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9/12/16
1
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¤tmedications
– 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
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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