Neuropharmacology In TBI: What We Know & What We Don’t

Neuropharmacology In TBI: What We Know & What We Don’t

Neuropharmacology in TBI: What We Know and What We Don’t.
Heidi Fusco, M.D. Assistant Professor of Rehabilitation Medicine Mount Sinai Rehab Hospital Jaime M. Levine, D.O. Assistant Clinical Professor Rusk Rehabilitation

Agenda/Goals of this lecture
Why use neuropharmacology after brain injury Neurotransmitter pathways Rules of neuropharmacology Agents/medications to support Motor recovery Aphasia recovery Healthy sleep Arousal Behavioral Regulation Attention and processing speed Cognition Memory Visual Spatial function Executive function

Agenda/Goals of this lecture continued
Review the recent literature regarding the range of recommendations in pharmacological treatments in brain injury, Consolidate recommendations Give examples from our own practices Withdrawing of an Agent Questions

Heidi Fusco, MD Personal practice background
Assistant Professor at Mount Sinai Rehabilitation Hospital, NYC 70%: inpatients with mild, moderate, and severe (TBI, CVA, ICH, Tumor) 30%: outpatients with brain injury and focus on function, return to work, treatment of comorbid medical problem's (spasticity, pain etc.) Teaching residents and medical students Training TBI Fellowship at Rusk w/mentors: Drs. Flanagan, Levine, and Im. PM&R Residency at Spaulding w/mentors: Drs. Chae, Giap and Herman

Why use Neuropharmacology after brain injury?
TBI is primary cause of injury-related death and disability. 3.2 million people living with disability from TBI in US (JNT 2007). Injury to brain can alter levels of neurotransmitters in the brain, possibly contributing to behavioral, cognitive, and functional deficits. Target of neuropharmacology is to minimize decline in function by: Reducing neurochemical disturbances Promoting neurotrophic factors and healing Essentially supplement deficient neurotransmitters

In addition, we know this:
PT, OT, SLP, Cognitive Therapy Prevention of another brain injury Point A: Impairment due to brain injury (Deficits in ADL’s, Ambulation, Communication, Cognition) Point B: Greater independence, Functional Abilities Time: Recovery, Plasticity, Healing, Compensation and Learning

Neuropharmacologic Augmentation?
Can we answer this?: PT, OT, SLP, Cognitive Therapy Prevention of another brain injury Point A: Impairment due to brain injury (Deficits in ADL’s, Ambulation, Communication, Cognition) Point B: Greater independence, Functional Abilities Time: Recovery, Plasticity, Healing, Compensation and Learning Neuropharmacologic Augmentation?

A very brief word on Neurotransmitter pathways
Serotonergic Adrenergic Cholinergic Dopaminergic

Serotonergic Pathways
Origin: Raphe Nucleus Pathways/Actions: Frontal cortex – mood Basal ganglia – movements, obsession and compulsions Limbic Area – anxiety and panic Hypothalamus – appetite Brainstem – sleep Cerebellum, Medulla, and SC – pain modulation, breathing, temp regulation, and motor control Affects of medications: Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitors

Adrenergics: Norepinephrine/Epinephrine
Origin: Locus ceruleus (Pons) Lateral tegmental area (Pons/medulla) Actions: Frontal cortex – mood Prefrontal cortex – attention Limbic cortex – emotions, energy, fatigue Cerebellum – movement Brainstem – blood pressure Affects of medications: Amphetamines directly release pools of dopamine and NE from locus ceruleus and block catecholamine reuptake. Modafinil affects dopamine, histamine, alpha-1 adrenergic agonist and inhibits GABA.

Dopaminergic Origin: Midbrain (Substantia nigra)
Ventral tegmental area Sites of Action: Nigrostriatal – cognition, arousal, working memory, attentional aspects of motor initiation Mesolimbic – emotional behaviors Tuberoinfundibular – prolactin secretion Altering medications: Amantadine: non-competative N-methyl-Daspartate receptor antagonist, increases dopamine in striatum presynaptically and postsynaptically. Methyphenidate: enhance dopaminergic transmission from the frontal neocortex. Bromocriptine: doamine agonist, binds to both pre and post synaptic D-2 receptors. Modafinil:affects dopamine, histamine, alpha-1 adrenergic agonist and inhibits GABA.

Cholinergic Origin: Nucleus Basilis of Meynert (basal forebrain)
Sites of Action: Thalamus – arousal Cortex – arousal and motor coordination Forebrain – attention Hippocampus – memory and learning Altering medications: Donepezil/Rivastigmine: aceylcholinesterase inhibitors

Keep in mind: Different Neurotransmitter pathways travel through the same region in the brain i.e., frontal lobe injury affects all the pathways Problems in function after brain injury are not due to a deficiency in any specific one neurotransmitter. I.e. Parkinson's, is due to lack of central dopamine

Neuropharmacology in TBI: What We Know and What We Don’t
Jaime M. Levine, D.O. Assistant Clinical Professor Rusk Rehabilitation

Jaime M. Levine, D.O. Clinical Background and Training
Clinical Assistant Professor of Rehabilitation Medicine at NYULMC Medical Director of Brain Injury Rehabilitation at Rusk Completed Neurorehabilitation Fellowship at JFK-Johnson Rehab Institute Mentors: Drs. Malone and Lopez Currently I am a “Rehab Hospitalist” Medical Director of a 22-bed acute rehab unit at Rusk Mix of acquired and traumatic brain injury Provide PM&R consultations in our acute care hospital at NYULMC Medical Director of a TBI-Subacute rehab facility where I spent one ½ day per week Queens Nassau Rehabilitation and Nursing Center Neuropharmacology in TBI: What We Know and What We Don’t.

Goals of Neuropharmacological Intervention in Post Stroke Rehabilitation
Patient recover in four ways: SYNERGY Spontaneous recovery Controlling medical complications Interdisciplinary Rehabilitation *Pharmacological interventions* Help us prognosticate functionally Only one chance in acute rehab, so helps patients “get the most from it!” Neuropharmacology in TBI: What We Know and What We Don’t.

Rules of Thumb Healthy brain versus injured brain will impact response to medications Remember, you are in charge! What specifically are you targeting? What is your goal? Start low, go slow Make use of interdisciplinary team Inform team at onset and with dose adjustments A side effect to one patient, is a targeted intervention in another! Limit polypharmacy If fatigue is a side effect, dose at bedtime If orthostasis a side effect, choose an SNRI Dosing subject to change during recovery Consider dosing schedule Varies by setting Neuropharmacology in TBI: What We Know and What We Don’t.

Informed Consent Essential
With each medication Most often off-label usage Side effects/interactions are real Low potential for harm overall, but must be very cautious Family should be treated as part of the team Neuropharmacology in TBI: What We Know and What We Don’t.

How do we Measure Outcomes?
Barthel Index Modified Rankin Scale Fugl-Meyer Assessment of Motor Response After Stroke Agitated Behavioral Scale Rancho Los Amigos Scale JFK-Coma Recovery Scale, Revised Functional Independence Measure (FIM) O-Log GOAT Various Neuropsychology Indices Aphasia Scales Western Aphasia Battery (WAB) Psycholinguistic Assessment of Language Processing in Aphasia (PALPA) Neuropharmacology in TBI: What We Know and What We Don’t.

Best Way to Measure Outcome?
Feedback from the interdisciplinary team Weekly assessment of goals Neuropharmacology in TBI: What We Know and What We Don’t.

Disclaimer Much research in Motor and Aphasia recovery is done in stroke and acquired brain injury populations. Scarce research done on pharmacological augmentation of Motor and Aphasia recovery in the TBI population. Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery: What We Know and What We Don’t.
Presentation Title Goes Here

Agents to Support Motor Recovery
SSRI’s Fluoxetine Citalopram SNRI’s Reboxetine Levodopa Amphetamine-like compounds Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery (SSRI’s) What We Know:
SSRI’s have utility in non-depressed patients with stroke, with good functional results. Depression occurs in about one third of patients with stroke Some antidepressants may act directly on the injured neuronal structures and modulate spontaneous reorganization Question of reopening a window of plasticity FMRI studies have shown improvement in motor cortex after single dose of fluoxetine or paroxetine. (Pariente et al. 2001) Should everyone with an ischemic stroke be on an SSRI? Neuropharmacology in TBI: What We Know and What We Don’t.

FLAME trial showed that in patients with ischemic stroke and moderate to severe motor deficits, the early prescription of fluoxetine with physical therapy led to enhanced motor recovery after three months. Double-blind, placebo-controlled trial, nine stroke centers with ischemic stroke, hemiplegia/hemiparesis, and Fugl-Meyer motor scale score of 55 or less, years old. Excluded patients with depression Randomly assigned to either fluoxetine (20mg QD) or placebo. All had PT Primary outcome measure was change on FMMS between day 0 and day 90. Results: FMMS score improvement at day 90 was significantly greater in the fluoxetine group. Greater number of functionally independent patients (Modified Rankin Scale 0-2) Less number of depressed patients Side effects: hyponatremia, GI distress didn’t stop treatment Even at 20mg dose there was less depression among stroke patients. Depression-preventive mechanism. Neuropharmacology in TBI: What We Know and What We Don’t.

Patients treated with citalopram for three months post stroke had a better recovery from disability one year after stroke than patients who did not receive antidepressant therapy.* Suggests lasting effect Citalopram can enhance dexterity in chronic stroke patients.** Eight chronic stroke patients (> 6 months) Double-blind, placebo-controlled, single-dose crossover design Motor function assessed: nine-hole-peg-test, hand grip strength Results: Should everyone w/an ischemic stroke be on an agent for motor recovery? Asa/statin/ssri? An automatic add-on agent? Did not turn into standard of care, but as the evidence has strengthened as far as ssri’s making difference, fmri studies showing, opening up a plasticity window (newer), there is more excitement. Find this paper!! Beginning of acute rehab is best time to start- plasticity window can be reopened. Fluoxetine has major impact on plasticity. Juvenile like plasticity, visual cortex of rodents. Evidence for hemorrhagic patients not out there? Negligible r/o plt dysfxn w/ssri’s so risk of hemorrhagic stroke. 1-2 weeks later. Sertraline had some negative effect? All ssri’s not the same. Don’t use interchangeably. Citalopram and fluoxetine have most evidence. Fluoxetine 20mg dose for motor recovery (Chalet paper); when titrate up it’s for mood/depression to 40mg which is lowest effective dose for treating depression. Strongest evidence. Standard go-to. Citalopram for older patients. Celexa/lexapro well tolerated for older patients. 10mg or 20mg for motor/40mg for mood. Citalopram significant improved performance on nine hold peg test for paretic hand but not for the unaffected hand. Grip strength remained unchanged *Mikami K, Jorge RE, Adams HP Jr, David PH, Leira EC, Jang M, Robinson RG. Effect of antidepressants on the course of disability following stroke. Am J Geriatr Psychiatry **Zittel S, Weiller C, Liepert J. Citalopram improves dexterity in chronic stroke patients. Neurorehabil Neural Repair. 2008;22: Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery (SSRI’s) What We Don’t:
Do SSRI’s Have a Similarly Beneficial Effect in Patients with Traumatic Brain Injury? The treatment effect of motor recovery with fluoxetine persist beyond 90 days? How do these agents behave in a hemorrhagic stroke? The FMRICH study is protocoled and underway. Fluoxetine for motor recovery after acute intracerebral hemorrhage (FMRICH): study protocol for a randomized, double-blind, placebo-controlled, multicenter trial. Evidence for platelet dysfunction with SSRI. Need to wait 1-2 weeks post-hemorrhage to use? Why might SSRI’s improve motor function? Possible upregulation of brain-derived neurotrophic factor, a protein important during activity-dependent remodeling Improved serotonergic transmission and increased cortical activation Can lesioned-brain plasticity be modulated by medications? And will this improve final functional status of patients? SSRI’s are not interchangeable. Negative effect of sertraline? Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery (SNRI’s) What We Know:
Reboxetine induced a significant improvement in tapping speed and grip strength in ten patients with chronic stroke. Reboxetine inhibits the reuptake of noradrenaline. 10 chronic stroke patients, double-blind, placebo-controlled crossover trial. Less likelihood of spontaneous recovery due to chronicity. Subjects had impairments in fine motor control and upper extremity paresis. Excluded depressed patients. Received reboxetine 6mg daily or placebo Results: Zittel S, Weiller C, Liepert J. Reboxetine improves motor function in chronic stroke: A pilot study. J Neurol. 2007;254: A single dose enhanced hand tapping speed and grip strength of affected hand. No improvement seen in the Nine-Hole-Peg Test As evidence for those gets stronger, can consider incorporating into clinical practice, but not yet. Wouldn’t start with that. Would start w/ssri. Effexor for patients who need more activation. Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery (SNRI’s) What We Don’t:
Is it easier to modulate simple movement than influence complex motor tasks? What about venlafaxine, or other more commonly used SNRI’s? What is the effect for motor recovery following TBI? Why do these agents cause sedation in some patients, but have activating properties in others? Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery (Levodopa) What We Know:
Currently there is limited evidence for supporting or refuting the use of levodopa to support post-stroke motor recovery. Levodopa is a dopamine precursor that is metabolized to dopamine in the brain. I found seven randomized, double-blind, placebo-controlled studies looking at levodopa use in chronic stroke patients: Four studies showed some degree of improvement.* One study showed improvement which was not statistically significant.** Two studies showed no significant difference between levodopa group and control.*** *Scheidtmann et al 2001, Floel et all 2005, Rosser et al 2008, Acler et al 2009 **Sonde et al 2007 ***Lokk et al 2001, Restenmeyer et al 2007 Tried to stick w/strict evidence-based use of medications. No levodopa b/c was shown to be effective, but then some studies showed it was not actually that affective. Many papers couldn’t replicate Scheidtmann. Resurfacing along w/other modalities (TMS), that having l-dopa on board, has beneficial effects. Harm is no minimal, aside from some gi upset, hallucinations. Very little harm. Mixed evidence. Start w/ssri  remains plegic. What else (while doing no harm) can we offer the patient to help them? 25/100 tid  if plegic and tolerating med well, can increase to 1.5 or 2 tabs If not candidates for ssri’s (hx of drug reaction or patients w/hemorrhagic stroke) can start w/levodopa. Side effects: gi and hallucinations Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery (Levodopa) What We Don’t:
This agent is still so commonly used! Why is that? The dopamine precursor levodopa was found to increase speed, overall success, and long-term retention of novel word learning in healthy individuals (Knecht et al. 2004) fMRI studies where levodopa was onboard showed some increased activation, and also showed better response to transcranial magnetic stimulation. Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery (Amphetamines) What We Know:
Currently there is limited evidence for supporting or refuting the use of amphetamines to support post-stroke motor recovery. Found 4 recent studies looking at amphetamines and motor performance following stroke: 1 showed benefit and 3 didn’t. Dexamphetamine dosed at 10mg twice weekly for 5 weeks along with PT improved arm motor control. (Schuster et al. 2011) Amphetamine dosed at 10mg twice weekly for 10 sessions with PT showed no additional benefit. (Gladstone, 2005) D-amphetamine dosed at 5mg on day 0 and 4, then 10mg twice weekly for 35 days, with PT showed no additional benefit. (Sprigg et al. 2007) D-amphetamine at 10 doses of 10mg twice weekly showed no significant benefit. (Platz et al. 2005) Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery What We Know:
Donepezil may improve the FIM motor score in elderly cognitively impaired patients post stroke. Dr. Ellen Whyte et al, 2008 40 patients, all over 60 year old 12 week open label trial of : galantamine 24 mg or donepezil 5-10mg Outcome measure: FIM motor and apathy evaluation Results: Donepezil group had 14 point greater boost in FIM motor score Change in apathy associated with FIM gain How? Theory: acetylcholinesterase inhibitors improve learning ability and participation activation of motor cortex reorganization?

Agents to Support Motor Recovery Other Agents Being Looked At:
Statins  Neuroprotection at the acute phase followed by an increase in the cerebral blood flow, leading eventually to improved functional outcome. (Giannopoulos et al. 2012) Phosphodiesterase inhibitors  Sildenafil promotes vasodilation, enhances angiogenesis, neurogenesis, and synaptogenesis when initiated at 24h post stroke. (Zhang et al. 2005) Niacin  improves functional outcomes in rats post stroke (Chen et al. 2007) Glibenclamide  Sulfonylureas may halt oxidative stress and inflammation in the hippocampus after reperfusion (Abdallah et al. 2011). Another study showed retrospectively that patients taking this post stroke had a better neurological outcome (Kunte et al. 2007) Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery, Summary of Take Home Points from the Literature:
SSRI’s have utility in non-depressed patients with stroke, with good functional results. FLAME trial showed that in patient with ischemic stroke and moderate to severe motor deficits, the early prescription of fluoxetine with physical therapy led to enhanced motor recovery after three months. Patients treated with citalopram for three months post stroke had a better recovery from disability one year after stroke than patients who did not receive antidepressant therapy. Citalopram can enhance dexterity in chronic stroke patients. Donepezil may improve the FIM motor score in elderly cognitively impaired patients poststroke. Reboxetine induced a significant improvement in tapping speed and grip strength in ten patients with chronic stroke. Currently there is limited evidence for supporting or refuting the use of levodopa to support post-stroke motor recovery. Currently there is limited evidence for supporting or refuting the use of amphetamines to support post-stroke motor recovery. Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Motor Recovery Anecdotes from My Practice:
Ischemic stroke patients: Without an obvious contraindication, all patients with an ischemic stroke in the acute rehab phase should be on an SSRI! Fluoxetine has the strongest evidence. Start 20mg for motor recovery  Increase to 40mg if develop signs of depression No drug holiday  continue onwards, with need for follow-up Citalopram has the second strongest evidence Agent of choice in the elderly because well-tolerated Start at 10mg, titrate to 20mg for motor recovery  Titrate to 40mg if develop signs of depression In a patient with hemiplegia, and no improvement on SSRI, often add levodopa 25/100 tab TID, and titrate up to 1.5 or 2 tabs TID Not strong enough evidence to use an SNRI for motor recovery in my opinion TBI patients: Would not offer SSRI first-line to promote motor recovery Would use dopamine promoting agents such as levodopa For tbi: try to avoid anti-dopaminergics, doing things that boost dopamine levels (amantadine, amaphetamines), levodopa Would not offer ssri for tbi. Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Aphasia Recovery: What We Know and What We Don’t.

Agents to Support Aphasia Recovery
Dopaminergic agents Levodopa Bromocriptine Amantadine Cholinergic Donepezil NMDA receptor agonist Memantine Piracetam: GABAergic Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Aphasia Recovery (Dopaminergics) What We Know:
The evidence for the efficacy of dopaminergic agents in aphasia therapy is mixed. Levodopa and bromocriptine are the main agents used, most commonly bromocriptine  Observed in the 1970’s that Parkinsonian patients showed improved speech function following levodopa therapy. Gill and Leff (2013) reviewed 15 studies done between 1988 and 2012 that used dopaminergic agents in aphasia. Most studies dosed up to 30mg daily for bromocriptine 7/15 reported a positive effect of dopaminergic therapy 2 were RCT’s (Seniow. 2009, Leman et al, 2011) The rest showed no differences Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Aphasia Recovery (Amantadine) What We Know:
Amantadine may have a beneficial effect on language performance in patients with aphasia. Amantadine increases the release of dopamine and norepinephrine, has a weak antagonism of NMDA receptor, and has slight anticholinergic effects. Studies done have been small, single case reports. Arciniegas et al. 2004, Barrett and Eslinger 2007 Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Aphasia Recovery (Cholinergics) What We Know:
Donepezil has been shown to improve the severity of aphasia and motor aspects of speech in poststroke aphasia. Berthier et al studied 26 patients, RCT, double-blind, for efficacy of donepezil in chronic poststroke aphasia. Dose was 5mg x 4 weeks, then 10mg daily x 12 weeks, then 4 week wash-out = 20 week trial Age < 70 with duration of aphasia > 1 year Results: Donepezil significantly improved the severity of aphasia on the Western Aphasia Battery and the picture naming subtest of the PALPA (Psycholinguistic Assessment of Language Processing in Aphasia). Between-group differences were no longer significant at week 20, so there is no lasting benefit when discontinued. Adverse effects: donepezil group with irritability, seizure, headache, abnormal dreams, insomnia, fatigue Reach same ceiling, but reach it faster, so get more out of acute rehab experience. TBI: one of the reasons I don’t favor donepezil is b/c it acts on ach and can have mild sedation, also gi upset Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Aphasia Recovery (NMDA-receptor ag) What We Know:
Memantine alone or combined with constraint-induced aphasia therapy in chronic poststroke aphasia patients improved aphasia severity. These effects persisted on long-term follow-up. Theory: Acute stroke causes neuronal and myelin sheath damage in part due to over-activation of NMDA receptors  calcium influx  excitotoxic cell death. Drugs that modify the NMDA receptor, like memantine, may augment synaptic plasticity in language areas. Randomized, double-blind, placebo-controlled trial of both memantine and CIAT Memantine 20mg daily or placebo x 16 weeks  drug + CIAT x 2 weeks  drug alone x 2 weeks  washout x 4 weeks Results: Berthier et al. 2009 Lack of specific evidence, not used much. Effective at controlling agitation in mod-sev demented patients. Patients c/o sedation. Memantine group showed significantly better improvement on Western Aphasia Battery compared w/placebo while given and after washout. Combination of memantine and CIAT showed best effect and was long-term Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Aphasia Recovery What We Don’t:
Regarding dopaminergic agents: the evidence is mixed, but in terms of cognitive models, at what level are they working? Dopamine is implicated in modulating a whole range of cognitive functions, including reward, attention, memory and problem-solving, so perhaps language recovery is affected through these channels? Regarding donepezil: How does it improve language? May affect neurovascular organization and promote reorganization of cortical networks and blood flow regulation Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Aphasia Recovery, Summary of Take Home Points from the Literature:
The evidence for the efficacy of dopaminergic agents in aphasia therapy is mixed. Donepezil has been shown to improve the severity of aphasia and motor aspects of speech in poststroke aphasia. Memantine alone or combined with constraint-induced aphasia therapy in chronic poststroke aphasia patients improved aphasia severity. These effects persisted on long- term follow-up. Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Aphasia Recovery Anecdotes from My Practice:
Donepezil has mixed evidence but I use it anyway. Start at 5mg for 5-6 days, then increase to 10mg. Avoid drug holiday because effect is only seen while taking the drug. Side effects: mild sedation and GI effects Reach same ceiling, but reach it faster, so get more out of acute rehab experience. TBI: I don’t favor donepezil because may cause mild sedation Don’t have much experience with memantine because there’s only one good study, but due to good side effect profile would consider its use. Effective in elderly demented patients to control agitation, can be sedating Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Better Sleep: What We Know and What We Don’t.

Agents to Support Healthy Sleep
Melatonin Ramelteon Amitryptiline Trazodone Piracetam: GABAergic Neuropharmacology in TBI: What We Know and What We Don’t.

Agent to Support Healthy Sleep (Melatonin) What We Know:
Melatonin has value for sleep disorders following head injury. Consensus is that about 30% of patients following head injury have insomnia. Little published on its use in TBI One case report of a 15-year old girl with head trauma who developed a delayed sleep phase syndrome. (Nagtegaal, J.E. 1997) Physiological markers monitored: Sleep-wake rhythm, plasma melatonin, body temp, wrist activity All markers returned to normal after treatment with 5mg melatonin A few studies on melatonin in neurologically impaired children with neutral to favorable results. Ramelteon is a pharmaceutical grade analogue of melatonin Jorge et al, 2010 Neuropharmacology in TBI: What We Know and What We Don’t.

Agent to Support Healthy Sleep (Melatonin and Amitriptyline) What We Know:
Melatonin has value for sleep disorders following head injury. Kemp et al (2004) did a randomized double-blind controlled cross-over trial with melatonin (5mg) or amitriptyline (25mg). Minimum 6 months post-TBI 16-65 y/o Sleep variables measured: Alertness Duration Quality Latency Also measured neuropsychological functioning and mood Results: Melatonin: improved daytime alertness Amitriptyline: improved sleep duration and shortened latency Most patients were unimpaired on neuropsychological tests of attention and speed of processing No changes in cognitive performance or mood No adverse drug effects Neuropharmacology in TBI: What We Know and What We Don’t.

Agent to Support Healthy Sleep (Trazodone) What We Think We Know:
Trazodone is a multifunctional drug that helps patients with TBI sleep. Mechanism of action is unique: has dose-dependent actions Hypnotic actions at low doses due to blockade of: 5-HT2A receptors H1 histamine receptors Alpha1 adrenergic receptors Higher doses block the serotonin transporter (SERT) and have antidepressant properties (Stahl, 2009) Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Healthy Sleep Take Home Points From the Literature:
Melatonin has value for sleep disorders following head injury. Trazodone is a multifunctional drug that helps patients with TBI sleep. Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Healthy Sleep Anecdotes from My Practice:
Ramelteon at 4mg dosing is great to have onboard. Few to no contraindications Viewed as a “supplement” not drug to some Trazodone mg QHS Caution in young men Avoid with other serotonergics, especially at higher doses Antidepressant effect at higher doses Mirtazapine 7.5mg, may increase to 15mg Antidepressant effects Good results Can increase appetite Neurontin Back-load dosing Instead of 300mg Q8, can give 300mg QAM and 600mg QHS Benzodiazepines, “Z” drugs, are never my top choice Baclofen for nighttime spasms Tizanidine similarly Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Support Arousal: What We Know and What We Don’t.

Agent to Improve Arousal
Dopaminergics: Amantadine Bromocriptine Sedative/hypnotic Zolpidem Stimulants Methylphenidate Modafinil Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Improve Arousal (Dopaminergics) What we Know:
Amantadine is the agent of choice for treating profound hypoarousal following TBI, especially when a patient has a disorder of consciousness. Giacino et al enrolled 184 patients in the vegetative or minimally conscious states following TBI Patients currently receiving inpatient rehab 4-16 weeks post-TBI Randomized, placebo-controlled 4 week treatment period, 2 week washout period Used Disability Rating Scale Results: The amantadine group had faster recovery during the treatment phase Recovery slowed during the washout phase for the amantadine group End points were equal No significant adverse events Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Improve Arousal What we Know:
Amantadine and/or methylphenidate may improve emergence from coma in hypoxic ischemic encephalopathy resulting from cardiac arrest. Retrospective cohort study from Patients received either amantadine, methylphenidate, or both. Outcome measures were: Primary Outcome: Command following Secondary Outcomes: Survival to hospital discharge, cerebral performance category, modified Rankin scale Results: Patients receiving neurostimulants trended toward improved rate of command following, as well as improvements on the secondary outcome measures Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Improve Arousal (Zolpidem) What we Know:
A very small number of patients with disorders of conscious are responders to zolpidem, and it is not possible to distinguish responders in advance. Zolpidem has been reported to cause temporary recovery of consciousness in VS and MCS patients. (Whyte et al, 2014) 84 participants Traumatic and non-traumatic DOC of at least 4 month duration Results: 4 definite responders were identified No features were predictive of response Indicators included: Increased movement, social interaction, command following, functional object use Response lasted 1-2 hours Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Improve Arousal What we Don’t:
What is the mechanism of action behind these agents improving consciousness? How can we identify zolpidem responders in advance? Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Improve Arousal Take Home Points From the Literature:
Amantadine is the agent of choice for treating profound hypoarousal following TBI, especially when a patient has a disorder of consciousness. Amantadine and/or methylphenidate may improve emergence from coma in hypoxic ischemic encephalopathy resulting from cardiac arrest. A very small number of patients with disorders of conscious are responders to zolpidem, and it is not possible to distinguish responders in advance. Neuropharmacology in TBI: What We Know and What We Don’t.

Agents to Improve Arousal Anecdotes from My Practice:
Vitamin A Methylphenidate Have not integrated zolpidem because I cannot identify responders in advance For milder injuries Provigil as a general wakefulness-promoting agent Preferred in the elderly over methylphenidate Start test dose of 50mg at 7am, then increase slowly to max of 100mg at 7am and noon Can linger, so eliminate afternoon dose if trouble sleeping Methylphenidate if attention also an issue Comorbid depression Activating antidepressants, such as venlafaxine Start 25mg daily, then increase to 150mg total daily dose Can also support blood pressure if orthostasis an issue Neuropharmacology in TBI: What We Know and What We Don’t.

Withdrawing of Agent Standard of practice is to disentangle natural recovery from medication effect. Role of drug holiday Anyone on a neurostimulant deserves a drug holiday to see if natural recovery caught up or not. Acute rehab phase is a good time because have feedback from interdisciplinary team Mostly for short-acting meds Caveat is donepezil: if patient is on the agent and is making gains in language function, usually just continue through acute rehab phase Evidence of no sustained effect Always better to be on fewer meds When in doubt, stop it! Neuropharmacology in TBI: What We Know and What We Don’t.

Neuropharmacology in TBI: What We Know and What We Don’t.
Heidi Fusco, MD Assistant Professor of Rehabilitation Medicine Mount Sinai Rehab Hospital and Icahn School of Medicine

Agents to Support Behavioral Function Recovery:
What We Know and What We Don’t.

There exists in the literature excellent reviews:
Chew E1, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury--a state-of-the-art review. J Rehabil Res Dev. 2009;46(6): Wheaton P, Mathias JL, Vink R.Impact of pharmacological treatments on cognitive and behavioral outcome in the postacute stages of adult traumatic brain injury: a meta-analysis.J Clin Psychopharmacol Dec;31(6): Presentation Title Goes Here

Agents to Support Behavioral Regulation
Propranolol Amantadine Methyphenidate Valproic Acid Quetiapine

Agents to Support Behavior What We Know:
Behavior problems include: agitation, restless, irritability, aggression, disinhibition. Reported incidence of agitation after brain injury is 10-96% in literature (Baguley et al 2006, Fleminger et al 2006, Singh et al 2014). Significance: affects participation in brain injury rehabilitation and discharge disposition. Neuroanatomy: injury to prefrontal, biorbital frontal, temporal lobs associated with agitation.

Treat the treatable causes. Neurologic Environment: Too much or not enough stimulation, i.e. room changes, restraints Sleep disorders: Insomnia, sleep behavior disorder, daytime somnolence Medical: infectious, metabolic, endocrine, nutritional, bowel and bladder Pain: headache, neuropathic/central, multi-trauma, feeding tube, ulcer, spasticity, thrush, contracture, arthritis, GI related, etc. Mood: anxiety/depression and lack of emotional regulation Language: not being able to communicate needs Medications: that have CNS side effects

There is evidence suggesting some medications have deleterious effects on brain injury recovery. Kline et al “Chronic administration of antipsychotics impede behavioral recovery after experimental traumatic brain injury.” Rao et al “Agitation in closed head injury: haloperidol effects on rehabilitation outcome.” Hoffman et al “Administration of haloperidol and risperidone after neurobehavioral testing hinders the recovery of traumatic brain injury-induced deficits.” Benzodiazepines impair cognitive function and worsen confusion (Larson et al 2010, Bryczkowski et al 2014, McNett et al 2012). Diphenhydramine can cause paradoxical agitation and elderly, patients with dementia or with brain injury due to anticholinergic effects (Rothberg 2013, Chen 2012, Ochs 2011).

There is recent evidence supporting pharmacological management of aggression and agitation. Fleminger et al 2008: Cochrane review examined studies documenting effects of beta blockers, Methylphenidate and Amantadine on agitation and aggression Found best evidence for beta blockers: pindolol and propranolol during early and late injury. Later, Meta-analysis by Patricia Wheaton, et al 2011 found sportive studies for stimulant methylphenidate in reducing agitation and aggression.

Amantadine found to have supportive evidence in reducing irritability and aggression. Hammond et al, October 2014, JHTR Amantadine 100 mg every morning and noon is effective and safe in reducing frequency and severity of aggression and irritability (with sufficient CrCl) N=76, parallel-group, randomized, double-blind, placebo-controlled trial Greater than 6 months post TBI Ages 16-65, 28 days of treatment CrCl > 60m/dL Aggression and irritability measured on NPI-1, and NPI-A and NPI- Distress Found significantly reduced irritability and aggression in the amantadine group Questioned raised- does amantadine improve aggression by improving cognitive function, still no support for this. Amantadinen 100 at 8 and noon vs. placebo

Valproic Acid found to have supportive documentation in reducing irritability and aggression. Showalter and Kimmel, 2000 Case series N=29 describing valproic acid for agitation Prior to treatment, all patients had received benzodiazapines and/or neuroleptic, no control of agitation All patients started with ABS scores 30-40’s Majority (around 60%) of patients had resolved agitation within 7 days after achieving mean dose of 1257mg/day Subgroup (30%) had resolution of agitation symptoms with mean dose of 714mg/day and then dose continued Depakote has new data in animal models as protecting against cell death and oxidative stress after brain injury. (Lee et al 2014, Zhang et al 2014)

Agents to Support Behavior What We Don’t Know:
What do we do when patient refuses all oral medications (valproic acid, amantadine and propranolol doesn’t come IV/IM). What is long term effects of atypical antipsychotics on neurorecovery? While haloperidol, a typical antipsychotic that primarily blocks D2, atypical antipsychotics, such as quetiapine and olanzapine exert effect over many receptor sites which include the serotonergic , dopaminergic, histamine, aplha-1 adrenergic, and muscarinic receptors. This is better, as we usually are trying to promote dopamine, but we do not have literature on these agents in the long term. Literature includes atypicals combined with haloperidol. Olanzapine may be beneficial in treating agitation with psychosis after TBI, limited evidence to support this, Umansky, 2000.

Agents to Support Behavioral Practice recommendation:
Most importantly: omit contraindicated drugs, modify environment, and treat medical/mood disorders. If patient still presents as mildly agitated, with intermittent behavioral confusion and poor motivation Trial amantadine, start 50 mg in morning and at noon, observe effect for 2-3 days, then increase to 100 in morning and at noon.

Agents to Support Behavioral Practice recommendation:
If patient presents as mildly agitated, with intermittent behavioral confusion and poor motivation and depression Trial methyphenidate. I start 2.5mg at 8 and noon, and increase by 5 mg total per day every 2 days until patient participating in therapy. Per literature recommendations, 0.3mg/kg per day in divided doses (around 20mg total/day for 70 kg person). With both these medications: Can make more/less confused. Can make more/less irritable. Side effects of methylphenidate include irritability, poor sleep, appetite suppression. Side effects of amantadine include orthostatic hypotension, livido reticularis, QTC prolongation. Watch CrCl.

Agents to Support Behavior Practice recommendation:
If patient presents as severely agitated and confused, refusing medications and therapy Start Beta-blockers (propranolol). Patients will usually take for blood pressure. Start mg QID and hold for SBP<110 and HR<60. Increase until effective, within BP and HR parameters. Start QID in case patients miss a dose. Not q 6, do not wake a patient up for agitation mediations. Monitor for hypotension, sleepiness or depression. Contraindicated in asthma, heart block/cardiac.

Agents to Support Behavior Practice recommendation:
Valproic Acid: Is an AED/Mood stabilizer/treats headaches Prefer over other AEDS as other AEDs can cause (agitation and confusion and cognitive impairment. Short acting, comes in ER and Sprinkles. If patient presents as severely agitated and aggressive, and refusing medications: I start 250 BID or TID for patients age>65 and 500 BID or TID<65. Continue for 4 days of dosing and then check LFT, valproic acid level and CBC. Dose valproic acid for agitation less than 125ug/mL (but if also used for sz ppx needs to be > 50ug/mL). Eventually, as patient leaves agitated stages of recovery, try to wean off, or convert to BID dosing. Levetiracetam and phenytoin Why TID- because patients usually miss/refuse a dose- “take for headaches, or sz.”

Agents to Support Behavior Practice recommendation Note:
Valproic Acid has life threatening side effects. Easily monitored. Check LFT, valproic acid level and CBC after 4 days and then q week for 4-8 weeks until stable. Can cause elevated LFTs, leukocytopenia and elevated ammonia level. Can induce PCOS symptoms and is teratogenic (Hu et al 2011) (I do not routinely discharge female patients home on valproic acid) If patient presents with severe agitation and delirium Trial quetiapine, but with close monitoring (EKG q day or TIW) and WBC (q week). Start 25 BID and increase as needed with 12.5 q 6. If above + psychosis and hallucinations: olanzapine (5mg qhs). Why TID- because patients usually miss/refuse a dose

Agents to Support Behavior Summary of Take Home Points from the Literature:
Agitation is fairly common after brain injury, with incidence of 10-30% and in some reports 90%, and poses a danger to the patient and caregivers, interferes with rehabilitation, and affects disposition. Clinician must evaluate and treat for treatable of agitation/behavioral problems that include environment, neurologic, metabolic, pain, medication, etc. Stable environment is key as well as removing contraindicated medications. Amantadine, methylphenidate, propranolol, valproic acid have evidence for treatment of agitation after brain injury. Quetiapine can be used in severe cases of severe agitation, however olanzapine has slightly more support when agitation exists with psychosis. Check levels, CBC and LFT as well as EKG where indicated. Remember rules for any medication use: Start low and go slow, and remove when agents agitation begins to resolve.

Agents to Support Cognitive Recovery:

Agents to Support Cognitive Recovery:
Cognition is: Attention and Processing Speed Memory Executive Functioning Scher et al 2011

Agents to Support Attention and Processing Speed
Methyphenidate Atomoxetine Bromocriptine Amantadine Donepezil Rivastigmine Piracetam: GABAergic

Agents to Support Attention and Processing Speed What We Know:
The evidence for the efficacy of Methyphenidate is supportive. Point counter/point by Dr. William Walker: Willmott and Ponsford 2006 demonstrated significant effect of methyphenidate on processing speed in patients with severe TBI during acute rehab N=20, mod-severe TBI, RCT on inpt unit Methyphenidate 0.3mg/kg dosed twice per day over 2 weeks Found enhanced processing speed Most effective in patients with slower processing speed Later analysis in 2009 by Willmott and Ponsford et al, found to be safe (HR, BP) Whyte et al 2004, chronic TBI N=34 Mod TBI, yrs TBI at least 3 months prior Found positive effects on processing speed, caregiver ratings of attn. Later analysis demonstrated safe, but recommended BP and HR monitoring (Alban, Hopson, Ly and Whyte et al 2004)

Neuropharmacology in TBI: What We Know and What We Don’t. The evidence for the efficacy of Methyphenidate is supportive. INCOG (international team of researchers and clinicians) only recommends Methyphenidate for attention and processing speed (JHTR, Ponsford et al 2014). Theory: TBI disrupts function of frontotemporal and midbrain reticular formation. Again,0.3 mg/kg in divided doses for inpt and post acute, ages 16-60 Methylphenidate use not demonstrated to increased sz frequency (Van der Feltz-cornelis, 2006). New animal studies suggest methyphenidate might be neuroprotective when administered shortly after TBI (improve axonal sprouting, reduction of pro-inflammatory signals, Rau et al 2014, Kim et al 2011). Neurologic severity: foot fault errors MRI reports- not sure how to interpret

Agents to Support Attention and Processing Speed What We Don’t Know:
Neuropharmacology in TBI: What We Know and What We Don’t. The evidence for the efficacy of Methyphenidate is supportive, but it is unclear when to start. In point counter/point by Dr. William Walker: Start methylphenidate in acute rehab In counter point, Dr. Flora Hammond: Although methylphenidate can help improve processing speed, does not improve working memory or errors There is no evidence supporting methylphenidate's effect on functional outcome and disposition from acute rehab Concern over increase in irritability and affect on sleep We also do not have recommendations for use in patients > 65 years of age.

Neuropharmacology in TBI: What We Know and What We Don’t. The evidence for the efficacy of other catecholaminergics is mixed. Atomoxetine is new agent, pure norepinephrine reuptake inhibitor, and thought to exert effect by increasing noradrenergic activity in the locus ceruleus and in the prefronal cortex. Not Scheduled II medication and does not require monthly prescriptions. In theory, has a limited abuse potential, and limited SE. Ripley et al 2014, studied Atomoxetine for attention deficits after brain injury Dose was 40 mg BID, randomized double blind. N=55, > 1 year from injury with complaints of attention deficits. Results: Atomoxetine did not significantly improve performance on measures of attention. In a review, Ripley 2014 found Atomoxetine is: Not superior to methylphenidate in children with ADHD; ?Effects in brain injury. No clinical studies in DOC for arousal. In combo with SSRI, beneficial for depression in non TBI.

Agents to Support Attention Recovery What We Know:
Donepezil has some evidence for attention and memory recovery. Donepezil 10 mg/day found to improve sustained attention in post acute (Zhang et al 2004). 24 week, RCT, double blind crossover N=18 post acute TBI Donepezil x 10 weeks then placebo x 10 weeks then washout x 4 weeks Found donepezil increased neuropsych testing scores Subjective improvement and improvement in processing speed, verbal memory and divided attention with treatment of donepezil, N=10, (Khateb et al 2005). Donepezil found to impair cognition in patients with normal cognition (Beglingert et al 2005).

Agents to Support Attention and Processing Speed What We Don’t Know:
Why is atomoxetine not superior than methyphenidate? Do dopaminergic effects of methylphenidate have more roll in attention, that atomoxetine doesn’t have. Dextroamphetamine, amantadine, bromocriptine have variable (positive or nonsignificant) results in literature and need more clinical studies.

Agents to Support Attention and Processing Speed (Methylphenidate) Practice Recommendations:
When prescribing for slow processing speed, if I am concerned with cardiac, I start 2.5 at 8 and noon, then slowely increase by 5mg total every other day. Continue to titrate up to 5-10 mg at 8am and noon while inpt, or 5 mg total a week as outpatient. Never order it BID or Q12. When need authorization for outpatients need dx of ADD/ADHD. Regarding decreased po intake, I often find it wakes patients up enough to eat and participate in therapies (promotes GI tract function). If patient also has with depressive sx, start as same time as low dose SSRI to bridge onset time of ssri. Although documented to not cause sz, still wary

Agents to Support Attention and Processing Speed Summary of Take Home Points from the Literature:
Methylphenidate relatively safe, and recommended to improve attention, processing speed, concentration and vigilance but limited evidence that it improves functional outcome. Atomoxetine does not significantly improve performance on measures of attention. Cholinesterase inhibitors have preliminary evidence for recovery of attention.

Agents to Support Memory Recovery:

Agents to Support Memory Recovery
Catecholaminergics Methyphenidate Dextroamphetamine Mixed amphetamine salts Cholinergics Donepazil Rivastigmine

Agents to Support Memory Recovery What We Know about Memory:
Working Memory: Attending to a stimulus no longer present In theory, improving attention and processing speed will improve working memory Declarative Memory Encoding, consolidation, and recall of facts, events and personal information In theory, augmenting cholinergic pathway may be useful Procedural Memory Learning, storing and retrieval of motor sequences All research underway

Agents to Support Memory Recovery What We Know:
In a pilot study, patients with CVA taking donepezil had significant improvements in the MMSE and FMRI showed increased activation in various regions. Chang et al, 2011 Purpose: evaluate effect of donepezil on cognitive impairment in patients with right hemispheric stroke 14 patients with right hemispheric stroke Donepezil 5mg daily or placebo x 4 weeks fMRI performed before and after Results: Donepezil group had significant improvements in MMSE during post-treatment evaluation compared to pretreatment evaluation FMRI showed increased activation in prefrontal areas, inferior frontal lobes and inferior parietal lobe

Acetylcholinesterase inhibitors have mixed evidence in supporting memory recovery in TBI Zhang et al 2004, as discussed previously supported Donepezil. Physiostigmine and Lecithin have not been supported in the literature (Chew and Zafonte 2009). Rivastigmine without effect (next slide).

Rivastigmine did not demonstrate evidence in recovery after TBI (Silver et al 2006). Rivastigmine is inhibitor of acetycholinesterase and butyrylcholinesterase Theory: Cholinergic innervation of cerebral cortex (nucleus basalis of meynert) plays role in attention and memory N=157, RCT, double blind > 12 months post TBI (post acute) Outcome measures CANTAB, RVIP, HVTL (neuropsych measures) Gave 3-6mg/day vs placebo over 12 weeks Post hoc analysis found benefit in verbal memory in the more impaired patients (>25% impairment on the HVLT at baseline) Later analysis in 2009 revealed rivastigmine dosed up to 38 weeks is safe

Patients with CVA who received Escitalopram, compared with placebo, had higher scores in tests of global cognitive functioning, especially verbal and visual memory. Jorge et al, 2010: Age years old Treatment began within 3 months of stroke and continued for one year Three groups Placebo Problem solving therapy Escitalopram 10mg in the AM if < 65 and 5mg in the AM if > 65 Outcome measures: Repeatable Battery for Assessment of neuropsychological Status: a minute battery Functioning in 5 domains (immediate memory, visuospatial/constructional, language, attention, and delayed memory) Domains evaluated in 12 individual subtests Age corrected norms Results: Compared with placebo or PST, escitialopram group had higher scores in all areas, especially verbal and visual memory Not influenced by stroke type Independent of effect of depression

INCOG guide lines recommendations: (International group of researchers and clinicians with published recommendations for management if cognition after TBI, summer 2014 in JHTR) Compensatory strategies Environmental supports and reminders Consider the specifics of the person, for prescribing the aids Key Instructional practice Group based interventions for mild to mod memory deficits Restorative techniques have no supporting evidence No mention of medications

Agents to Support Memory What We Don’t Know:
Mixed study results on memory improvement with methylphenidate (Chew and Zafonte 2009). Donepezil, rivastigmine and other cholinesterase inhibitors also have mixed effects on memory Role of memantadine or amatadine?-only 1 small study with memantadine and patients with brain injury New studies on CDP-choline, and nicotinic agonists and histamine antagonists underway

Agents to Support Memory Practice Recommendations:
Treat attention and processing speed deficits with medications (which may in turn improve working memory). Compensation technique and environmental cues most useful. If memory impairments and weakness/cognitive dysfunction due to CVA, trial donepezil: 5mg x 4 weeks then increase to 10mg Caution: Bradycardia or if on av nodal blocking agents, and have seen it cause agitation and aggression Trial escitalopram if CVA, depression, and poor memory. Donepezil agent of choice in patients with CVA, cognitive and linguistic deficits.

Agents to Support Memory: Summary and take home points
Need additional studies to support use of medications for memory recovery after traumatic brain injury. Escitalopram and Donepezil are supported in the literature for memory recovery in CVA.

Agents to Support Executive Function:

Agents to Support Executive function What We know:
There exits evidence to support use of amantadine. Meythaler et al 2002 found amantadine improved neurorecovery in TBI with DAI in Double-Blind randomized crossover 6 week trial 35 patients with TBI, GCS of 10 or less Amantadine 200mg/day/placebo given in first 6 weeks or 2nd 6 weeks Improved MMSE, DRS, GOS, and FIM cognitive Score in amantadine group in first 6 weeks, and no improvement in next 6 on placebo. No sig effect on GOAT In group on amantadine in weeks 6-12, statistical sig improvment in MMSE, DRS, GOS, an FIM cog after active drug No sig effect on GOAT Conclusion: rapid functional improvement on amantadine when given in first 3 months after injury

Agents to Support Executive function What We know:
There exits evidence to support use of amantadine. Kraus et al 2005 found improvements of tests of executive function after treatment with amantadine in patients with chronic TBI N=22, amantadine 200mg BID Outcome measures: neuropsychological testing (pre and post-12 week treatment) and PET scanning on 6 participants Results: Significant improvements on tests of executive function Analysis of PET data demonstrated significant increase in left prefrontal and medial temporal cortex glucose metabolism This correlated with improvement in measures of executive function Memory and attention did not significantly improve

Agents to Support Executive function
The evidence to support the use of Atomoxitine is limited and conflicting. In animal models with experimental TBI, low dose atomoxetine attenuated cognitive deficits after experimental TBI in a water maze study (Reid and Hamm 2008) Performed worse with higher doses No effect when started 11 days post injury However: remember Ripley et al, 2014: In adults with TBI at least 1 year from injury atomoxetine dosed at 20 mg 2 x /day for 2 weeks did not improve scores on measures of attention (Ripley et al, 2014)

Agents to Support Executive function What We Know:
Citicoline does not improve cognition and function when used acutely or subacutely. Citicoline is an endogenous compound, thought to have neuroprotecticve properties. Citicoline is an approved therapy for TBI in 59 countries COBRIT: Citicoline Brain Injury Treatment Trial was a large phase 3 double blind, RCT among 1213 patients at 8 US trauma centers to investigate Citicoline vs. placebo in pts. with TBI (mild, mod and severe), Zafonte et al 2012 90 days if citicoline 2000mg vs placebo initiated within 24 hours of injury At 90 days measured TBI clinical trials network core battery (trails a and b, GOS-E, COWAT, CVLT, PSI, DS and WAISIII, Stroop 1 &2) At 90 days there was no sig difference btwn 2 groups on the battery Favorable imrpovement for the GOS-E in the citicholine group COBRIT questions worldwide use of Citicholine Only theories as to why Citicoline was not beneficial:

The evidence to support the use of bromocriptine is limited McDowell et al 1998 examined low dose bromocriptine on frontal lobe (working memory and executive function) N=24, double blind placebo controlled crossover Gave bromocriptine 2.5 mg with testing 90 minutes later Bromocripine improved tests of executive function and dual task performance, but not working memory or attention

The evidence to support the use of SSRIs is limited. Horsfield et al 2002 studied Prozac mg/day after TBI N=5, 8 months Cog and Memory tests: at baseline and after 8 months: Trails A, attention motor speed test, part of WAIS II, Some portions of test, but need addtiional research Sertraline caused psychomotor slowing in further studies (next slide)

Agents to Support Executive Function What We Don’t Know:
Conflicting results in the literature. Large recent meta-analysis “Impact of Phamacolological Treatemtns on Cognitive and Behavioral Outcome in the Postacute States of Adult TBI,” Wheaton et al 2011, found: SSRIs: Citalopram and carbamezepine improve psychosocial function. Serotonin increases post concussive sx and decrease psychomotor speed. Milnacipran (serotonin and Noradren) improvement on cog testing (MMSE). Dopaminergics: Methyphenidate supported for psychosoical, cognitive, but mixed results on attention. Amantadine improved global outcome on DRS (Maythaler 2002). Cholinergic: Support of donepazil for attention and memory (Zhang et al 2004), but no improvement with physiostigmine and lecithin. Peptide Treamtents: Lysine/vasopressin had 1 study supporting improved memory, cerebrolysine improved memory and attention, no studies support desmopressin use. CDP-Choline may improve memory, but impair attention.

Agents to Support Executive function Summary and Practice Recommendations:
Amantadine has most support for improving executive function after TBI, but is not supported in memory or attentional recovery. It is unclear how bromocriptine improves executive function. Citicoline and atomoxetine do not have literature that supports use in promoting cognitive function after TBI. When treating executive function deficits, it is important to treat other impairments (emotional and behavior disturbances and motor dysfunction). The literature is limited in medication use to treat executive function deficits.

Consider Costs For Treatments That Are Not Guaranteed
Amantadine: $2-8 per day Bromocriptine: $2-8 per day Donepazil: $8-14 per day Rivastigmine: $3-6 per day CDP choline: pennies per day Sertraline: $21 per month Prozac: is $13 per month Valproic acid: $60 per month Propranolol: $4 per month From (Wortzel and Arcinegas 2012 Goodrx.com)

Summary of Take Home Points (1/4)
SSRI’s have utility in non-depressed patients with stroke, with good functional results. FLAME trial showed that in patient with ischemic stroke and moderate to severe motor deficits, the early prescription of fluoxetine with physical therapy led to enhanced motor recovery after three months. Patients treated with citalopram for three months post stroke had a better recovery from disability one year after stroke than patients who did not receive antidepressant therapy. Citalopram can enhance dexterity in chronic stroke patients. Donepezil may improve the FIM motor score in elderly cognitively impaired patients post stroke. Reboxetine induced a significant improvement in tapping speed and grip strength in ten patients with chronic stroke. Currently there is limited evidence for supporting or refuting the use of levodopa to support post-stroke motor recovery. Currently there is limited evidence for supporting or refuting the use of amphetamines to support post-stroke motor recovery.

The evidence for the efficacy of dopaminergic agents in aphasia therapy is mixed. Donepezil has been shown to improve the severity of aphasia and motor aspects of speech in poststroke aphasia. Memantine alone or combined with constraint-induced aphasia therapy in chronic poststroke aphasia patients improved aphasia severity. These effects persisted on long-term follow-up. Melatonin has value for sleep disorders following head injury. Trazodone is a multifunctional drug that helps patients with TBI sleep. Amantadine is the agent of choice for treating profound hypoarousal following TBI, especially when a patient has a disorder of consciousness. Amantadine and/or methylphenidate may improve emergence from coma in hypoxic ischemic encephalopathy resulting from cardiac arrest. A very small number of patients with disorders of conscious are responders to zolpidem, and it is not possible to distinguish responders in advance.

Agitation is fairly common after brain injury, with incidence of 10-30% and in some reports 90%, and poses a danger to the patient and caregivers, interferes with rehabilitation, and affects disposition. Clinician must evaluate and treat for treatable of agitation/behavioral problems that include environment, neurologic, metabolic, pain, medication, etc. Stable environment is key as well as removing contraindicated medications. Amantadine, methylphenidate, propranolol, valproic acid have evidence for treatment of agitation after brain injury. Quetiapine can be used in severe cases of severe agitation, however olanzapine has slightly more support when agitation exists with psychosis. Check levels, CBC and LFT as well as EKG where indicated. Remember rules for any medication use: Start low and go slow, and remove when agents agitation begins to resolve. Methylphenidate relatively safe, and recommended to improve attention, processing speed, concentration and vigilance but limited evidence that it improves functional outcome.

Atomoxetine does not significantly improve performance on measures of attention. Cholinesterase inhibitors have preliminary evidence for recovery of attention. We need additional studies to support use of medications for memory recovery after traumatic brain injury. Escitalopram and Donepezil are supported in the literature for memory recovery in CVA. Amantadine has most support for improving executive function after TBI, but is not supported in memory or attentional recovery. It is unclear how bromocriptine improves executive function. Citicoline and atomoxetine do not have literature that supports use in promoting cognitive function after TBI. When treating executive function deficits, it is important to treat other impairments (emotional and behavior disturbances and motor dysfunction). The literature is limited in medication use to treat executive function deficits.

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Neuropharmacology In TBI: What We Know & What We Don’t

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Neuropharmacology In TBI: What We Know & What We Don’t

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