Psychopharmacology After Brain Injury Mel B. Glenn, M.D. · Medications • Medications for...

Psychopharmacology After Brain Injury

Mel B. Glenn, M.D.Spaulding Rehabilitation HospitalHarvard Medical SchoolBoston, MANeuroRestorative (Massachusetts), Dedham, MACommunity Rehab Care, Watertown, MA

Disclosures

• Advisor, Traumatic Brain Injury Model Systems grant, National Institute on Disability, Independent Living, and Rehabilitation Research, U.S. Dept. of Health and Human Services

Areas Covered

Part 1: Attention, alertness, & initiation

Part 2: Affective and executive disorders

Look For Symptom’s Underlying Causes

• Pre-injury disorders

• Medical disorders

• Sleep disorders

• Sensory or motor disorders

• Medication-adverse effects

• Reactive: depression, anxiety

• ABI-provoked psychiatric disorders: depression, anxiety, psychosis

• Neuropsychological disorders

PRINCIPLES OF DIFFERENTIAL DIAGNOSIS• Symptoms can fool you– e.g., Abulia/apathy can be a symptom of depression or be

neurologically-based

– e.g., “Hallucinations” may be visual-perceptual + executive function problem; or memory problem

– e.g., Reduplicative phenomenon (Capgras syndrome): “imposters”

– e.g., Aggression/agitation-can be provoked by under-arousal, poor initiation, depression, and/or disinhibition

Look For Symptom’s Underlying Cause

PART 1: ATTENTION, ALERTNESS, & INITIATION

Attention, Alertness, & Initiation

• Why attention, alertness, & initiation?– All foundations to cognition and behavior

– Basic to everyday functioning

– Tend to be affected by same medications

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Attention, Alertness, And Initiation:Non-pharmacologic Treatments

• Optimize medical condition• Treat sleep disorders• Cognitive rehabilitation• Exercise• Diet• Meditation• S.A.D. lights (Sinclair et al, 2014)

• Transcranial electrical or magnetic stimulation

Case Report

• A 23 y.o. male with TBI is transferred to the rehabilitation unit 10 days after injury. He is restless and paces up and down the halls, but is not aggressive. He is up much of the night and sleeps on and off during the day. He is on quetiapine 50 mg 2x/day, levetiracetam750 mg 2x/day and amantadine 200 mg 2x/day.

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Insomnia & Disrupted Sleep-wake Cycle

• Change or discontinue long-acting alerting drugs, e.g.– Amantadine to once daily (or reduce dose if once daily)– Sustained-release methylphenidate & amphetamines– Make sure last doses are not being given late

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Insomnia & Disrupted Sleep-wake Cycle: Medications

• Melatonin – Melatonin levels can be low after TBI (Shekleton et al, 2010)

– Low doses (0.5-3 mg) may work best– Very short half-life (20-50 minutes)– Time-release melatonin-RCT of 2 mg ER in chronic TBI showed

improved sleep quality & efficiency (Grima et al, 2018)

Insomnia & Disrupted Sleep-wake Cycle: Medications

• Medications for insomnia can be a double-edged sword

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• Ramelteon (Rozerem): melatonin receptor agonist (Atkin et al, 2018)

• Trazodone-better sleep quality, fewer awakenings (Yi et al, 2018)

• Magnesium: improved sleep time in elderly (Abbasi et al, 2012)

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• Orexin receptor antagonists– Suvorexant (Belsomra)

• May prevent delirium in ICU/acute care/stroke (Hatta et al, 2017; Azuma et al, 2018; Kawada et al, 2018)

• Some abuse potential (schedule IV), probably less than zolpidem (Shoedel et al, 2016)

– Lemborexant (Dayvigo)• Causes impaired balance & cognition 4 hours after taking• Generally no AM cognitive or driving impairment, but some have impaired driving in

AM at higher dose (10 mg)(Eisei Co., Ltd, 2019)

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• Other alternatives– Other sedating antidepressants

• Mirtazepine (Remeron): half-life 20-40 hrs; weight gain

• Tricyclics (amitriptyline, nortriptyline) when pain is an issue

– Long 1/2-lives

– ACh effect

(Larson & Zollman, 2010)

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– Benzodiazepines• Lorazepam-cognitive side effects in AM (Dawson et al, 2008)

• Oxazepam-no cognitive side effects in AM (Feldmeir et al, 1983)

– Other GABA agonists• Zolpidem (Ambien)-after 10 mg: cognition, driving impaired in AM

(Leufkens et al, 2009)


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• Eszoplicone (Lunesta)– Conflicting evidence on cognitive, driving impairment in AM (Boyle et al, 2008;

FDA, 2014)

– FDA changed starting dose to 1 mg due to impairment (FDA, 2014)

• Zaleplon (Sonata): no AM cognitive effects when given in evening, but yes if given in the middle of the night (Larson & Zollman, 2010)


Case Report

• A 23 y.o. male with TBI is transferred to the rehabilitation unit 10 days after injury. He is restless and paces up and down the halls, but is not aggressive. He is up much of the night and sleeps on and off during the day. He is on quetiapine 50 mg 2x/day, levetiracetam750 mg 2x/day and amantadine 200 mg 2x/day.

Case Report

• You see a 45 y.o. man in consultation on a rehabilitation unit. He is 40 days since a TBI. He is combative when asked to cooperate with nursing treatments or is challenged in therapies, but otherwise is quiet and initiates very little. He is sleeping through most of the night, but is still sleepy on and off during the day. He is largely coherent, but mildly confused. His ability to sustain attention and stay on task are short. His working memory and memory are impaired. He is on mirtazapine 15 mg at bedtime.

Alertness, Initiation, Attention

– Withdraw offending agents if appropriate• Anticonvulsants

– Worst offenders: phenytoin, phenobarbital, topiramate (Javed et al, 2015)

– Not as bad: carbamazepine (Javed et al, 2015), valproic acid– Sedating, but not otherwise cognitive-impairing?: gabapentin (Javed et al,

2015; Kay et al, 2016)» Once daily gastroretentive gabapentin (Gralise)-gradual absorption, less

sedation, less driving impairment than gabapentin (Irving, 2012; Schmidt & Rao, 2018)

– Levitiracetam: studies indicate less cognitive-impairing » can be sedating for some» can cause irritability

(Koo et al, 2013; Javed et al, 2015; Schoenberg et al, 2017)


– Withdraw offending agents if appropriate• Benzodiazepines: diazepam, lorazepam, clonazepam• Other hypnotics: diphenhydramine (Benadryl)• Anticholinergic drugs-chronic use associated with dementia in

general population (Collamati et al, 2016; Richardson et al, 2018)

– Sedating antihistamines: diphenhydramine, chlorpheniramine– Tricylic antidepressants: doxepin, amitriptyline– Overactive bladder inhibitors: oxybutynin (Ditropan), tolterodine

(Detrol), trospium (Sanctura), others


– Withdraw offending agents if appropriate• Antispasticity agents: benzodiazepines, baclofen, tizanidine (Shah et al,

2006)

• Muscle relaxants: cyclobenzaprine (Flexeril)• Neuroleptics/typical antipsychotics (e.g., chlorpromazine, haloperidol,

etc.)• Atypical antipsychotics (e.g., quetiapine, olanzepine)

Other Off-label Uses


• Dopaminergic & Noradrenergic– Methylphenidate->14 RCT’s

• Processing speed, attention to task/sustained attention, reaction time

after TBI (Whyte et al, 2004; Wilmott & Ponsford, 2010; Kim et al, 2012; Wilmott et al,

2013; Johansson et al, 2014; 2015; Zhang & Wang, 2017; Dorer et al, 2018; Kurowski et al,

2019 [children])-All RCT’s

• Fatigue, SF-36 vitality & social functioning scales after TBI (Johansson et al,

2014; 2015; Zhang & Wang, 2017)-RCT’s


– Methylphenidate (continued)• Working memory after TBI (Maktelov et al, 2017;

Johansson et al, 2014; McDonald et al, 2017)-All RCT’s

– Effects dose dependent at 0, 5, & 20 mg 3x/day (Johansson et al, 2014;

2015)

– Effect still good after 6 months of treatment in responders (Johansson et al, 2017)

• Word-list learning and nonverbal learning (Brown Location Test)-

(McDonald et al, 2017)-RCT


• Dopaminergic & Noradrenergic– Methylphenidate

• Cognitive, post-concussive, & PTSD complaints in mild TBI &/or

PTSD (McAllister et al, 2016)-RCT

• Apathy after TBI (Kant, 2002)

• Side effects: jitters/irritability, anxiety, hypertension, tachycardia,

anorexia, psychosis

• Does not provoke seizures at therapeutic doses (Wroblewski et al, 1992)


• Dopaminergic & noradrenergic– Dextroamphetamine

• RCT: non-significant differences from placebo & small effect sizes

for attention, speed, & function in pts 2 months p-TBI (N=32)

• Side effects: similar to methylphenidate

(Hart et al, 2018)–


• Dopaminergic & noradrenergic– Lisdexamfetamine (Vyvanse)

• Prodrug-slowly converted to dextroamphetamine• Decreases “liking” effect (Domnitei & Madaan, 2010)

• RCT in pts with TBI: shows benefit for sustained attention, response speed consistency & endurance, WM, subjective initiation, and other executive skills (Tramontana et al, 2014)

• Side effects: same


• Dopaminergic & noradrenergic– Modafinil (Provigil)

• small RCT shows beneficial effect on daytime sleepiness after TBI (Kaiser, 2010)

• RCT shows no effect on daytime sleepiness or fatigue (Jha et al, 2008)

• Non-TBI studies show improved attention too• Side effects: Headache, nausea; less frequent, but can cause anxiety &

psychotic behavior

Presenter

Presentation Notes

Modafinil-Improved alertness, tracking, following commands in uncontrolled study of patients with DOC (Dhamapurkar et al, 2016)


• Dopaminergic & noradrenergic– Armodafinil (Nuvigil)

• R-enantiomer of modafinil• RCT of mild-mod TBI with EDS: improved Clinical Global Impression-

Severity of Illness scale & increased sleep latency, but not Epworth Sleepiness Scale (Menn et al, 2014)

Presenter

Presentation Notes

Modafinil-Improved alertness, tracking, following commands in uncontrolled study of patients with DOC (Dhamapurkar et al, 2016)


• Dopaminergic– Bromocriptine

• agonist at dopamine D2 receptors, some serotonin & alpha-adrenergic

receptors

• inhibits the release of glutamate

– No improvement or worse attention in TBI (Whyte et al, 2008)

– Alertness/activation-many case reports, uncontrolled studies in VS/MCS

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• NMDA receptor antagonists– Amantadine (also dopaminergic & noradrenergic) (Deep et al, 1999;

Sommerauer, 2011)

• RCT-speeds recovery in patients in MCS (Giacino et al, 2012)

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• NMDA receptor antagonists-amantadine• RCT-speeds recovery in MCS patients

– Enrolled 4-16 weeks p-injury

– Benefit (effect size) greater for those enrolled

later than those enrolled early

– Benefit (effect size) same for those in vegetative state vs. MCS

(Giacino et al, 2012)

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• NMDA receptor antagonists

– Amantadine for cognitive impairment

• RCT in irritable participants with TBI

– no difference in improvement in attention/speed

– placebo better for learning/memory & general

cognition at 28 days, not 60 days

(Hammond et al, 2018)

• Pilot study: trend for improvement in inpatients (Meythaler, 2002)

• Side effects: nausea, orthostatic dizziness, edema, livedo reticularis,

depression, anxiety/jitters, psychosis, arrhythmias, constipation


– NMDA antagonists

• Memantine (Namenda)-also dopaminergic & upregulates BDNF

gene– Increased prefrontal glucose metabolism on PET scan correlated with

improved MMSE in TBI (Kim, 2010)


• Noradrenergic– Atomoxetine (norepinephrine transporter inhibitor )

• RCT showed no effect on attention in TBI (Ripley et al, 2014)

– Protriptyline (norepinephrine reuptake inhibitor tricyclic antidepressant)• Case series shows positive effects in ABI (Wroblewski et al, 1993)

• Anticholinergic, lowers sz threshold, 60-200 hr half-life

Alertness, Initiation, Attention, Speed

• Acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine)– Studies are mixed on attention, WM (immediate memory), speed of

processing after TBI (Zhang et al,2004; Silver et al, 2006; McAllister et al, 2016; Campbell et al, 2018)

• Alpha-2 adrenergic agonist: guanfacine– Improved WM in participants with mTBI 1 month p-injury compared

to placebo (N = 13/14)– healthy controls not improved

(McAllister et al, 2011)

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Occasional Dramatic Improvement in Patients with DOC• Zolpidem (Ambien)

– 5-20% improved transiently on CRS (4.8%), most already in MCS (Thonnard et al, 2013; Whyte et al, 2014; Bomalaski et al, 2017)

– Some cases of sustained effect with continued treatment (Clauss et al, 2000; Clauss & Nel, 2006; Whyte et al, 2014)

– Doses• Usually 10 mg, some 20 mg (Whyte et al, 2014; Bomalaski et al, 2017)

• 1 case up to 30 mg without adverse effects (Clauss et al, 2000)

• Benzodiazepines-effect usually not sustained with continued treatment (Glenn: personal communication)

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• You see a 45 y.o. man in consultation on a rehabilitation unit. He is 40 days since a TBI. He is combative when asked to cooperate with nursing treatments or is challenged in therapies, but otherwise is quiet and initiates very little. He is sleeping through most of the night, but is still sleepy on and off during the day. His speech is largely coherent, but mildly confused. His ability to sustain attention and stay on task are short. His working memory and memory are impaired. He is on mirtazapine 15 mg at bedtime.

PART 2: AFFECTIVE AND EXECUTIVE DISORDERS

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Non-pharmacologic Treatments

• Optimize medical condition

• Treat sleep disorders

• Treat other disabilities

• Individual counseling/psychotherapy

• Motivational interviewing

• Group therapy

• S.A.D. lights

• Acupuncture

• Meditation

• Exercise

• Diet

• Behavioral interventions

• Transcranial magnetic stimulation

(Gertler et al, 2015)

Case Report

• A 20 year-old woman is seen as an outpatient 2 months after a TBI. She is on amantadine 200 mg 2x/day. She is making rapid gains in attention, memory, and executive skills. She is becoming aware of her cognitive impairment. She calls herself “stupid” and on several occasions states that she wishes that she had not lived. She is tearful at times. Counseling has had a limited effect.

Depression

• Withdraw offending agents (e.g., amantadine, baclofen, varenicline, corticosteroids, gabapentin, cyclobenzaprine)

Depression

• Is it okay to give an antidepressant to someone with a “real” reason to be depressed?– Should they work it out without drugs?– What if they are too cognitively impaired?– Will the antidepressant work?– Will it diminish their ability to benefit from psychotherapy?– Will it take away their creativity?

If there had been Prozac in the 19th century…

Depression

• SSRI’s (e.g., escitalopram, citalopram, sertraline, fluoxetine, fluvoxamine, paroxetine, vilazodone-also 5-HT1a receptor agonist) – Mixed results of studies, but meta-analysis showed positive effect of

antidepressants for people with TBI (Salter et al, 2016)

– RCT negative for sertraline in depression after TBI (Fann et al, 2017), but• 68% had anxiety• 69% had a H/O alcohol or drug dependence

– Sertraline prevented depression in acute TBI in 2 trials (Novack et al, 2009; Jorge et al, 2016)

Depression

• SSRI’s:– Side effects: nausea, diarrhea, decreased libido, erectile dysfunction,

anorgasmia, HA, dry mouth, insomnia, sedation, anxiety, suicidal ideation, hemorrhage, hemorrhagic stroke (Haccam & Mrkobrada, 2012; Khokhar et

al, 2017-TBI >65 study), small increase in all-cause mortality for > 65 y.o.– Citalopram & escitalopram associated with QT prolongation above 40 &

20 mg, respectively• Ray et al (2017) found no increased risk of sudden cardiac death or

all-cause mortality in a large TN Medicaid population on these drugs compared with other SSRI’s`

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Depression

• Serotonin receptor agonist/antagonist– Vortioxetine (Trintellix™)

• Inhibits serotonin (5-HT) reuptake • Agonist at 5-HT1a receptors• Partial Agonist at 5-HT1b receptors• Antagonist at 5-HT3, 5-HT1d, and 5-HT7 receptors• More improvement in cognition in MDD than duloxetine (McIntyre et al,

2016)

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Depression

– Agomelatine• melatonin receptor agonist and 5-HT2C receptor antagonist

resulting in frontal norepinephrine and dopamine disinhibition• Not FDA approved in U.S.—never submitted• Approved in Europe by EMA

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Depression

• SNRI’s (e.g.,venlafaxine, desvenlafaxine, duloxetine, levomilnacipran)– Withdrawal syndrome = use extended-release forms

(continued)

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Depression

• SNRI’s – Side effects: similar to SSRI’S but

– Most can raise blood pressure– Duloxetine can cause elevated LFT’s– Increased risk of ischemic stroke with SNRI’s

& PPA’s* in > 65 y.o. after TBI (Khokhar et al, 2017)

*Phenylpiperizone antidepressants: trazodone & nefazodone

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Depression

• Tetracyclics– Mirtazapine (Remeron™)-sedating, causes weight gain– Mianserin (not available in U.S.)– Maprotiline (not available in U.S.)

Depression

• Bupropion-noradrenaline & dopamine reuptake blocker– Not associated with sexual side effects– Use cautiously (seizures at high doses?)

• 1-yr seizure rate at max 300 mg/day in non ABI, non-epileptic, non-eating disorder population = 0.15% (Dunner et al, 1998)

• Risk in smoking cessation, some with h/o seizures = 0.05% (n=168,000) (Bevins et al, 2008)

• Increased risk with IR forms, but not extended release (Alper et al, 2007)

Depression

• Esketamine (Spravato™) Nasal Spray– NMDA receptor antagonist– Adjunctive for treatment-resistant depression– Administered under supervision– Side effects: sedation, syncope, dizziness, vertigo, anxiety, dissociation

Depression

• Methylphenidate (Lee et al, 2005; Zhang & Wang, 2017-RCT)

• Methylphenidate plus L-dopa improve mood in stroke (Delbari et al, 2011)

Depression

• Antidepressant Augmenters– Atypical antipsychotics (e.g., aripiprazole, olanzepine)

– Some anticonvulsants (lamotrigine, valproate, carbamazepine)

– Methylphenidate (off-label)

– T3

Pathological Laughing And Crying (Pseudobulbar Affect)

• PBA: Paroxysmal stereotyped laughing & crying with little or no provocation


• Center for Neurologic Study-Lability Scale (CNS-LS) for pseudobulbar affect (PBA)

Using the scale below, write the number that describes the degree to which each item applies to you DURING THE PAST WEEK. Write only 1 number for each item, then add the numbers and enter the total at the bottom. • Never Rarely Occasionally Frequently Most of the time

1 2 3 4 5

Questions• I find that even when I try to control my laughter I am often unable to do so • I find that I am easily overcome by laughter • There are times when I won’t be thinking of anything happy or funny at all, but then I’ll suddenly be overcome by

funny or happy thoughts • Others have told me that I seem to become amused very easily or that I seem to become amused about things

that aren’t really funny • I find myself crying very easily • There are times when I feel fine one minute, and then I’ll become tearful the next over something small or for no

reason at all • I find that even when I try to control my crying I am often unable to do so

• It is said that a score of 13 or more may suggest PBA. It provided the best sensitivity (0.84) and specificity (0.81). (Moore et al, 1997)

NOTE: You get 1 point for “Never”. If the 4 laughing items are “NEVER” & the 3 crying items are “Occasionally”, you get 13.


• Mean prevalence of PBA across 6 neurologic conditions including TBI:– 10.1% with Pathological Laughing and Crying Scale (PLACS) ≥ 13– 9.4% with CNS-LS ≥ 21– 37.5% CNS-LS ≥ 13

(Work et al, 2011)

• Mean prevalence of PBA in military with TBI:– 22% with CNS-LS ≥ 21– 70% CNS-LS ≥ 13– PTSD present in 46%– Major depression present in 26%

(Fonda et al, 2015)


• PBA: Paroxysmal stereotyped laughing & crying with little or no provocation– Antidepressants (SSRI’s preferred)– Methylphenidate – Lamotrigine, valproate, carbamazepine– Levodopa– Amantadine– Dextromethorphan/quinidine (Nuedexta-FDA approved for PBA)

• Open label study showed significant improvement and good tolerance(Hammond et al, 2018)

• Did not distinguish affective lability from PBA (Engelman et al, 2014)• Mean PHQ-9 score was 13.9 (upper border moderate depression), improved with

DM-Q

(continued)


– Dextromethorphan/quinidine (Nuedexta™)• Inhibitor of CYP2DS metabolism• Interacts with many other drugs to change levels (desipramine, citalopram,

amiodarone, amphetamine, fluoxetine, ciprofloxacin, levofloxacin, quetiapine, trazodone, tramadol, etc., etc.)

• Can prolong QT interval• Other side effects: diarrhea, nausea, dizziness, headache,

somnolence, fatigue, dry mouth

(Arciniegas & Wortzel, 2014; Pattee et al, 2014)

Emotional Or Affective Lability

• AL: Displaying intense emotions in response to meaningful stimuli that ordinarily would induce more modest emotional responses.– Antidepressants (SSRI’s preferred)– Methylphenidate – Lamotrigine, valproate, carbamazepine– Levodopa– Amantadine

(Arciniegas & Wortzel, 2014)

– Detromethorphan/quinidine? (Neudexta™)

Anxiety

• Benzodiazepines

• Buspirone

• Antidepressants (Especially SSRI’S, SNRI’S)

• Treat insomnia

Case Report

• A 20 year-old woman is seen as an outpatient 2 months after a TBI. She is on amantadine 200 mg 2x/day. She is making rapid gains in attention, memory, and executive skills. She is becoming aware of her cognitive impairment. She calls herself “stupid” and on several occasions states that she wishes that she had not lived. She is tearful at times. Counseling has had a limited effect.

Case Report

• There is no improvement when she is tapered off of amantadine. There is no change in attention, processing speed, initiation, or alertness. Her depressive symptoms improve with the addition of sertraline. Six months after her injury she is still making cognitive gains, though has substantial cognitive impairment, particularly in the areas of working memory and executive skills. Her only medication is sertraline.

Executive Function

• Methylphenidate– Participants with TBI improved performance on N-back test

(working memory, attention)-RCT (Manktelow et al, 2017)– Other RCT’s showing gains in working memory (Johannson et al, 2014;

McDonald et al, 2017)

• Lisdexamfetamine (Vyvanse™)– RCT in pts with TBI: shows benefit for working memory;

subjective initiation & organization(Tramontana et al, 2014)

Executive Function

• Bromocriptine (1.25-2.5 mg)• Improved on Stroop (Roesch-Ely et al, 2005-RCT, non-BI), dual-task, FAS,

trailmaking, WCST (McDowell et al, 1998-randomized, placebo crossover; TBI)

• Working memory (verbal span, 8-second delayed spatial localization)-No(Mcdowell et al, 1998)

• Working memory-No for 4-sec delayed spatial localization, Yes for 8-sec (Luciana et al, 1992-RCT, non-BI)

• Working memory-No for N-back test at 1 month p-mTBI; Yes for healthy controls (McAllister et al, 2011)

• Some rare but dangerous side effects, including pulmonary fibrosis

Executive Function

• Vitamin D– placebo controlled RCT of Norwegian adolescents

– Vitamin D group demonstrated improvement in Tower of Hanoi

performance with increase in vitamin D levels (44 nmol/L to 62 nmol/L)(Grung et al, 2017)

Case Report

• There is no improvement when she is tapered off of amantadine. There is no change in attention, processing speed, initiation, or alertness. Her depressive symptoms improve with the addition of sertraline. Six months after her injury she is still making cognitive gains, though has substantial cognitive impairment, particularly in the areas of working memory and executive skills. Her only medication is sertraline.

CASE REPORT

• 25 y.o. man with TBI. Bifrontal contusions are seen on CT scan. He is started on levetiracetam for prevention of seizures. He is started on amantadine to facilitate recovery. He remains unconscious for 3 weeks, then gradually emerges and is transferred to the rehabilitation unit. He is restless and aggressive, trying to get out of bed, pulling on his g-tube, hitting staff who try to stop him.

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Post-traumatic Confusionin the ICU & Rehabilitation Unit

• Priorities– Patient & staff safety– Rehabilitation progress

• Treat insomnia (trazodone), pain• Taper & stop levetiracetam if possible

– After 7 days• Consider not treating with drug

– use 1:1, net bed, wait

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• Atypical antipsychotics (e.g., quetiapine, olanzapine, aripiprazole) (off-label)– RCT of quetiapine vs. placebo for delirium

in critically ill non-TBI patients• Shorter duration of delirium• Less agitation• Fewer days of PRN haloperidol• More likely to be discharged to home or rehab• More sedation

(Devlin et al, 2010)

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• Benzodiazepines (e.g., lorazepam, clonazepam) (off-label): • can cause disinhibition, sedation, impaired memory & attention

• generally not recommended

• Get off medications as soon as possible

Case Report

• 25 y.o. man with TBI. Bifrontal contusions are seen on CT scan. He is started on levetiracetam for prevention of seizures. He is started on amantadine to facilitate recovery. He remains unconscious for 3 weeks, then gradually emerges and is transferred to the rehabilitation unit. He is restless and aggressive, trying to get out of bed, pulling on his g-tube, hitting staff who try to stop him.

Case Report

• 14 days later, he has made gains and is no longer restless, but becomes verbally and occasionally physically aggressive when he does not get what he wants. He says that staff are trying to poison him. He is sleeping well. He is on amantadine 200 mg 2x/day.

Medications ForAggression & Irritibility

• Classification of Aggressive Behavior: Pharmacology– Psychotic: antipsychotics– Impulsive: see forthcoming slides– Predatory (organized or instrumental): none

(Nolan et al, 2003; Meyer et al, 2016)

• Other Contributors/Classes: Pharmacology– Dysphoric (Depressive): antidepressants– Paradoxical (impaired initiation or alertness): stimulants or

amantadine

Medications For Aggression & Irritibility

• Impulsive aggression, disinhibition– Amantadine: RCT (Hammond et al, 2014, 2015, 2017)

• No difference in rating by observers, but 68.3% placebo response• Significant difference in ratings by physicians & participants before

correction for multiple analyses

• In subjects with mod-severe aggression– participant ratings significantly different between groups on some

measures

– but not observer ratings (56% placebo response rate)

Medications For Aggression & Irritibility

• Impulsive aggression– Anticonvulsants (e.g., valproate, carbamazepine, oxcarbazepine)

(Huband, Cochrane Review, 2010)

– Beta-blockers (e.g., propranolol, pindolol) (Greendyke & Kanter, 1986; Plantier

et al, 2016)

– Lithium (Glenn & Joseph, 1987; Glenn et al, 1989)

– Atypical antipsychotics• Atypical antipsychotics (e.g., quetiapine-sedating; aripiprazole-

activating; clozapine-most effective?) (off-label): no well-done studies(Meyer et al, 2016)

Medications ForAggression & Irritibility

• Atypical antipsychotics– Less EPS– Less tardive dyskinesia– Can cause

• Diabetes mellitus• Weight gain• Hyperlipidemia• Small risk of cardiac arrest-get EKG, look for QT prolongation• Stroke risk increased, especially in elderly• Sedation varies

Case Report

• 10 days later, he has made gains and is no longer restless, but becomes verbally and occasionally physically aggressive when he does not get what he wants. He says that staff are trying to poison him. He is sleeping well. He is on amantadine 200 mg 2x/day.

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• Summary– Determine underlying cause of symptoms– Withdraw potentially offending medications– Treat non-pharmacologically when feasible– Add stimulants or dopaminergics– Try others as needed

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