Amphetamines for Recovery of Cognition in Chronic Traumatic Brain Injury: Speeding Up Recovery

Michaela C. Lysogorski, PharmD PGY1 Pharmacy Resident

South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center The University of Texas Health Science Center San Antonio

January 20, 2017

Learning Objectives 1. Describe the epidemiology and pathophysiology of traumatic brain injury (TBI)2. Examine amphetamine pharmacology and interpret the pharmacologic basis for their utility in TBI treatment3. Critically evaluate available evidence describing the role of amphetamines in TBI patients4. Apply evidence-based findings and provide appropriate treatment recommendations regarding the use of

amphetamines in patients with chronic TBI

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Traumatic Brain Injury1

I. Traumatic brain injury (TBI) is a traumatically induced structural injury and/or physiological disruption in brain function as a result of external force and is indicated by new onset or worsening of at least one of the following clinical signs immediately following the event

a. Any period of loss or decreased level of consciousness b. Any loss of memory for events immediately before or after the injury c. Any alteration in mental state at the time of the injury

i. Confusion ii. Disorientation

iii. Slowed thinking d. Neurological deficits that may or may not be transient

i. Weakness ii. Loss of balance

iii. Change in vision iv. Praxis v. Paresis/plegia

vi. Sensory loss vii. Aphasia

e. Intracranial lesion II. Classification of TBI Severity

Table 1. Severity of TBI1

Criteria Mild (mTBI) Moderate Severe Structural Imaging Normal Normal or abnormal Normal or abnormal

Loss of Consciousness (LOC) 0-30 min >30 min and <24 hours >24 hours Alteration of Consciousness/

mental state (AOC)* Up to 24 hours >24 hours; severity based on other criteria

Posttraumatic amnesia (PTA) 0-1 day >1 and <7 days >7 days Glasgow Coma Scale (GCS)** 13-15 9-12 <9 Note: if patient meets criteria in more than one category of severity, the higher severity level is assigned * alteration of consciousness must be immediately related to trauma to the head ** best available score in first 24 hours. GCS Scoring System located in Appendix A

III. Post Injury Periods a. Immediate: 0- 7 days post injury b. Acute: 1-6 weeks post injury c. Post-Acute: 7-12 weeks post injury d. Chronic: > 12 weeks post injury

Epidemiology2-7

I. Estimated prevalence a. 1.5-2 million cases occur in the United States each year b. 2.5-6.5 million Americans currently live with disabilities related to TBI

II. Morbidity/Mortality a. 375,000 hospitalizations per year b. Complications of TBI can prevent a return to premorbid level of function

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c. Leading cause of death in patients under age 45 d. Death rates are highest in patients 75 years of age and older

Table 2. Morbidity/Mortality Associated with TBI Severity6

Injury Severity Morbidity/Mortality Mild 5-10% likelihood of death or vegetative state; 85% chance of moderate disability

Moderate Variable Severe 85% chance of death or remaining vegetative at GCS scores < 5

III. Cost a. CDC estimates annual cost of TBI is $56.3 billion b. Indirect costs due to lost productivity may drive the annual cost up to $100 billion

Pathophysiology of TBI3,4,8-23

I. Causes of TBI

II. Vulnerable Brain Regions

Falls40%

Assaults11%

Motor Vehicle Accidents

14%

Sports Injuries16%

Other/ Unknown19%

Dorsolateral prefrontal cortex (executive function, working memory,

sustained/complex attention, memory retrieval, abstraction, judgment, insight, problem solving)

Amygdala (emotional learning and memory,

fear conditioning)

Orbitofrontal cortex (emotional and social responding,

social behavior) Temporal polar cortex (memory retrieval, sensory-limbic

integration)

Entorhinal-hippocampal complex (declarative memory, sensory gating,

attention)

Ventral brain stem (arousal, ascending modulatory

neurotransmitter systems)

Cerebellum (coordination, working

memory, mood regulation)

Figure 1. TBI Causes

Figure 2. Brain regions vulnerable to TBI and associated Sequelae Adapted From: McAllister et al, 2011.15

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III. Mechanism of injury a. Primary Injury

i. Describes the type of trauma occurring at the time of insult and can be sub-divided into the following

1. Focal lesions a. Associated with blows to the head producing hematomas and cerebral

contusions b. Most common contusions occur in the frontal lobes and temporal lobes c. Impact on morbidity and mortality determined by location, size, and progression d. May produce focal cognitive and sensory motor deficits

2. Diffuse axonal injury (DAI) a. Extensive white matter damage due to shearing forces that traverse large areas

of the brainstem (see Appendix B) b. Primarily responsible for initial loss of consciousness c. Commonly produced by motor vehicle accidents and can occur without any

striking to the head d. Axons are not torn at the moment of injury, but rather undergo sequential, focal

changes that lead to swelling and disconnection over multiple hours after injury, eventually leading to degeneration of downstream fibers

ii. In clinical practice, focal lesions and diffuse axonal injury frequently coexist iii. Deficits related to DAI tend to recover over an extended period of time whereas the recovery

related to focal lesions/contusions depend on size and location b. Secondary injury relates to biochemical neuronal damage that progressively develops following injury due to

systemic physiologic responses to injury and results in more severe and widespread brain damage i. Depending on the location of injury, damage can occur to a variety of neurotransmitter

networks involved in cognition ii. Damage leads to release of biochemical substances which initiate continued cell membrane

breakdown and ionic shifts leading to neuronal death 1. Biochemical substances include excitatory amino acids, cytokines, and free radicals 2. Electrolyte disturbances noted include potassium, sodium, calcium, and magnesium

Neurophysiology of Secondary Injury9,11,15,20

I. Catecholaminergic a. Neurotransmitters of catecolaminergic pathways

i. Dopamine (DA) 1. Slow, continuous release enhances response to environmental cues

a. Agonism of D1 and D2 receptors in the prefrontal cortex (PFC) is implicated in working memory

b. Receptors in the hippocampus facilitate maintenance of long term potentiation, which is a critical step in memory formation

2. Levels initially rise after TBI, followed by a hypodopaminergic functional state at 2 weeks post-injury

3. Reuptake via dopamine transporter (DAT) is the primary mechanism controlling DA half-life

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ii. Norepinephrine (NE) 1. Role in cognition

a. High affinity for alpha 2 adrenergic (A2A) receptors, with stimulation increasing neuronal signaling

b. Conversely, stimulation of alpha 1 adrenergic (A1A) receptors impairs working memory

2. Levels initially rise after injury, followed by reduction in chronic phase 3. Norepinephrine transporter primarily controls reuptake

b. Mechanisms of Impairment in TBI i. DA and NE modulate cognitive functions commonly impaired in TBI victims

1. Information processing speed 2. Attention 3. Memory and learning 4. Executive function

ii. Catecholaminergic neurons originate and project into areas commonly impacted by primary insult iii. Increased susceptibility of catecholaminergic neurons to disruption

1. Dopaminergic neurons and axons have high baseline activity, causing mitochondrial stress and increased vulnerability to neurotoxins when the brain is under acute stress

2. Axon length and diffuse projection patterns lead to increased propensity for shearing 3. Neuronal projections are poorly myelinated, making them more susceptible to injury

iv. Abnormalities in catecholaminergic systems noted following TBI 1. Dopaminergic pathways

a. 25% reduction in neurons noted 28 days post-TBI b. Reductions in DA release in surviving neurons proposed to be related to a reduced

amount of DA per vesicle c. Impaired DAT and D2 receptor binding

2. Noradrenergic pathways a. Studies are more limited, with less consistent findings b. During stress or fatigue, noradrenergic neuron firing loses specificity and occurs in

response to off-task and task-relevant stimuli, leading to increased distractibility c. Reduced norepinephrine turnover in chronic phase, alterations in A1A receptor

binding, and neuronal cell loss may also play a role II. Cholinergic Systems

a. Acetylcholine (ACh) i. Role in cognition

1. Sustained attention a. Learning and reaction time b. Memory performance

2. Levels initially rise during excitotoxic period post head injury, but are depleted over time ii. Impairment in TBI

1. Vulnerability to damage in part mediated by physiology of cholinergic neurons a. Neurons use choline to form ACh and to form cell membranes b. Choline depletion following excitotoxicity may cause neurons to use choline found

in cell membranes for ACh synthesis, leading to neuronal death

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2. Animal studies of damage isolated to areas densely populated by cholinergic neurons have demonstrated memory deficits, which are reversed by administration of an acetylcholine agonist

3. Mechanisms of impairment include c. Reduced cholinergic receptor expression d. Impaired affinities of muscarinic receptors e. Decreased levels of ACh

III. Serotonergic Pathways a. Serotonin

i. Role in cognition 1. Implicated in aversive learning 2. Deficits can indirectly lead to impaired cognition due to depression

ii. Levels increase during excitotoxicity period following TBI and decrease over several weeks post injury b. Serotonergic projections from the brainstem enter the cerebral cortex through common sites of contusion

during TBI, which is postulated to contribute to neurocognitive and neurobehavioral impairment Complications of TBI7,9,15

I. Acute a. Elevated Intracranial Pressure (ICP), hydrocephalus, and seizures b. Hyponatremia c. Hypertension d. Hypothalamic and endocrine dysfunction e. Bowel and bladder dysfunction f. Increased muscle tone and contractures

II. Chronic (see Appendix C) a. Neurocognitive and neurobehavioral deficits

i. Most common complaint following TBI, presenting challenges to independent living, social re-adaptation, and return to work

ii. Manifestations include 1. Impairments of

a. Arousal & attention b. Learning & memory c. Frontal executive function d. Language & communication

2. Substance abuse, depression, anxiety, and other psychiatric disturbances b. Decreased Level of Consciousness and Motivation c. Impaired mobility

Treatment of Neurocognitive & Neurobehavioral Deficits of TBI1,4,24-26

I. Clinical Guidance Tools a. Department of Defense (DoD) Neurotrauma Pharmacology Workgroup, 2014

i. Identified methylphenidate as one of the leading drug candidates for traumatic brain injury treatment based upon review of 13 small randomized controlled trials yielding promising results

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b. VA/DoD Practice Guidelines, 2016 i. Focus solely on mTBI

ii. Patients should receive a short-term trial of cognitive rehabilitation treatment to assess responsiveness to strategy training, including memory aids and cognitive assistive technologies

iii. Do not offer medications to ameliorate neurocognitive effects attributed to mTBI c. Colorado Department of Labor and Employment, 2012

i. Stimulants, cholinesterase inhibitors, or dopamine enhancers may be considered in some cases of TBI with impaired cognitive function

ii. Methylphenidate and other amphetamines are among the agents suggested II. Non-Pharmacologic Treatment

a. Cognitive Rehabilitation Therapy i. Most consistently recommended modality for patients with cognitive symptoms that do not

resolve within 30 to 90 days and have been refractory for treatment of other conditions ii. Often includes a multidisciplinary team including Neuropsychologists, Occupational Therapists,

and Speech-Language Pathologists b. Psychoeducation c. General Health Management (e.g. diet, exercise, management of comorbid conditions)

III. Pharmacotherapeutic Treatment Options a. There are no FDA approved medications for the treatment of neurocognitive and neurobehavioral

consequences of TBI

Table 3. Pharmacotherapy of Behavioral & Cognitive Consequences of TBI24

Drug Class Agents Used Deficit Targeted Selective Serotonin

Reuptake Inhibitors (SSRIs) Sertraline and Citalopram have been most frequently

studied Motor speed, recent memory deficits, attention, depression

Serotonin and Norepinephrine Reuptake

Inhibitors (SNRIs) Duloxetine and Venlafaxine Motor speed, recent memory

deficits, attention, depression

Antiepileptics Divalproic Acid, Valproate, Carbamazepine, Lamotrigine, Levetiracetam

Problem solving, recent memory deficits, behavioral

Beta Blockers Propranolol Agitation, aggression Tricyclic Antidepressants

(TCAs) Amitriptyline and Desipramine have been most studied Agitation, pain

Anti-Parkinsonian Drugs

Amantadine Attention, concentration, alertness

Carbidopa/Levodopa Vegetative state and coma

Bromocriptine Speech deficits, restlessness, vegetative state, akinetic mutism

Acetylcholinesterase Inhibitors Donepezil, Galantamine, Rivastigmine Memory, attention, general

cognition

Stimulants Modafinil, Armodafinil Memory, motor, attention deficits

Methylphenidate, Amphetamine/ Dextroamphetamine, Dextroamphetamine salts, Lisdexamfetamine Attention and memory deficits

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Pharmacology of Amphetamines6,17,18,27

I. Rationale for Stimulant Use in TBI a. In attention deficit disorder (ADD), stimulants improve symptoms of inattention, distractibility,

disorganization, and hyperactivity b. Clinical parallels can be drawn between ADD and TBI in their behavioral, psychologic, and cognitive

symptoms, providing a symptomatic rationale to test the efficacy of stimulants in TBI patients II. Mechanism of Action

a. Chronic DA receptor, synthetic protein, and DAT changes noted post TBI result in impaired neurotransmission

i. Reduced neuronal sensitivity to DA ii. Decreased DA production

iii. Altered DA half-life b. Amphetamines target neurobiological changes post-TBI to improve neurotransmission

i. By targeting DAT, clearance of synaptic dopamine is decreased and dopamine is redistributed into the synaptic cleft

ii. Enhances activity of dopaminergic projections into striatum, limbic cortex, and frontal cortex iii. Inhibition of monoamine oxidase also reduces neurotransmitter metabolism, resulting in

improved neuronal activity in adrenergic and serotonergic systems

III. Safety Concerns a. Hyperarousal, insomnia, and weight loss b. Elevated blood pressure/heart rate c. Increased risk of sudden death, stroke, and myocardial infarction in patients with pre-existing heart

conditions

Figure 3. Pharmacology of Amphetamines Source: www.adhd-institute.com

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Literature Evaluation

McAllister TW, et al. Randomized placebo-controlled trial of methylphenidate or galantamine for persistent emotional and cognitive symptoms associated with PTSD and/or traumatic brain injury. Neuropsychopharmacology. 2016;41:1191-8.28

Objective Determine impact of galantamine (GAL) or methylphenidate (MPD) on reduction of cognitive and emotional symptoms in patients with mTBI, post-traumatic stress disorder (PTSD), or both.

Methods Study Design 12 week double-blind, randomized, placebo controlled trial Population

Inclusion Criteria

• Clinically significant cognitive complaints, indicated by a T-score > 60 on the Postmorbid Cognitive Scale of the Ruff Neurobehavioral Inventory

• Diagnosis of PTSD and/or history of mTBI Exclusion criteria

• Current use of medications that potentiate cholinergic function • Lifetime history of stimulant abuse or dependence, alcohol use disorder,

substance use disorder in the past 6 months, severe depressive symptoms, or other psychiatric conditions

Outcome Measures (See Appendix D for description of outcome measures)

Primary Outcome

• Mean 12-week change in cognitive symptoms measured by Postmorbid Cognitive Scale of Ruff Neurobehavioral Inventory (RNBI)

Secondary Outcomes • Digit Symbol Test • Rivermead Post Concussive Symptoms Questionnaire (RPSQ) • Patient Health Questionnaire-9 (PHQ9) to assess depressive symptoms

Safety was assessed as the number of reported adverse events Interventions • GAL 4mg BID x 4 weeks, then 8mg BID x 4 weeks, then 12mg BID x 4 weeks (n=11)

• MPD 5mg BID x 4 weeks, then 10mg BID x 4 weeks, then 20mg BID x 4 weeks (n=9) • Placebo BID (n=12)

Results Baseline Characteristics

• 32 Total Participants o 15 participants (47%) were civilians without history of military service.

Distribution did not differ across treatment groups o 44% of participants solely had mTBI; 22% had comorbid mTBI and PTSD o Average age 41.19, 56.25% male

• MPD o 22% had comorbid mTBI/PTSD, 44% solely had mTBI o Baseline RNBI 58.78

Results

Primary Outcome • MPD treatment was associated with significant improvement in cognitive

complaints relative to placebo at 12 weeks, with a mean change of -12.0884 (p=0.036; 95%CI -23.1783 to -0.9984), effect size 0.337 (95% CI -0.642 to 1.304)

• GAL treatment did not differ from placebo, with a mean change of -6.3823 at 12 weeks (p=0.2151; 95% CI -16.3757 to 3.6110)

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Results (continued) Secondary Outcomes • MPD associated with improvements on Digit Symbol Test (p=0.011), though mean

change values were not provided • RPSQ: MPD -12.0600, (p-value=0.0078, 95% CI -20.5520 to -3.5681), effect size

0.886 (95% CI -0.329 to 2.061), vs. GAL -6.7202, (p-value=0.1141), • PHQ-9: MPD -5.6124, (p-value=0.0009, 95% CI -8.7793 to -2.4455), effect size 0.497

(95% CI -0.493 to 1.471), vs. GAL -3.9102 (p-value=0.0101, 95% CI -6.8016 to -1.0188), effect size 0.157 (95%CI -0.893 to 1.228)

Safety • No difference in number of reported adverse events (p>0.9999)

Discussion Critique Strengths

• Primary outcome measure specific to cognitive symptoms • Other psychotropic medication use permitted if the participant was on a stable

dose for a minimum of 4 weeks prior to the study • Inclusion of patients with PTSD

Limitations • Lack of statistical power • Patient population was not limited to TBI • TBI patients had only mild injury severity • Authors failed to recognize non-significant effect sizes • Exclusion of patients with severe depressive symptoms may limit utility in general

TBI population due to frequent comorbidity Implications Methylphenidate improves cognitive complaints and symptoms of depression in patients

with PTSD and/or mTBI, though effect sizes do not reflect this improvement

Whyte J, et al. Effects of methylphenidate on attention deficits after traumatic brain injury: a multidimensional, randomized, controlled trial. Am J Phys Med Rehabil. 2004; 83(6): 401-20.29

Objective To determine the clinical efficacy of MPD on attention deficits resulting from TBI and clarify which domains of attention are responsive to MPD

Methods Study Design 6 week multidimensional, randomized controlled trial consisting of a pilot phase followed

by an independent replication of promising drug effects. Participants reported to study center from 9:30AM to 3:30PM on weekdays for structured classroom activities

Population Inclusion Criteria

• Non-penetrating TBI of at least moderate severity • Injury occurred at least 3 months prior to enrollment • Capable to perform tasks for 10-15 minutes semi-independently • Subjective complaint of attention difficulties

Exclusion Criteria

• Premorbid neurologic disease, psychosis, major affective disorder, mental retardation, or ADHD

• Taking psychotropic medications other than anticonvulsants • Current abuse of alcohol or illicit drugs or history of substance use

significant enough to place patient at risk of long term neurologic effects

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Outcome Measures

(See Appendix D for description of outcome measures)

Initial accuracy o Sustained Arousal and Attention Task (SAAT) 50/50 & 20/80

Accuracy decline o SAAT 50/50 & 20/80

Initial speed o SAAT 50/50 & 20/80 o Choice Reaction Time Test o Dual Task o Test of Everyday Attention o Inattentive Behavior Task

Speed decline o SAAT 50/50 & 20/80

Initial response bias o SAAT 50/50 & 20/80

Decline in responding o SAAT 50/50 & 20/80

Divided attention o Dual task o Task of Everyday Attention

Sustained attention to response task Family ratings

o Cognitive Failures Questionnaire o Rating Scale of Attentional Behavior

Staff ratings o Cognitive Failures Questionnaire o Rating Scale of Attentional Behavior

Inattention- individual o Inattentive Behavior Task (average duration of off-task episodes)

Inattention- individual rate o Inattentive Behavior Task (rate of off task episodes)

Inattention- group o Classroom attentiveness

* No safety outcome measures were evaluated Interventions Patients were randomized to one of two conditions where they received MPD dosed at

0.3mg/kg/dose BID, or placebo for one week, then crossed over to the other intervention for the subsequent week. This was repeated for a total of 6 weeks Condition #1 started with MPD and switched to placebo in the second week Condition #2 started with placebo and switched to MPD in the second week

Results Baseline Characteristics

34 participants analyzed Mean age of 37 years 85% male, 65% Caucasian Mean disability rating scale 4 (moderate); range 1 (mild) to 8 (moderate to severe) Median time post-injury 3.2 years; range 4 months to 34.2 years

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Results

Table 4. Mean Results for Performance Variables Showing Significant Drug Effects Factor Task MPD Placebo P-value Initial Speed SAAT 50/50 response time 804 msec 797 msec

P<0.001

SAAT 20/80 response time 775 msec 789 msec Choice response time (slope coefficient)

387 510

Dual task response time 449 msec 457 msec Test of Everyday Attention map search, number of symbols circled in 2 min

45.8 44.8

Test of Everyday Attention, telephone search, time per target

5.73 sec 6.31 sec

Inattentive Behavior Task, number of items sorted

484 458

Family Ratings

Cognitive Failures Questionnaire 10.89 11.99 p=0.01

Rating Scale of Attentional Behavior 13.48 16.13 Inattention- Individual

Morning Classroom – individual activities, % on task

93.6 92.0

p=0.01

Afternoon Classroom – individual activities, % on task

96.5 90.8

Inattentive Behavior – task 1, average duration of off-task episodes

2.72 sec 3.69 sec

Inattentive Behavior – task 2, average duration of off-task episodes

1.25 sec 1.47 sec

Inattentive Behavior – task 3, average duration of off-task episodes

1.52 sec 3.48 sec

Individual Score

Sustained Attention to Response Task, response time before error of commission

400 msec 410 msec p=0.03

Discussion Critique Strengths

Study population limited to TBI patients Included patients with more severe injuries Crossover design allowed patients to serve as their own controls Classroom setting allowed for intensive follow up with patients

Limitations Lack of statistical power and small sample size Excluded patients taking other psychotropic medications Some subjects were recruited via advertisement Descriptive statistics only provided for variables showing significant effects Outcome measures non-validated and focused on attention, not cognition Safety was not assessed

Implications MPD, in combination with intensive classroom educational activities, has positive effects on performance speed in numerous tasks of attentiveness in a post-acute adult TBI population

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Tramontana MG, Cowan RL, Zald D et al. Traumatic brain injury-related attention deficits: Treatment outcomes with lisdexamfetamine dimesylate (Vyvanse). Brain Inj. 2014; 28(11): 1461-72.30

Objective To determine the effects of lisdexamfetamine dimesylate (LDX) in treating attention deficits due to moderate-to-severe TBI

Methods Study Design 12 week, randomized, double blind, placebo controlled, crossover trial

Cases were randomly assigned to one of two treatment sequences, alternating on whether stimulant treatment or placebo came first

Population Inclusion Criteria

• Closed head injury rated as moderate/severe • Injury sustained 6-36 months prior to enrollment and considered to be

neurologically stable • Persistent problems with focused or sustained attention

Exclusion Criteria

• Penetrating head injury • Pre-injury history of diagnosed ADHD • Psychiatric conditions requiring pharmacologic treatment • Lifetime history of psychostimulant abuse or dependence • Other substance abuse within the past 6 months • Current treatment with psychotropic medications within the past 6 weeks

Outcome Measures

(see Appendix D for description of outcome measures)

Primary outcomes

Trail Making Test – Part A (focus-execute) Conners Continuous Performance Test (CPT, sustain) Digit Span- forward and backward (encode) Stroop Color/Word Test; Trail Making Test- Part B (shift) Digit Symbol-Coding, letter fluency, category fluency (processing speed/control) Paced Auditory Serial Addition Test (PASAT; working memory) Verbal Paired-Associate Learning, Benton Visual Retention Test (short-term

memory) Conners Adult ADHD Rating Scale (CA ARS) Behavior Rating Inventory of Executive Function- Adult (BRIEF-A) Quality of Life Inventory (QOLI) Beck Depression Inventory (BDI-II) and Beck Anxiety Inventory (BAI)

Safety measures • Self-reported adverse events • Blood pressure, heart rate, and weight • Psychiatric symptom assessment

Interventions Participants received LDX or placebo for 6 weeks; at the end of 6 weeks changed arms Subjects in the LDX treatment phase initiated dosing at 30mg on day one and

continued for one week. If tolerated, increased to 50mg at week 2 and again at week 3 to a maximum dosage of 70mg

Results Baseline Characteristics

13 participants analyzed 69% male, 84.6% Caucasian, mean age 28.85 Cause of injury was MVA in 69.2% Injury severity rating of moderate for 53.8% of participants and severe for 46.2%

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Results

Safety • Weight loss of 5lbs or more over 6 weeks reported in 7 patients during LDX

treatment vs. 1 patient during placebo treatment • Mean systolic and diastolic blood pressures were higher while on LDX treatment

than placebo (124.5 vs. 118.3, and 71.9 vs. 68.5, respectively). This was determined to be non-significant

Table 5. Main Treatment Differences Variable On LDX

(mean (SD)) Off LDX

(mean (SD)) p-value

Conners CPT Hit Reaction Time- Interstimulus Interval

58.08 (17.97) 65.93 (17.61) 0.047

Conners CPT Hit Reaction Time Standard Error

54.26 (18.21) 61.04 (15.68) 0.047

Digit Span-Backward Scaled-score

11.60 (3.86) 9.40 (4.40) 0.003

CAARS Inattention/ Memory Problems

51.25 (13.29) 56.33 (12.39) 0.040

BRIEF-A Subscale Organization of Materials

48.55 (7.95) 56.00 (12.76) 0.047

Discussion Critique Strengths

Establishes LDX efficacy in the context of numerous rating scales Inclusion/exclusion criteria strict enough to target desired patient population

Limitations Study was not powered to detect treatment difference Small sample size Population restricted to closed head injury

Implications Positive treatment effects of LDX were observed in both self-ratings and performance measures assessing different aspects of attention regulation, with the most predominant effect noted within the sustain element of attention.

Summary of Literature28-30

I. Data is limited based upon small sample size and significant limitations of studies II. Available studies all use different rating scales to determine outcomes and in many cases these scales were not

validated III. Evidence regarding the utility of amphetamines for the treatment of cognitive disturbances associated with

varying degrees of TBI severity indicates improvements in speed of information processing, though the impact of this intervention on thought accuracy is lacking

Recommendations1,7,9,17,19,28-30

I. If untreated, cognitive deficits associated with TBI can lead to significant morbidity II. Current literature on the utility of amphetamines for neurocognitive deficits associated with chronic phase TBI,

though marked by significant limitations, provides the strongest support for the utility of amphetamines in patients who meet the following criteria

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a. Persistent cognitive complaints with documented deficits on neuropsychology functional assessments b. Failure or suboptimal response to non-pharmacologic treatment options c. 90 days or more post-injury d. Age 20 or older e. Lack of cardiac conditions f. Lack of substance abuse history

III. If started, patients should remain on the medication for at least 6 to 12 weeks Conclusion/Summary28-30

I. Amphetamine use for recovery of cognition in TBI patients can improve a patient’s level of functioning a. Methylphenidate has the most clinical experience and is therefore the preferred agent, though other

amphetamines such as lisdexamfetamine and mixed amphetamine salts may be used II. Amphetamines are not a “cure all”- patients should participate in supportive therapies such as cognitive

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Appendices

Appendix A. Glasgow Coma Scale Scoring System7,17,19 Eye Opening (E) Verbal Response (V) Best Motor Response (M)

Spontaneous 4 Oriented 5 Obeys command 6

To loud voice 3 Confused, disoriented 4 Moves to localized

pain 5

To pain 2 Inappropriate words 3 Flexion withdrawal

from pain 4

No response 1 Incomprehensible

sounds 2 Abnormal flexion 3

No response 1 Abnormal extension 2 No response 1

Note: Coma Score = E + M + V

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Appendix B. Pathophysiology of Diffuse Axonal Injury11

Appendix C. Neurocognitive & Neurobehavioral Sequelae of TBI9,15,31

Deficit Predominant Brain Regions Involved Predominant Neurotransmitter

Systems Involved Working Memory

Dorsolateral prefrontal, parietal, and cerebellar cortices; subcortical white matter

Dopamine, norepinephrine, ?acetylcholine

Short-term Memory

Frontal and hippocampal cortices Acetylcholine

Attention Frontal, cingulate, and parietal cortices, subcortical white matter,

reticular activating system Dopamine, norepinephrine,

acetylcholine Processing

Speed Subcortical white matter tracts Catecholamines, acetylcholine

Agitation Frontal and temporal lobes Serotonin, dopamine

Aggression Orbitofrontal, dorsolateral, prefrontal and anterior cingulate

cortices; amygdala Serotonin

Initial Insult

Mechanical shearing of endothelial cells in small vessels

Mechanical stretching and disruption of axonal plasma membranes

K+ efflux and Ca2+ influx Excitatory amino

acid release

Impaired regulation of BBB

and cerebral blood flow

Mechanical breakage of

microtubules and proteolytic

breakdown of neurofilament

proteins

Axonal transport defect

Focal ischemia

Binding of glutamate to

NMDA receptors

Neuronal depolarization

Acute widespread neuronal

suppression

Increased membrane pump activity to

restore ionic balance

Glucose consumption, glycolysis with lactate

accumulation

Energy crisis in damaged neurons

Acute failure in neuronal function

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Appendix D. Description of Outcome Measures Utilized by Clinical Trials Test Description

Whyte et al, 2004

Sustained Arousal and Attention Task 50/5029

Participants presented with 161 stimuli with an average interstimulus interval of 6 seconds and instructed to respond as quickly and accurately as possible to the

targets and ignore the foils. Target rate was 50%

Sustained Arousal and Attention Task 20/8029

Modified version of Sustained Arousal and Attention Task 50/50 which used a 20% target rate, based on the hypothesis that the individual’s attentional lapses may be

more frequent if fewer responses were required

Distraction Task29

Stimuli presented with a 50% target rate. Brightly colored shapes moved rapidly up and down either above or below the stimuli, just before or after stimulus

presentation.

Choice Reaction Time Task29

Participant required to press a numeric key on a keyboard in response to the presentation of a digit on the screen. Number stimulus remained on the screen until

the participant responded

Dual Task29

Designed to assess the ability of the participant to divide attention across two concurrent tasks. Participant first asked to respond as quickly as possible, by

pressing the spacebar on a keyboard, to dots that appeared in pseudo-random locations on the monitor. Mean response time defined the participant’s baseline

speed. The participant was then asked to listen to and repeat strings of digits read to them by the research assistant while still responding to the dots.

Sustained Attention to Response Task29

225 digits presented randomly, one at a time, in the center of a monitor during a 4.5min interval. Participant was required to press a response key as quickly as

possible for all digits that appeared except for the number 3

Test of Everyday Attention29

Assesses selective attention, sustained attention, and attentional switching by simulating naturalistic tasks, such as looking up items on a map, looking for phone

numbers in a directory, determining which floor to get off an elevator, and checking winning lottery numbers

Inattentive Behavior Task29

Participant asked to perform three tasks at a worktable: making a collage, sorting items into their correct bowls, and working on a complex jigsaw puzzle, while being

videotaped. During the session, a research assistant carried out a series of distractions (e.g., making a phone call, playing a noisy computer game, dropping a

book) on cue. Off-task events defined with respect to direction of eye gaze. Rates of off-task behavior calculated separately for each task as events per minute

Classroom Attentiveness29

Participants were observed as they participated in classroom activities during four 1-hour sessions each day; a group activity and an individual activity in both the

morning and the afternoon. During each session, a research assistant sat in the classroom to observe & code off task behavior

Cognitive Failures Questionnaire29

Assesses participant’s perceived frequency of everyday lapses in attention using a 5-point Likert scale ranging from “very often” to never”

Rating Scale of Attentional Behavior29

14-item, 5-point Likert scale designed to assess observable attention related behaviors, completed by caregivers & research staff.

19

Test Description

Tramontana et al, 2014

Trail Making Test – Part A35 *

Focus-execute function tested; 25 circles are distributed over a sheet of paper, numbered 1-25. Participant must draw lines to connect the numbers in ascending order, as quickly as possible, and without lifting the writing utensil from the paper.

Cognitive impairment defined as > 78 seconds required to complete the task. Conners Continuous

Performance Test (CPT)36

Sustain function tested; participants must press the spacebar on a keyboard each time they are presented with any letter except letter “X”

Digit Span- forward and backward37 *

Encode function tested; digit sequences are read aloud by an examiner beginning with a length of two digits and two trials are presented at each increasing list length.

Testing ceases when the subject fails to accurately report either trial at one sequence length or when the maximal list length is reached

Stroop Color/Word Test38 *

Shift function tested. The participant is first asked to name the color of a bar of X’s to establish patient’s ability to differentiate between colors. Then, names of colors are printed in conflicting ink colors and participants are asked to name the color of

the ink rather than the word.

Trail Making Test- Part B35 * Shift function tested; 25 circles distributed over a sheet of paper, including numbers

(1-13) and letters (A-L). Participants must draw lines to connect the circles in an ascending pattern, alternating between numbers and letters (i.e., 1-A-2-B-3-C, etc.)

Digit Symbol-Coding, letter fluency, category fluency39 *

Tests processing speed/control; consists of a key consisting of the numbers 1-9, each paired with a unique symbol, followed by a list of digits. Under each digit, the subject should write down the corresponding symbols as fast as possible. The

number of correct symbols within the allotted time is measured

Paced Auditory Serial Addition Test (PASAT)36

Evaluates working memory; one of the most frequently used tests to assess attentional processing. Participants are presented with a number at a routine time

interval and must add the number to the previously presented number. The participant must respond prior to the presentation of the next digit for a response to

be scored as corrected

Verbal Paired-Associate Learning41

Evaluates short-term memory; subjects must learn eight unrelated words across four study test trials, followed after 30 minutes by a delayed recall test and a recognition

test. This yields a memory acquisition score, a learning score, and delayed recall recognition scores.

Benton Visual Retention Test42

Assessment of visual perception and visual memory; individual is shown ten designs, one at a time, and asked to reproduce each one exactly as possible on plain paper from memory. Test is untimed, results are professionally scored by form, shape,

pattern, and arrangement on paper.

Conners Adult ADHD Rating Scale (CA ARS)43

Assesses self-report and observer-ratings of ADHD symptoms. Includes 93 items derived from DSM symptom criteria for ADHD, among other sources, rated using a

4-point Likert scale.

Behavior Rating Inventory of Executive Function- Adult

(BRIEF-A)33

Contains 75 items used to measure different aspects of executive functioning or self-regulation in a patient’s everyday environment. Scales are combined to form two

broad index scores (behavioral regulation index, metacognition index), and an overall composite score.

20

Test Description

Quality of Life Inventory (QOLI)44

Comprehensive five minute assessment that yields an overall score and profile of problems and strengths in 16 areas of life including love, work, and play that

measure satisfaction and well-being. Beck Depression Inventory

(BDI-II)45

21-item self-report rating inventory that measures characteristic attitudes and symptoms of depression. Items are rated on a 4-point Likert scale. Higher total

scores are indicative of more severe depression. Beck Anxiety Inventory (BAI)46 21-item self-report inventory used to measure severity of anxiety.

McAllister et al, 2016

Ruff Neurobehavioral Inventory (RNBI) Post-injury

Cognitive Scale32-33

Self-report questionnaire assessing an individual’s perception of their cognitive health. The cognitive domain includes subscales measuring attention and

concentration, executive functioning, learning and memory, and speech and language and includes 24 items.

Rivermead Post Concussive Symptoms Questionnaire

(RPSQ)33

Used to assess symptoms of headaches, dizziness, nausea and/or vomiting, noise sensitivity, sleep disturbance, fatigue, irritability, and depression. Score ranges from

0-52, with higher scores indicative of greater severity of symptoms

Patient Health Questionnaire-9 (PHQ9) to assess depressive

symptoms34

Self-administered depression scale, which scores each of the 9 DSM-IV criteria on a range of “0” (not at all) to “3” (nearly every day). Considered a reliable and valid

measure of depression severity

Digit Symbol Test* See description under Tramontana et al

*= Validated test of cognition