Drugs for behavior disorders after traumatic brain injury: Systematic review and expert consensus leading to French recommendations for good practice

Review

Drugs

for

behavior

disorders

after

traumatic

brain

injury:

Systematic

review

and

expert

consensus

leading

to

French

recommendations

for

good

practice

D.

Plantier

*

,

J.

Luaute´

,

the

SOFMER

group

a_{DepartmentofPhysicalMedicineandRehabilitation(PM&R),NeurologicalRehabilitation,Rene´e-SabranHospital,UniversityHospitalofLyon,boulevard}

E´douard-Herriot,83400Hye`res,France

b

PhysicalMedicineandRehabilitation,NeurologicalRehabilitation,Henry-GabrielleHospital,UniversityHospitalofLyon,69230Saint-Genis-Laval,France

c

NeuroscienceResearchCenterofLyon(CRNL)IMPACTteam,InsermU1028,CNRS,UMR5292,69500Bron,France

1. Introduction

Behavioraldisordersaftertraumaticbraininjury(TBI) repre-sent the main impairment for patients after their accident

[1,2].Thecaremanagementofthesebehavioraldisordersishighly relevant for families and society. Behaviors, such as agitation, opposition, disinhibition, irritability, impulsiveness, bulimia, hypersexuality, Kluver and Bucy Syndrome, hostility, aggres-siveness, verbal and physical violence, anxiety and depression (seeStephanetal.inthisissue)requiretheconsensusfromexperts

whounderstandthespecificcharacteristicsofpeoplewithTBI.The pharmacologicalapproachishighlyspecializedandisbasedona comprehensive clinical experience. The most recent data from internationalliteraturesuggestusingbeta-blockers,neuroleptics, antiepileptics,antidepressants,benzodiazepines,amantadineand otherdrugs.

TheSOFMERFrenchSocietyofPhysicalMedicineand Rehabili-tationundertheauspicesoftheFrenchHighAuthorityforHealth (HAS) decided to elaborate recommendations of good practice (RGP), in response to the announcement in 2010 of a specific governmentactionplanforpatientswithTBI.Throughasystematic reviewoftheliterature,theobjectiveofthisworkwastoorganize carepathways, provide a practical caremanagement guideand

ARTICLE INFO Articlehistory: Received29June2015 Accepted18October2015 Keywords:

Traumaticbraininjury Behavioraldisorders Neuroleptics Antidepressants Beta-blockers Moodstabilizers Benzodiazepines Amantadine ABSTRACT

Objective:Therearenohandbookorrecommendationsfortheuseofpharmacologicalagentstotreat

neurobehavioraldisordersaftertraumaticbraininjury(TBI).Thisworkproposesasystematicreviewof

theliteratureandauserguideonneuroleptics,antidepressants,beta-blockers,moodstabilizersand

othermedicationsforirritability,aggressiveness,agitation,impulsivity,depression,apathy...

Method:Steering,workingandreadinggroups(62people)wereformedunderthecontroloftheFrench

HighAuthorityforHealth(HAS)incollaborationwiththeSOFMERscientificsociety(FrenchSocietyof

PhysicalandRehabilitationMedicine).ArticlesweresearchedbyHASofficersintheMedlinedatabase

from1990to2012,crossingTBIandpharmacologicalagents.TheHASmethodtoselect,readandanalyze

papersisclosetothePRISMAstatements.

Results:Outof772references,89wereanalyzed,coveringatotalof1306peoplewithTBI.Thereis

insufficientevidenceto standardize drugtreatments forthesedisorders.Thereare howeversome

elementstoestablishconsensusrecommendationsforgoodclinicalpractice.Propranololcanimprove

aggression(Bgrade).Carbamazepineandvalproateseemeffectiveonagitationandaggressionandare

recommendedasfirstlinetreatment(ExpertConsensus [EC]).There isnoevidenceofefficacy for

neuroleptics.Theirprescriptionisbasedonemergencysituationforacrisis(loxapine)butnotfor

long-termuse(EC).Antidepressantsarerecommendedtotreatdepression(EC)withahigherstandardofproof

forSelectiveSerotoninReuptakeInhibitors(SSRI,gradeB).Otherproductsaredescribed.

Conclusion: The choice of treatment depends on the level of evidence, target symptoms, custom

objectives,clinicalexperienceandcautionstrategies.

ß2015ElsevierMassonSAS.Allrightsreserved.

* Correspondingauthor.

E-mailaddress:[email protected](D.Plantier).

Available

online

at

ScienceDirect

www.sciencedirect.com

http://dx.doi.org/10.1016/j.rehab.2015.10.003

improvetheeffectivenessoftherapeuticmodalities.These recom-mendations concern adult patients with traumatic brain injury presentingwithbehavioraldisordersintheacuteandchronic post-traumaticstages.Thesepatientsarestillhospitalizedorlivingat home or in an institution. The professionals concerned are physicians,healthcarepersonnel fromthe unitscaring forthese patients,personnelofmedico-socialinstitutesorspecializedcare networks.

The population of patients with TBI is more sensitive to pharmacologicaltreatments,itisaparticularpopulationandit deserves specific studies that are difficult to implement in randomized, double-blind vs. placebo protocols. Multicenter studiesare oftennecessarytoobtaina sampleof patientlarge enoughandhomogeneoustoobtainsufficientstatisticalpower (e.g. age, time since injury, identical measure scales and identical concept definitions). Almost all systematic review studies,controlledornot-controlledstudiesandoriginalstudies come to the conclusion that further studies with a better methodologyare needed. The relevanceof thisworkis a dual one. On the one hand, proposing a systematic review of the literature to provide therapeutic solutions according to the available level of evidence and on the other hand bring consensus expert opinions when studies are insufficient to drawaconclusion.

2. Methodology

AccordingtoHAScriteria,themethodologyinvolvedatotalof 62peopledividedinto3workinggroups,and4stages:

elaborationofaframeworkletterwithquestionsdevelopedby the Steering committee (6 people: 3 professors of PM&R, 1lawyer,1directorofamedicalstructure);

selection,analysisofthescientificliteratureandelaborationofa scientificrationalebytheprojectmanagers(8people:1librarian, 2HASphysicians,1PM&Rprofessor,4PM&Rphysicians); the elaboration of recommendations, based on the scientific

rationale,byaworkinggroup(23people:5projectleadersPM&R physicians, 3 psychologists, 2 people representing families, 4 PM&R physicians, including 1 professor, 4 psychiatrists, 1 director of a medical structure, 1 professor of physical education,1MDPH(DepartmentalHomeforDisabledPersons) physician,1socialworker,1lawyer);

thecriticanalysisofallproposalsbyareadinggroup(30people: 7 psychologists, including 3 professors, 10 PM&R specialists, includingaprofessor,amagistrate,alawyer,aphysiotherapist,a socialworker,2healthcaremanagers,2peoplerepresentingthe families,onepersonrepresentingtheinsurancecompanies,one director of a medical structure, a psychiatrist, a physician workingintheprisonsystem).

TheHAS methodologyis explainedin details in this special issue,intheeditorial(seeMathe´ andLuaute´).Thiseditorialreports 6questions,ourworkfocusesondrugtherapeutics.

Theliteratureresearchwasperformedby theHAS literature researchteamusingasthemaindatabaseMedlineoverthe1990– 2012period.Someadditionalarticlesrelatedtothefinalselection but anterior to 1990 were also analyzed. Literature search strategies are detailed in Box 1. A complimentary search was performedcoveringtheperioduptoJune2015withoutusingthe HASresearchteam.Eacharticleselectedwasanalyzedaccordingto theliteraturereviewmethodologyusingreadinggridsinorderto attributetoeacharticleascientificlevelofevidence[3].According tothelevelofevidenceofthestudiesonwhichthey recommen-dationsarebased,theyhaveavariablegrade,scoredfromAtoC, seeTable1.

Table1

Graderecommendations.

Levelofscientificevidenceprovidedby theliterature(treatmentstudies)

Graderecommendation

Level1 Establishedscientific evidence

A Highpowerrandomizedcomparativetrials Meta-analysisofrandomizedcontrolledtrials Decisionanalysisbasedonwell-conducted

studies

Level2 Scientificpresumption B

Low-powerrandomizedcomparativetrials Non-randomizedcomparativestudies

well-conducted Cohortstudies

Level3 Lowlevelofevidence C

Case-controlStudies Level4(NP4)

Comparativestudieswithconsiderablebias Retrospectivestudies

Caseseries

Eachselecteditemwasanalyzedaccordingtotheprinciplesofcriticalliterature reading.Basedonthisliteraturereview,theworkinggroupproposed,whenever possible,recommendations.Dependingonthelevelofevidenceofstudiesonwhich theyarebased,therecommendationshaveavaryingdegree,fromAtoCaccording tothescaleproposedbytheHAS.Intheabsenceofstudies,therecommendations arebasedonaprofessionalconsensus(EC,ExpertConsensusWorkingGroup).

Box1. Literaturesearchstrategyforalltypesofstudies. (‘‘BrainInjuries’’(Majr:NoExp)OR‘‘CraniocerebralTrauma’’ (Majr:NoExp)AND‘‘DrugTherapy’’(Mesh)Or‘‘Central Ner-vous System Stimulants’’ (Mesh) OR ‘‘Methylphenidate’’ (Mesh) OR ‘‘Dopamine Agents’’ (Mesh) OR ‘‘Dopamine’’ (Mesh)OR ‘‘Amantadine’’(Mesh)OR‘‘DopamineAgonists’’ (Mesh)OR‘‘Bromocriptine’’(Mesh)Or‘‘Levodopa’’(Mesh)OR ‘‘AntidepressiveAgents’’(Mesh)OR‘‘Sertraline’’(Mesh)OR ‘‘Fluoxetine’’ (Mesh) OR ‘‘Paroxetine’’ (Mesh) OR ‘‘Citalo-pram’’(Mesh)OR‘‘tianeptine’’(SupplementaryConcept)OR ‘‘Trazodone’’(Mesh)OR‘‘Amitriptyline’’(Mesh)OR ‘‘Clomip-ramine’’(Mesh)OR‘‘Trimipramine’’(Mesh)OR‘‘Mianserin’’ (Mesh)OR‘‘mirtazapine’’(SupplementaryConcept)OR ‘‘mil-nacipran’’(SupplementaryConcept)OR‘‘duloxetine’’ (Supple-mentaryConcept)OR‘‘Iproniazid’’(Mesh)OR‘‘venlafaxine’’ (Supplementary Concept) OR ‘‘Cholinesterase Inhibitors’’ (Mesh)OR‘‘Physostigmine’’(Mesh)OR‘‘donepezil’’ (Supple-mentary Concept) OR ‘‘rivastigmine’’ (Supplementary

Con-cept) OR ‘‘Adrenergic beta-Antagonists’’ (Mesh) OR

‘‘Propranolol’’(Mesh)OR‘‘Haloperidol’’(Mesh)OR ‘‘Metho-trimeprazine’’(Mesh)OR‘‘Clozapine’’(Mesh)OR‘‘quetiapine’’ (SupplementaryConcept)OR‘‘ziprasidone’’(Supplementary Concept)OR ‘‘Anticonvulsants’’ (Mesh) OR‘‘Valproic Acid’’ (Mesh)OR‘‘Carbamazepine’’(Mesh)OR‘‘lamotrigine’’ (Sup-plementary Concept)OR ‘‘Lithium’’ (Mesh) OR ‘‘zolpidem’’ (Supplementary Concept) OR ‘‘modafinil’’ (Supplementary Concept)OR‘‘BrainInjuries/drugtherapy’’(Majr)OR ‘‘Cranio-cerebralTrauma/drugtherapy’’(Majr)AND‘‘Meta-Analysisas Topic’’ (Mesh) OR ‘‘Meta-Analysis’’ (Publication Type) OR ‘‘Review Literature asTopic’’ (Mesh) OR Meta-Analysis OR ReviewLiteratureOrQuantitativeReviewOR‘‘Random Allo-cation’’(Mesh)OR‘‘RandomizedControlledTrialsasTopic’’ (Mesh)OR‘‘RandomizedControlledTrial’’(PublicationType) OR Random*’’ (Title) OR‘‘Comparative Effectiveness Re-search’’(Mesh)OR‘‘ComparativeStudy’’(PublicationType) Or compar*(title) NOT ‘‘Critical Care’’ (Mesh) OR ‘‘Child’’ (Mesh)OR‘‘Infant’’(Mesh)OR‘‘Pediatrics’’(Mesh)OR ‘‘Ado-lescent’’(Mesh)OrCriticalcareORchild*ORinfan*Or pae-diatr*orpediatr*ORadolescent*.

Intheabsenceofstudies,therecommendationsarebasedona consensus of opinions from the experts of the workinggroup (ExpertConsensus,EC),afterhavingconsultedthereadinggroup. The absence of an evidence grade does not mean that the recommendationsarenotrelevantanduseful.Itmust,however, inciteteamstoconductfurtheradditionalstudies.

3. Results

Inall,106referenceswerefoundon‘‘drugtherapy(question4) and meta-analyses, systematic literature reviews, randomized controlled studies, comparative studies’’.Out of these16 were selected.Regardingarticlesfocusingonalltypesofstudies(except reviews, randomized controlled studies, comparative studies), 666referenceswerefound,and73wereselected.

The reasons for rejecting the studies were most often the inadequateselectionoftheacutephaseintheICUpost-injury, includingtargetedarticlesonneuro-protection (285rejections total),letterstotheauthor,comments,news,editorials(56 rejec-tions),targetstudiesonimprovingcognitiveperformanceorona productstimulatingrecovery(64rejections),absenceor insuffi-cientnumberofpatientswithTBIinthestudy(mixedpopulation) for16rejections,oranimalstudies(13rejections).Thediagrams representingtheselectionprocessforthearticlesareillustrated in Figs. 1 and2. The greatest difficulty wasto selectarticles, treatinginthepurestmannerpossible,behavioraldisorders post-TBIandthusdiscard studieswherethe mainobjectivewasto improve memory, attention and cognitive performance or recoveryin general. At theend, 89references were identified andconcerned 1306peoplewithTBI.Resultsare expressedby products and pharmacological class, including beta-blockers, neuroleptics, antidepressants, antiepileptics, amantadine and otherdrugs.

3.1. Useofbeta-blocker:33patientsincluded

The mechanism of action of beta-blockers on behavioral disorders remains unclear.Beyond their cardiovascular actions, beta-blockersprotectagainstsocialanxietyandhavebeenusedto treatagitationoraggressivenesspost-TBI(Table2).

RegardingthetreatmentofagitationoraggressivenessafterTBI, fourstudies,albeitolderones,areregularlylisted[4–7].Norecent studiesexist.Regardinghighdosesofpropranolol(upto420mg/ day), the study of Brooke et al. [4] conducted on 21 patients showeditsefficacyonepisodesofpost-traumaticaggressiveness, with reduced intensity for the most severe episodes, yet no significantchangeswerenotedforthefrequencyoftheseepisodes (level1to2,gradeB).

Fortheotherthreestudies,populationsareheterogeneous.The study by Greendyke et al. [7] included 9 patients treated by propranolol but only 4 of them had TBI (level 4, gradeC). For pindolol[5,6],thepopulationsstudiedincludedrespectively5/11 and3/13patientswithTBI(level4,gradeC)Pindololdosesused varied between 20 to 100mg/day. Adverse effects to the administration of beta-blockers are low blood pressure and bradycardia [8,9]. Finally, a report of 2 cases [10] points to metoprolol (level 4) but concerned stroke patients, not TBI patients.

InFrance,theuseofbeta-blockersinthisprescriptioncontext (agitationaggressiveness)isoutsideofthemarketing authoriza-tion(MA)delivered.Therecommendedusualdosesofpropranolol donotexceed320mg/dayincardiology.

The efficacyof this product is validated by theprescription habitsofUSexperts[11].Inthepopulation,oftenquiteyoung,of patients with TBI, this prescription is well tolerated and can representanalternativetotheprescriptionofpsychotropicdrugs. Thereseemstobeanefficacyonimpulsivity.Inclinicalpractice,

Fig.1.PRISMAflowdiagramofthestudyselectionprocessformeta-analyzes,systematicreviews,randomizedcontrolledtrials,controlledtrials.PRISMA:preferredreporting itemsforreviewsandmeta-analyses[3].

dosesof40to80mginoneortwotakesareoftenquiteeffective. Nostudywasfoundregardingthetreatmentofanxietyby beta-blockersafterTBI.

Recommendations

Beta-blockersdonothaveamarketauthorizationinthecare managementofagitationand/oraggressivenessand/or irrita-bilitybuttheanalysisoftheliteratureshowsthat,incertain cases,theycanimprovethesedisorders.Theirprescriptionin thisindicationmustbeevaluatedaccordingtoeachindividual

case and based on the criteria associated with treatments prescribedwithoutMAontopofprecautionsofuserelated tothistherapeuticclass.Theuseofpropranololinthe treat-mentofagitationand/oraggressivenessand/orirritabilityis proposedatthedosageof40to80mgperdayevenifcertain studieshavereportedaneffectwithhigherdoses.Justlikein patientswithnoTBI,itisrecommendedtostartthetreatment progressivelyanditismandatorytoweanfrombeta-blockers progressivelybecauseofthecoronaryrisk.Itispreferableto perform an ECG before starting a beta-blocker treatment (Expertsconsensus[EC]).

Fig.2.PRISMAflowdiagramofthestudyselectionprocessforalltypesofstudies(exceptreviews,comparativestudies,meta-analyzes).PRISMA:preferredreportingitemsfor reviewsandmeta-analyses[3].

Table2

Beta-blockersuse,33peopleafterTBIincluded.

Article Studydescription Levelof evidence

Conclusions

Brookeetal.,1992[4] Randomizedpropranololversusplacebostudyin 21severeTBIagitated.Studyof18months, startingdose60mg/dayto420mg/day incrementsof60mgevery3days.Study duration:8weeks,theinitialphaseafterhead injury.OvertAggressionScale

Level1or2 GradeB

Theintensityofagitationwassignificantlylowerinthe propranololgroup(P<0.05).Nosignificantdifferenceinthe numberofagitationepisode.Reduceduseofrestraintmeasurein thetreatedgroup.Absenceofcognitiveeffectorinteractionwith othertreatments

Limits:fairlysmallpopulation,11patients/10placebo Greendykeand

Kanter,1986[6]

Randomizeddouble-blindplacebocrossover studyversuspropranolol,in10patientswith organicbraindisease.Beginning80mg/dayto 520mg/d.4of9patientsaretraumaticbrain injured.Subjects25to75years,inclusionof1to 30yearslater

Level4 GradeC

Reductionofaggressivebehavior(P<0.05)withnoapparent sedativeeffect.Hypotensionorbradycardiain7/9patients Limits:populationheterogeneityinage,timeofinclusionand causesofthebraindamage

Noevaluationscale Greendykeetal.,

1986[7]

Randomizeddouble-blindplacebocrossover studyversuspindolol,11patientswithorganic braindisease.Impulsivebehavior,explosive. Subjects‘‘severelydemented’’,aging28to76,5/ 11patientsofTBI

Level4 GradeC

Significantdecreaseinthenumberofcrisis(P<0.05).Optimal responsedose:40to60mg/day

Limits:populationheterogeneityinage,timeofinclusionand causesofthebraindamage.Noevaluationscale

Greendyke,1989 Randomizeddouble-blindplacebocrossover versuspindolol,13patientswithorganicbrain disease.3/13areheadinjuries.OvertAggression Scale.Pindolol20mg/twicedaily

Level4 GradeC

8of13patientsimprovedwithoutastatisticallysignificant difference.Pindololseemstodecreasetheverbalandphysical aggressionandimprovequalityoflifeofthesepatients Limits:populationheterogeneityinage,timeofinclusionand causesofthebraindamage

3.2. Useofneurolepticsandantipsychoticdrugs:52patientsincluded. 3.2.1. Generalities

Tworeviews[12,13]hardlyreported theuseofneuroleptics whereas other authors report their frequent use in behavioral disorderspost-TBI[8,9,14–20](Table3).Reviewarticles underli-ned thelack of a strong methodology and insufficient level of evidence.

According to the study conducted among expert healthcare professionals[11,21]neurolepticsarenotoneofthe5drugsmost used to treat agitation post-TBI. Haloperidol or risperidone is used by non-experts. There are no standards or consensus regardingthe useof neuroleptics.A greater sensitivityto their adverseeffectspost-TBIwasdescribed.Theuseofolanzapinewas suggested[13].

3.2.2. AdverseeffectsofneurolepticsafterTBI

3.2.2.1. Neurolepticmalignantsyndrome(NMS). Thereseemstobe agreaterexposuretotheriskofneurolepticmalignantsyndrome (NMS) post-TBI [22–26]. This syndrome is reported as a rare occurrence.Theuseofhaloperidolwasmostoftenreportedforthe 10casespublished[22–24,26–28].Itconcernedyoungadults.A casewasreportedunderrisperidone[24].ForLevyetal.,[18]NMS is not dose-dependent. Conversely, the review of 9 cases by Bellamyetal.[29]reportedtheexactoppositewiththeonsetof neurolepticmalignantsyndromeunderhighdosesofhaloperidol. Themostrecentreview[26],underliningthechallengesinmaking thediagnosis,reportedthatin90%ofthecases,thefirstsymptoms appearedonaverage10daysafterthebeginningoftheneuroleptic treatment.Ahypodopaminergicstateofthebrainrelatedtothe traumawasbroughtup.

3.2.2.2. Potentially noxious effects of neuroleptics on recovery abilities. On animal models(rat) [29] haloperidol was reported to affect recovery after damage to motor cortical areas and interactswiththeneuronalrecoveryprocess.ForWilsonetal,[30]

multipleadministrationsolanzapinewouldnotimpactcognitive functions,converselytohaloperidol.Anotherstudy[31]showeda

deteriorationofmotorandcognitiveperformancesafterchronic administrationofhighdosesofhaloperidolorrisperidone.Unique orrepeatedlowdosesofhaloperidolorrisperidoneseemsafevs. continuous high doses negatively affecting recovery (animal study). A year later, the same team [32] showedthat chronic administrations (during 19 days) of low or higher doses of haloperidolorrisperidonepreventedmotorandcognitive recov-ery.Thiseffectdidnotseemrelatedtothesedativeproperties[33], butrathertothealterationofneurotransmittersystems.

In humans,a studyconductedon 11 people [34]treated by haloperidolafterTBIvs.controlsreportedasignificantincreaseof thedurationofthepost-traumaticamnesiainthetreatedgroup (level2).Anotherstudy[35],describedacognitiveimprovementof patientsafterhavingstoppedtakingneuroleptics,butthestudy onlyincluded3subjectsandhadpotentialbiases(level4).Thus, we haveseveral studiesdescribing thenegative interference of neuroleptic treatments with the biological and brain plasticity process,essenceoftherecoveryproject[15,16,18].However,these studiesdonotbringforwardrealevidenceonascientificlevel. 3.2.2.3. Neuroleptics and apathy post-TBI. No study was found usingneurolepticspost-TBItotreatapathy.Reviewstudiesonthis symptom in otherneurological or psychiatric pathologies (low level of evidence) reported an improvement of apathy in schizophrenia,major andnon-psychoticdepression and Alzhei-mer’sdiseasewithsecond-generationneuroleptics[36–40]. 3.2.2.4. Practicaladvicefortheuseof neurolepticspost-TBI. Inthe absenceofconsensusproposals,thecombineddataofthedifferent studiesanalyzed[8,12,14,15,18–20,23,25,28,35,41–45]candefine practicalrulestothespecificuseofneurolepticspost-TBI.

Firstdonoharm,donotprescribeneuroleptics.Ifpossiblewait orproposeanothernon-pharmacologicalapproach(institutional and/orpsychotherapeutic)oranalternativetoneuroleptics:e.g. beta-blockers, mood stabilizers. In the absence of objective agitationor aggressiveness, itis recommendedtolimit theuse ofneurolepticstocaseswhenothercaremanagementtherapeutics havefailed.Regardlessofthepharmacologicalapproachtaken,itis

Table3

Neurolepticsuse,52peopleafterTBIincluded.

Article Studydescription Levelofproof Conclusions KimandBijlani,

2006[47]

Quetiapine,25to300mgto800mg,a6-weekopenstudy prospectivelyfor7patients.Treatmentofaggressivenessafter TBI.Anyseverity.OvertAggressionScale(OAS)andClinical GlobalImpression(CGI)

Level3 GradeC

Goodefficacyandtoleranceoftheproduct

Reducingirritabilityandaggressionwithimprovedcognitive functioning

Akathisiainonesubject Michalsetal.,

1993[50]

Clozapine.9patientsserieswithpsychoticsymptomsor aggressionaccessrefractorytootherstreatments

Level3 GradeC

Clozapineisusefulinthetreatmentofpsychosisand aggressivebehavior(partialimprovementofstrangeness, agitation,hallucinations),despitesideeffects(2seizures/ 9patients)

Noe´ etal.,2007[46] Ziprasidone,20a` 80mg/day,5casesreports,managementof behavioraldisordersofpatientswithseveretraumaticbrain injury(TBI)duringtheperiodofpost-traumaticamnesia(PTA). AgitatedBehaviourScale(ABS)

Level3 GradeC

EfficacyofziprasidoneincontrollingagitationduringthePTA period.Despitethesmallsizeofthesample,ziprasidone reducedsymptomsofagitationquicklyandwithgood tolerability,safetyandnosideeffects

Raoetal.,1985[34] Opencontrolledprospectivestudyin26agitatedpatientsafter severeTBI.Agroupof11requiredhaloperidol.Measureofthe lengthofcoma,duration,ofpost-traumaticamnesiaduration (PTA),functionalstatus,CT-scanresults

Level3 GradeC

Nosignificantdifferenceindemographics,lengthofcomaand rehabilitationsuccess.ThedurationofPTAissignificantly longerinthegrouptreatedwithhaloperidol,P<0.05 Limits:weakstatisticalnumbers(11subjects) Stanislav,1997[35] Casestudyinvolving3subjectsafterheadinjury.Evaluationof

functioningdifferencesbefore,duringandafter discontinuationofantipsychoticdrugs

Level4 GradeC

Thereisacognitiveimprovementofpeopleafterstopping neuroleptics

Limits:3subjectsonly,methodologicalbias UmanskyandGeller,

2000[51]

Casereport.Olanzapine(20mg/day)forpsychotic manifestationsfollowingasecondsevereclosed-headinjury

Level3 GradeC

After6monthsoftreatmenttheindividualnolongerheard persecutoryvoices,hadnondelusionalsymptomsorrage outburstsandexhibitedimprovementsinmood,behaviorand followupcompliance

VianaBdeetal., 2010[49]

Casereport.Olanzapine,10mg/daypsychoticdisordersafter craniocerebralgunshotwound.Delusionsreligious persecution,auditoryhallucinations

Level3 GradeC

Progressivesignificantregressionafteramonthofpsychotic symptomswiththepossibilitytoinitiatearehabilitation program

necessarytoviewtheproblematicoftheefficacyononesymptom in thecontextof individualneurological recovery.Neuroleptics mighthaveanegativeimpactonneuronalplasticity,thushavinga reverseeffectontherehabilitation’smainobjective.

Incaseofemergencyandacuteaggressivenesstheprescription ofneuroleptics canbeenvisionedin theabsenceof contraindi-cations.

Outsideoftheacutecrisisoremergencysituation,tostart a neuroleptictreatment,itispreferableto:

start with a small dosage go slowlyand progressively when increasingthedosagecontinuouslyreassesstheclinical presen-tation;

onesingleproductatatime(monotherapy); becarefulofinteractionsbetweenproducts; monitortheepileptogenicthreshold;

the experience of TBI consequences, from awakening to the chronic phase can alert prescribing physicians on the high sensitivityofTBIpatientstosedativedrugs,therulebeingthe ‘‘minimumeffectivedose’’.

Prefertheuseofanatypicalneuroleptic(2ndgeneration)that haslesssideeffects[9,14,18,20,23],especiallylessextrapyramidal sideeffects.Antipsychoticshaveabetterbenefit/riskratio.

Severalauthorsestimatethatoneshouldnotuseneuroleptics onthelongtermtotreataggressivenessafterTBIexceptincaseof priorpsychiatricdisease[8,18,20,43–45].Thepremorbid person-alityandpsychiatrichistorycanguidethetherapeuticchoices. 3.2.2.5. Data per product (second generation, atypical neurolep-tics). Somestudies(Table3)withalowlevelofevidence(level3 to 4) concerned case reports reporting the effectiveness of ziprasidone in agitation [46], quetiapine and olanzapine after aggressivenessor post-traumatic psychosis[47–49] or clozapine inthissymptomwithhematologicrisks[50].Anothercasereport (severeTBI)showedtheefficacyofolanzapineonhallucinations[51].

Recommendations

Thereisnosufficientevidenceregardingtheefficacyof neu-roleptics in the treatment of behavioral disorders such as irritability,aggressivenessorapathypost-TBI.

Observation:Thereareno‘‘new’’norspecificsideeffects relatedtotheuseofneurolepticspost-TBI.However,thereare severalspecificitiesthatneedtobeaccountedfor:

 greaterexposuretoneurolepticmalignantsyndrome;  sedativeeffectthat could increasetherisk offallsor

dysphagia;

 potentialnoxiouseffectsonbrainplasticityandthuson therecoverypotential.

Incaseofemergencyoracuteagitationandaggressiveness crisis,theprescriptionofaneurolepticcanonlybeenvisioned intheabsenceofcontraindications,toobtainaquicksedation inordertoprotectthepatientfromself-harm,protecthis/her closedonesorthehealthcareteam.Loxapine(Loxapac*_)hasa marketing authorization in its injectable form for treating ‘‘casesof agitation, aggressiveness and anxiety associated with psychotic disorders, or certain personality disorders’’ (EC).Thelong-termuseofneurolepticsforthetreatmentof behavioraldisordersinpatientswithTBImustbeavoideddue tosideeffects,exceptincaseofpriorpsychiatricdisease(EC). Intheabsenceoftherapeuticalternatives,theuseof neurolep-tic must respect the usual prescription guidelines of this therapeutic class. Furthermore, in patients with TBI, it is

recommendedtoabidebyprescriptionguidelinescommonto thedifferenttherapeuticagents(seeabove).Morespecifically, regarding neurolepticsit is essentialtotake additional pre-cautions(EC):(i)takeintoaccounttheepileptogenicrisk,since thethresholdmightbelowerthanusual,(ii)usepreferentially anatypicalneuroleptic(2ndgeneration)becauseitleadstoless sideeffects,especiallylessextrapyramidalsideeffects,(iii)be awareofthecardiovascularrisks.

3.3. Useofantidepressants,348patientsincluded

Thescientificliteraturereportingtheeffectsofantidepressants afterTBIisquitescarce(Table4).Theeffectoftheseproductson moodandbehaviorhasrarelybeenstudied.Thespecificactionof antidepressantsonbehavioraldisordersremainstobevalidated. Noargumentinfavororagainsttheuseofantidepressantsin apathy wasfound. Regardingagitation and aggressiveness, the levelofevidenceislowandcontrastswiththerelativelyfrequent useof antidepressants. For depressionitself, their usefulness is morefrequentlydemonstrated.

3.3.1. Agitationaggressiveness

Severalargumentssupporttheuseofantidepressantstotreat agitation and aggressiveness. Animal studies have shown that serotonin levels were negatively correlated to aggressiveness

[14].Dopaminergicandnoradrenergiccircuits,greatlyinvolvedin executivefunctions [52–55],arecommonly disruptedafter TBI, whichcouldpromotetheonsetofbehavioraldisorders[56].

Conversely, antidepressants can have adverse effects and increaseconfusion,sleepiness(atallstages ofthecare manage-ment)and/or anxiety,inducenausea, anticholinergiceffects for someandincreasetheriskofsuicidalattempts.

Based ona surveyconductedon USmedical specialists[11], antidepressants areoneofthe5mostfrequentlyuseddrugsto treatagitationinpatientswithTBI.

Regardingagitationandaggressiveness,articlesarescarce.The onlystudywithacontrolgroup,sertraline(100mg/d,11patients) vs.placebo,didnotshowsignificanteffectsonagitation(level2). Butthenumberofpatientswaslowandthestudydurationwas only 15 days [57]. According to Lombard et al. [59] the antidepressanteffectcannotbereachedbefore2weeks.These authors consider that Selective Serotonin Reuptake Inhibitors (SSRIs) havea non-acceptabledelayofaction forthecontrolof acute agitation. A series of 13 patients with TBI [58] under sertraline200mg/dwithoutagroupcontrol,unveiledasignificant effectonirritabilityandaggressiveness(level3),whereasnoeffect wasnotedondepressionsymptomsafter8weeksoftreatment.In two patients presenting withKlu¨ver-Bucy syndrome (agitation, hyperorality,hypersexuality)aftersevereTBI,theuseofsertraline upto150mg/dwasfollowedbyanimprovementinafewdaysof disordersthatwereresistanttootherdrugs[55](level3).Forone ofthesetwocases,theassociationwithaneurolepticseemedto haveincreasedtheeffectofsertraline.

Amitriptyline is not commonly used in agitation after TBI

[14]. Itis considered bysome authorsas thepharmacological agent of choice in thetreatment of behavioraldisorders after frontal brain damage [8]. A retrospective study comparing 20agitatedpatientstreatedwithamitriptylinetoacontrolgroup of38nonagitatedpatients[54]foundforpatientsinthestageof post-traumatic amnesia a great efficacy on agitation for 12 patients out of 17 after 7 daysof treatment (beginning at 25mg/d up to 150mg/d, level 3). For a 32-year-old agitated patientwithTBIandbifrontaldamage,amitriptylinewasreported tobeeffectivein2weeksonangerburstswithanimprovementof attention[59](level3).

Table4

Useofantidepressants,348peopleafterTBIincluded.

Article Studydescription Levelofevidence Conclusions Ashmanetal.,

2009[62]

Randomized10weeksdouble-blindsertraline(early25mgupto 200mg/day)versusplaceboin52volunteersafterTBI.Using HamiltonRatingScaleforDepression(HAM-D).

Chronicphase:1714yearsaftertheaccident

Level1 GradeA

Nosignificantdifferencebetweenthetwogroupsondepression measures,anxietyandqualityoflife.Thereisanimprovementof 3scores(depression,anxiety,qualityoflife)inthe2groups(59% sertralinegroup,32%placebogroup)

Limits:heterogeneouspopulation Dinanand

Mobayed, 1992[71]

Cohort6-weekstudyofamitriptyline(upto250mg),13mildTBI withdepressionmatchedwith13depressedpatientswithoutTBI. UsingmodifiedHamiltonRatingScaleforDepression

Level2 GradeC

Only4patientsshowedmarkedimprovementinMTBIgroup versus11indepressedpatientswithoutTBI.Depressionfollowing MTBIisrelativelyresistanttotricyclicantidepressantstreatment. AmitriptylineiseffectiveinsomeTBIcases

Fannetal., 2000[63]

Non-randomizedsingle-blind8-weekstudy,sertraline25–150mg/ dayversusplacebo.15patientsafterMildTBIinmajordepression, onaverage10.6monthslater.ModifiedHamiltonRatingScaleand DSM-IIIcriteria

Level3 GradeC

Statisticallysignificantimprovementindepression,psychological disorder,hatred,aggressionandpostconcussivesymptoms Limits:norandomizedgroupandsingle-blind

Horsfieldetal., 2000[64]

Therearedatathatshowthatfluoxetineisableofneuronal remodeling

Openpilotstudy,fluoxetine(20–60mg/day)administeredtoa groupoffiveheadinjurywithmoderateornon-depressed depression.Initialcognitivetestsandaftereightmonths

Level4 GradeC

Fluoxetineimprovesmood,andperformanceontheTrailMaking TestPartA,andWAIS-III

Althoughfluoxetinehashadbeneficialeffectsoncertainmeasures ofcognition,moreworkisneededtolinktheseimprovementswith theneuronalremodeling

Jacksonetal., 1985[59]

Amitriptylinecasestudy.32-year-oldman,severeagitationafter TBIandinjurytothefrontallobes.Failureofotherstreatments

Level3 GradeC

Efficiencyin2weeks,withcessationofanger,agitation,without significantcognitivesideeffects.Respectforcognitiveperformance Kanetanietal.,

2003[65]

Milnacipran(30to150mg/d)reuptakeinhibitorofserotoninand norepinephrine(SNRIs),totreatdepressionaftermildtomoderate TBI.Openstudyofsixweeksfor10patients(4menand6women) from28to74years.DSM-IVHamiltonScale(HAM-D).Cognitive statuswasassessedbytheminimentaltest(MMSE)

Level4 GradeC

OnthebasisofaHAM-Ddecreasemorethan50%responseratewas 66.7%,theremissionrateof44.4%.Significantlygreater improvementincognitivefunctionsinpatients.Milnacipranisa safeandeffectivedrugfordepressionafterECTandcouldbeused asfirstline

Kantetal., 1998[58,72]

Opentrialwithoutcontrolgroup,sertraline50–200mg/day.Using ModifiedOASscale.

13irritableandaggressivepatientsaftersevereTBI(n=2), moderate(n=6)ormild(n=5).

Study8weeks,irritabilityanddepressionareevaluatedevery 2weeks

Level4 GradeC

Significantreductioninirritability,aggressionandcriticalaccess, noeffectondepressivesymptomsafter8weeks.

TheSRIareusefulforthetreatmentofirritabilityandaggression afterTBI,theimprovementisnotduetotheimprovementof depressivesymptoms

Limits:lackofcontrolgroup.Alcoholusefor2patientsanddrug usefor1

Leeetal., 2005[25]

Randomized4-weekdouble-blindplacebostudyvs.sertralineor methylphenidateandNeuropsychiatricsequelaeaftermildto moderateTBI.Thirtypatients,methylphenidate(5mg/dayto 20mg/day),sertraline(25mgto100mg/day)placebo.Beforeand after4weeks,13testsondepression,qualityoflife,cognitive performance,sleep

Level2 GradeB

Methylphenidateandsertralinehadsimilareffectsondepressive symptoms.Methylphenidateseemssuperiorinimproving cognitivefunctionandmaintainingdaytimealertness. Methylphenidatealsohasbettertolerancethansertraline

Meythaleretal., 2001[57]

Prospectiverandomizedstudysertraline(100mg/day)versus placeboinimprovingwakefulnessandalertnessafterTBIininitial rehabilitationphase.11patients.ABS,AgitatedBehaviorScale, OrientationLog,GalvestonOrientationandAmnesiaTest(GOAT)

Level2 GradeB

Placeboandmedicationhavethesamelevelsofimprovementfor the3tests.Nosignificantdifferencesbetweenthetwogroups Nonegativeeffectonrecoveryorsideeffects.

Limits:smallsample–Expectedeffectsfromthefirstweek,short essay(2weeks).Significantbias

Mysiwetal., 1998[54]

RetrospectiveAmitriptylinestudy,20agitatedpatientswith post-traumaticamnesiastageafterTBI.OrientationGroupMonitoring System

Level4 GradeC

Significantimprovementoftheagitationfor12/17patientswithin 7daysafterproductinitiation

Nointeractionwithcognitiverecovery Newburnetal.,

1999[66]

RetrospectivecaseseriesofMoclobemide(450–600mg/day), 26patientswithTBIanddepressiondiagnosis

HamiltonDepressionscore(HAM-D)

Level4 GradeC

ReductionoftheHAM-D81%.Fastaction,17respondersJ3. Reducingirritabilityscoresby57%and39%formentalpain. Moclobemidemaybeaneffectivetreatmentformajordepression afterECT,controlledstudiesarelacking

Perinoetal., 2001[67]

Openprospectivestudyof12weeksofcitalopram(20mg/day)and carbamazepine(CBZ)(600mg/day)in20depressedpatientsafter severeTBI.MIF,BriefPsychiatricRatingScale(BPRS)andClinical GlobalImpressionScale(CGI)

Level4 GradeC

(a)CitalopramcombinedwithCBZreducesdepressionand behavioraldisordersafterTBI,P<0.05.(b)Thesedisordersmustbe takencareofassoonaspossibleduringtherehabilitationperiod. Sincecombinationtherapywasused,itisnotpossibletodetermine whetheroneortheotherdrugwasprimarilyresponsibleofthe improvement

Rapoportetal., 2008[68]

Openstudycitalopram(20mgto50mg/day)for6weeksand 10weeksin54patientswithmajordepressionfollowingmildto moderateTBI

HamiltonDepressionScale(HAM-D)

Level4 GradeC

Theresponserateiscomparabletotheresultsofthetestingof patientswithmajordepressionbuthasnothadTBI

Rapoportetal., 1999[69]

Randomizeddouble-blindstudycitalopram(20–50mg/day)versus placeboin65patientswithmajordepression.Iscontinuous treatmentwithcitaloprampreventsarelapseofdepressionafter TBI?RemissionScore7forHamiltonRatingScale.Relapseif HAM16

Level2 GradeB

11relapsesofdepression(52.4%)

RelativeriskofrecurrenceofdepressionafterTBIis50%.Itisbetter tostopthetreatmentandsecondarilytakecitalopramfor depressionrelapse

Limits:10versus11placebosubjectscitalopram,3outputsstudy including1fordiarrhea

Slaughteretal., 1999[55]

TwocasesofKlu¨ver-BucysyndromeaftersevereTBIposingcare problem

Level3 GradeC

BenefitoftheSRItotreatKlu¨ver-BucySdafterTBI Tengetal.,

2001[60]

Casestudy.AnagitatedmanaftersevereTBIintherecoveryphase. Failureofothersproducts.TreatmentwithBupropion(Zyban)

Level3 GradeC

TheuseofZyban(150mg/day)isnotdiscussedinanyotherstudy. Inthiscase,itistheonlytreatmentthatcouldsignificantlyreduce agitationandimprovecognitivefunction

Wroblewski etal.,1996[70]

Randomized,placebo-controlledprospectivecrossoverstudy aboutdesipramine(150–300mg/j).10individualswithsevereTBI anddepression.ProductnotcommercializedinFrance

Level3 GradeC

Ofthe7patientswhocompletedthestudy,6improvedon desipraminetreatment.2studyoutputs:aseizure,amanicturn Significantmethodologicalflawsandsmallsamplesizelimitedthe strengthofthefindings

Interestingly,oneshouldnotetheeffectivenessofbupropion (Zyban1

)atquitehighdoses(150mg/d)ina20-year-oldwoman describedasveryagitatedafterthefailureofloxapine,haloperidol, propranolol, methylphenidate, diazepam and paroxetine [60]

(level 3).This treatment cannot berecommended today based oncurrentscientificknowledge.

SSRIs present less side effects and a profile of side effect differentfromtricyclicsthatcangeneratesedation,aswellasother side effects such as cardiologic ones, anticholinergics with constipation and urine retention, as well as lowering the epileptogenic threshold [8,9]. Neither SSRIs nor tricyclic anti-depressantshaveamarketingauthorizationinFranceforagitation oraggressiveness.

3.3.2. Depression

TheliteraturereviewsbyAlderfer etal.,2005[52]and Fann et al., 2009 [61] reported the best level of evidence for noradrenergicandspecificserotonergicantidepressants(NaSSAs) forthetreatment ofdepression.Arandomized,double-blindvs. placebostudy afterTBI withsertraline(25to200mg/day)[62]

validatedafter10weeksoftreatmentanimprovementinmood, qualityoflifeandanxiety(level2).

Otherstudiesalreadypointedoutthisresultwithsertraline

[25,63](level 4). A studyon fluoxetine (Prozac1

),to look for cognitiveeffectsandimpact onbrainplasticity [64],foundan

improvement on mood as well as memory and attention

performances (level 4). A work on milnacipran (Ixel1 , 30 to 150mg/day) after light to moderate TBI [65] for a 6-week duration,describedanimprovementofdepressionandcognitive performances (level 4). This antidepressant is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). The use of moclobemide (Moclamine1

) post-TBI [66] in an open study showed the good efficacy of the product (level 4). Regardingcitalopram(Seropram1

),a2001study[67]described an 81% response rate after TBI (level 4). An open study on 54patientswithlighttomoderateTBItreatedwithcitalopram

[68], reported a 46%response rate with a remission at 26.9% after 10 weeksof treatment. Theseresults are comparable to resultsofpatientssufferingfrommajordepression,withoutTBI (level 4). A randomized, double-blind study citalopram vs. placeboreportedthelimitsof pursuingthetreatmenttoavoid depressionrecurrence.Itispreferabletostopthetreatmentand secondarilystartagainoncitalopramincaseofrecurrence[69]

(level2).

Regardingtricyclic antidepressants, a randomized,crossover studyfocusedondesipramine(notmarketedinFrance)vs.placebo

[70].Thesamplesweresmall(6patientswithTBIvalidatedthe study),(level3).Foramitriptyline,astudyon13patientswithTBI comparedto13patientswithdepressionshoweda4/13response rateinthegroupofpatientswithTBIvs.11/12inthegroupwithout TBI [71]. Authors concluded that depression after TBI was relatively resistant to treatment by tricyclic antidepressants (level4).

Justlikethetreatment for aggressiveness, thetreatment for depressionmustseekthebestbenefit/riskratio,whichtendsto prefer SSRIs rather than tricyclic antidepressants as first line treatment.

3.3.3. Apathy

For apathy, no specific study was found regarding this specific symptom sometimes identified by certain authors in cognitivefunctions.Apathyisoftensymptomaticofadepressive state [72], antidepressants could be envisioned as an initial treatment.Theeffecton awakeningcouldalso havea positive impact.

3.3.4. Otherdisorders

Theuseofparoxetineandcitalopramseeminterestinginthe treatment of pathological cries [73] even if results must be validatedinfurtherstudiesonlargersamples(level3).

Recommendations

Antidepressantsaremainlyusedtotreatdepressionaccording totheusualrecommendationsandintheframeworkoftheir MA.Intheabsenceofcontraindications,theycanbeusedafter TBI(EC).Theprescriptionofantidepressantsinthecontextof thetreatmentofdepressioninallthestagesofitsprogression, mustabidebytheguidelinesforclinicalpracticepublishedby theANAESin2002:‘‘managementofanisolateddepressive episodeinadultoutpatients’’(EC).Specifically,itwasindicated thatthechoiceofanantidepressantshouldpreferentiallybe basedonspecificcriteria:

 therapeuticuseoflateraleffects(forexample,looking forsedation,anxiolyticeffectorstimulation);

 thepreferentialindicationofatherapeuticclassinsome psychiatriccomorbidities,forexampleSelective Seroto-ninReuptakeInhibitors(SSRIs)andspecifically sertra-lineforobsessivecompulsivedisorders;

 themixedeffectSSRI+adrenergic(SSNRI)oncognitive disordersforexamplemilnacipran(Ixel1

)atthedoseof 30to150mg(EC).

Observation:Antidepressantscanbeeffectiveinanindirect manneronagitationandaggressivenesswhenconsideringthat depression or anxiety are promoting factors. Amitriptyline showed a certain efficacy on agitation from the dose of 25mgperday.Paroxetineandcitalopramcanimprove patho-logicalcriesofcertainpatientsafterTBI.SSRIscouldhavea positiveimpactonbrainplasticityandthusontherecovery potential.Sertralineshowedsomeefficacyonagitation, aggres-sivenessandirritabilitywithdosesgoingupto200mgperday. AnimprovementofKlu¨ver-BucySyndrome(agitation, hyper-orality, hypersexuality) after severe TBI, was reported with sertralineupto150mg/d.Thepositiveeffectmighthavebeen majoredby associating sertraline with aneuroleptic. Inthe absenceofspecificindications,itisrecommendedtochoose thebesttoleratedantidepressant,thelessdangerous oneincase of massive absorption,and the simplest to prescribe atan effectivedose.SSRIs,SSNRIsandothernon-tricyclic,non-MAOI antidepressantdrugsaretheones most adaptedto these criteria. During the awakening period, tricyclic antidepressants and especiallyamitriptylineatalowdosecanalsobeproposedto treatagitation(EC).AntidepressantsdonothaveaMAinFrance totreatagitationand/oraggressiveness,sotheprescriptionof thesemoleculesshouldbeevaluatedforeachindividualcase accordingtothecriteriaassociatedwithtreatmentsprescribed outsideofaMAontopoftheusualrecommendations(EC).

3.4. Antiepilepticmoodstabilizersandotherantiepilepticdrugs, 555patientsincluded

3.4.1. Carbamazepine(CBZ),valproate(VPA)andphenytoin Carbamazepine (CBZ) and valproate (VPA) are antiepileptic agentscommonlyusedasmoodstabilizerstotreatagitationafter TBI[8,12,14](Table5).VPAhasthereputationofhavinglessside effects[8,14,74].InFranceVPAandCBZdonothaveamarketing authorizationforagitation,irritabilityoraggressiveness.

StudiesdescribingcognitivesideeffectsofVPAorCBZafterTBI are contradictory. A review on phenytoin, CBZ and VPA from 1991 reported that these three medicines seemed to exert a negativeeffectoncognitiveandmotorfunctions.Thesedisorders

getworsewithserumlevels[75].Inthisrandomized,double-blind CBZand phenytoinvs. placebo study,authorsfoundanegative impact on cognitive performance for these two products [76]

(level 2). Conversely, a prospective, randomized, double-blind study comparing 279 patients with TBI receiving valproate or phenytoin,showedthatthevalproatetreatmentdidnothaveany negativeorpositiveneuropsychologicaleffects[74](level1).

AccordingtothesurveyconductedonUSphysicians[11],CBZis listedas theprimary treatmenttotreat agitationafterTBI.The work conducted 10 years later [21] on agitation, anger and irritabilityreportedsodiumvalproateasthemaintreatment.

RegardingtreatmentofagitationandaggressivenessbyVPA,a prospectivestudyon29patients,including23whopresentedwith TBIdescribedanimprovementin26patients[77].Theefficacywas

described as rapid, with doses comprised between 1000 and 1800mgperday(mean1200mg)ofsodiumvalproate(level3).

Formoreheterogeneousdisorders(bipolar,psychotic)another retrospectivestudy[78]reportsagoodefficacyandgoodtolerance for11patientsafterTBI(level4).Anotherseriesof5subjects(4TBI/ 5)reportedtheefficacyofVPAwhereothertreatmentshadfailed

[79](level3).

Regarding the use of carbamazepine (400 to800mg/day) in 10patientsagitatedwithangerburstsinaprospectiveopen8-week studyreportsagoodefficacy[80](level3)withnonegativecognitive effects. A studyon 7 aggressivepatients with TBI reported the efficacy of carbamazepine (400 to 900mg/day) in the 4 days followingthebeginningoftreatments,andinfourcasesCBZwas associatedwithhaloperidol,allowingthedecreaseofneuroleptics

Table5

Antiepilepticsuse,555peopleafterTBIincluded.

Article Descriptionofstudy Levelofproof Conclusions Azouvietal.,1999[80] Prospectiveopentrialofcarbamazepine(400–800mg/day,

8weeks)onagitationandaggressivebehaviorin 10patientswithasevereTBI

AgitatedBehaviorScale(ABS),KatzAdjustmentScale(KAS) forsocialfunctioning,MiniMentalStatusExamination (MMSE)

Level3 GradeC

Statisticallysignificantimprovement(P<0.05)on irritabilityanddisinhibitioninparticular,theABSandKAS score.NoglobalcognitivechangefoundonMMSEscores CarbamazepinemighthelptoreduceagitationafterTBI

ChahineandChemali, 2006[87]

Aretrospectivestudyabout4youngpatientswith pathologicallaughterand/orpathologicalcryingfollowing TBI.Alamotriginetreatment

Level3 GradeC

Thefourpatientsweresuccessfullytreatedwith lamotrigine

ChathamShowalter, 1996[81]

Useofcarbamazepinefor7combativepatientswith multipletraumaincludingTBI

Level4 GradeC

Thiscohorthadaclinicaldecreaseincombativenesswithin 4daysaftercarbamazepine

ChathamShowalterand Kimmel,2000[77]

Retrospectivestudyfor22monthsinarehabilitationunitof agroupof29subjectsforDivalproexunderagitation.23TBI patients,5strokes,1vasculitis

Level4 GradeC

For26ofthe29patients,effectivein7daysatadoseof 1250mg/day.Aneffectivealternativetoantipsychoticsand benzodiazepinesagainstimpulsivityanddisinhibitionafter braininjury

Dikmenetal.,2000[74] Randomizeddouble-blindstudy,Valproate(VPA)versus. Phenytoin,comparisonbetweenpreventionofepilepsyand neuropsychologicaleffectsat1and6months.279adults randomizedwithin24hoursoftheinjury,batteryof neuropsychologicalmeasuresat1,6and12months

Level2 GradeB

NonegativenorpositiveneuropsychologicaleffectsofVPA. VPAseemstohaveabenignneuropsychologicaleffects profile.However,forthisstudy,theVPAdoesnotprevent post-traumaticcrises

Noplacebogroup Gos´cin´skietal.,1997[82] 4patientswithpost-traumaticlesionslocalized

bitemporallydevelopedKluver-Bucysyndrome Treatmentwithcarbamazepine

Level4 GradeC

Severalsymptomsrespondeddramaticallyto

carbamazepine.Ausefulagentintreatmentofthisunusual syndrome

KimandHumaran, 2002[78]

Retrospectivestudy,11patientsafterTBI,Divalproexalone orwithotherpsychotropicproposedonneurobehavioral symptoms

Level4 GradeC

Divaproexiswell-supportedafterTBI

Limits:heterogeneityofpatientsandtreatments,3bipolar, 2psychotics,2personalitychanges

Mattes,2005[84] Randomizeddouble-blindoxcarbazepine(1200–2400mg/ day)versusplacebofor10weeks.48aggressivepatients, multiplemedicalcauses

GlobalOvertAggressionrating,OvertAggression Scale-Modified

Level2 GradeB

Consistentevidenceinfavorofoxcarbazepine,comparedto placebo(P=0.012).Oxcarbazepineseemstobringbenefitto aggressiveadultsregardlessofthecauseoftheaggression. Limits:Mixtureofpathologies.9patientsdiscontinueddue toadverseeffects,45completingthestudyatleast4weeks Mattes,2008[89] Randomizeddouble-blindlevetiracetam(3000mg/day)

versusplacebofor10weeks,inaggressivepatients(noTBI study)

OvertAggressionScale-Modified

Level2 GradeB

Of40patients(20ineachtreatmentgroup),34completed atleast4weeksoftreatmentwithdouble-blindmedication. Therewasnooverallstatisticalevidenceoflevetiracetam benefit

Perinoetal.,2001[67] Openprospectivestudyof12weeksofcitalopram(20mg/ day)andcarbamazepine(CBZ)(600mg/day)in

20depressedpatientsaftersevereTBI.MIF,BriefPsychiatric RatingScale(BPRS)andClinicalGlobalImpressionScale (CGI)

Level4 GradeC

(a)CitalopramcombinedwithCBZreducesdepressionand behavioraldisordersafterTBI,P<0.05.(b)Thesedisorders mustbetakencareofassoonaspossibleduringthe rehabilitationperiod.Sincecombinationtherapywasused, itisnotpossibletodeterminewhetheroneortheother drugwasprimarilyresponsiblefortheimprovement Pachetetal.,2003[86] Singlecasestudy.Effectivenessoflamotriginetotreat

aggressiveandagitatedbehaviorina40-year-oldmalewho sustainedasevereTBI.

Level3 GradeC

Asubstantialdecreaseinbehaviorproblematicanda significantimprovementinneurobehavioralfunctioning wereobservedafterlamotriginetreatment

Smithetal.,1994[76] Double-blindversusplacebostudy,phenytoinand carbamazepine(CBZ)prophylaxisofepilepsyafterTBI. 40of64patientsreceivingphenytoinand42of 127receivingCBZfrom6to44months.Neuropsychological teststwiceduringa4-weekbaselineperiod,attheendofa 4-to5-weekperiodofcontinueddrugtreatmentor placebo,andafter4weeksofnotreceivingmedication. Attentionandpsychomotortests,speed,memory,verbal fluency,emotionalstate

Level2 GradeB

PatientsingroupsCBZandphenytoinhadasignificant improvement(P<0.01)onseveralmeasuresofmotor performanceandexecutivespeedwhenstopping medication.Bothtreatmentsappeartohavenegative effectsoncognitiveperformance,particularlythespeedof psychomotortasks

Wroblewskietal., 1997[79]

Singlecasestudy.Effectivenessofvalproate(VPA)on destructiveandaggressivebehaviorsin5patientsafter acquiredbraininjury(4TBI)

Level3 GradeC

Forthese5cases,effectivenessinonetotwoweekswhere othertreatmentshavefailed.Fewersideeffects,VPA compliespotentialparticipationinrehabilitation TBI:TraumaticBrainInjury.

intake[81](level4).APolishcaseseriesof4subjectswith Klu¨ver-Bucy Syndrome after post-traumatic bilateral temporal injury, showeda verygoodefficacyofCBZ[82](level4).Finally,Perino et al. reported the efficacy of the citalopram/CBZ (600mg/d) combinationin20subjectswithmajordepressionandbehavioral disorders,amongthe37subjectsofaprospectiveopenstudy[67]

(level4).

3.4.2. Oxcarbazepine(OXC)(Trileptal1 )

ThereisnostudyonbehavioraldisorderstreatedbyOXCafterTBI. OXCappearstohaveanefficacysimilartoCBZandlesssideeffectsin children, adolescents and adults suffering from partial seizures

[83].Arandomized,double-blindOXCvs.placebostudy(24people pergroup)broughtconvincingevidenceofthesuperiorityofOXCfor thetreatmentofaggressiveness,independentlyofmedicalcauses

[84](level2).Thesameauthorpublishedafocusonoxcarbazepinein thetreatmentofaggressivenessinprison[85].Thesearchforthe slightestsideeffect andanefficacy,evenapartiallyproven one, guidestowardsusinganti-seizuredrugsasfirstlinetreatmentfor aggressiveness.Nowadays,awideruseofOXCisbeingdiscussed. 3.4.3. Lamotrigine(Lamictal1

)

Onlyonecasestudywasfound,concerninga40-year-oldpatient with severe TBI treated successfully for his aggressiveness by lamotrigine[86](level3).Thereare4publishedcasesoflaughsand spasmodiccriestreatedsuccessfullybylamotrigine[87](level3). 3.4.4. Gabapentin(Neurontin1

)

No study was found on gabapentin and neurobehavioral disorderspost-TBI.Thereisonepublishedcaseofaggravationof agitationafterTBIassociatedwiththeprescriptionofgabapentin forneuropathicpain[88].

3.4.5. Levetiracetam(Keppra1 )

Another study on aggressive patients without TBI seems to underlinethelackofefficacyof levetiracetamonthis symptom

[89](level2).

Recommendations

The use of antiepileptic agents for epilepsy treatment or prophylaxisafterTBIsuggestsanefficacyofcarbamazepine, sodiumdivalproateandsodiumvalproateinthetreatmentof agitationandaggressiveness. Carbamazepine (CBZ) (Tegre-tol1

)andsodiumvalproate(VPA)(Depakine1

)are recommen-ded as first line treatment after TBI to treat agitation, aggressiveness,angerand irritabilityespeciallyinthe pres-enceofmoodswings.Nevertheless,theuseofantiepileptic drugshavingamoodstabilizingeffect,hasnotbeenvalidated byamarketingauthorizationtotreatagitation,aggressiveness, angerandirritabilityandtheprescriptionofthesemolecules mustbeevaluatedforeachindividualcase,accordingtothe criteriaassociatedwithtreatmentsprescribedoutsideaMAon topoftheusualprecautionsofuse(EC).

Observation:TheefficacyofVPAisdescribedasrapid,witha relativelystandardizeddoseof1250mgofsodiumdivalproate. ThegoodefficacyofCBZwasreportedwithadoseof400to 900mg/day without negative cognitiveside effects. An im-provement of post-traumatic Klu¨ver-Bucy syndrome was reportedforCBZtreatment.Someauthorspromotetheuse ofoxcarbazepine(OXC)(Trileptal1

)insteadofCBZduetoits efficacyonagitationandaggressivenessandabetterprofileof sideeffects.RegardingLamotrigine(Lamictal1

),an improve-mentofaggressivenessandspasmodiccriesandlaughswas reported in case studies. Levetiracetam (Keppra1

) has no positiveeffectsonaggressivenesspost-TBI.Itshouldbe avoi-dedafter TBIbecauseof therisks ofbehavioraland mood disordersinducedbythisdrugagent(EC).

3.5. Benzodiazepines

According to the survey conducted on US physicians [11], benzodiazepines(BZD)arenotusedbytheexpertgroupandare firsthandusedbynon-experts(5thplace).Thesimilarworkdating from2007[21]pointedtothesameresultsforagitation,whereas BZDwerenotlistedfortreatingangerorirritability.

Regardingagitationandaggressiveness,thereviewsdescribed the potential noxious effects of benzodiazepines (BZD) after a strokeorbraindamage[9]. Somebothersome sideeffectswere reportedsuchasparadoxicalagitation,especiallyinoldersubjects oranamnesticeffectbynature,whichmightpromoteconfusionin people in the post-traumatic amnesia. For some authors, BZD shouldonlybeusedinemergencysituationsand shouldnotbe usedonthelongterminthetreatmentofagitationpost-TBI[8,9].It is preferable tolimit itsusetosituations where anxietyis the predominantsymptomandforepisodicagitation.Oneshouldtake intoaccountitssedativeeffectanditslimitationwithanegative impactoncognitiverecovery.

AnAustralianmeta-analysis[90]assessedtheeffectsof long-termuseofbenzodiazepines(morethan1 year)on thenormal population,withoutTBI.Theusereportedtheevidenceofaglobal cognitiveimpactonallthevariablesassessed(sensoryprocesses, memory,processingspeed,attention/concentration,general intel-ligence, workmemory,psychomotor speed,problem resolution, motorcontrolandperformances,verbalreasoning)(level1).

Recommendations

Thereisnotenoughevidenceontheefficacyof benzodiaze-pines in the treatment of agitation or aggressiveness in patientswithTBI.BZDcanbeusedinsituationofemergency andshouldnotbeusedonthelongterminthetreatmentof agitationafterTBI.Theusewillbelimitedtosituationswere anxietyisthepredominantsymptomandprivileginga short-termuse(symptomaticprescription)(EC).AfterTBI,theuseof benzodiazepinesmusttakeintoaccounttherisktogenerateor aggravate awareness, attention and/or memory disorders, potentialrespiratorydepression,riskof aparadoxicaleffect onagitation,andits inhibitionofbrainplasticitycapacities. Thereisalsoariskofdependenceandaddiction(EC).

3.6. Amantadine,295patientsincluded

Regarding the treatment of agitation with amantadine, US expertslistthisproductamongthe5firstones[11],before beta-blockers(Table6).Amantadine isanantiparkinsonian, antiviral agent,whichincreasestheavailabilityofpre-andpost-synaptic dopaminergicmarkersinthestriatum.ItisalsoaNMDA(NMethyl DAspartate)receptorantagonists[14,25,91–95].

About aggressiveness or agitation, literature few data are available.TwoaggressivesubjectswithTBIwereimprovedunder amantadine (level3)[96].A retrospectivestudyon a heteroge-neous population (including patients with TBI) reported a spectacular improvement of 2 out of the 3 agitated subjects (level4)[97].Arandomized,double-blindvs.placebo,crossover study analyzed the recovery of 10 patients in a rehabilitation centerintheiracutestage[98]andconcludedtotheabsenceof significantdifference(levels2–3)inspiteofanimprovement.We can note the reported benefit of amantadine on neurological recovery[99]withagoodmethodology(level1).

For apathy, no article was found describing the use of amantadineforthisspecifickeyword.Anarticledescribed,fora caseofsevereTBIafter6months,theuseofamantadineatthedose of 300mg/day withsuccess in a motivational syndrome [100]

amantadinewasassessedtotreatcertainaspectsoffrontallobe disorder(includingimpulsiveness,disinhibitionanda motivation-alsyndrome)[93].Animprovementoffrontallobedisorderwas reportedforallpatients(level4).Othercasestudiesreportedthe useofamantadineinthemultipleetiologiesofapathyincluding traumaticbraininjury [101](level3).In motivational language deficits (impaired linguistic ability, non-fluent aphasia) after stroke,amantadinecouldimpactverbalfluency[102]but there werenopatientswithTBIinthestudy(level4).

Furthermore,amantadineisusedasawakefulness-promoting

agent or for having a positive action on cognition

[25,49,91,92,95,103–106]. However, the level of wakefulness and cognitive disorders has been associated with behavioral disorders(seetheotherarticlesinthisspecialissue).

AmantadineisusedinTBIforfatigue,distraction,rigidityand bradykinesia,toimprovethelevelofvigilance[106,107], orienta-tion, initiation, propositional movements, attention, concentra-tion,processingspeed,frontallobefunctioning[92,93,97]oreven motorlearning[108].

Review articlesare sometimescontradictory. The review by Sawyeretal.,2008concludedthatatthedoseof200–400mg/day, amantadineseemedtosafelyimprovewakefulnessandcognition afterTBI[109].According toMeyeret al.,2010,thereis strong evidencefortheusefulnessofamantadinetoimprovewakefulness after TBI in children or adolescents [110]. Conversely, the

meta-analysis of randomized controlled studies by Frenette etal.in2012,regardingtheefficacyandsafetyofdopaminergic agonists (including amantadine) in traumatic brain injury, reportedamorecautiousconclusion[111].Importantsourcesof biasesinthestudiesconstitutedamajorpreoccupation.Giventhe absenceofconsensusonclinicalresults,theabsenceofevaluation forsafetyofuse,andthehighriskofbiasinthereviewsreportedin thisstudy,otherresearchstudiesareneededbefore recommend-ing dopaminergic agonists after severe TBI. Finally, a recently published4-weekmulticenter,randomizedvs.placebostudy[112]

about184subjectswithsevereTBIinapersistentvegetativestate (PVS)orminimallyconsciousstate(MCS)4to16weeksaftertheir accidentaddedtothedebate.Authorsdescribedafasterrecovery underamantadinewithincreasingdosesupto400mg/dayinthe twogroupsofpatientswithPVSorMCS.Amantadinetriggersan increaseofthefunctionalrecoveryprocess(level1).

Overall,inthestudiesanalyzed,theoptimaldoseofamantadine variedbetween50to400mgperday.Anincreasedsurveillancewas reportedforpatientssufferingfromepilepticseizuresandcardiac disorders.Abrutalendingofthetreatmentwasassociatedwiththe onsetofmalignantneurolepticsyndromeinonecasestudy[113]. Regarding the effect of amantadine on sleep, a study on 43patientswithTBI(12weretreatedwithamantadine,31made upthecontrolgroup)didnotevidencechangestotheamountof sleepwiththisdrug[114](level4).

Table6

Amantadineuse,295peopleafterTBIincluded.

Article Descriptionofstudy Levelofproof Conclusions Chandleretal.,

1988[96]

Twocasesofrecoveringbraininjurypatientswith difficult-to-treatdestructivebehavior,whoseagitationand aggressionrespondedtoamantadine

Level3 GradeC

Direct-actingdopamineagonistssuchasamantadinemay bethepreferredtreatmentforpatientswithbehavior problemsintheacutestagesofrecoveryfromcoma Hammondetal.,

2014[115]

Double-blindrandomizedprospectivestudyamantadine 200mg/day(n=36)versusplacebo(n=36)morethan 6monthsafterTBIwithirritabilityandaggressionfor 28days.UsingtheInventoryNeuropsychiatricirritability (NPI-I)

Level1 GradeA

Agitationandaggressionaresignificantlydecreased (P=0.0016)infrequencyandseverityintheamantadine group

Nodifferenceintheoccurrenceofsideeffectsbetweenthe twogroups

Hammondetal., 2015[116]

Double-blind,randomized,multicentreprospectivestudy amantadine(n=75)200mg/dayversusplacebo(n=82) morethansixmonthsafterTBIwithirritabilityandfor 60days.J28andJ60Evaluation.UsingtheNeuropsychiatric Inventory(NPI-I)andClinicalGlobalImpression(CGI)

Level3 GradeC

Despiteasignificantimprovementintheamantadine group,thereisnosignificantdifferencebetweenthetwo groupsatD28andD60.Nodifferenceintheoccurrenceof sideeffectsbetweenthetwogroups

Placeboeffectmayhavemaskedthedetectionofadrug effect(throughobservation)

Krausetal., 1997[93]

Sevencaseseries(6withTBI,1withmeningitis)with ‘‘frontallobesyndrome’’includingimpulsivity,

disinhibition,poormotivation.Usingamantadine,400mg/ day.Patientsreceivedneuropsychiatricexaminationsand serialneuropsychologicaltesting

Level4 GradeC

Allpatientsshowedsomedegreeofpositiveresponse.One hadsideeffectsthatresolvedupondiscontinuationofdrug

Meythaleretal., 2002[99]

Aprospective,randomized,double-blind,amantadine (200mg/day)versusplacebo-controlled(6weeks), crossoverdesign.35subjects,whohadaTBIwithaGlasgow ComaScalescoreof10orlesswithinthefirst24hoursafter admission

Level2 GradeB

Improvementinvarioustests,(P<.05),inthegroupthat receivedamantadineduringthefirst6weeks,buttherewas noimprovementinthesecond6weeksonplacebo(P>.05). Therewasaconsistenttrendtowardamorerapid functionalimprovementregardlessofwhenapatientwas startedonamantadineinthefirst3monthsafterinjury Nickelsetal.,

1994[97]

Retrospectivereviewof12subjects(10withTBI)withbrain injurywhoweretreatedwithamantadine

Level4 GradeC

Tenofthe12subjectsexhibitedsomeimprovementin cognitiveand/orphysicalfunctionwhileonamantadine. Twoofthethreesubjectswithsevereagitationshowed dramaticresolutionoftheagitation.Eightofnine low-arousalsubjectsdisplayedanincreasedlevelof responsiveness.Amantadinemayplayarolein neurobehavioralrecoveryofbraininjury Schneideretal.,

1999[98]

Aprospective,randomized,double-blind,amantadine versusplacebo-controlled(2weeks),crossoverdesign. Subjectswere10adulttraumaticbraininjurypatientsinan acutebraininjuryrehabilitationunit.Variouscognitive tests

Levels2–3 GradeB

Nosignificantdifferenceforamantadineversusplacebo althoughpatientsgenerallyimproved

Limits:smallsamplesize,heterogeneouspopulation,acute timecourse,andlargenumberofdependentvariables VanReekumetal.,

1995[100]

Casestudy.Severeamotivation,apathy,andabulia, significantlyretardrehabilitationfollowingsevereTBI.A double-blind,amantadine(300mg/day)placebo-controlled study.Fourtreatmentperiodsof2weeksduration

Level4 GradeC

Thisonecasestudysuggestspossiblebenefitwith amantadineforpatientswithamotivationalsyndromeafter traumaticbraininjury.Therewerenosideeffects

Recommendations

Thereisnosufficientevidenceoftheefficacyofamantadinein thetreatmentofagitation,aggressiveness,andanxietyafter TBI.

Observation:Animprovementofapathy,the decision-mak-ingprocessormotivational disorderswasreportedincase studies with amantadine at the dose of 300mg per day. AmantadinehasnoMAto treatapathy,theprescriptionof thisdrugshouldbeevaluatedforeachindividualcase accord-ingtothecriteriaassociatedwithtreatmentsprescribed out-sideaMAontopoftheprecautionsofuse(EC).

Therealmofpublicationsaboutamantadineprogressesfaster than the other drugs reported in this review. Two articles publishedin 2014 and 2015, outside of the framework of this work,whichendedin2012,alreadycontradictthe recommenda-tionsabove(Table7).TheworkofHammondetal.[115]tendsto demonstratewithahighlevelofevidence(gradeA)theefficacyof amantadine on irritability and aggressiveness at the dose of 200mg per day. Thus, the frequency and severity of these symptomsaredecreased.Itisamonocenterstudy.Theextension ofthis study on a multicenter level [116]didnot validatethis result.Astrongplaceboeffect(observationbias)wasunderlinedin bothstudies.Nodifferentadverseeffectwasreportedinthetwo studiescomparedtotheplacebogroup.Amantadinewasdescribed aswelltolerated.

3.7. Otherproducts,23patientsincluded. 3.7.1. Buspirone(Buspar1

)

This non-benzodiazepine treatment does not seem to have sedativeoraddictiveeffects,interactionwithanti-seizuredrugs,or leadtorespiratorydepression[8,13,117](Table7).Thelatencyof actionbeforeitsanxiolyticeffectis2to3weeksand12to36hours toimproveagitation[8].Theanxiolyticeffectcouldimprovethe agitation of certain patients who have an anxious component

[25,117].

Tworetrospectivestudiesonseriesof13and8patientstreated bybuspironeafterTBIforagitationoraggressivenessreporting the efficacy and good tolerance of the product (level 4)

[118,119]. These data are validated by two case studies (level3)afterTBI[120,121].

Review articles on the care management of agitation or aggressivenessreportedbuspironeasapossiblealternativeafter TBI.NonewarticlewasidentifiedonthespecificTBIpopulation since1998.

Recommendation

InsomepatientswithTBI,buspironedidimproveagitation, aggressivenessandirritability.Accordingtotherelativelylow levelofevidence,thistreatmentshouldnotbeproposedasfirst linetreatment.Controlledstudiesarenecessary(EC).

3.7.2. Hydroxyzine(Atarax1 )

Hydroxyzinecanbeusedforitsanxiolyticeffect.Thistreatment haslessrespiratorydepressionrisksthanotherbenzodiazepines. Wecannotethatitsadministrationiscounterindicatedinpatients withcognitivedisordersorconfusionsyndromeduetotheriskof aggravationrelatedtothepharmacodynamicsoftheproduct. 3.7.3. Useofhormonalagents

Onlyonereviewbroughtuphormonalagentsinthetreatment ofagitationpost-TBI,whentheclinicalsymptomsareexpressedas sexualdisinhibition[8].

Acasestudyreportedthegoodefficacyofmedroxyprogesterone

[122] in aman withhypersexual behavior(level3).A studyon 40 menincluding5patientswithTBItreatedwith medroxypro-gesteroneaftersexualaggression,comparedtherateofaggression recurrences toa control group of 21 untreated men. Thestudy showedarecurrencerateof18%underprogesteronevs.58%without treatment(level3).However,thestudywasnottargetedforTBI patients.Anotherarticlereportedagoodefficacyofestrogensonone caseinepisodesofaggressioningeneral(notjustsexualaggression)

[123](level3). 4. Discussion

Generally,thelevelofevidence(intheHASsense)topromote theuseofmedicationstoimprovebehavioraldisordersafterTBIis quite low. The efficacy of beta-blockers and mood stabilizers antiepileptic agents appears more adequate for irritability and aggressiveness.Theseproductscouldbeadministeredasfirstline treatmentintheabsenceofcontraindications,associatedwitha non-pharmacological care management. Neuroleptics and anti-depressants remain useful but as a second-line treatment. Neurolepticskeeptheirplaceasfirstlinetreatmentinemergency cases but will be relayed by a mood stabilizer or beta-blocker outside of a documented psychiatric context. Antidepressants, especiallySSRIsareusefulindepressionafterTBI.Amantadinecan beusedafterindividualcaseassessmentinapathyorirritability and aggressiveness. Buspirone and hydroxyzine are alternative medications. The choice of the molecule must be discussed

Table7

Otherproductsuse,23patientsafterTBI.

Article Descriptionofstudy Levelofproof Conclusions Gualtieri,1991[118] Retrospectivestudyofaseriesof13patientsafterTBI

stirredtreatedwithbuspirone10–45mg/day

Level4 GradeC

RespondersaremildTBIwithoutmotorandseverecognitive impairment.3respondershadpost-traumaticagitationwith akathisiaand4wererestless,irritableoraggressivewith temporallesions

Holzer,1998[120] Singlecasestudy.45-year-oldman,bilateralfrontal contusions.Attackbehavior,failureofother treatments.Test60mgofbuspironefor4months

Level4 GradeC

Everythingisimproving,hegainsindependenceandcanstarta conversation

Rateyetal.,1992[121] Twocasestudy,oneafterTBI.Aggressiveexplosive behavior.Addingbuspironeitstreatment(nadolol, lithium,CBZ)

Level4 GradeC

Markedimprovementafter5mg2buspirone

Stanislavetal., 1994[35]

Retrospectivestudy,buspirone(30–60mg/day)for 36monthsin20subjectsaged15to55years. 10validatesonly3monthsoftreatment8/10hadaTBI

Level4 GradeC

9ofthe10subjectshadanimprovementatendpoint.Buspirone iswelltoleratedandcanbeeffectiveinthetreatmentof aggressionandothermaladaptivebehaviorsafterTBI TBI:traumaticbraininjury.