Reviews

Efficacy and Safety of Dopamine Agonistsin Traumatic Brain Injury: A Systematic Review

of Randomized Controlled Trials

Anne Julie Frenette,1 Salmaan Kanji,2 Laura Rees,3 David R. Williamson,1 Marc M. Perreault,4

Alexis F. Turgeon,5 Francis Bernard,6 and Dean A. Fergusson2

Abstract

In the intensive care unit, dopamine agonists (DA) have been used in traumatic brain injury (TBI) patients to augmentor accelerate cognitive recovery and rehabilitation. However, the efficacy and safety of DA in this population is notwell established. We conducted a systematic review of randomized controlled trials (RCTs) examining the clinicalefficacy and safety of DA in patients with TBI. We searchedMEDLINE, EMBASE, and the Cochrane Central Registerof Controlled Trials, comparingDA to either placebo, standard treatment, or another active comparator. Therewas norestriction for age, date, or language of publication. Sensitivity analyses were planned to evaluate the potential effectof timing of TBI, age, drugs, and year of publication on efficacy. Among the 790 citations identified, 20 RCTsevaluating methylphenidate, amantadine, and bromocriptine were eligible. Significant clinical heterogeneity wasobserved between and within studies, which precluded any pooling of data. Efficacy outcomes included mainlyneuropsychologicalmeasures of cognitive functioning. A total of 76 different neuropsychological tests were used, butmost of them (59%) only once. Only 5 studies systematically assessed safety. No trend could be drawn from theanalysis of efficacy and safety. Important sources of bias in the studieswere ofmajor concern. Considering the absenceof consensus regarding clinical outcome, the lack of safety assessment, and the high risk of bias in the included trials,more research is warranted before DA can be recommended in critically ill TBI patients.

Key words: adult brain injury; dopamine agonists; traumatic brain injury

Introduction

Traumatic brain injury (TBI) is a leading cause ofmorbidity and mortality and is responsible for 50,000

deaths and 235,000 hospitalizations every year in the UnitedStates (Corrigan et al., 2010; Thurman andGuerrero, 1999). Asmany as 15–50% of patients surviving TBI will experiencelong-term disabilities, including neuropsychiatric sequelaesuch as sleep disturbances, arousal and attention disorders,cognitive impairment, depression, and aggressive behavior(Bales et al., 2009; Corrigan et al., 2010; Green et al., 2008;Fleminger, 2008; Ruttan et al., 2008).

Neurotransmitters such as dopamine influence cognitiveprocesses, movement control, and emotion (Bales et al., 2009;Thurman and Guerrero, 1999). Central dopaminergic path-way dysfunction may contribute to some of the neuropsy-

chiatric sequelae in patients recovering from TBI (Bales et al.,2009). In the intensive care unit, step-down units, or on theward, dopamine agonists (DA) are anecdotally used in pa-tients recovering from TBI in an attempt to augment vigilanceor accelerate cognitive recovery and rehabilitation. However,the efficacy and safety of DA in this population is not clear(Francisco et al., 2007; Siddall, 2005; Tenovuo, 2006). The aimof the present systematic review was to determine the clinicalefficacy and safety of DA in TBI patients compared to placebo,active control, or standard treatment (Moher et al., 2009).

Methods

Search strategy

Randomized controlled trials (RCTs), were identified usingboth electronic andmanual search strategies. In June 2010, we

1Department of Pharmacy, Hopital du Sacre-Coeur de Montreal, Faculty of Pharmacy 6Department of Intensive Care, Hopital du Sacre-Coeur de Montreal, University of Montreal, Montreal, Quebec, Canada.

2Department of Pharmacy, Ottawa Hospital, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.3Rehabilitation Center, Ottawa Hospital, Ottawa, Ontario, Canada.4Department of Pharmacy, Montreal General Hospital, Faculty of Pharmacy Universite de Montreal, Montreal, Quebec, Canada.5Department of Intensive Care, Hopital de l’Enfant-Jesus de Quebec, Quebec, Canada.

JOURNAL OF NEUROTRAUMA 29:1–18 (January 1, 2012)ª Mary Ann Liebert, Inc.DOI: 10.1089/neu.2011.1812

1

searched MEDLINE, EMBASE, and the Cochrane CentralRegister of Controlled Studies from the earliest accessibledate. We combined terms defining the study treatment (DA)and the study population (TBI). A specific filter was applied toMEDLINE and EMBASE search strategies to identify RCTs(Lefebvre et al., 2009; Scottish Intercollegiate GuidelinesNetwork, 2009). The bibliographies of all identified RCTs andthe reviews retrieved were manually searched for additionalstudies. The search strategy was reviewed by a qualifiedlibrarian. The full search strategy for MEDLINE is presentedin Appendix 1.

Eligibility criteria

We sought studies of TBI patients, without age restrictions,comparing the effect of the administration of a DA, includingmethylphenidate, bromocriptine, amantadine, levodopa, ro-pinirole, pramipexole, apo-morphine, cabergoline, and per-golide, to either placebo, standard treatment, or another activecomparator. We included studies addressing clinical efficacyusing any primary outcome measures and/or safety. Therewas no restriction for date or language of publication. Weexcluded unpublished studies, animal studies, and studiesassessing dopamine agonists in any other type of brain injury.Studies of mixed populations with TBI representing morethan 80% of patients, or for which data of TBI patients couldbe isolated, were included.

Study selection

Every study citation retrieved was evaluated by two in-dependent reviewers (A.J.F. and S.K.), according to the pre-viously described inclusion/exclusion criteria. Disagreementswere resolved by consensus.

Data extraction and validity assessment

Each study was evaluated independently and in duplicateby two reviewers (A.J.F. and S.K., M.M.P., D.R.W., F.B., orMarie-Soleil Delisle). Any disagreement was resolved by athird independent reviewer. Information was collected usinga standardized case report form that was revised after pilottesting on 5 studies by 5 different reviewers. Descriptivevariables for each trial were collected, including language ofpublication, country of randomization, source of funding,sample size, and objectives. Information on the study designincluded the type of RCT, blinding, method of randomization,number of participating centers, and screening and enrolmentof patients. Clinical variables including patient demographicdata, past medical history, concomitant drugs permitted,timing of DA administration since the injury, description ofthe TBI (i.e., mechanism of trauma, severity of TBI, severity ofglobal illness, and radiological findings), and evaluation ofthe pre-intervention level of functioning, cognitive function,and quality of life, were also collected if reported. Clinicaloutcomes included length of stay (intensive care unit [ICU]and hospital), mortality, side effects, functional scales, post-traumatic symptoms, and neuropsychological test outcomes.

Methodological quality was assessed using the rating in-strument developed by the Cochrane Handbook for Sys-tematic Reviews of Interventions (Higgins and Altman, 2008).In order to assess the carry-over effect in crossover studies, awashout period was considered appropriate when equal to at

least 5 half-lives of the study drug from the last dose, whenmore than one dose was administered in the study. Based onclinical considerations, an a priori washout period of 2 days ormore for a single-dose trial was considered suitable. In thesecrossover studies, we considered not reporting the results ofbaseline assessment after the washout period, and the inclu-sion of patients who dropped out after the first study period,as inappropriate (Higgins et al., 2008).

Data synthesis

Data related to study design, drug treatment, and patientdemographics, were described for each study. Pre-morbidconditions were described using three categories: functionalstatus, cognitive or psychological impairment, and quality oflife, when available. Severity of TBI and illness was assessedusing severity scales (Glasgow Coma Scale, Acute Physiologyand Chronic Health Evaluation II, and Injury Severity Score),and radiological findings (computed tomography [CT] scan),when available. Clinical outcomes measured by neuropsychi-atric questionnaires and scoring tools were categorized as ei-ther behavioral or cognitive outcomes. Cognitive outcomeswere further categorized into the following domains: attention,speed of processing and reaction time, memory, and executivefunctioning, according to the predominant domain measuredby the test (Patry and Mateer, 2006; Tsaousides, 2009). Sus-tained attention, focused attention, selective attention, alter-nating attention, and divided attention, were classified underattention. Clinical outcomes not falling into cognitive or be-havioral categories were classified as ‘‘other outcomes.’’

Sensitivity analyses were performed to evaluate the poten-tial effect of the following sub-groups on efficacy: early versuslate TBI, children versus adults (16 years of age or older), typeof drugs, and year of publication. Year of publication wasdichotomized into the following categories: before 1995, and1995 and after, based on the increased use of computer-based neuropsychological tests after 1994. Patients were con-sidered to have an early TBI if they were still in an acute carefacility (ICU or ward). Patients recruited in rehabilitationcenters or in the community were considered to have late TBI.

Safety was assessed by retrieving all adverse events re-ported. We specifically looked for information on pre-determined side effects that were clinically relevant in theevaluation of DA administration safety in TBI, in addition tothe reported findings. Information regarding how safety wasassessed in the individual studies was also collected. Eva-luation of side effects was considered appropriate, if (1) theauthors were using a prospectively validated side-effectchecklist or a pre-defined objectively measured endpoint; (2)if the method of assessing specific side effects was provided;and (3) if the timing for side-effect evaluation was providedand clinically relevant (Loke et al., 2008).

Results

Study selection

The search strategy identified 790 citations. Twenty studieswere included in the systematic review (Fig. 1). Demo-graphics of the study are listed in Table 1. One study pub-lished in Chinese only provided descriptive results that wereimpossible to analyze with regard to the objectives of thisstudy and was therefore rejected. Among those included, 14

2 FRENETTE ET AL.

evaluated methylphenidate, 4 evaluated amantadine, and 2evaluated bromocriptine. No study evaluating the use oflevodopa, apo-morphine, ropinirole, pramipexole, cabergo-line, or pergolide in TBI was identified.

Study characteristics

Twenty studies evaluated the administration of a DA in TBI,including a total of 480 patients (Alban et al., 2004; Beers et al.,2005; Gualtieri and Evans, 1988; Kim et al., 2006; Lee et al., 2005;Mahalick et al., 1998; McDowell et al., 1998; McMahon et al.,2009; Meythaler et al., 2002; Moein et al., 2006; Mooney andHaas, 1993; Plenger et al., 1996; Schneider et al., 1999; Speechet al., 1993; Whyte et al., 1997,2004,2008; Williams et al., 1998;Willmott and Ponsford, 2009; Willmott et al., 2009; Table 1).Dopamine agonists were compared to placebo in all but 2studies (Beers et al., 2005; Kim et al., 2006). One these studiesreported a comparison between amantadine and standard care(Beers et al., 2005). Sertraline was used as a comparator tomethylphenidate in the other study (Kim et al., 2006). Of the 20included studies, 14 (70%) used a crossover design, 5 (25%)useda parallel design, and 1 (5%) used a time series analysis. Themajority of studies (80%) were single-center studies. All studieswerepublished in English, and themajoritywas from theU.S.A.Other countries represented were Iran, Australia, and Korea.

Dosage regimen

Dosage did not vary much among the methylphenidatestudies (0.3–0.6mg/kg per day for adults). However, dura-

tion of treatment and follow-up period ranged from 1 day to 1month. A similar observation can be drawn regarding thedoses of amantadine that were used (200–300mg/kg/d inadults, and 4–6mg/kg/d in children). Duration of treatmentamong the studies using amantadine varied from 2 to 12weeks. A higher variation of dosing was seen among the 2studies using bromocriptine (2.5–10mg/d). One study used asingle dose (McDowell et al., 1998), and the other study fol-lowed patients for 4 weeks (Whyte et al., 2008).

Patient characteristics

Seven of the 20 studies included children (Beers et al., 2005;Gualtieri and Evans, 1988; Mahalick et al., 1998; McDowellet al., 1998; McMahon et al., 2009; Whyte et al., 1997; Williamset al., 1998), 3 of them exclusively (Beers et al., 2005; Mahalicket al., 1998; Williams et al., 1998). No study included patientsover 65 years old, although age was not always mentioned asan exclusion criterion. Some information on baseline level offunctioning and psychological and cognitive conditions wasavailable in 12 of 20 studies (Alban et al., 2004; Beers et al.,2005; Gualtieri and Evans, 1988; Kim et al., 2006; Lee et al.,2005; McMahon et al., 2009; Meythaler et al., 2002; Mooneyand Haas 1993; Whyte et al., 1997,2004,2008; Willmott andPonsford, 2009).

The level of functioning prior to randomization was as-sessed using different scales, including the Disability RatingScale (Alban et al., 2004; Whyte et al., 1997,2004,2008), theGlasgowOutcome Scale (Gualtieri, 1988; Gualtieri and Evans,1988; Mooney and Haas, 1993), and the Rancho Los Amigos

Records after duplicates removed (n = 790)

Records screened(n = 790)

Records excluded(n =754)

Full-text articles excluded (n = 16)

Reasons: 2 posters only

9 not RCT3 not TBI

1 duplicate1 impossible to analyse data

Full-text articles assessed for eligibility

(n = 36)

Studies included in qualitative synthesis

(n = 20)

Records identified through database searching

(n =925)

Additional records identified through other sources

(n = 0)

FIG. 1. Flow chart of the study (RCT, randomized controlled trial; TBI, traumatic brain injury).

DOPAMINE AGONISTS AND TRAUMATIC BRAIN INJURY 3

Tabl

e1.

Dem

ograph

icsofth

eInclu

ded

Studies

Study

Study

design

Interventional

arm

Com

parative

arm

Patients

randomized

(analyzed)

Children/

adults1

Location

atrandomization

Tim

ingfrom

injury

atrandomization

Description

ofTBI

Willm

ottet

al.,

2009

RCT Crossover

MPH 1day

/2·6

day

s

Placeboonalternate

day

s·6day

s40

(40)

0/40

Reh

abilitation

center

Ran

ge12

–462

day

sMean68

.39–77

.09

day

s

SevereTBI(PTA,

GCS)

Willm

ottan

dPonsford,

2009

RCT Crossover

MPH 1day

/2·6

day

s

Placeboonalternate

day

s·6day

s40

(40)

0/40

Reh

abilitation

center

12–4

62day

sSevereTBI(PTA,

GCS)

Moeinet

al.,

2006

RCT Parallel

MPH

from

day

2untildisch

arge

Placebofrom

day

2untildisch

arge

80(80)

0/80

Intensivecare

unit

£48

hMildTBI(G

CS)

Kim

etal.,20

06RCT Parallel

MPH·1dose

Placebo·1dose

18(18)

0/18

Reh

abilitation

center

Mean1.6–0.5years

MPH:3.6–3.4

years

placebo

N/A

Lee

etal.,20

05RCT Parallel

MPH·4weeks

Sertraline·4weeks

OR

Placebo·4weeks

30(30)

0/30

Unclear

Meanyears

MPH

34.8–3.9;

sertraline

31.9–5.8;

placebo

30–6.5

MildTBI(PTA,

LOC)

Whyte

etal.,

2004

RCT Crossover

MPH

3weeks/

6Placeboon

alternated

weeks·3w

eeks/

6

39(34)

0/39

Reh

abilitation

centeran

doutpatients

Med

ian:3.2years

Ran

ge4months–

34.2

years

SeverebluntTBI

(PTA)

Alban

etal.,

2004

RCT Crossover

MPH

3weeks/

6Placeboon

alternated

weeks3

weeks/

6

35(33–35)

0/35

Reh

abilitation

centeran

doutpatients

Med

ian:3.2y

Ran

ge4months–

34.2

years

SeverebluntTBI

(PTA)

Mah

alicket

al.,

1998

RCT Crossover

MPH·14

day

sPlacebo·14

day

s14

(14)

14/0

Notmen

tioned

/unclear

Ran

ge1–

60months

Mean14

.4–14

.87

months

Mild,moderate

andsevereTBI

(GCS)

William

set

al.,

1998

RCT Crossover

MPH·4day

splacebo·4day

s10

(10)

10/0

Outpatients

Med

ian1.5year

Mean2.7–3.0

years

N/A

Whyte

etal.,

1997

RCT Crossover

MPH

1day

/2·6

day

sPlaceboonalternate

day

s·6day

s19

(9)

1/19

In-an

doutpatients

from

arehab

ilitation

center

Med

ian14

5day

sSeverebluntTBI

(GCS) (continued)

4

Tabl

e1.

(Continued

)

Study

Study

design

Interventional

arm

Com

parative

arm

Patients

randomized

(analyzed)

Children/

adults1

Location

atrandomization

Tim

ingfrom

injury

atrandomization

Description

ofTBI

Plenger

etal.,

1996

RCT Parallel

MPH

30day

sPlacebo·30

day

s23

(23)

0/23

Inpatients

from

trau

macenter

N/A

acute

phase?

Moderateto

severeTBI

(GCS)

Speech

etal.,

1993

RCT Crossover

MPH·1week

Placebo·1week

12(12)

0/12

Outpatients

Med

ian32

months

Ran

ge14

–108

months

Moderateto

severeblunt

TBI(PTA,

LOC)

Mooney

and

Haa

s19

93Ran

domized

Pre-post

MPH

regim

ennot

men

tioned

Placeboregim

ennot

men

tioned

38(38)

0/38

Outpatients

Mean27

.1–21

.1months

SeverebluntTBI

(PTA,LOC)

Gualtierian

dEvan

s,19

88RCT Crossover

MPH·12

day

sPlacebo·12

day

s15

(14)

4/15

Outpatients

Mean46

.8–41

.3months

Ran

ge5–

144

months

SevereTBI

(GCS)

Beers

etal.,

2005

RCT Parallel

AM ·

12weeks

Stan

dardcare

·12

weeks

37(variable)

37/0

Outpatients

6to

–36

months

62%

£2years

Mild,moderate,

severeblunt

TBI

Mey

thaler

etal.,

2002

RCT Crossover

AM

·6weeks

Placebo·6weeks

35(35)

0/35

Emergen

cydep

artm

ent

2–6weeks

SeverebluntTBI

(GCS)

McM

ahon

etal.,20

09RCT Crossover

AM

4·3weeks

Placebo·3weeks

7(5)

5/7

Unclear

4–10

weeks

SevereTBI

(GCS)

IncludingTBI,

strokean

dan

oxia

Schneider

etal.,19

99RCT Crossover

AM

·2weeks

Placebo·2weeks

18(10)

0/18

Reh

abilitation

center

N/A

Moderateto

severeTBI

(GCS)

McD

owell

etal.,19

98RCT Cross

over

B·1dose

Placebo·1dose

24(19–

23)

1/24

Reh

abilitation

center

27day

s–30

0months

Severebluntor

pen

etrating

TBI(G

CS)

(1an

eurysm

)W

hyte

etal.,

2008

RCT Crossover

B·4weeks

Placebo·4weeks

21(12)

0/21

Inpatientan

doutpatientfrom

clinical

services

Med

ian3.3years

3months–23

.5years

SeverebluntTBI

(PTA)

RCT,randomized

controlled

trial;MPH,methylphen

idate;

AM,am

antadine;

B,bromocriptine;

PTA,post-traumatic

amnesia;GCS,

Glasgow

ComaScale;

LOC,loss

ofconsciousness;TBI,trau

matic

brain

injury;N/A,notap

plicable.

1Adultsaredefi

ned

as‡16

years

old.

5

Scale (Gualtieri and Evans, 1988). Patients were described asseverely disabled in 2 studies (McMahon et al., 2009; Mey-thaler et al., 2002), moderately disabled in 3 studies (Albanet al., 2004; Whyte et al., 1997,2004), and mildly to moderatelydisabled in 2 studies (Gualtieri and Evans, 1988; Mooney andHaas, 1993).

Patients were described as having significant behavioral orcognitive deficits in 3 studies (Beers et al., 2005; Meythaleret al., 2002; McMahon et al., 2009), one of them including onlycomatose patients (McMahon et al., 2009). Other studies re-porting cognitive status included patients with intellectualquotient within normal range (Alban et al., 2004; Gualtieri andEvans, 1988; Speech et al., 1993; Whyte et al., 2004; Williamset al., 1998; Willmott and Ponsford 2009; Willmott et al., 2009),or with mild cognitive impairment (Kim et al., 2006; Lee et al.,2005). No study reported quality of life prior to randomization.

Severity of TBI

Location of patients at randomization can be found in Table1. Of note, only 3 studies included patients in a critical care

setting (intensive care unit, trauma unit, or emergency de-partment). Heterogeneity among andwithin studies arises forthe most part from the time elapsed from trauma to ran-domization, varying from less than 48 h to 34.2 years post-TBI.Information on global severity of illness at the time of injury(e.g., Abbreviated Injury Scale, Injury Severity Score, or AcutePhysiology and Chronic Health Evaluation II) was not avail-able in any of the studies. Only 7/20 (35%) studies reportedCT scan findings (Alban et al., 2004; Lee et al., 2005; Mahalicket al., 1998;McDowell et al., 1998;Moein et al., 2006; Schneideret al., 1999; Whyte et al., 2004), and it was not possible tocalculate aMarshall or Rotterdam score (Saatman et al., 2008).Severity of TBI was assessed using 3 different tools: loss ofconsciousness after injury, presence of post-traumatic amne-sia, and the GlasgowComa Scale. Nine studies (45%) includedexclusively patients suffering from severe TBI (Alban et al.,2004; Gualtieri and Evans, 1988; Meythaler et al., 2002;Mooney and Haas, 1993; Whyte et al., 1997,2004,2008; Will-mott and Ponsford, 2009; Willmott et al., 2009).

Studies describing the mechanism of trauma includedonly blunt TBI, except for 2 patients with penetrating TBI

Willmott and Ponsford 2009Moein 2006

Kim 2006

Lee 2005

Whyte 2004

Mahalick 1998

Williams 1998

Whyte 1997

Plenger 1996

Speech 1993

Mooney 1993Gualtieri and Evans 1988McMahon 2009

Beers 2005

Meythaler 2002

Schneider 1999

Whyte 2008

Mcdowell 1998

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Amantadine

Amantadine

Amantadine

Amantadine

Bromocriptine

Bromocriptine

Stu

dy

Dru

g

Sus

tain

ed A

rous

al a

nd/o

r Atte

ntio

n ta

sk (

50/5

0 &

20/

80)

Con

trol

led

Ora

l Wor

d A

ssoc

iatio

n te

st

Tow

er o

f Lon

don

Por

teus

Maz

e

Str

oop

Inte

rfer

ence

task

Wis

cons

in C

ardS

ortin

g te

st

FIG. 2. Tests assessing executive functioning.

6 FRENETTE ET AL.

(McDowell et al., 1998), 1 aneurysm (McDowell et al., 1998), 1stroke (McMahon et al., 2009), 1 cerebral anoxia (McMahonet al., 2009), and 1 suspected assault with unknown lesions(McDowell et al., 1998). These patients were included in theanalysis since it was not possible to exclude them from thedata provided.

Efficacy outcomes

Pooled estimates of outcome measures were planned, butwere not calculated due to the inconsistent outcomemeasuresused. Efficacy outcomes included mostly neuropsychologicaltests. Only one study used length of stay as a primary out-come, and showed both reduced hospital and intensive careunit stays with methylphenidate (Moein et al., 2006).

Neuropsychological assessment. A total of 76 differentneuropsychological tests were used to assess efficacy out-comes (see Figs. 2–7). Of these, 45 (59%) tests were only usedin one study. Of note, individual results of tests were not

provided in 31 out of 128 assessments (24%). The tests werecategorized into cognitive- and behavioral-predominant do-mains, except for 4 tests (Selective Attention Task, SymbolDigit Modalities Test, Sustained Arousal and/or AttentionTask 50/50 or 20/80, and Wisconsin Sorting Card Test), thatwere included in 2 domains.

Executive functioning. Executive functioning was as-sessed by a total of 6 tests in 8 studies. Three tests showedstatistically positive results in at least one study (Fig. 2). Only‘‘Sustained Arousal’’ and ‘‘Attention tasks,’’ an experimentaltest, showed positive results in two different studies (Whyteet al., 1997,2004). These two studies evaluated methylpheni-date in rehabilitating severe TBI.

Attention. A total of 21 tests were used to evaluate at-tention in 15 studies (Fig. 3). Of these, 10 tests (48%) yieldedstatistically positive results in at least one study. Two tests(Ruff 2&7 and Sustained arousal and attention tasks) hadstatistically significant positive results confirmed by two

Moein 2006

Kim 2006

Lee 2005

Whyte 2004

Mahalick 1998

Williams 1998

Whyte 1997

Plenger 1996

Speech 1993

Mooney 1993

McMahon 2009

Beers 2005

Meythaler 2002

Schneider 1999

Whyte 2008

Mcdowell 1998

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Amantadine

Amantadine

Amantadine

Amantadine

Bromocriptine

Bromocriptine

Stu

dy

Dru

g

Dis

trac

tion

task

Dua

l Tas

k

Sus

tain

ed A

ttent

ion

to R

espo

nse

task

Test

of e

very

day

atte

ntio

n

Ruf

f 2&

7 (a

ll su

bset

s)

Sym

bol D

igit

Mod

aliti

es te

st

Mod

ified

Pos

ner

Par

adig

m

Gor

don

Dia

gnos

tic S

yste

m

Con

tinuo

us P

erfo

rman

ce te

st

Dig

it sp

an (

WA

IS-R

)

Ser

ial D

igit

Lear

ning

(al

tern

ativ

e)

Lette

rCan

cella

tion

test

A&

B tr

ails

Sen

tens

e R

epet

ition

task

Spa

tial d

elay

ed-r

espo

nse

Sel

ectiv

e A

ttent

ion

task

Lette

r N

umbe

r S

eque

ncin

g ta

sk

Two-

back

wor

king

mem

ory

Sel

ectiv

e R

emin

ding

test

(or

alte

rnat

ive)

Rea

ding

spa

n

Sus

tain

ed a

rous

al a

nd a

ttent

ion

task

s (5

0/50

& 2

0/20

)

Willmott and Ponsford 2009

Gualtieri and Evans 1988

FIG. 3. Tests assessing attention (WAIS-R, revised Wechsler Adult Intelligence Scale).

DOPAMINE AGONISTS AND TRAUMATIC BRAIN INJURY 7

different studies (Mahalick et al., 1998; Whyte et al.,1997,2004; Willmott and Ponsford, 2009). All these studiesevaluated methylphenidate in a heterogeneous populationincluding mild to severe TBI. Out of the 21 tests, 9 (43%) wereexperimental measures.

Reaction time. Processing speed and reaction time wasevaluated in 8 studies, using a total of 8 different tests (Leeet al., 2005; Plenger et al., 1996; Speech et al., 1993; Whyteet al., 1997, 2004, 2008; Williams et al., 1998; Willmott andPonsford, 2009; Fig. 4). Five of them were experimental. Po-sitive results were shown by 3 tests. Choice reaction time task,a test used in all 8 studies, yielded positive results in 50% ofsubjects (Lee et al., 2005; Whyte et al., 1997; Willmott andPonsford, 2009). Studies showing positive results evaluatedmethylphenidate in mild and severe TBI, with duration oftreatment varying from 6 days to 4 weeks.

Memory. Memory was assessed by only 4 studies (Gual-tieri and Evans, 1988; Plenger et al., 1996; Schneider et al.,1999; Speech et al., 1993), using a total of 4 tests (Fig. 5). Alltests are published. Only 2 studies report individual test re-sults, both not showing any statistically significant difference.

Mood and behavior. A total of 21 tests were used toevaluate mood or behavior (Fig. 6). No trend can be drawn

from the analysis of the results. A total of 6 studies showedpositive results on a behavioralmeasure (Beers et al., 2005; Leeet al., 2005; McDowell et al., 1998; Mooney and Haas, 1993;Whyte et al., 1997,2004), but none of these positive resultswere replicated in another study.

Other measures. A total of 20 tests could not be classifiedas either a cognitive domain measure or a behavior measure,and are thus classified as other measures (Fig. 7). Of these, theWoodcock-Johnson battery, measuring general intellectualability, specific cognitive abilities, scholastic aptitude, orallanguage, and achievement, showed positive results in onestudy (Lee et al., 2005). The Disability Rating Scale, whichmeasures general functional changes over the course of re-covery from TBI, yielded positive results in one study (Plen-ger et al., 1996), which were not corroborated by a second(Meythaler et al., 2002).

In summary, no clear beneficial effect could be drawn inany of the predefined categories of outcome (see Figs. 2–7).Predetermined sensitivity analyses did not provide additionalinformation.

Safety outcomes

Twelve of 20 studies reported evaluation of adverse events(Alban et al., 2004; Beers et al., 2005; Lee et al., 2005;McMahon

Moein 2006

Kim 2006

Lee 2005

Whyte 2004

Mahalick 1998

Williams 1998

Whyte 1997

Plenger 1996

Speech 1993

Mooney 1993

McMahon 2009

Beers 2005

Meythaler 2002

Schneider 1999

Whyte 2008

Mcdowell 1998

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Amantadine

Amantadine

Amantadine

Amantadine

Bromocriptine

Bromocriptine

Stu

dy

Dru

g

Cho

ice

Rea

ctio

n Ti

me

task

Sel

ectiv

e A

ttent

ion

task

Sym

bol D

igit

Mod

aliti

es te

st

Men

tal A

rithm

etic

Tes

t

Ste

rnbe

rg M

emor

y S

cann

ing

test

Rap

id A

utom

atiz

ed N

amin

g te

st

Pha

sic

Aro

usal

task

Pac

ed A

udito

ry S

eria

l Add

ition

test

Willmott and Ponsford 2009

Gualtieri and Evans 1988

FIG. 4. Tests assessing processing speed and reaction time.

8 FRENETTE ET AL.

et al., 2009;Meythaler et al., 2002; Moein et al., 2006; Mooneyand Haas 1993; Plenger et al., 1996; Schneider et al., 1999;Whyte et al., 2008; Williams et al., 1998; Willmott et al.,2009). However, only 5 studies (Alban et al., 2004; McMa-hon et al., 2009; Plenger et al., 1996; Williams et al., 1998;Willmott et al., 2009) systematically assessed safety usingpre-defined objective measures or a tool for at least one sideeffect.

Two RCTs evaluating methylphenidate reported results ofside effects in a second publication as a primary outcome:Whyte and associates (2004) in Alban and associates (2004),and Willmott and Ponsford (2009) in Willmott and associates(2009). Although both studies mentioned a statistically sig-nificant increase in blood pressure and heart rate, their clinicalsignificance was not described. Among the 10 remainingstudies using methylphenidate, 5 reported the evaluation ofside effects (Table 2). No study reported systematic measuresof aggressive behavior, agitation, or delirium. All four studiesusing amantadine reported side effects. Most side effects were

reported as minor, and resolved spontaneously upon dis-continuation of the study drug.

Itching and tremors were the most common side effectsreported among patients on bromocriptine. However, theincidence did not differ significantly from placebo.

Five patients were withdrawn from the study because ofeither probable or possible side effects (Beers et al., 2005;Schneider et al., 1999; Whyte et al., 2008). These includedvomiting, dizziness, and elevated blood pressure, light-headedness and behavioral agitation, and rash and seizure.

Risk of bias

The analysis of risk of bias revealed that the majority ofstudies did not provide enough information on sequencegeneration and allocation concealment to assess their appro-priateness (Table 3). All but one study (Mooney and Haas,1993) were double-blinded, but the efficacy of randomizationwas rarely assessed. Of note, in 2 studies, the majority of

Moein 2006

Kim 2006

Lee 2005

Whyte 2004

Mahalick 1998

Williams 1998

Whyte 1997

Plenger 1996

Speech 1993

Mooney 1993

McMahon 2009

Beers 2005

Meythaler 2002

Schneider 1999

Whyte 2008

Mcdowell 1998

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Amantadine

Amantadine

Amantadine

Amantadine

Bromocriptine

Bromocriptine

Stu

dy

Dru

g

Ser

ial D

igit

Lear

ning

(al

tern

ativ

e)

Ben

ton

Vis

ual R

eten

tion

Test

Wec

hsle

r M

emor

y S

cale

Riv

erm

ead

Beh

avio

ural

mem

ory

test

Willmott and Ponsford 2009

Gualtieri and Evans 1988

FIG. 5. Tests assessing memory.

DOPAMINE AGONISTS AND TRAUMATIC BRAIN INJURY 9

patients or caregivers correctly guessed their attrition(Speech et al., 1993; Willmott and Ponsford, 2009). None ofthe studies had a published version of their protocol. There-fore, the selective reporting item could not be evaluated.Other sources of bias could be found in themajority of studies,and are described in Table 3. Based on the Cochrane Hand-book for Systematic Reviews, crossover design was consid-ered appropriate if the randomized population included onlystable patients (Higgins et al., 2008). Based on this criterion,crossover design was considered inappropriate in all stud-ies. The most common bias retrieved in parallel designstudies was selection bias. A lack of information did notallow comparison of groups to determine the efficacy ofrandomization.

Discussion

In this systematic review, we identified 20 RCTs evaluatingthe effect of DA on different functional outcome measures.However, considering the important clinical inconsistencies, a

meta-analysis of the included studies could not be performed.As an effect, we could not draw meaningful conclusionsregarding the efficacy of dopamine agonists in the patientrecovering from TBI. The main factors contributing toour inability to pool data were the lack of consistencyconcerning patient severity of trauma, timing from injury,pre-randomization psychological and cognitive condition,and most importantly, the wide range of clinical outcomemeasures used in the different studies. While other system-atic reviews of pharmacological therapies including dopa-mine agonists exist (Fleminger et al., 2006; Sivan et al., 2010;Writer and Schillerstrom, 2009), this is the first to focus on theuse of these drugs specifically in patients suffering from TBI,and to evaluate both cognitive and behavioral outcomes inaddition to other meaningful clinical outcomes from an acutecare point of view. Methodological limitations of other re-views include the use of a unique database, inclusion of non-randomized trials, an incomplete search strategy descrip-tion, language restriction, and lack of rigorous evaluation ofbias (Sivan et al., 2010; Writer and Schillerstrom, 2009).

Moein 2006

Kim 2006

Lee 2005

Whyte 2004

Mahalick 1998

Williams 1998

Whyte 1997

Plenger 1996

Speech 1993

Mooney 1993

McMahon 2009

Beers 2005

Meythaler 2002

Schneider 1999

Whyte 2008

Mcdowell 1998

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Amantadine

Amantadine

Amantadine

Amantadine

Bromocriptine

Bromocriptine

Stu

dy

Dru

g

Cla

ssro

om a

ttent

iven

ess

Sel

f rat

ing

Cog

nitiv

e F

ailu

res

Que

stio

nnai

re

Car

egiv

er C

ogni

tive

Fai

lure

Que

stio

nnai

re

Con

ners

Rat

ing

Sca

le

Wis

cons

in C

ardS

ortin

g te

st

Inat

tent

ive

Beh

avio

ur ta

sk

Rat

ing

Sca

le o

f Atte

ntio

nal B

ehav

iour

Kat

z A

djus

tmen

t Sca

le-B

ellig

eren

ce

Gen

eral

Psy

chop

atho

logy

clu

ster

sco

re K

atz

Pro

file

of M

ood

Sta

tes

- an

ger

host

ility

Adu

lt A

ctiv

ity s

cale

Exa

min

er's

Rat

ing

Sca

le

Beh

avio

ur R

atin

g In

vent

ory

of e

xecu

tive

func

tions

Neu

robe

havi

oura

l rat

ing

scal

e

Bec

k D

epre

ssio

n in

vent

ory

Ham

ilton

Rat

ing

scal

e fo

r D

epre

ssio

n

Riv

erm

ead

Pos

tcon

cuss

ion

Sym

ptom

s Q

uest

ionn

aire

Sm

ithK

line-

Bee

cham

Qua

lity

of L

ife S

cale

Leed

s S

leep

Eva

luat

ion

Que

stio

nnai

re

Cho

nnam

Epw

orth

Sle

epin

ess

Sca

le

Pos

tcon

cuss

iona

l sym

ptom

s in

terv

iew

Willmott and Ponsford 2009

Gualtieri and Evans 1988

FIG. 6. Tests assessing mood and behavior.

10 FRENETTE ET AL.

The impressive number of different tests used to assessneuropsychological outcomes in the included studies may bedue to different reasons, such as the lack of a gold standard, thebroad range of year of publication, the familiarity with a par-ticular battery of tests available, and the resources availableto researchers in different settings. Many studies used non-validated or experimental tools to assess outcomes. Moreover,clinical interpretation of statistically significant results was of-ten difficult due to a lack of effect size and reliable change indexreporting, the use of composite measures, and the lack ofreproducibility of the neuropsychological tests among thepatients. Choice of outcomemeasures and their analysis in TBIis still a matter of debate (Bagiella et al., 2010;Maas et al., 2010).Heterogeneity in outcomemeasures precludes any comparisonbetween studies, and consequently from drawing conclusionsregarding the efficacy of DA in TBI. Different groups haveproposed various validated outcome combinations, includingquality of life, neurobehavioral and neuropsychological status,

and global functional outcome, but none has reached the statusof a gold standard (Shukla et al., 2011). Future studies shouldaim at evaluating outcomes that are well described in the lit-erature, validated, appropriate for international use, have wellestablished normative data, are applicable to a broad spectrumof TBI, and are easy to administer (Wilde et al., 2010). Conse-quently, the Traumatic Brain Injury Outcome Workgroup hasproposed selected outcomes evaluating different domains ac-cording to those recommendations in both adults and pediatricpopulations (McCauley et al., 2011;Wilde et al., 2010). Perhapsthese recommendations should guide future studies regardingthe efficacy of DA in TBI.

The poor methodological quality of the included studieswas another concerning finding. The majority of studies useda crossover design, which may be appropriate when highinter-patient heterogeneity is likely, such as in a TBI popula-tion. However, patient condition should be stable in order toavoid the natural evolution of the condition to account for the

Moein 2006

Kim 2006

Lee 2005

Whyte 2004

Mahalick 1998

Williams 1998

Whyte 1997

Plenger 1996

Speech 1993

Mooney 1993

McMahon 2009

Beers 2005

Meythaler 2002

Schneider 1999

Whyte 2008

Mcdowell 1998

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Methylphenidate

Amantadine

Amantadine

Amantadine

Amantadine

Bromocriptine

Bromocriptine

Stu

dy

Dru

g

Wec

hsle

r Tes

t of A

dult

Rea

ding

Crit

ical

Flic

ker

Fus

ion

Thr

esho

ld

Com

pens

ator

y Tr

acki

ng te

st

MM

SE

Woo

dcoc

k-Jo

hnso

n ba

ttery

Per

due

Peg

boar

d

Dev

elop

men

tal T

est o

f Vis

ual-M

otor

Inte

grat

ion

Non

Ver

bal F

luen

cy te

st

Wec

hsle

r In

telli

genc

e S

cale

Gal

vest

on O

rient

atio

n an

d A

mne

sia

test

Bos

ton

Nam

ing

test

Pur

suit

Rot

or

FIM

-CO

G

Com

a/ne

ar c

oma

scal

e

Com

a re

cove

ry s

cale

-rev

ised

Wee

-FIM

Dis

abili

ty R

atin

g S

cale

Gla

sgow

out

com

e sc

ale

GC

S

Fin

gert

appi

ng

Willmott and Ponsford 2009

Gualtieri and Evans 1988

FIG. 7. Other tests (MMSE, Mini-Mental State Examination; FIM-COG, Functional Independence Measure trademark-cognitive; Wee-FIM, Functional Independence Measure for Children; GCS, Glasgow Coma Scale).

DOPAMINE AGONISTS AND TRAUMATIC BRAIN INJURY 11

Tabl

e2.

Evalu

ation

ofSa

fety

andSideEffec

ts

Bromocriptine

Amantadine

Methylphenidate

Side

effects

Number

ofevents

Studies

Com

ments

Number

ofevents

Studies

Com

ments

Number

ofevents

Studies

Com

ments

Rash/itch

ing

3Whyte

etal.,

2008

3Schneider

etal.,1999;

Beers

etal.,2005

1patient

withdrawn

becau

seofrash

(Sch

neider

etal.,

1999)

5Alban

etal.,

2004

Seizures

N/A

None

1Mey

thaler

etal.,2002;

Beers

etal.,2005

2Moeinet

al.,

2006

Delirium/

confusion/

hallucinations

0Whyte

etal.,

2008

N/A

None

4Alban

etal.,

2004

Hem

odynam

icch

anges

2Whyte

etal.,

2008

1patientwithdrawn

becau

seof

decreased

blood

pressure

(Whyte

etal.,2008)

N/A

None

?Lee

etal.,2005;

Alban

etal.,

2004;Moein

etal.,2006

Number

ofev

ents

missing

(Lee

etal.,2005)

Statisticallymore

prevalen

tthan

with

placebo(p

<0.05)

(Moeinet

al.,2006;

Alban

etal.,2004)

Dizziness/

lightheaded

ness

2Whyte

etal.,

2008

1patientwithdrawn

becau

seof

lightheaded

ness

and1patient

withdrawnbecau

seofdizziness(W

hyte

etal.,2008)

N/A

None

4Alban

etal.,

2004

Diarrhea/

constipation

4Whyte

etal.,

2008

?Beers

etal.,2005

Number

ofev

ents

missing

2Alban

etal.,

2004

Number

ofev

ents

missing

(Lee

etal.,2005)

Nau

sea/

vomiting

2Whyte

etal.,

2008

1patientwithdrawn

becau

seofvomiting

(Whyte

etal.,2008)

1?Beers

etal.,2005;

McM

ahonet

al.,

2009

Number

ofev

ents

missing

2?

Alban

etal.,

2004;Lee

etal

2005

Number

ofev

ents

missing

(Lee

etal.,2005)

Headache

N/A

None

N/A

None

?Plenger

etal.,

1996

Number

ofev

ents

missing

Anxiety

1Whyte

etal.,

2008

N/A

None

7Alban

etal.,

2004

Tremors

2Whyte

etal.,

2008

N/A

None

4Alban

etal.,

2004

Sleepdisorder/

drowsiness

1Whyte

etal.,

2008

?Numbersofev

ents

missing(Beers

etal.,

2005)

Nodifference

found

onsleep

questionnaire

(McM

ahonet

al.,

2009)

12Alban

etal.,

2004

Statisticallymore

prevalen

tthan

withplacebo

(p<0.05)(A

lban

etal.,

2004)

Number

ofev

ents

missing(Plenger

etal.,

1996;Willm

ottet

al.,

2009)

Others

1sexu

aldisab

ility

Whyte

etal.,

2008

N/A

None

4Irritability;11

reduction

inap

petite;

2difficu

ltyin

urinating;

2blurred

vision;

6dry

mouth;

2weakness;

1sexu

aldisab

ility

Alban

etal.,

2004;

Willm

ott

etal.,2009

Number

ofev

ents

for

irritabilitymissing

(Willm

ottet

al.,2009)

Irritabilityan

dreductionin

appetite

statisticallymore

prevalen

tthan

with

placebo

?=totalnumber

ofev

ents

impossible

tocalculate

since

datawerenotprovided

byat

leastonestudy.

Allsideeffectswerepredetermined

exceptforsideeffectslisted

inthe‘‘o

thers’’section.

12

Tabl

e3.

RiskofBiasAssessm

ent

Riskof

bias

assessmentitem

s

Study

(drug)

Sequence

generation

Allocation

Blinding

Outcom

edata

Selective

reporting

Other

threats

tovalidity

Willm

ottet

al.,

2009

(MPH)

LL

H 75%

ofpatients

guessed

correctlytheir

attrition

LU

H Crossover

designless

suitab

leforpatients

inlower

range

oftimingpost

TBI

Carry-over

effect

possible

Moeinet

al.,

2006

(MPH)

H Based

onhosp

ital

record

number

H Based

onhosp

ital

record

number

LL

UH Im

possible

toassess

similarity

ofgroups

Possible

confusionbias

affectinglength

ofstay

Kim

etal.,20

06(M

PH)

LL

LL

UH Im

possible

toassess

ifgroups

aresimilar

Lee

etal.,20

05(M

PH)

UU

UH Missinginform

ationon

excluded

patients

UL Im

possible

toassess

similarity

ofgroups

Choiceoftoolan

dcomparator

(dep

ression)

Whyte

etal.,

2004

(MPH)

UU

LH Participan

tsthat

can’t

perform

atask

or

hav

esched

ule

conflicts

are

withdrawn

UH Crossover

designless

suitab

leforunstab

lepatients

Riskofcarry-over

Low

external

validity

Mah

alick

etal.,1

998

(MPH)

UU

LL

UH Crossover

less

suitab

lefor

unstab

lepatients

Riskofcarryover

William

set

al.,

1998

(MPH)

UU

LH Several

measu

resnot

completedbyall

subjects

UH Crossover

less

suitab

lefor

unstab

lepatients

Low

external

validity

Gualtierian

dEvan

s,19

88(M

PH)

UU

LL

H Rep

orting

resu

ltsfor

resp

onders

only

H Crossover

less

suitab

lefor

unstab

lepatients

Riskofcarry-over

Mooney

and

Haa

s,19

93(M

PH)

UU

H Simple

blind

LU

H Impossible

toassess

similarity

ofgroups

(continued)

13

Tabl

e3.

(Continued

)

Riskof

bias

assessmentitem

s

Study

(drug)

Sequence

generation

Allocation

Blinding

Outcom

edata

Selective

reporting

Other

threats

tovalidity

Speech

etal.,

1993

(MPH)

UU

H 12patients

and10

observerscorrectly

guessedattrition

UU

H Crossover

less

suitab

lefor

unstab

lepatients

Riskofcarryover

Whyte

etal.,

2008

(B)

UU

LH Patients

randomized

notan

alyzeddueto

seriousad

verse

even

tsPatients

consentedbut

dropped

or

withdrawn

UH 1/

3ofpatients

did

not

crossover

Low

external

validity

Crossover

less

suitab

lefor

unstab

lepatients

Riskofcarry-over

McD

owell

etal.,19

98(B)

UU

LH Number

ofpatients

varieswithtest

UH Crossover

less

suitab

lefor

unstab

lepatients

Riskofcarryover

McM

ahon

etal.,20

09(A

M)

UU

LH 2patients

withdrawn

from

analysis

UH Crossover

less

suitab

lefor

unstab

lepatients

Beers

etal.,

2005

(AM)

LU

H Paren

tsaw

areof

allocation

H Patients

lost

tofollow

upan

dtheir

allocationisunknown

Resultsonoutcome

provided

only

for13

patients

UH Stan

dardtreatm

entis

not

described

Impossible

toassess

ifgroups

aresimilar

Mey

thaler

etal.,20

02(A

M)

UU

UL

H Number

of

patients

screen

edin

unknown

H Crossover

designunsu

itab

leforacute

patients

Riskofcarry-over

Schneider

etal.,19

99(A

M)

UU

LH Missingdatafrom

8su

bjectswhodid

not

complete

thestudy

UH Tim

ingfrom

injury

unknown

U,uncertainrisk

ofbias;H,highrisk

ofbias;L,low

risk

ofbias;MPH,methylphen

idate;

B,bromocriptine;

AM,am

antadine.

14

benefit or harm. Evolution and brain recuperation from a TBImay continue to occur up to several years after injury and isnot predictable (Lammi et al., 2005). A crossover design alsomandates a washout period between treatments, which has tobe long enough to avoid a carry-over effect. It has been shownthat dopamine receptors can downregulate during treatmentand upregulate following cessation of therapy in patientssuffering from Parkinson’s disease (Thobois et al., 2004). Inthe studies identified, the washout period was often not longenough to avoid a carry-over effect. The use of a parallel de-sign, which would overcome the carry-over problem, is lim-ited by the heterogeneity of the TBI population, which poses amethodological challenge. Similarity of the study groups seenin this population is often impossible to achieve unless largesample sizes are used, and pre-specified covariate adjust-ments are made (Maas et al., 2004,2010).

Assessment of safety was not consistent between studies,and a lack of rigor in the methodology of side-effect evalua-tion was considered a major limitation. Although somestudies did use a questionnaire or a standardized tool to as-sess side effects, they often relied on self-reporting of symp-toms. The studies also often failed to look prospectively forpotentially concerning side effects in a TBI population. Neu-rological and psychiatric adverse reactions such as seizures,delirium, hallucinations, and insomnia should be targeted askey safety outcomes, since they are clinically relevant in theTBI population, and are associated with the use of dopamineagonists in other human populations and animal models(Barone et al., 1992; Wood, 2010). A lack of information re-garding diagnosis of these side effects was also an issue.

Despite the results of our review, the dopaminergic systemis an obvious target for research of cognitive impairments inTBI. Dopamine receptors are known to be present in manyareas of the brain important to cognition, and are oftendamaged post-TBI (the hippocampus, striatum, and frontalcortex; Bales et al., 2009). The role of dopamine receptors incognitive domains such as attention, working memory, ex-ecutive functioning, and speed of processing is still a matter ofdebate (Nieoullon, 2002). However, some observations inhumans showing impairment in visuospatial, executive, andverbal fluency tests related to induced parkinsonism lead oneto think that dopamine participates in cognition (Burrusset al., 2000; Nieoullon, 2002; Stern et al., 1990). Radioimagingstudies in patients with Parkinson’s disease, schizophrenia,and attention-deficit/hyperactivity disorder provides sup-porting evidence (Bruck et al., 2001; Duchesne et al., 2002;Heilman et al., 1991; Tanaka, 2006).

The influence of dopaminergic drugs on neuronal plasticity,a concept of brain adaptation to injury over time, is also aconcerning feature (Ampuero et al., 2010; Larson and Zollman,2010). Dysfunction of the molecular processes influencingneuronal plasticity in the hippocampus may be a potentialcause for temporal and spatial memory impairment seen in TBI(Ampuero et al., 2010; Falo et al., 2006). The role for dopaminepathways in this process is unclear, but some data suggest thata modification of plasticity occurs with the exposure of variousneurotransmitter agonists and antagonists, including dopa-mine (Bales et al., 2009; Meintzschel and Ziemann, 2006). Forexample, benzodiazepines and haloperidol have been incrim-inated as possible causes of adverse effects on neuronal plas-ticity (Ampuero et al., 2010; Falo et al., 2006). Proper safetyevaluation of dopamine agonists in TBI is therefore warranted.

Conclusion

This systematic review is the first to evaluate the effect ofthe administration of dopamine agonists on different do-mains of cognition, behavior, and safety in TBI patients.Because of the significant clinical heterogeneity in the out-comemeasures used in the different studies, pooled analysescould not be performed, and consequently clear conclusionsabout the efficacy or safety of dopamine agonists in TBIpatients are difficult to draw. Despite the low incidence ofadverse events reported, most studies did not systematicallyscreen for them. In summary, our systematic review does notsupport the use of dopamine agonists as part of the treat-ment regimen for improving functional outcome measuresin either the acute or sub-acute phases of care in TBI patients.Future studies should first aim at standardizing and vali-dating a neuropsychological battery of tests in TBI. A clinicaltrial of dopamine agonists in TBI could then be designedusing standardized outcome measures with clear clinicalsignificance, including a validated neuropsychological bat-tery of tests. It should also use a parallel design in a largesample with predefined covariates, and should systemati-cally screen for potential side effects.

Acknowledgments

The authors would like to thank Ms. Marie-Soleil Delisle,Ms. Marie Frenette, andMs. Jodi Peters for their help with thisstudy.

Author Disclosure Statement

No competing financial interests exist.

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Address correspondence to:Anne Julie Frenette, BPharm, M.Sc.Hopital du Sacre-Coeur de Montreal

Faculty of PharmacyUniversity of Montreal

5400 Gouin OuestMontreal, Quebec, Canada, H4J 1C5

E-mail: anne.julie.frenette@umontreal.ca

(Appendix follows/)

DOPAMINE AGONISTS AND TRAUMATIC BRAIN INJURY 17

Appendix 1. Search Strategy for MEDLINE

1 head trauma.mp. 99192 head injury.mp. 366813 head injuries.mp. 111774 brain trauma.mp. 24215 ‘‘brain injuries’’.mp. or expBrain Injuries/ 1053836 cerebral trauma.mp. 9987 cerebral injury.mp. 25928 cerebral injuries.mp. 6669 ‘‘craniocerebral trauma’’.mp. or exp Craniocerebral Trauma/ 21137310 craniocerebral injury.mp. 92011 craniocerebral injuries.mp. 100812 brain injury.mp. 8193713 Traumatic brain injury.mp. 2421514 Traumatic brain injuries.mp. 127515 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 23495316 exp Dopamine Agonists/ 13445117 dopamine agonist$.tw. 1128518 bromocriptine.tw. 1222719 amantadine.tw. 530020 levodopa.tw. 1413421 methylphenidate.tw. 829222 apomorphine.tw. 1588723 ropinirole.tw. 105824 pramipexole.tw. 136725 pergolide.tw. 202526 cabergoline.tw. 159127 exp Dopamine Agents/ 29840028 or/16-27 31259329 15 and 28 363030 Randomized controlled trial.pt. 57270931 Controlled clinical trial.pt. 16080832 randomized.ab. 54810033 placebo.ab. 33807734 Drug therapy.fs. 139336235 randomly.ab. 35954036 group.ab. 258074537 trial.ab. 50674938 37 or 36 or 35 or 34 or 33 or 32 or 31 or 30 462654639 38 and 29 92540 remove duplicates from 39 790

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