Journal of Head Trauma Rehabilita- Six randomised controlled trials were identified that met our in- tion were handsearched from the first issue through to volume 16, clusion criteria.
issue 5 (2002) and volume 17, issue 3 (2002) respectively. An up- Four of these trials evaluated the efficacy of beta-blockers ( date of the handsearching was done electronically using Pubmed covering the same two journals from 2002 to 2006.
Two of the trials of beta-blockers seemed to include some of thesame patients (). One trial A Web of Science citation index search and reference lists of rel- evaluated the efficacy of the central nervous system stimulant, evant trials and review articles were checked for suitable trial re- methylphenidate (One trial evaluated a drug used in parkinsonism and related disorders, amantadine (The drugs which have been identified have been classified accord- Data collection and analysis
ing to the British National Formulary categories with the excep-tion of beta-blockers which have been collated separately under The review was guided by a steering committee of Dr Keith An- the title "other".
drews, Dr Tom McMillan and Dr Richard Greenwood.
Studies were also classified according to the patient's stage of recov-ery following the brain injury. We wished to distinguish betweenstudies of early agitation during the post-traumatic confusional Selection of studies
state and those of later aggression in patients who were not con- One author (DLO) screened the titles, abstracts, and keywords of fused. We, therefore, classified studies according to the following citations from electronic databases for eligibility. The quality of DLO's screening was assessed by a second author (SF) who read arandom sample of 100 papers, for further in-depth review. A high • A = patients described as in a confused state, and/or Rancho level of concordance was achieved as only one paper was disputed, level IV, and/or described as being in PTA; a paper which was subsequently excluded from the review.
• B = patients described as no longer confused, and/or out of Papers judged to be potentially eligible based on title and/or ab- stract were retrieved in full and these were independently assessed For a description of Rancho Los Amigos levels of cognitive func- against the inclusion criteria by both authors.
tioning please refer to Six papers were screened as eligible for inclusion in this review.
In the absence of adequate information in the paper to make this The reference list of each paper was searched and a Web of Sci- assignment we classified papers according to: ence Citation search conducted. Papers identified from this pro-cess were retrieved in full and were independently assessed against • 1 = cohorts less than six months post-injury; the inclusion criteria by both authors.
• 2 = cohorts greater than six months post-injury; • 9 = not stated.
Therefore, early studies are indicated by A or 1, and late studies Assessment of risk of bias in included studies
The quality of the RCTs were assessed independently by both au- Data from the included studies were extracted according to the thors using a validated scale (). This measure assesses headings in the included tables. A short description of each study the likelihood of bias in RCTs based on the adequacy of randomi- is given in the text.
sation, blinding and information provided on withdrawals anddropouts. The scale grades the trial out of five with five indicatinga good quality design. Disagreement on methodological quality 4.4 Central nervous system stimulants
was resolved, where necessary, by discussion.
methylphenidate: 2A six-week evaluation of the effect of treatment withmethylphenidate, 30 mg per day, using a randomised placebo con-trolled design. The 38 subjects, aged 18 to 50 years (mean age 29 years) had all suffered severe TBI with mean coma length of Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
17 days, mean post-traumatic amnesia of 56 days and time post- Patients were rated with the nurses observational scale for inpa- injury of more than two years (mean 27 months, SD 21 months).
tient evaluation (NOSIE). During the trial all regular psychotropic Nineteen subjects were allocated to each arm.
medication was stopped apart from paraldehyde and phenobar- Various measures of anger were made before and at the end of six bital as required (the same being true for the weeks' treatment.
study).
: pindolol: 2This study was a randomised controlled trial of pindolol (up to 4.9 Drugs used in parkinsonism and related disorders
60mg per day), using a cross-over design. The treatment and placebo periods were of only two weeks. The authors appear to This study tested the hypothesis that amantadine would decrease have used many of the same participants as an earlier study ( agitation and improve cognitive functioning in patients with TBI ) looking at propranolol (see above).
using a randomised, double-blind, placebo-controlled, cross-over The study authors give no information about the assessment scale design. The six-week trial was divided into two-week blocks of used to rate the behaviours. They also state that the treatment or- amantadine/placebo, withdrawal, placebo/amantadine. Patients der was randomly determined for each patient group rather than were randomly allocated to one of the two treatment orders. Aman- each individual. It is not clear what they are referring to in this tadine was gradually increased to a maximum dose of 150mg twice statement. Ten of the 11 patients had ABI and were all were de- scribed as "severely demented". The mean age range was 28 to 76 The 10 patients were aged 19 to 56 years (mean age 31 years) years, the mean age being 54 years.
and had suffered a closed head injury. The majority had an initial Glasgow coma scale score (GCS) of below nine and all showed The first part of this study evaluated the efficacy of pindolol in impairments in attention/concentration. No data were provided managing verbal and physical aggression in 13 (10 ABI), brain- on the time between injury and treatment. However, the patients damaged male patients using a double-blind, placebo-controlled, were described as being in an acute brain injury unit and as a large cross-over design. In the first part of the study (21 weeks) patients increase in orientation over the six-week trial was observed, it is were randomly allocated to either group A (pindolol) or group likely the injury to treatment interval was less than six months.
B (placebo). At week 10, there was a six week cross-over interval Outcome measures consisted of the neurobehavioural rating scale where pindolol was tapered down for group A and introduced (NRS) and standard neuropsychological tests of attention, orien- for group B. At week 21 patients entered the second phase of the tation, memory, executive/flexibility and behaviour. These tests study. The objective of this phase was to determine whether pin- were administered at pre-trial and at two-week intervals.
dolol would ameliorate problematic behaviours (not necessarilyagitation/aggression) which were preventing the patients from be-ing placed at a lower level of care. In this phase pindolol was re- Other (beta-adrenoceptor blocking drugs)
introduced for those on the placebo and all of the patients weremaintained on the drug for a further 12 weeks.
The 10 patients with ABI were aged 38 to 72 years (mean age 60.3 This is a study of 21 subjects with severe TBI (GCS score below years). No data were given on the time between injury and treat- eight), in a combined trauma and rehabilitation centre over an 18 ment although the sample was described as a group of "chronically month period, whose main problems were agitation. The subjects hospitalised" patients, suggesting the interval between injury and were randomly assigned to a double-blind, placebo-controlled trial treatment was greater than six months. Entry criteria for the study of propranolol, beginning with 60mg a day and increasing to a required patients to be presenting with behavioural problems that maximum of 420mg. No details were given regarding the time prevented them being placed at a lower level of care. In phase one post-injury. The study lasted eight weeks.
of the study all psychotropic medication was discontinued. Sup- Episodes of agitation were measured using the overt aggression plementary medication included phenobarbital and paraldehyde scale (OAS) which rates the type and severity of the episode.
as required.
A variety of outcome measures were administered pre-trial, at A randomised, double-blind, placebo-controlled, cross-over study cross-over and post-trial including: geriatric interpersonal evalua- of propranolol to a dose of 520mg a day (maximum recommended tion scale (GIES), nurses observation scale for inpatient evaluation dose in BNF is 320mg/day). Active and placebo periods were of (NOSIE) and Sandoz Clinical Assessment-Geriatric (SCAG). In- 11 weeks duration with a cross-over period in between (the total cidence of agitation and/or aggression were recorded in the nurs- study period was 25 weeks). Nine patients completed the study, ing log and quantified using the overt aggression scale (OAS).
of whom eight had ABI (age range 27 to 75 years; mean age 51 See 'Characteristics of included studies' table for additional infor- years). The participants were 1 to 30 years post-injury. It seems very likely that seven or eight of these patients are the same asthose in the study.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Risk of bias in included studies
specified. The placebo and pindolol were powdered and adminis-tered in capsules. Of the 15 patients recruited, 13 completed the (* score on the scale).
trial: one patient was transferred to another hospital for surgery, , methylphenidate: *1 and one patient died.
A randomised, pre-test, post-test, control group design. Partici- See 'Characteristics of included studies' table for additional infor- pants were randomly assigned to receive either methylphenidate or an inert placebo. The randomisation procedure was not specified.
The study was single-blind with the participants being unaware ofthe treatment group they were in. No information was providedon withdrawals or dropouts.
Effects of interventions
Because of the differences in the types of drugs used to treat agi- A randomised double-blind, placebo-controlled, cross-over study tation and aggression and the different outcome measures used in design. Participants were randomly assigned to one of two treat- the various trials, a pooled analysis was not undertaken.
ment groups by the pharmacy. Group one received amantadinethen the placebo after a two-week withdrawal period while grouptwo received the placebo followed by the amantadine. The ran- 4.4 Central nervous system stimulants
domisation procedure was not specified. A thorough description of withdrawals and dropouts was provided.
Mean scores and their standard errors on the anger outcome mea- sures for the placebo group and treatment group at pre-treatment A randomised double-blind, placebo-controlled design. The ran- and six weeks post-treatment.
domisation procedure used was not specified. The drugs (activeand placebo) were prepared by the pharmacy and sent under con-cealed allocation. The authors did not specify the number of par- State trait anger scale (STAS)
ticipants who dropped out of the trial because of discharge from Placebo (n = 19) Mean = 26 (SE = 1.8)Pre test State Mean = 29 (SE = 2.0)Post test State A randomised double-blind, placebo-controlled cross-over study Mean = 20 (SE = 2.3)Pre test Trait design. Participants were randomly allocated to receive either the Mean = 20 (SE = 1.5)Post test Trait active drug or placebo for 11 weeks, followed by a three weektapering period. In the final 11 weeks those in the placebo group Treatment (n = 19) were then given the active drug and those previously on the active Mean = 34 (SE = 2.5)Pre test State drug received the placebo. The randomisation procedure was not Mean = 24 (SE = 1.3)Post test State specified. Blinding was maintained by the hospital pharmacy and Mean = 22 (SE = 1.9)Pre test Trait remained unbroken until the trial was completed. Placebo and Mean = 18 (SE = 1.6)Post test Trait active drug were administered in an equal number of identically (The improvement in anger scores (post-test minus pre-test) was appearing capsules. One patient dropped out of the study, because statistically significant across the two groups.) he/she was unable to tolerate the placebo period.
Source of support: not stated.
pindolol: *3A randomised double-blind, placebo-controlled cross-over studydesign. The treatment order was randomly determined for each 4.9 Drugs used in parkinsonism and related disorders
patient group rather than each individual. It is not clear what the authors were referring to in this statement. Blinding was main- No significant difference was found in any of the outcome mea- tained by the hospital pharmacy and remained unbroken until the sures between patients receiving amantadine and placebo.
trial was completed. Placebo and active drug were administered in No data were given for means or standard deviations.
an equal number of identically appearing capsules. There was no Source of support: not stated.
statement on withdrawals or dropouts.
, pindolol: *4A randomised double-blind, placebo-controlled cross-over study Other (Beta-adrenoceptor blocking drugs)
design. Participants were randomly assigned to one of two groups.
Group A received pindolol for 10 weeks followed by the placebo The average maximum intensity of agitated episodes was signifi- for a further 10 weeks (six day tapering interval). Group B receive cantly reduced by propranolol.
the placebo then pindolol. The randomisation procedure was not (Wilcoxin matched pairs test, z = -2.028, P < 0.05).
Data presented in (figures taken from graphs).
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Brookes 1992b (average maximum intensity of agitated episodes)
Active drug
Dose (mg)
Propranolol had no significant effect on reducing the average number of agitated episodes.
(Wilcoxin matched pairs test, z = -1.5213).
Data presented in (figures taken from graphs).
Table 2. Brookes 1992b (average number of agitated episodes)
Active drug
Dose (mg)
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Source of support: National Institute on Disability and Re- trials (RCTs); one looking at agitation in the weeks following in- habilitation Research, Department of Education and Harborview jury and the other at aggressive behaviour months and years after Injury Prevention and Research Centre, Centers for Disease Con- injury (; ). However, these studies used relatively small and heterogeneous samples of patients. Two of the three studies from the same research group appeared to haveused largely the same cohort. Further, large doses of beta-block- The number of assaults and attempted assaults was significantly ers were used; many clinicians would be wary of using such large reduced by propranolol (F = 6.50 [1,7 df ], P < 0.05, analysis of doses, particularly for treating a symptom which is not a standard variance). In the seven patients who responded to propranolol, the indication for the drug and in a situation where the patient may number of assaults fell from 88 during the eleven-week placebo to not be in a position to give informed consent. However, several of 52 during the eleven-week active period.
the excluded studies using lower levels of evidence, lend support No data were given for means or standard deviations.
to the value of beta-blockers.
Source of support: not stated.
Methylphenidate is no longer available in the UK for routine pre-scription. The evidence in favour of psychostimulants is poor and must be weighed against the real risks of adverse mental side ef- Pindolol was found to produce a significant reduction in assaultive fects, particularly in a population of patients who are often vul- episodes (Wilcoxon matched pairs signed ranks test P < 0.05).
nerable to drug abuse.
No data were given for means or standard deviations.
In a number of studies, the improvement seen on medication was Source of support: Sandoz Pharmaceuticals.
observed within two to six weeks of starting medication. This oc-curred in both early and late post-injury cohorts and regardless of whether the symptom was agitation or aggression. The improve- Pindolol had no significant effect on the incidence of agitation ment was maintained over the treatment period, but in one RCT and/or aggression although six patients showed a decrease in overt the placebo group also improved, though more slowly, so that by aggression scale (OAS) scores.
seven weeks there was no difference in agitation between the twogroups (This observation that improvements on No data were given for means or standard deviations.
medication occur within weeks of starting medication is consis- Source of support: not stated.
tent with clinical practice. Patients often report early gains on anew drug to treat agitation and/or aggression, but several monthslater, despite having remained on the medication, levels of agita-tion and/or aggression deteriorated to baseline levels.
D I S C U S S I O N
There was little evidence of a differential drug effect on agitationas opposed to aggression. Beta-blockers were found to be useful for This systematic review has highlighted the lack of high quality both agitation and aggression ( evaluations of medication for the management of agitation and/or whether occurring early or late post-injury.
aggression in patients with acquired brain injury (ABI). This mayreflect the difficulties of carrying out research in this area. Reasons Overall, the research in this area is characterised by studies us- for this may be that staff are understandably not tolerant of aggres- ing low levels of evidence. These are descriptive case reports that sion and fear entry into a trial will delay treatment, the patients are provide data that cannot be easily evaluated and therefore are of not usually in a position to give informed consent, symptoms of little value. Firstly, it is usually impossible to evaluate whether the agitation and aggression fluctuate spontaneously, the population patient did in fact respond to the medication. Secondly, even if of patients with ABI are very heterogeneous and there are many the patients did respond, one cannot be sure that they did so at other factors that will influence outcome apart from medication.
the expense of other unreported cases, who did not respond, or Nevertheless, the sensitivity of patients with ABI to adverse side even got worse. Systematically collected case series at least begin effects, particularly confusion which is likely to make the agitation to get round this second difficulty, though they are still exposed and/or aggression worse, means that it is important that medica- to publication bias.
tions are prescribed on the basis of good evidence.
In summary, this review has highlighted the need for quality re- Of the six studies identified, the best quality evidence, al- search evaluating the efficacy of drugs used in the management of though still somewhat limited, is for beta-blockers ; agitation and/or aggression in patients who have suffered an ABI.
A further limitation of the work that has been published is the nolol has been found to be effective in two randomised controlled little attention paid to the potential for harm, and the effects of Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
medication on the functional outcome of patients, especially in tion and/or aggression in ABI are required.
the longer term.
Given the lack of evidence for any drug or class of drugs beingeffective, this review suggests that RCTs are appropriate, given thecurrent state of clinical information. Research clinicians are justi- fied in arguing that they have no prior reason to believe that one Implications for practice
drug treatment is better than another or that one drug treatmentis better than placebo.
Numerous drugs have been tried in the management of agitationand/or aggression in acquired brain injury (ABI) but without firm We would encourage the clinician to use a specific protocol with all evidence of their efficacy. It is therefore important to choose drugs patients, using whichever drug the individual clinician considers with few side effects and to constantly monitor, in the individual, appropriate. If this were done consistently on every consecutive the evidence that the medication is helping.
patient then useful information would rapidly be acquired.
Beta-blockers have the best evidence to support their efficacy and Case reports should not be published unless there is evidence that deserve more attention. However, if they are going to be used, it the authors have systematically included in their series all patients should be done with caution and preferably with the informed treated with the drug. More attention should be paid to N-of-1 consent of the patient.
research methods. These have the advantage of being relevant tothe individual patient as well as being able to provide evidence Carbamazepine is often the drug of choice yet hard evidence that about overall efficacy across subjects (if they are collected system- it is effective is completely lacking. Nevertheless, in our clinical atically). N-of-1 methods are particularly suitable for rehabilita- experience carbamazepine seems to be well tolerated and is gen- tion, because of the chronicity of symptoms.
erally without adverse mental/neurological side effects. Valproatemay be an alternative treatment, though at present there is little Care must be taken in looking at other drug effects. Patients with evidence to support its use.
aggressive behaviour are often placed on cocktails of medication.
It may be the removal of a noxious drug when a new drug is started The evidence suggests that drug effects on agitation and aggression that is the therapeutic event. Or the drug under study may in fact are seen early, within two to six weeks of starting medication. This be working by raising levels of another, active, drug already being would suggest that if no benefit is observed by the end of six weeks, then the drug should be tailed off and another one tried after asuitable interval.
There is no evidence that the drug response of agitation early afterbrain injury is different from that of later aggression. There is evidence that both respond to propranolol.
Dr Ken Stein and Dr Phil Alderson wrote a protocol for a review ontreatment of agitation after brain injury which was helpful when Implications for research
we came to writing ours. We acknowledge the help of Professor Better research evaluations of drugs for the management of agita- Tom McMillan and Dr Keith Andrews.
R E F E R E N C E S
References to studies included in this review
Greendyke 1986b {published data only}
Greendyke RM, Kanter DR. Therapeutic effects of pindolol onbehavioral disturbances associated with organic brain disease: a Brooke 1992b {published data only}
double-blind study. Journal of Clinical Psychiatry 1986;47(8):
Brooke MM, Patterson DR, Questad KA, Cardenas D, Farrel- Roberts L. The treatment of agitation during initial hospitalization Greendyke 1989 {published data only}
after traumatic brain injury. Archives of Physical Medicine and Greendyke RM, Berkner JP, Webster JC, Gulya A. Treatment of behavioral problems with pindolol. Psychosomatics 1989;30(2):
161–5.
Greendyke 1986a {published data only}
Greendyke RM, Kanter DR, Schuster DB, Verstreate S, Wootton J.
Mooney 1993 {published data only}
Propranolol treatment of assaultive patients with organic brain Mooney GF, Haas LJ. Effect of methylphenidate on brain injury- disease. A double-blind crossover, placebo-controlled study. Journal related anger. Archives of Physical Medicine and Rehabilitation 1993; of Nervous and Mental Disease 1986;174(5):290–4.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Schneider 1999 {published data only}
Duffy 1996 {published data only}
Schneider WN, Drew-Cates J, Wong TM, Dombovy ML.
Duffy JD, Kant R. Clinical utility of clozapine in 16 patients with Cognitive and behavioural efficacy of amantadine in acute neurological disease. Journal of Neuropsychiatry and Clinical traumatic brain injury: An initial double-blind placebo-controlled study. Brain Injury 1999;13(11):863–72.
Elliott 1977 {published data only}
Elliott FA. Propranolol for the control of belligerent behaviour References to studies excluded from this review
following acute brain damage. Annals of Neurology 1977;1(5):
489–91.
Abraham 1990 {published data only}
Fann 2000 {published data only}
Abraham G, Jarrett F. Propranolol in the treatment of Fann JR, Uomoto JM, Katon WJ. Sertraline in the treatment of postencephalitic psychosis. Canadian Journal of Psychiatry - Revue major depression following mild traumatic brain injury. Journal of Canadienne De Psychiatrie 1990;35(1):104–5.
Neuropsychiatry and Clinical Neurosciences 2000;12(2):226–32.
Azouvi 1999 {published data only}
Fauman 1978 {published data only}
Azouvi P, Jokic C, Attal N, Denys P, Markabi S, Bussel B.
Fauman MA. Treatment of the agitated patient with an organic Carbamazepine in agitation and aggressive behaviour following brain disorder. Journal of the American Medical Association 1978; severe closed-head injury: results of an open trial. Brain Injury Geracioti 1994 {published data only}
Barnhill 1989 {published data only}
Geracioti TD Jr. Valproic acid treatment of episodic explosiveness Barnhill LJ, Gualtieri CT. Two cases of late-onset psychosis after related to brain injury. Journal of Clinical Psychiatry 1994;55(9):
closed head injury. Neuropsychiatry, Neuropsychology and Giakas 1990 {published data only}
Bellus 1996 {published data only}
Giakas WJ, Seibyl JP, Mazure CM. Valproate in the treatment of Bellus SB, Stewart D, Vergo JG, Kost PP, Grace J, Barkstrom SR.
temper outbursts. Journal of Clinical Psychiatry 1990;51(12):525.
The use of lithium in the treatment of aggressive behaviours with Glenn 1989 {published data only}
two brain-injured individuals in a state psychiatric hospital. Brain Glenn MB, Wroblewski B, Parziale J, Levine L, Whyte J, Rosenthal M. Lithium carbonate for aggressive behavior or affective instability Bouvy 1988 {published data only}
in ten brain-injured patients. American Journal of Physical Medicine Bouvy PF, van de Wetering BJ, Meerwaldt JD, Bruijn JB. A case of organic brain syndrome following head injury successfully treated Greendyke 1984 {published data only}
with carbamazepine. Acta Psychiatrica Scandinavica 1988;77(3):
Greendyke RM, Schuster DB, Wooton JA. Propranolol in the treatment of assaultive patients with organic brain disease. Journal Cantini 1992 {published data only}
of Clinical Psychopharmacology 1984;4(5):282–5.
Cantini E, Gluck M, McLean A. Psychotropic-absent behavioural Gualtieri 1991a {published data only}
improvement following severe traumatic brain injury. Brain Injury Gualtieri CT. Buspirone for the behavior problems of patients with organic brain disorders. Journal of Clinical Psychopharmacology Chandler 1988 {published data only}
Chandler MC, Barnhill JL, Gualtieri CT. Amantadine for the Gualtieri 1991b {published data only}
agitated head-injury patient. Brain Injury 1988;2(4):309–11.
Gualtieri CT. Buspirone: neurpsychiatric effects. Journal of Head
Trauma and Rehabilitation
1991;6:90–2.
Chatham 1996 {published data only}
Haas 1985 {published data only}
Chatham-Showalter PE. Carbamazepine for combativeness in acute Haas JF, Cope DN. Neuropharmacologic management of behavior traumatic brain injury. Journal of Neuropsychiatry and ClinicalNeurosciences sequelae in head injury: A case report. Archives of Physical Medicine Chatham 2000 {published data only}
Hale 1982 {published data only}
Chatham Showalter PE, Kimmel DN. Agitated symptom response Hale MS, Donaldson JO. Lithium carbonate in the treatment of to divalproex following acute brain injury. Journal of organic brain syndrome. Journal of Nervous and Mental Disease Neuropsychiatry and Clinical Neurosciences 2000;12(3):395–7.
Cohn 1977 {published data only}
Hooshmand 1974 {published data only}
Cohn CK, Wright JR, DeVaul RA. Post head trauma syndrome in Hooshmand H, Sepdham T, Vries JK. Kluver-Bucy syndrome.
an adolescent treated with lithium carbonate-case report. Diseases of Successful treatment with carbamazepine. Journal of the American the Nervous System 1977;38(8):630–1.
Cornier 1983 {published data only}
Horne 1995 {published data only}
Cornier P. [The use of a sedative neuroleptic agent, sultopride, in Horne M, Lindley SE. Divalproex sodium in the treatment of posttraumatic Korsakoff syndrome in a young adult]. [French].
aggressive behavior and dysphoria in patients with organic brain Semaine Des Hopitaux 1983;59(20):1556–7.
syndromes [letter]. Journal of Clinical Psychiatry 1995;56(9):430–1.
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Iruela 1992 {published data only}
brain injury secondary to motor vehicle crashes. Brain Injury 2001; Iruela LM, Ibanez-Rojo V, Gilaberte I, Oliveros SC. New possible indications of pimozide [letter; comment]. Journal of Clinical Meythaler 2002 {published data only}
Meythaler J, Brunner R, Johnson A, Novack T. Amantadine to Jackson 1985 {published data only}
improve neurorecovery in traumatic brain injury-associateddiffuse Jackson RD, Corrigan JD, Arnett JA. Amitriptyline for agitation in axonal injury: a pilot double-blind randomized trial. Journal of head injury. Archives of Physical Medicine and Rehabilitation 1985; Head Trauma Rehabilitation 2002;17:300–13.
Michals 1993 {published data only}
Jackson 1989 {published data only}
Michals ML, Crismon ML, Roberts S, Childs A. Clozapine Jackson RD, Mysiw WJ. Abnormal cortisol dynamics after response and adverse effects in nine brain-injured patients. Journal traumatic brain injury. Lack of utility in predicting agitation or of Clinical Psychopharmacology 1993;13(3):198–203.
therapeutic response to tricyclic antidepressants. American Journal
of Physical Medicine and Rehabilitation
1989;68(1):18–23.
Morikawa 2000 {published data only}
Kant 1998 {published data only}
Morikawa M, Iida J, Tokuyama A, Tatsuda H, Matsumoto H, Kant R, Smith-Seemiller L, Zeiler D. Treatment of aggression and Kishimoto T. [Successful treatment using low-dose carbamazepine irritability after head injury. Brain Injury 1998;12(8):661–6.
for a patient of personality change after mild diffuse brain injury].
[Japanese]. Nihon Shinkei Seishin Yakurigaku Zasshi 2000;20(4):
Kim 2001 {published data only}
Kim KY, Moles JK, Hawley JM. Selective serotonin reuptakeinhibitors for aggressive behavior in patients with dementia after Munoz 1997 {published data only}
head injury. Pharmacotherapy 2001;21(4):498–501.
Munoz P, Gonzalez Torres MA. [Organic personality disorder: Kneale 1991 {published data only}
response to carbamazepine]. [Spanish]. Actas Luso-Espanolas De Kneale TA, Eames P. Pharmacology and flexibility in the Neurologia, Psiquiatria y Ciencias Afines 1997;25(3):197–200.
rehabilitation of two brain-injured adults. Brain Injury 1991;5(3):
Mysiw 1988 {published data only}
Mysiw WJ, Jackson RD, Corrigan JD. Amitriptyline for post- Lee 2001 {published data only}
traumatic agitation. American Journal of Physical Medicine & Lee MA, Leng MEF, Tiernan EJJ. Resperidone: a useful adjunct for behavioural disturbance in primary cerebral tumours. Palliative Nickels 1994 {published data only}
Nickels JL, Schneider WN, Dombovy ML, Wong TM. Clinical use Levine 1988 {published data only}
of amantadine in brain injury rehabilitation. Brain Injury 1994;8
Levine AM. Buspirone and agitation in head injury. Brain Injury Lewin 1992 {published data only}
Pachet 2003 {published data only}
Lewin J, Sumners D. Successful treatment of episodic dyscontrol Pachet A, Friesen S, Winkelaar D, Gray S. Beneficial behavioural with carbamazepine. British Journal of Psychiatry 1992;161:261–2.
effects of lamotrigine in traumatic brain injury. Brain Injury 2003;
17(8):715–22.
Lipper 1976 {published data only}
Lipper S, Tuchman MM. Treatment of chronic post-traumatic Parmelee 1988 {published data only}
organic brain syndrome with dextroamphetamine: first reported Parmelee DX, O'Shanick GJ. Carbamazepine-lithium toxicity in case. Journal of Nervous and Mental Disease 1976;162(5):366–71.
brain-damaged adolescents. Brain Injury 1988;2(4):305–8.
Mansheim 1981 {published data only}
Patterson 1987 {published data only}
Mansheim P. Treatment with propranolol of the behavioral sequelae Patterson JF. Carbamazepine for assaultive patients with organic of brain damage. Journal of Clinical Psychiatry 1981;42(3):132.
brain disease. Psychosomatics 1987;28(11):579–81.
Maryniak 2001 {published data only}
Pinaudeau 1979 {published data only}
Maryniak O, Manchanda R, Velani A. Methotrimeprazine in the Pinaudeau M, Bedou G, Garidou JP, Delport Y, Borne G. [A clinical treatment of agitation in acquired brain injury patients. Brain study in neurosurgical diseases. A report on eighty cases (author's transl)]. [French]. Semaine Des Hopitaux 1979;55(31-32):1404–6.
Mattes 1985 {published data only}
Mattes JA. Metoprolol for intermittent explosive disorder.
Pinner 1988 {published data only}
American Journal of Psychiatry 1985;142(9):1108–9.
Pinner E, Rich CL. Effects of trazodone on aggressive behavior inseven patients with organic mental disorders. American Journal of McAllister 1985 {published data only}
McAllister TW. Carbamazepine in mixed frontal lobe and
psychiatric disorders. Journal of Clinical Psychiatry 1985;46(9):
Pourcher 1994 {published data only}
Pourcher E, Filteau MJ, Bouchard RH, Baruch P. Efficacy of the Meythaler 2001 {published data only}
combination of buspirone and carbamazepine in early post- Meythaler JM, Depalma L, Devivo MJ, Guin-Renfroe S, Novack traumatic delirium [7]. American Journal of Psychiatry 1994;151(1):
TA. Setraline to improve arousal and alertness in severe traumatic Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Rao 1985 {published data only}
Zimnitzky 1996 {published data only}
Rao N, Jellinek HM, Woolston DC. Agitation in closed head Zimnitzky BM, DeMaso DR, Steingard RJ. Use of risperidone in injury: haloperidol effects on rehabilitation outcome. Archives of psychotic disorder following ischemic brain damage. Journal of Physical Medicine and Rehabilitation 1985;66(1):30–4.
Child and Adolescent Psychopharmacology. 1996;6(1):75–8.
Ratey 1983 {published data only}
References to ongoing studies
Ratey JJ, Morrill R, Oxenkrug G. Use of propranolol for provokedand unprovoked episodes of rage. American Journal of Psychiatry Warden 2000 {published data only}
Warden DL, Bastolla AM. The Defense and Veterans Brain Injury Ratey 1992 {published data only}
Center. Sertraline versus placebo for symptoms following traumatic Ratey JJ, Leveroni CL, Miller AC, Komry V, Gaffar K. Low-dose brain injury. ClinicalTrials.gov. Identifier:NCT00208585.
buspirone to treat agitation and maladaptive behavior in brain-injured patients: two case reports [letter]. Journal of Clinical Baguley 2006
Rowland 1992 {published data only}
Baguley IJ, Cooper J, Felmingham K. Aggressive behavior following Rowland T, Mysiw WJ, Bogner J, et al.Trazodone for post traumatic brain injury: how common is common?. Journal of Head traumatic agitation (abstract). Archives of Physical Medicine and Schiff 1982 {published data only}
Brailowsky S, Knight RT, Efron R. Phenytoin increases the severity Schiff HB, Sabin TD, Geller A, Alexander L, Mark V. Lithium in of cortical hemiplegia in rats. Brain Research 1986;376:71–7.
aggressive behavior. American Journal of Psychiatry 1982;139(10):
1346–8.
Brooke 1992a
Schreier 1979 {published data only}
Brooke MM, Questad KA, Patterson DR, Bashak KJ. Agitation and Schreier HA. Use of propranolol in the treatment of restlessness after closed head injury: a prospective study of 100 postencephalitic psychosis. American Journal of Psychiatry 1979;136
consecutive admissions. Archives of Physical Medicine and Stanislav 1994 {published data only}
Brooks 1987
Stanislav SW, Fabre T, Crismon ML, Childs A. Buspirone's efficacy Brooks N, Campsie L, Symington C, Beattie A, McKinlay W. The in organic-induced aggression. Journal of Clinical effects of severe head injury on patient and relative within seven years of injury. Journal of Head Trauma and Rehabilitation 1987;2
(3):1–13.
Stanislav 2000 {published data only}
Stanislav SW, Childs A. Evaluating the usage of droperidol in Bushman 2001
acutely agitated persons with brain injury. Brain Injury 2000;14(3):
Bushman BJ, Anderson CA. Is it time to pull the plug on the hostile versus instrumental aggression dichotomy?[Review] [54 Stewart 1985 {published data only}
refs]. Psychological Review 2001;108(1):273–9.
Stewart JT. Carbamazepine treatment of a patient with Kluver- Cook 1992
Bucy syndrome. Journal of Clinical Psychiatry 1985;46(11):496–7.
Cook DJ, Guyatt GH, Laupacis A, Sackett DL. Rules of evidence Szlabowicz 1990 {published data only}
and clinical recommendations on the use of antithrombotic agents.
Szlabowicz JW, Stewart JT. Amitriptyline treatment of agitation Antithrombotic Therapy Consensus Conference. Chest 1992;102:
associated with anoxic encephalopathy. Archives of Physical Medicine and Rehabilitation 1990;71(8):612–3.
Teng 2001 {published data only}
Corrigan JD, Mysiw WJ. Agitation following traumatic head Teng CJ, Bhalerao S, Lee Z, Farber J, Morris H, Forna T, Tucker W.
injury: equivocal evidence for a discrete stage of cognitive recovery.
The use of bupropion in the treatment of restlessness after Archives of Physical Medicine and Rehabilitation 1988;69(7):487–92.
traumatic brain injury. Brain Injury 2001;15(5):463–7.
Cowdry 1988
Wolf 2001 {published data only}
Cowdry RW, Gardner DL. Pharmacotherapy of borderline Wolf SS. Violent behavior and traumatic brain injury. Trauma personality disorder; alprazolam, carbamazepine, trifuoperazine and tranylcypromine. Archives of General Psychiatry 1988;45:111–9.
Wroblewski 1997 {published data only}
Dikmen 1991
Wroblewski BA, Joseph AB, Kupfer J, Kalliel K. Effectiveness of Dikmen SS, Temkin NR, Miller B, Machamer J, Winn HR.
valproic acid on destructive and aggressive behaviours in patients Neurobehavioural effects of phenytoin prophylaxis of posttraumatic with acquired brain injury. Brain Injury 1997;11(1):37–47.
seizures. Journal of the American Medical Association 1991;265(10):
Yudofsky 1981 {published data only}
Yudofsky S, Williams D, Gorman J. Propranolol in the treatment of DSM-IV 1995
rage and violent behavior in patients with chronic brain syndromes.
Diagnostic and Statistical Manual of Mental Disorders. Fourth American Journal of Psychiatry 1981;138(2):218–20.
Edition. Washingon, DC: American Psychiatric Association, 1995.
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Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Feeney 1982
Jadad 1996
Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol and Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, experience interact to affect rate of recovery after motor cortex Gavaghan DJ, et al.Assessing the quality or reports of randomised clinical trials: Is blinding necessary?. Controlled Clinical Trials
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Foster 1989
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head injury: observations on the use of the Glasgow Outcome Scale.
Journal of Neurology, Neurosurgery and Psychiatry 1981;44:285–93.
French 1989
Lezak 1978
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Gardner 1985
Lu CS, Ryu SJ. Neuroleptic malignant-like syndrome associated Gardner DL, Cowdry RW. Aprazolam-induced dyscontrol in with acute hydrocephalus. Mov Disord 1991;6(4):381–3.
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Vincent 1986
Vincent FM, Zimmerman JE, Van Haren J. Neuroleptic malignant
syndrome complicating closed head injury. Neurosurgery 1986;18
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Indicates the major publication for the study Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of included studies [ordered by study ID]
Brooke 1992b
Double-blind, randomised, placebo-controlled 8-week trial of propranolol.
Treatment: n = 11.
Placebo: n = 10.
21 patients.
Inclusion criteria:severe, traumatic closed head-injury.
LOC > 1 hourGCS < 8.
Presenting with agitation.
Propranolol (or placebo) 60mg/day increased to maximum dose of 420mg/day a) Overt aggression scale (OAS) providing scores on the intensity and frequency of agitation episodes.
b) Use of restraints.
c) Use of supplementary medicine.
Risk of bias
Allocation concealment? Double-blind, randomised, placebo-controlled trial of propranolol using a cross-over design.
11- week block of placebo/active drug, 3-week withdrawal, 11- week block of active drug/placebo.
8 of 9 patients had ABI. Mean age 51 years, range 27-75 years.
Same cohort used in Greendyke 1986b.
Propranolol 80mg/day increased to a maximum dose of 520mg/day.
a) Frequency of assaultive behaviour.
b) Frequency of supplementary medication.
c)The Nurses observation scale for inpatient evaluation (NOSIE).
Risk of bias
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Allocation concealment? Double-blind, randomised, placebo-controlled trial of pindolol using a cross-over design.
Treatment and placebo periods = 2 weeks.
10 of 11 patients had ABI.
Mean age 51.5 years, range 28-76 years.
All male and presenting with aggressive and explosive behaviour secondary to brain disease or injury. Allwere described as 'severely demented'.
Pindolol 10mg/day increased to a dose of 60mg/day.
a) Frequency of assaultive behaviour.
b) Frequency of supplementary medication.
c) Behavioural ratings of lethargy, hostility, uncommunicativeness, uncooperativeness and repetitive be-haviour.
Risk of bias
Allocation concealment? Double-blind, randomised placebo-controlled trial of pindolol using a cross-over design.
10 of 13 patients had ABI.
Mean age 60.3 years, range 38-72 years.
Pindolol 5mg increased to 20mg bid.
a) Geriatric interpersonal evaluation scale (GIES).
b) Nurses observation Scale for inpatient evaluation (NOSIE).
c) Sandoz clinical assessment-geriatric (SCAG).
d) overt aggression Scale (OAS).
e) Clinical global assessment (CGA).
Means and standard deviations were not provided for any outcome measure.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Risk of bias
Allocation concealment? Mooney 1993
A randomised, pre-test, post-test, placebo-controlled, 6- week trial of methylphenidate using a single-blind design.
Treatment: n = 19Placebo: n = 19 38 patients with serious TBI (LOC >/= 6 hours, PTA = >/= 24 hours). Mean age 29.45 years (SD 10.02).
ITI > 2 years.
Exclusion: major mental disorder or LD and substance abuse in last 6 months.
Methylphenidate increased to 30mg/day a) State trait anger scale (STAS-state and trait anger).
b) Katz adjustment scale (KAS-Belligerence).
c) Anger-hostility score of the profile of mood states (POMS-anger hostility).
d) Measures of attention and memory.
e) General measures of psychological and social adjustment.
Risk of bias
Allocation concealment? Double-blind, randomised, placebo-controlled, 6-week trial of amantadine using a cross-over design.
10 patients. Mean age 31 years (range 19-56). Majority GSC < 9.
Inclusion:closed head injury,no prior psychiatric history.
Aged between 18-55 years,deficits in attention and/or concentration.
Amantadine 100mg/day increased to maximum of 300mg/day.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
a) Neurobehavioural rating scaleb) Standard neuropsychological tests.
Grouped into sub-tests measuring: attention, orientation, memory, executive/flexibility and behaviour.
These tests were administered at pre-trial and at 2-week intervals.
Means and standard deviations were not provided for any outcome measure.
Risk of bias
Allocation concealment? LOC = Loss of consciousnessITI = Injury to treatment intervalGCS = Glasgow coma scale scorePTA = Post-traumatic amnesiaLD = Learning disabilities Characteristics of excluded studies [ordered by study ID]
Other (beta-adrenoceptor blocking drugs, bupropion): propranolol.
Single case report. Used an AB rather than an ABA design. Baseline measures were not taken before theintervention was administered and no quantitative measure of aggression and/or agitation were used.
4.8 Antiepileptics: carbamazepine.
Case series study design.
4.8 Antiepileptics: carbamazepine.
Case reports. Used an AB rather than an ABA design. Baseline measures were not taken before the interventionwas administered and no quantitative measure of aggression and/or agitation were used.
4.2.3 Antimanic drugs: lithium.
Case reports. Used an AB rather than an ABA design. Less than six patients were recruited.
4.8 Antiepileptics: carbamazepine.
Single case report. Baseline measures were not taken before the intervention was administered and no quantitativemeasure of aggression and/or agitation was used.
4.8 Antiepileptics: carbamazepine.
Single case report. Used an AB rather than an ABA design.
4.9 Drugs used in parkinsonism and related disorders: amantadine.
Case series study design. Used an AB rather than an ABA design. Less than six patients were recruited.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4.8 Antiepileptics: carbamazepine.
Case series study design. Baseline measures were not taken before the intervention was administered and noquantitative measure of aggression and/or agitation was used.
4.8 Antiepileptics: valproate (Divalproex).
Retrospective chart review.
4.2.3 Antimanic drugs: lithium carbonate.
Single case report. Used an AB rather than an ABA design. Baseline measures were not taken before theintervention was administered and no quantitative measure of aggression and/or agitation were used.
4.2.1 Antipsychotic drugs: sultopride.
Single case report. Used an AB rather than an ABA design. No quantitative measure of aggression and/oragitation were used.
4.2.1 Antipsychotic drugs: clozapine.
Retrospective chart review. Baseline measures were not taken before the intervention was administered and noquantitative measure of aggression and/or agitation was used.
Other (beta-adrenoceptor blocking drugs, bupropion): propranolol.
Case reports. Baseline measures were not taken before the intervention was administered and no quantitativemeasure of aggression and/or agitation was used.
4.3 Antidepressant drugs: sertraline.
Case series. Agitation and/or aggression were not the main presenting symptoms, all patients were suffering fromdepression. However, on sertraline, aggression (measured using the brief anger and aggression questionnaire)significantly decreased from baseline to post-treatment.
4.2.1 Antipsychotic drugs: haloperidol.
Case reports. Used an AB rather than an ABA design. Less than six patients were recruited.
4.8 Antiepileptics: valproic acid.
Single case report. Used an AB rather than an ABA design. Baseline measures were not specified and noquantitative measure of aggression and/or agitation was used.
4.8 Antiepileptics: valproate.
Single case report. Used an AB rather than an ABA design. Post-traumatic epilepsy.
4.2.3 Antimanic drugs: lithium.
Case series. Baseline measures were not taken before the intervention was administered and no quantitativemeasure of aggression and/or agitation was used.
Other (beta-adrenoceptor blocking drugs, bupropion): propranolol.
Repeated baseline single case study design. Six of the eight patients were acquired brain injury (ABI) but datawas available for only four of the ABI patients. Used an AB rather than an ABA design.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4.1 Hypnotics and anxiolytics: buspirone.
Case reports. Used an AB rather than an ABA design.
4.1 Hypnotics and anxiolytics: buspirone.
Case reports. Mild TBI case reports: aggression and/or agitation were not the presenting symptoms. Severe TBIcase reports: no baseline measures were recorded before the treatment was administered and no quantitative dataregarding aggression and/or agitation were presented.
4.2.3 Antimanic drugs: lithium.
Single case report. Baseline measures were not specified and no quantitative measure of aggression and/oragitation was used.
4.2.3 Antimanic drugs: lithium.
Case report. Used an AB rather than an ABA design. No quantitative measure of aggression and/or agitationwas used.
4.8 Antiepileptics: carbamazepine.
Single case report. Used an AB rather than an ABA design.
4.8 Antiepileptics: divalproex sodium.
Case report. Used an AB rather than an ABA design. No quantitative measure of aggression and/or agitationwas used.
4.2.1 Antipsychotic drugs: pimozide.
Single case report. Used an AB rather than an ABA design.
4.3 Antidepressant drugs: amitriptylineSingle case report. Used an AB rather than an ABA design.
4.3 Antidepressant drugs: amitriptyline or desipramine.
Case series/RCT but no outcome data and no controlled comparison.
4.3 Antidepressant drugs: sertraline.
Case series. Non-blind, 8-week open trial of sertraline.
4.3 Antidepressants: sertraline.
Case reports. Used an AB rather than an ABA design. Less than six patients were recruited.
4.8 Antiepileptics: carbamazepine.
Single case report. Used an AB rather than an ABA design. Baseline measures were not specified and noquantitative measure of aggression and/or agitation were used.
4.2.1 Antipsychotic drugs: risperidone.
Case reports. Baseline measures were not specified and no quantitative measure of aggression and/or agitationwere used 4.1 Hypnotics and anxiolytics: buspirone.
Single case report. Used an AB rather than an ABA design.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4.8 Antiepileptics: carbamazepine.
Single case report. Used an AB rather than an ABA design.
4.4 Central nervous system stimulants: dextroamphetamineSingle case report. Used an AB rather than an ABA design. Also, aggression and/or agitation were not the mainpresenting symptoms.
Other (beta-adrenoceptor blocking drugs, bupropion): propranolol.
Single case report. Used an AB rather than an ABA design.
4.2.1 Antipsychotic drugs: methotrimeprazine.
Retrospective chart review. Baseline measures were not taken before the intervention was administered and noquantitative measure of aggression and/or agitation was used.
Other (beta-adrenoceptor blocking drugs, bupropion): metoprolol.
Single case report. Used an AB rather than an ABA design. Baseline measures were not taken before theintervention was administered and no quantitative measure of aggression and/or agitation was used.
4.8 Antiepileptics: carbamazepine.
One case (case 2) meets clinical criteria but fails ABA.
4.3 Antidepressant drugs: sertraline.
Study described as a "case series using a randomised placebo controlled cross-over design". Agitation was notthe main presenting symptom.
4.9 Drugs used in parkinsonism and related disorders: amantadine.
Study described as a "case series using a randomised placebo controlled cross-over design". Agitation was notthe main presenting symptom.
4.2.1 Antipsychotic drugs: clozapine.
Case series study. No quantitative data regarding aggression and/or agitation were presented. Not all patientswere presenting with aggression and/or agitation as their main problem.
4.8 Antiepileptics: carbamazepine.
Single case study report. Used an AB rather than an ABA design.
4.8 Antiepileptics: carbamazepine.
Single case report. Used an AB rather than an ABA design.
4.3 Antidepressant drugs: amitriptyline.
Case series: patients maintained on amitriptyline throughout PTA or to discharge.
4.9 Drugs used in parkinsonism and related disorders: amantadine.
Retrospective chart review. Used an AB rather than an ABA design. Less than six patients were recruited.
4.8 Antiepileptics: lamotrogine.
Single case report. Used an AB rather than an ABA design.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4.2.3 Antimanic drugs: lithium.
Case reports. Used an AB rather than an ABA design. Less than six patients were recruited.
4.8 Antiepileptics: carbamazepine.
Case series design. Less than six patients (4 = ABI, case 1, 3, 4 + 5) were recruited.
4.2.1 Antipsychotic drugs: tiapride.
Case series design but poorly defined. Baseline measures were not taken before the intervention was administeredand no quantitative measure of aggression and/or agitation was used.
4.3 Antidepressant drugs: trazodone.
Case reports. Baseline measures were not taken before the intervention was administered and no quantitativemeasure of aggression and/or agitation was used.
4.8 Antiepileptics: carbamazepine + buspirone.
Case series study design. Baseline measures were not taken before the intervention was administered and noquantitative measure of aggression and/or agitation was used.
4.2.1 Antipsychotic drugs: haloperidol.
Case series study design. Baseline measures were not taken before the intervention was administered and noquantitative measure of aggression and/or agitation was used.
Other (beta-adrenoceptor blocking drugs, bupropion): propranolol.
Single case report. Used an AB rather than an ABA design.
4.1 Hypnotics and anxiolytics: buspirone.
Single case report. Used an AB rather than an ABA design. Baseline measures were not taken before theintervention was administered and no quantitative measure of aggression and/or agitation were used.
4.3 Antidepressant drugs: trazodone.
Only an abstract was available as the paper was not published in full. This case series was a retrospective review oftrazodone for treating post-traumatic agitation in six patients where agitated behavior scale scores and orientationgroup monitoring group scale scores were available.
4.2.3 Antimanic drugs: lithium.
Single case report. Used an AB rather than an ABA design.
Other (beta-adrenoceptor blocking drugs, bupropion): propranolol.
Single case report. Baseline measures were not taken before the intervention was administered and no quantitativemeasure of aggression and/or agitation were used.
4.1 Hypnotics and anxiolytics: buspirone.
Case reports. No quantitative data regarding aggression and/or agitation were presented.
4.2.1 Antipsychotic drugs: droperidol.
Controlled group comparison of intramuscular droperidol with other agents administered intramuscularly tomanage agitation.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4.8 Antiepileptics: carbamazepine.
Single case report. Used an AB rather than an ABA design.
4.3 Antidepressant drugs: amitriptylineSingle case report using an ABA design. However, no quantitative measure of aggression and/or agitation wasused.
Other (beta-adrenoceptor blocking drugs, bupropion): bupropion.
Single case report. Used an AB rather than an ABA design.
Other (beta-adrenoceptor blocking drugs, bupropion): propranolol + leuprolide.
Case report. Baseline measures were not taken before the intervention was administered and no quantitativemeasure of aggression and/or agitation were used.
4.8 Antiepileptics: valproic acid.
Case reports. Used an AB rather than an ABA design. Less than six patients were recruited.
Other (beta-adrenoceptor blocking drugs, bupropion): propranolol.
Single case reports. Used an AB rather than an ABA design. Baseline measures were not taken before theintervention was administered and no quantitative measure of aggression and/or agitation were used.
4.2.1 Antipsychotic drugs: risperidone.
Single case reports. Used an AB rather than an ABA design. Baseline measures were not taken before theintervention was administered and no quantitative measure of aggression and/or agitation were used.
Please refer to the additional tables for further information.
Characteristics of ongoing studies [ordered by study ID]
Warden 2000
Trial name or title A randomized placebo-controlled trial of sertraline for the neurobehavioral sequelae of traumatic brain injury Patients will be active duty or other military beneficiaries, between 18 and 65 years of age, with traumaticbrain injury (within six months of injury). Males and non-pregnant females may participate.
Irritability, depression, frustration, anxiety and other post-concussive symptoms.
Study start: February 2000; Expected completion: February 2010Last follow-up: February 2005; Data entry closure: February 2010 Contact information Deborah L Warden, MD deborah.warden@amedd.army.mil Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Warden 2000
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
This review has no analyses.
A P P E N D I C E S
Appendix 1. Search strategy
Electronic searches were based on the following MEDLINE strategy, adapted as appropriate to the specifications of each
database;
#1. exp Craniocerebral-Trauma/
#2. diffus$ axonal injur$.ab,ti.
#3. ((injur$ or trauma$ or lesion$ or damage$ or wound$ or destruction$ oedema$ or edema$ or fracture$ or contusion$ or concus$
or commotion$ or pressur$) adj3 (head or crani$ or capitis or brain$ or forebrain$ or skull$ or hemisphere or intracran$ or orbit$ or
cerebr$)).ab,ti.
#4. exp Brain-Damage-Chronic/
#5. exp Coma-Post-Head-Injury/
#6. exp Glasgow-Coma-Scale/
#7. exp Hematoma-Subdural-Intracranial/
#8. exp Hematoma-Epidural-Cranial/
#9. exp Epilepsy-Post-Traumatic/
#10. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9
#11. exp Violence/
#12. exp Hostility/
#13. exp Irritable-Mood/
#14. exp Anger/
#15. exp Impulsive-Behavior/
#16. exp Paranoid-Behavior/
#17. exp Antisocial-Personality-Disorder/
#18. exp Impulse-Control-Disorders/
#19. exp Sexual-Harassment/
#20. exp Acting-Out/
#21. exp Psychomotor-Agitation/
#22. exp Self-Injurious-Behavior/
#23. exp Juvenile-Delinquency/
#24. exp Delirium-Dementia-Amnestic-Cognitive-Disorders/
#25. (agitat$ or aggress$ or violen$ or impuls$ or paranoi$ or irritabl$ or hostil$ or anger or angry or anti-social or impuls$ or
delinquen$ or delirium or dement$).ab,ti.
#26. #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25
#27. exp central nervous system agents/
#28. exp methotrimeprazine/
#29. (methotrimeprazine or lamotrigine or carbamazepine or valproic acid or sertraline).ab,ti.
#30. Triazines/tu [Therapeutic Use]
#31. Anticonvulsants/tu [Therapeutic Use]
#32. #27 or #28 or #29 or #30 or #31
#33. #10 and #26 and #32
#34. clinical trial.pt.
#35. exp animals/
#36. exp humans/
#37. #35 not (#35 and #36)
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
#38. #34 not #37#39. #33 and #38 These terms were combined with the following RCT/CCT search filter; Highly Sensitive Search Strategy - MEDLINE )
#1. clinical trial.pt.
#2. randomized.ti,ab.
#3. placebo.ti,ab.
#4. dt.fs.
#5. randomly.ti,ab.
#6. trial.ti,ab.
#7. groups.ti,ab.
#8. #1 or #2 or #3 or #4 or #5 or #6 or #7
#9. exp animals/
#10. exp humans/
#11. #9 not (#9 and #10)
#12. #8 not #11
W H A T ' S N E W
Last assessed as up-to-date: 21 August 2006.
Converted to new review format.
Protocol first published: Issue 4, 2001 Review first published: Issue 1, 2003 New citation required and conclusions have changed The searches were updated in June 2006, no new studiesfor inclusion were found, however, one ongoing study hasbeen identified (Warden 2000). The review text has beenrevised and updated.
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
SF updated the review (July 2006).
RG and SF designed the protocol and wrote the research proposal for application for funding. RG commented on the protocol andreview.
SF was involved in the designing and running of the search strategy, screened titles and abstracts for eligibility, extracted data, criticallyevaluated and quality assessed the included studies and wrote up the review. SF supervised the work of research assistant, DLO.
DLO assisted in the writing of the protocol and in the designing of the search strategy. Advice on the search strategy was provided byMartin Hewitt, information specialist, King's College. DLO screened titles and abstracts for eligibility, obtained references, contactedauthors for further information, extracted data, quality assessed the included studies and assisted in the writing of the review.
I N D E X T E R M S
Medical Subject Headings (MeSH)

∗Aggression; Adrenergic beta-Antagonists [∗therapeutic use]; Amantadine [therapeutic use]; Anxiety [∗drug therapy; etiology]; BrainInjuries [∗psychology]; Methylphenidate [therapeutic use]; Neuroprotective Agents [∗therapeutic use]; Pindolol [therapeutic use];Propranolol [therapeutic use]; Psychomotor Agitation [∗drug therapy; etiology]; Randomized Controlled Trials as Topic MeSH check words
Pharmacological management for agitation and aggression in people with acquired brain injury (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Source: http://www.sabin.scot.nhs.uk/files/cochrane-collaboration.pdf

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