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UnderstandingMedicationsUsedintheTreatmentofTraumaticBrainInjury

FloraHammond,MDChairman&Covalt Professor, Dept PhysicalMedicine&Rehabilitation

IndianaUniversity SchoolofMedicineChiefofMedicalAffairs, RehabilitationHospitalofIndiana

Project Director, CarolinasTBIModelSystem

Outline• Basicprinciples• Neurotransmitter systems• Evidencefortreatingcommonbehaviorswithmedications

• Specificmedicationconsiderations(inhandout)

• Summary&caseexamples

MedicationasaTreatment

• Correctdiagnosis• Lookforandtreatpossiblecauses• Medicationsastheproblem• PharmVs.Non-pharmapproaches

– Medicationsare notalwaystheright answer– Combiningpharmwithnon-pharmtreatments

• Individual, family, cognitive,behavioral, environmental

AssessmentforTreatment

• Timeline,type,frequency,severity,impact,precipitators,relievingfactors

• Othersymptoms,dailyfunctionandactivities• Useobjectiveratingscales,feedback• Noticeeffectofmisseddoses• Completelistofpast&currentmedications

– dosages,reasons prescribed, responses onandoffagent(s)

CommonProblemsWithPastTreatments• Misdiagnosis• Notproperlyapplied• Durationtooshort• Dosetoolow• Dosetoohigh• Notactuallytaken• Sometreatmentsnottried• Notcombinedwithothertreatments

• Contributeto/causeproblem

Look forandTreatOtherCauses• Phaseofrecovery• Sleep disturbance• Pain• Occultfracture• Substance withdrawal• Dehydration• Hypoxemia /Pulmonary

embolism• Infection/sepsis• Seizure /temporal lobe

seizure– Need tospecify“temporalor

nasopharyngeal leads”whenEEGordered

• Autonomicinstability

• Neuroendocrine ormetabolicdysfunction– Electrolyte imbalance, thyroid,

adrenal insufficiency,testosterone

– Hypoglycemia,hepatic• Depression• Anxiety• Stress /environment• Substance use• Musculoskeletal injury• Medicationsideeffectsor

toxicity ordrug interaction

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MedicationsastheProblem• Aggression

– Bromorcriptine, tranquilizers,hypnotics, levodopa,phenelzine, digitalis

• Depression– Antidepressants,

anticonvulsants, propranolol,narcotics, levodopa,metoclopramide, oralcontraceptives,benzos

• Hallucinations– Anticonvulsants, propranolol,

bromocriptine, amantadine

• Paranoia– Bromocriptine, amphetamines,

propranolol, corticosteroids,NSAIDS

• Cognitivedecline– Anticonvulsants, propranolol

• Sedation– Baclofen,clonidine, AntiAch

phenytoin, narcotics,benzodiazepam, phenergan,metaclopramide, antipsychotics

• Slowedmotorrecovery– NAblockade

FunctionSusceptibletoAlpha-1NABlockade

• Prazosin, haloperidol, risperdone, clonidine, tizanadine, phenoxybenzamine, & other drugs reducing NA levels, reinstates deficits.

Enhanced recovery from hemiplegia by drugs increasing NA synaptic activity: amphetamine.

Compliments of Dennis Feeney, PhD

EliminateMedications• Eliminatemedsthat are unnecessary,

potential forcausation,orhinderarousal,cognitive function,recovery– Anticholinergics– Benzodiazepams– Narcotics– GIproph&reflux(metaclopromide, H2

blocker),phenergan– Catecholamineantagonists (haloperidol,

risperdol, lorazepam, seroquel)– Antiepileptic Drugs– Antihypertensives (clonidine)

• Ifnotneeded: discontinue• Ifneeded: substitute

PharmacologicSelection• Addagents targeted toimprovefunctionwithminimal-norisk• Choices….

– Limitedevidencebaseà Largelyphysicianpreference&experience• Considercontext ofoccurrence ofthe behavior

– Depression, anxiety,psychosis• Considerlikelyinjurylocation,symptoms,evidenceforeffect in

BIandotherdiagnoses• ConsiderRisk:Benefit

– Consider drug-drug interactions, sideeffects&contraindications

• Chooseagents that accomplish>1need– (e.g.:tachycardia,headache,seizure mgmt,pain, insomnia, arousal,

cognition, processing speed, depression, anxiety)

RoleofMechanism• Considerusingdifferentmechanisms– Neurotransmitter– Locationofaction

• Augmentpartialresponsesthrusimilarmechanisms

• Likelyneedmorethan1medicationforoptimalresponse&multiplesymptoms

Go1,GoLow,GoSlow

• Startlow• Giveenoughtime• Graduallyincrease• Trytomakeonechangeatatime

• Don’tgiveuptooearly• Followprogress

irritability

Dose

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DurationofTreatment• Remission/carry-overeffectVs.ongoingneed• Relapserisk?• Dependsontreatmentpurpose?

– Seizure /Anticonvulsants• Dependson reason foruse

– Prophylaxis:Noroleafter1weekpost- injury– Treatment:2yearsseizurefree; negative EEG?, riskof sz?

– Depression/ Antidepressants• AmericanPsychiatricAssn formajordepression: Minimum16-20weeksaftercomplete remission of symptoms

– Other purposes• Haveyounoticedworsening if skipped dose(s)• Trialoff

DeterminantsofOutcome&Treatment

• Environment• Injurylocation(s)• Genetics• Neurotransmitterchanges

TreatmentOpportunity!

Neurotransmitters(nt)• Carrymessagestocontrolarousal,cognition&behavior– Somehinderfunction– Someenhance function(arousal,memory, initiation,selfcontrol)

• BIà Changesinntavailability&function

• Modulation(viamedications)mayhelp

• Medicationsofteninfluencemorethanonent

Neurotransmitters• Catecholamine

– Dopamine– Norepinephrine

• Serotonin• Acetylcholine• GABA

Dopamine(DA)• Predominantlocation&action

– Subcortex, including basalganglia,frontal lobe&hypothalmus

• Actions– Screeningout information, arousal,

apathy,initiation, attention,memory,hypothalamic function/autonomicstability, pleasure,extrapyramidal /motormovements

• TBIchanges– Acutelyelevated– Chronically decreased?

• MedicationExamples– Amantadine, bromocriptine,

sinemet, methylphenidate,modafanil

• Dopaminergic(DA)– bromocriptine– carbidopa/levodopa

• Mixeddopaminergic(DA)&noradrenergic(NA)– methylphenidate

– dextroamphetamine– other amphetamine salts

CatecholaminergicAugmentation

• Indirectdopaminergiceffectsvia:– uncompetitiveNMDAreceptor

antagonism

• amantadine

• memantine

– ?modafinil

– ?lamotrigine

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Norepinephrine(NE)• Predominantlocation&

action– Brainstem (locusCeruleus),

frontal lobe

• Actions– Arousal, attention, memory,

initiation, executivefunction,behavior, motor function

• TBIchanges– Acutelyelevated– Chronically decreased?

• MedicationExamples– Dexedrine,Tricyclic

antidepressants

Serotonin(SE) • Predominantlocation&action– Brainstem (caudallinear nucleus,

nucleus raphe, reticular formation),frontal lobe, hippocampus, substantianigra

• Actions– Arousal, depression, anxiety,emotional

lability, obsessive-compulsive disorder,appetite suppression, aggression,motorcontrol,memory

• TBIchanges– Acutely: siteofinjury maydictate– Unsurechronically

• MedicationExamples– Prozac,zoloft,paxil,luvox,trazodone,

effexor,BuSpar

Acetylcholine(Ach) • Predominantlocation&action– Medialtemporallobe,thalamus,

amygdala,hippocampus,basalganglia,olfactorybulb,cerebralcortex,brainstem

• Actions– Declarativememory,learning,executive

function,attention,mood,motivation,aggression,award,corticalarousal,motorcoordination,socialintelligence,inductionofREMsleep,sensorygating,EEGfastwaveactivity

• TBIchanges– Acutelyelevated– Chronicallydecreased

• MedicationExamples– ­Ach:Physostigmine– InhibitAchEsterase:Aricept,Exelon,

Cognex/Tacrine

CholinergicDeficiencyandDelirium

• Anticholinergicactivitymaycausedelirium• Anticholinergicactivityincommondrugs

– Significantanticholinergic: amitriptyline,desipramine,diphenhydramine,nortriptyline, oxybutinin

– Moderate anticholinergic: amantadine, CBZ– Mildanticholinergic:alprazolam,atenolol,buproprion,captopril,codeine,diazepam,digoxin,fentanyl,furosemide,haloperidol,loperamide,metoprolol,morphine,prednisone,ranitidine,trazodone, warfarin

Trzepacz PT. Sem Clin Neuropsychiatry 2000;5:132-148

AnticholinergicEffectsinCommonlyUsedMedications

AnticholinergicBurdenScale• Scoreof>3isconsideredclinicallysignificant– Severe (3points):amitriptyline,

desipramine,diphenhydramine,nortriptyline,oxybutinin

– Mod(2points):amantadine,CBZ– Mild(1points):alprazolam,

atenolol,buproprion,captopril,codeine,diazepam,digoxin,fentanyl,furosemide,haloperidol,loperamide,metoprolol,morphine,prednisone,ranitidine,trazodone,warfarin

GABA• MainCNSinhibitory neurotransmitter

– including:hypothalamus,hippocampus,cerebralcortex&cerebellar cortex

• Sedation,confusion,long-termcognitivedeficits,n/v,drynessofmouth,abnormaleyemovements,fatigue,immunosuppression

• Examples:Benzodiazepines,non-benzodiazepinehypnotics(e.g.:zolpidem),baclofen,barbiturates,progabide(gabrine),tiagabine(gabatril),ethanol

• Glutamate–GABAbalance– Glutamate increases aggression GABAdecreases aggression– Thoughttolaya roleinAlzheimer’s behavior

Trzepacz PT. Sem Clin Neuropsychiatry2000;5:132-148

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BiologyofCognition• Catecholamines (DA,NE)mayimprovearousal,speedofprocessing,sustainedattention/vigilance,possiblyexecutiveaspectsofattention

• Signal-to-noiseratio• ToomuchDAand/orNE:

• Increased cognitive “noise”(i.e.,irrelevant task/distractions)

• Deficient DA and/orNE:• “signal”missestarget

Non-TBIAggression

BiologyofAggression:Initiation&Modulation

Siever LJ: Neurobiology of Aggression Am J Psychiatry 2008;165:429-442.

Brain Circuitry & Neuromodulators of Non-TBI Aggression

Siever LJ: Neurobiology of Aggression Am J Psychiatry 2008;165:429-442.

Brain Circuitry

Cortical:

Corticallesion(trauma,tumor)Decreasedcorticalvolume

Orbitofrontal/cingulate cortexprocessinginefficiencyLimbic:

Hyperactivity ofamygdala/limbicsystemEmotional hypersensitivity

Kindling

Reduced serotoninIncreased DA & NE

Reduced GABA /Increased glutamateIncreased Ach

Non-TBI Aggression

ImplicationsforPharmacotherapyofAggressionSiever LJ:Neurobiology of Aggress ion. Am JPsychiatry 2008;165:429-442.

-Side effect profiles should be considered, especially relevant to brain injury

WHATISTHEEVIDENCEFORMEDICATION TREATMENTS?

EvidenceforMedicationTreatment• Littleresearchtosupportorrefute

– Case studies– Open-label caseseries– Few randomized,controlledtrials(RCTs), &thus,mostevidence at level ofoptions

• Trialanderror– Clinicianexperience– Literature inotherdiagnosticpopulations

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SummaryofLiterature:CognitionWarden2005

Problem Standards Guidelines OptionsGeneralcognition

- Avoid phenytoin Methylphenidate(DA)Amantadine(DA)

Attention&ProcessingSpeed

- Methylphenidate(DA)Donepezil(Ach)

Dextroamphetamine (DA/NE)Amantadine(DA)Physotigmine (Ach)

Memory - Donepezil(Ach) Methylphenidate(DA)CDPCholine1gram(cytidine diphosphatecholine)

ExecutiveFunction

- Bromocriptine(DA)

-

Problem Standards Guidelines Options

Depression - - TCA (Amitriptyline, Desipramine) (NE&SE)Sertraline (SE)Watchout for sideeffects(attn, conc,mem,arousal, seizure)

Anxiety - - -

Psychosis - - Atypicalantipsychotics (watchforweight gain&sedation)

Apathy - SSRI(SE)ifpartofdepression; couldmakeworse ifnotpartofdepressionStimulants &DAenhancers

Irritability - Beta-Blockers

Methylphenidate (DA),SSRI(SE),valproate,lithium, TCA (amitriptyline &desipramine) (NE&SE),buspirone (SE),amantadine (DA),carbamazepine

SummaryofLiterature:Mood&BehaviorWarden2005

Drug Depress Labil/Irritabil

Mania Psychosis Agitation/Aggression

Anxiety Apathy Cognition AERisk

Nortrityline ++ + - - +Desipramine ++ + - - +Amitriptyline + - +++ --- +++Protriptyline + + - ++ - +Fluoxetine +++ +++ - ++ ++Sertraline +++ +++ - ++ +ParoxetineLithium + ++ - +++Carbamazepine ++ +++ -- ++Valproate ++ +++ +++ +Benzodiazepine + --- +++Buspirone + ++ + + +Typicalantipsychotic

++ + -- +++

Atypicalantipsychotic

+++ + - +

Methylphenidat

++ ++ ++ ++ ++

Dextroaphetam ++ +++Amantadine + ++ ++ +Bromocriptine - - ++ + +L-Dopa/carb - - + + +Betablocker -- +++ - - -Donepezil ++ +

PhysicianPreferences:Francisco2007Problem “Expert”PMR Not“expert”PMR

Agitation Valproic acid (13)Propranolol (8)Nadolol (6)Trazodone (6)

Carbamazepine (5)

Lorazepam(9)Carbamazepine (8)Risperdone (8)

Anger Valproic acid (6)SSRI(5)

Valproic acid (11)Carbamazepine (7)

Irritability Valproic acid (8)Sertraline (7)

Carbamazepine (5)

Valproic acid (7)Sertraline (4)

Carbamazepine (6)

Emotional lability Valproic acid (6)Buspirone (6)Paroxetine (4)

Valproic acid (4)Paroxetine (3)Buspirone (2)

Anxiety Buspirone (14)Paroxetine (7)

Buspirone (13)Paroxetine (5)

Depression Paroxetine (11)Sertraline (10)Venlafaxine (10)

Paroxetine (11)Methylphenidate (5)

PhysicianPreferences:Francisco2007Problem “Expert”PMR Not“expert”PMR

Insomnia Trazodone(21)Zolpidem (15)Nortriptyline (9)

Trazodone(16)Zolpidem (9)

Nortriptyline (2)Benzodiazepams(7)

Hypoarousal Methylphenidate(19)Amantadine(10)Modafanil (6)

Methylphenidate(17)Amantadine(5)

Abulia Amantadine(14)Methylphenidate(13)Bromocriptine (7)

Methylphenidate(14)Amantadine(13)

Inattention Methylphenidate(17)Amantadine(10)Modafanil (9)

Methylphenidate(18)Amantadine(10)

Slowmentalprocessing Methylphenidate(17)Amantadine(9)Modafanil (2)

Methylphenidate(14)Modafanil (4)

MemoryDeficit Nothing(8)Donepezil(9)

Galantamine (9)Rivastigmine (6)

Nothing(9)Galantamine (8)Amantadine(4)

Irritability&Aggression• Standards:Insufficient• Guidelines:

– Beta Blockers:• Propranolol (420-520mg/daymax)

• Pindolol (40–100mg/day)

• Options:Methylphenidate,SSRI,valproate,lithium,TCA(amitriptyline&desipramine),buspirone,CES,homeopathy

• 7publishedRCTs– Amantadine (3),Methylphenidate (2),Beta blockers(4)

• Beers:n=27,peds, post-acute,150-200mgdaily,12wks, improvedbehavior

• Hammondn=76• Hammondn=168

• RCTsinprogress– Hammond:CBZ&Buspirone

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Summary• Misdiagnosis iscommon• Look for& treatothercauses• Multi-faceted approach isneeded• Historyofmeds triedandreactionsareimportant• Trial&error• 1atatime,startlow,graduallyincrease,reachmax-typicaldose beforegivingup, augmentresponse, tryothermechanisms, combine strategiesforbestresults,monitor fordrug-drug interactionsandside effects

• Often needmorethan1 approach

SummaryofBICognitive&BehavioralPharmacotherapies

• Criticalvariablesfortreatmentselection– injuryseverity– timepost-injuryandphaseofposttraumaticencephalopathy

– cognitive &behavioraltarget(s)

– impactonlifefunctions

• Cognition– catecholaminergicaugmentation /balance

– cholinergicaugmentation– mixedcatecholamine andcholinergicaugmentation

• Behavior– catecholaminergicaugmentation /balance

– cholinergicaugmentation– Anticonvulsants– Mixed

SPECIFICMEDICATIONS

Amantadine(Dopaminergic)• Trade name: Symmetrel• Mechanismofaction:Dopamine agonist&NMDAreceptor

antagonist• Literature:

– Irritability:FirstRCT forTBIirritability &aggression completed findingsubstantial improvement foramantadinegroup (Hammond,etal)

• Other uses:– VegetativeState/Minimally Conscious State,arousal, disinhibition,

hypersexual, lability, impulsivity, poor initiation, cognitive impairment,irritability, general cognitivefunction

• Sideeffects:– Hypotension, confusion, hallucinations, seizure, coma,death– Dose-related!– Creatinine clearanceis critical!

• 30-50:100mg/day• 15-29:100mgevery48hours• <15:200mgevery7days

Bromocriptine (Dopaminergic)• Tradename:Parlodel• Mechanismofaction:StimulatesDopaminereceptors• Literature:

– Executive function&initiation(RCT)• Otheruses:Coma/VS/MCSemergence• Dose:

– 2.5– 7.5mg/day(increasinggraduallyupto12.5– 15mgbidforcoma)

• Sideeffects:– Dizziness,drowsiness,faintness,syncope,nausea,vomiting,constipation,diarrhea, hallucinations

Methylphenidate(Dopaminergic)• Tradename:Ritalin• Mechanismofaction:

– Inhibitsthepostsynapticreuptakeofdopamine– Thoughttoactivatethebrainstemreticularactivatingsystemandcortex– Cognitive&behavioraleffectsarenotfullyunderstood

• MPmayimprovepost-TBIbehaviorthrougheffectsonattention,arousal,andinitiation.• Literature:

– Arousal,andprocessing speed, andaggression• Reduces aggress ion inADHD &TBIpopulations (2RCT’s ) withdoses 10mg-60mg/day

• Otheruses:– Initiation,attention,distractibility,vigilance,memory,ADHD,motorimpairment,

apathy,fatigue,agitation,depression• Contraindications:

– MAOI(monomamineoxidaseinhibitors)– Don’tusewithLinezolid(Zyvox)oruntil2weeksoff– Mayincreasedruglevelsofothermeds– Canworsenpsychosis

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Modafinil (DA,NA,Histamine)• Trade name: Provigil(narcolepsyagent)• Mechanismofaction:

– Increasesthereleaseofmonoamines– Alsoelevateshypothalamichistamine levelsleadingsomeresearchersto

considerModafinila"wakefulnesspromotingagent"ratherthanaclassicamphetamine-likestimulant

• Literature: Fatigue• Use especially if:Poorarousal,fatigue,depression,cocaine

addiction• Sideeffects:

– H/A,nausea,insomnia,anorexia,nervousness,increasedanxiety,drymouth,hypertension,tachycardia,chestpain,PVC’s,dizziness,parasthesias,pharyngitis,severeskinreactions(includingerythemamultiforme,Stevens-Johnsonsyndrome,toxicepidermalnecrolysis,anddrugrashwitheosinophiliaandsystemicsymptoms

• Contraindications:Cardiovascular condition

AcetylcholineEsteraseInhibitors(Cholinergic)• Examples:Donepezil (Aricept), Exelon (Rivastigmine)• Mechanismofaction:

– Reversible inhibitor oftheenzymeacetylcholinesterase• Literature:Attention andmemory,speed ofprocessing (post-hocanalysis)• Uses:Deficits inexecutivefunction• Dosingconsiderations:

– Doseatnight time– Steadystate isnotachievedfor15days– Sideeffectsrelated to rateofdose escalation&generally temporary

• Startat5mgandthenwait4-6weekstoincreaseto10mg• Sideeffects:

– Mostcommon:Nausea,diarrhea,insomnia,vomiting,musclecramp,fatigue,anorexia– Inf luenza,chestpain,urinaryincontinenceorretentionorfrequency,irritability,aggression,

restlessness,nervousness,lability,vertigo,ataxia, nystagmus,increasedordecreasedlibido,depression,seizure,paranoia,delusions,tremor,dysarthria,dysphasia,neuralgia,paresthesia,coldness,hyponatremia,neurodermatitis,bradycardia,heartblock,syncope,cholinergiccrisis

• Contraindications:– Knownhypersensitivitytodonepezilhydrochlorideortopiperidinederivatives,asthma,COPD

Zhang 2004, Silver 2006

SummaryofCholinesteraseInhibitorStudies• Physostigmine

– evidence:single case(1)w/double-blind (1),open-label caseseries (1),single-site double-blind placebo-controlled (2)

• Donepezil– single-case report (1),open-label caseseries (8),single-site double-

blind placebo-controlled trial (3),two-site double-blind placebo-controlled trial (1)

• Rivastigmine– multicenterRCT (1)with open-label extension (1),single-site double-

blind placebo-controlled (1)

• Galantamine– Open-label caseseries (1)

(Bogdanovitch et al. 1975; Eames and Sutton 1995; Goldberg et al. 1982; Levin et al. 1986; Cardenas et al. 1994; Taverni et al. 1998;

Whelan et al. 2000; Masanic et al. 2001; Bourgeois et al. 2002; Morey et al. 2003; Kaye et al. 2003; Walker et al. 2004; Zhang et al. 2004; Khateb et al. 2005; Tenovuo 2005; Trovato et al. 2006; Foster and

Spiegel 2008; Kim et al. 2009; Tenovuo et al. 2009)

Tricyclic Antidepressants (NE&SE)• Examples:

– Elavil(amitriptyline) [insomnia,neuropathicpain,lability, depression]– Nortriptyline (Sensoval,Aventyl,Pamelor,Norpress,AllegronandNortrilen)

[chronicfatiguesyndrome,chronicpain,migraines, labileaffect]– Desipramine(Norpramin,Pertofane)[ADHD,arousal]

• Mechanismofaction:(poorlyunderstood)– Inhibitsthere-uptakeofnorepinephrineandserotonin– Alsopossessaffinityformuscarinic &histamineH1receptorstovaryingdegrees

• Literature:– Acuteagitation:Amitriptyline 150mg– Depression: Amitriptyline, desipramine

• Otheruses:Poorsleepmaintenanceandneurogenicpain• Sideeffects:(differingprofiles)

– Sedation,seizure,lethalifoverdose,dysrhythmias,myocardialinfarction,hepaticdysfunction,hypertension,worseneddepression,suicidalthoughts,leukopenia,aplasticanemia,weightgain,decreaseeffectsofclonidine

• LevelsmaybeincreasedbySelectiveSerotoninReuptakeInhibitors• Contraindications:Acutemyocardialinfarction

SerotoninReuptakeInhibitors(Serotonergic)• Examples:Sertraline(Zoloft),citilopram(Celexa),paroxetine(Paxil),

fluoxetine(Prozac)[Antidepressantagent]• Literature:

– Depression:Sertraline(Caseseries,1RCT);fluoxetine– Irritability:Sertraline(Caseseries)– Affectivelability:Fluoxetine,sertraline,paroxetine(casestudies)

• Uses:Depressionandanxiety– 1st linefordepressionduetoTCASE’s

• Maycauseincreaseincarbamazepinelevels• Sideeffects:

– H/A,nausea,vomiting,diarrhea,constipations,insomnia,sedation,abnormaldreams,anxiety,tremor,dizziness,fatigue,impairedconcentration,agitation,anorexia,weightgain,rash,sexualdysfunction

• Contraindications:MonoamineOxidaseInhibitors(MAOI)

Trazodone (Serotonergic)• Tradenames:Desyrel, Beneficat, Deprax, Desirel, Molipaxin,

Thombran,Trazorel, Trialodine,Trittico [antidepressant]• Mechanismof action:

– Serotoninreuptakeinhibitor(lessanticholinergiceffectthantheTCAs)• Literature:

– Reportedhelpfulforaggressionduetoorganicmentaldisorders– Notstudiedinregardstobraininjuryirritability&aggression

• Useespeciallyif:– Poorsleepinitiation

• Sideeffects:– Priapism,dysrhythmias,hypotension,hypertension,seizure,worseneddepression,suicidalthoughts,potentialforserotoninsyndrome,leukocytosis,hemolyticanemia

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Buspirone (Dopamine&Serotonin)• Tradename:BuSpar[anxiolyticagent]• Mechanismofaction:

– AffinityforbrainD(2)-dopaminereceptors(bothanantagonistandagonist)andforthe5-HT(1A) receptors(agonist)

– Buspironedoesnotblocktheneuronalreuptakeofmonoaminesand,onchronicadministration,itdoesnotleadtochangesinreceptordensityinthemodelsinvestigated

• Literature: Aggression:Opencaseseries• Otheruses:anxiety,depression,somaticpreoccupation,

inattention,distractibility• Dosing:15mgthreetimesdaily• Expect lagof2-3weeks;allow4weekstoknowifdoseiseffective• Sideeffects:headache,dizziness,nausea,insomnia• Contraindications:

– Mayincreaseantipsychotic(haloperidol)levels– MonoamineOxidaseInhibitors(MAOI)

Beta-Blockers• Literature:

– Agitation &aggression• Propranolol(Inderal) (2) [1agitation,1aggression]• Pindolol[behaviorissuesingeneral;mixedpopulation]• Nadolol(Corgard) [aggression,non-traumaticBI]

• Otheruses:Hyperadrenergicstate,migraineheadache• Uselipophilic B-blockersforagitation

– Lipophilic:Propranolol,oxprenolol,metoprolol• CNSeffectappearsbenef icialforagitation

– Hydrophilic:Atenolol,nadolol• Lowerincidenceof CNS-relatedsideeffectsingeneralpopulation• Considerif patientissedatedonlipophilicagent

• Sideeffects:– Sedation,dizzy,light-headed,clinicaldepression,lowerHDL,increaseLDL,

decreasedBP&pulse(switchtopinodol)– Druginteractions:Increasedplasmalevelsofantipsychotics&AED

• Contraindications:Asthma,poorcirculation,diabetes,thioridazine

Anticonvulsants• Evidence:Aggression:Casereports,Caseseries• Uses:Seizure,aggression,dysinhibition,impulsivity,neuropathicpain

• Carbamazapine(Tegretol):3casestudies/series;RCTinprogress– Sideeffects:drowsiness,cognitiveimpairment,SJS,aplasticanemia,hyponatremia,hepaticdysfunction

• Valproicacid(Depakote):Casereports– Sideeffects:Weightgain,hemorrhagicpancreatitis,leukopenia,thrombocytopenia,neuraltubedefectrisk,hepaticdysfxn

• Neweranticonvulsants:limitedliterature– Oxycarbamazapine(hypoNa),lamotrigine/Lamictal,gabapentin

• Avoidphenytoin&phenobarbitalwhicharemoresedating• Labmonitoring

Lithium• Considerfor:

– Severeaggression,associatedmajordepression,bipolardisorder• Sideeffects:

– Toxicity,H/A,nausea,vomiting,diarrhea,polyuria,weightgain,tremor,dizziness,sedation,rash,leukocytosis,dysrhythmia,hypothyroidism

• Contraindications:– Renalfailure,severerenaldisease,dehydration,significantcardiacdisease,pregnancy,lactation,under12yearsofage,cautionwithdiuretics

• Manydruginteractions:– NSAIDs,ACEI,diuretics,thyroidagents

• Labmonitoringrequired

Benzodiazepines(GABA)• Examples:lorazepam(Ativan),diazepam(Valium)• Mechanismof action:EnhanceGABA receptor function• Uses:

– Agitation:Generallyreserveuseforimminentdanger– Anxiety:Avoid.UseSSRIorBuspironeinstead.

• Lotsofdruginteractions!• SideeffectsparticularlycommoninTBI!

– Sideeffects:drowsiness,dizziness,ataxia,slurredspeech,memoryimpairment,agitation,akathisia,psychomotorimpairment(includingdriving)

• Contraindications:– Severeliverdisease,ChronicObstructivePulmonaryDisease(COPD),sleepapnea

Antipsychotics (DopamineBlocking)• 1st generationvs.2nd generation

– 1st generation:Haloperidol(Haldol)– 2nd generation:risperdone(Risperdol),olanzapine(Zyprexa),quetiapine(Seroquel)

– Atypicalshavelesspropensityforextrapyramidalsymptoms– Bothtendtoblockreceptorstobrain’sdopaminepathways,butencompassawiderangeofreceptortargets

• AVOID.Ifneeded,useshort-acting.Usesparinglyfor:– Imminentdanger;psychoticfeatures(hallucinationsordelusions)

• Generally,don’tsolvetheproblem• Excludeothercausesforpsychosis• Sideeffects

• Tardivedyskinesia, neurolepticsyndrome,seizure,weightgain,sedation,prolongsPTA(Rao1985),decreasedarousal,weakness,diabetes,slowedmotorrecovery,hemiplegiareinstatement,thrombocytopenia

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Cases

Case1

• 28yomale• MildTBI• Frequentirritabilityandoccasionalaggressive behaviors– Mostlyaimedtowardsspouse

• Headaches– migrainecharacteristics

Case1:Considerations forTreatment

• Considertreatmentsthatmayhelpboththeheadaches andthebehavior• Beta-blocker• Anticonvulsant:carbemazepineorvalproate

• Catecholaminergicaugmentation• Cholinergicaugmentation

Trzepacz PT. Sem Clin Neuropsychiatry 2000;5:132-148

Case2

• 44yofemale• SevereTBI• Frequentirritabilityandoccasionalaggressive behaviors– Mostlyaimedtowardsspouseandchildren

• Depressedmood• Poorsleep

Trzepacz PT. Sem Clin Neuropsychiatry 2000;5:132-148

Case2:Considerations forTreatment

• Treatsleepdisturbance• Highlevelcognitiveimpairment• Treatdepression

• Serotonergicaugmentation

• Catecholaminergicaugmentation• Cholinergicaugmentation

Flora.hammond@rhin.com

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11

Questions?

InjuryLocation&Vulnerability• Frontallobe

– Emotions,reasoning,planning,problemsolving,judgment,creativity,partsofspeech,movement

• Temporallobe– Emotion,learning,meaning,memory,language,hearing,interpreting&processingauditorystimuli

• Parietallobe• Senses,languagefunctions

• Occipitallobe• Vision,abilitytorecognizeobjects

• Midbrain• Amygdala

• emotions• Hippocampus

• memory

• Thalamus• receivesand relays information to

cortex,brain, brainstem

A Cholinergic Synapse

PostsynapticTerminal

Adapted from McNeil. Alzheimer’s Disease: Unraveling the Mystery. 1995:1-48.

PresynapticTerminal

Action Potential

ACh receptors

AChE

ACh

Summated Potential

Synaptic vesicle

Pre-InjuryFactors:GeneticVariationsinNeurotransmitterMetabolism• Genetic variationsin

(Roberts e t a l . 1994, Nic ol l et a l. 1995; Sorb i e t al . 1995; Graham et a l . 1996; Jordan et a l . 1997; Friedman et a l. 1999; Ramas s amy et a l . 1999; Kutner et a l. 2000;

L ic htman et a l . 2000; White et a l. 2001; Crawford et a l. 2002; L iaquat e t a l . 2002; L ieberman et a l . 2002; Lynch et a l . 2002; Ly nc h et a l. 2003; Diaz-Arras tia e t a l .

2003; Kerr e t a l . 2003; L ipsy et a l. 2005; Mc All ister et a l. 2004; Zhou et al . 2008)

• Catechol-O-Methyltransferase (COMT)

• Influence DA & NE metabolism

-Met/Met – slow-Met/Val – intermediate-Val/Val – fast

• May influence neurobehavioral functions that are catecholaminergically -dependent

Cholinergic Augmentation:AcetylcholineImprovesCerebralProcessingEfficiency

• Improvesefficiencyofcerebralsignaling:– increases excitatory tone inreticulothalamic systems– improvesinformationgating inthehippocampusandthalamus

– increases the strength ofsignalsco-processed withglutamate inthehippocampussoastofacilitatelong-termpotentiation

– facilitates the effects ofother neurotransmitters:glutamate, GABA, dopamine,norepinephrine,andserotoninoninformationprocessinginfrontal,temporal,parietal, andcerebellar areas

Mesulam 2000a, 200b; Selden et al. 1998; Blokland 1995; Aigner 1995; Sarter and Bruno 1997; Sarter and

Turchi 2002