Crit Care Nurs Q

Vol. 43, No. 2, pp. 172–190

Copyright  c 2020 Wolters Kluwer Health, Inc. All rights reserved.

Pharmacologic Treatment of
Neurobehavioral Sequelae
Following Traumatic Brain
Injury
Jessica Traeger, PharmD, BCCCP; Brian Hoffman, PharmD;
Jennifer Misencik, PharmD; Alan Hoffer, MD;
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Jason Makii, PharmD, MBA, FCCM, FNCS, BCCCP

Traumatic brain injury (TBI) is a leading cause of disability in the United States. With decreasing
mortality rates, a higher number of patients are impacted by long-term neuropsychiatric seque-
lae, such as cognitive deficits, depression, anxiety, and sleep-wake disorders. These sequelae are
primarily driven by the disruption of key neurotransmitter homeostasis including dopamine, nore-
pinephrine, serotonin, and acetylcholine. Neurostimulants are centrally acting medications used
to assist in restoring these neurotransmitter abnormalities and are pharmacologic options to ame-
liorate symptoms in post-TBI patients. Examples of neurostimulants include amantadine, selective
serotonin reuptake inhibitors, tricyclic antidepressants, central stimulants (ie, methylphenidate),
modafinil, and donepezil. Large, well-powered studies have not been performed to validate their
use in patients with TBI, leaving uncertainty for these agents’ place in therapy. Current prac-
tice is driven by consideration of patient-specific factors to select the most appropriate agent.
This review provides clinicians with a summary of the available literature on neurostimulants fol-
lowing TBI to guide appropriate usage to help improve patients’ symptoms and optimize safety.
Key words: amantadine, neurobehavioral, neurostimulants, neurotransmitters, selective sero-
tonin reuptake inhibitors, traumatic brain injury

T RAUMATIC BRAIN INJURY (TBI) is a

leading cause of disability in the United
States, impacting between 3.2 and 5.3 million
Author Affiliations: Departments of Pharmacy
Services (Drs Traeger, Hoffman, Misencik, and Makii)
and Neurological Surgery (Dr Hoffer), University
Hospitals Cleveland Medical Center, Cleveland, Ohio;
and Case Western Reserve University School of
Medicine, Cleveland, Ohio (Dr Hoffer).
The authors have disclosed that they have no signif-
icant relationships with, or financial interest in, any
commercial companies pertaining to this article.
Correspondence: Jessica Traeger, PharmD, BCCCP,
Department of Pharmacy Services, University Hos-
pitals Cleveland Medical Center, 11100 Euclid Ave,
Mather B400, Cleveland, OH 44106 (Jessica.Traeger2@
UHhospitals.org).
DOI: 10.1097/CNQ.0000000000000301
people and resulting in almost 300 000 hos-
pitalizations per year.1 Traumatic brain injury
not only burdens the individual and care-
givers but also represents an annual eco-
nomic burden of more than $60 billion when
accounting for direct and indirect costs.2 One
analysis found that mortality rates are now
less than half of what they were in the mid-
1980s.3 With decreasing mortality rates, a
higher number of patients are faced with po-
tential long-term sequelae. Traumatic brain in-
jury can be classified into 3 main subtypes:
mild, moderate, or severe. Mild TBIs, which
account for the majority of patients, carry in-
creased morbidity; 30% to 53% of individu-
als who experience a mild TBI report having
disabling symptoms for at least 1 year postin-
jury. However, they typically do not alter life
expectancy.4-6 Moderate to severe TBIs are

172

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 Pharmacologic Treatment of Neurobehavioral Sequelae
associated with progressing degrees of loss of
consciousness as well as physical, cognitive,
and behavioral impairments that are likely to
persist.4
Long-term sequelae associated with TBI
can be categorized as cognitive deficits,
affective disorders, sleep-wake disorders,
and aggression. Cognitive deficits include
impaired attention, processing speed, mem-
ory, and executive functioning. Affective
disorders include depression, anxiety, bipolar
disorders, mania, and psychosis. These se-
quelae are associated with decreased quality
of life and increased long-term mortality.4 It
can be helpful for health care professionals to
recognize pharmacologic options, in addition
to nonpharmacologic treatment (ie, cogni-
tive behavioral therapy), for the variety of
disorders. A broad pharmacologic category
available to providers is neurostimulant med-
ications. Neurostimulants are centrally acting
agents that assist in restoring neurotransmit-
ter abnormalities associated with chronic
impairment and will be the focus of this
article.
METHODS
Authors worked independently to perform
a literature search using PubMed (1966
to November 1, 2019) using the MeSH
terms “traumatic brain injury,” “neurostim-
ulant,” “amantadine,” “methylphenidate,”
“donepezil,” “selective serotonin reuptake
inhibitors,” “tricyclic antidepressants,”
“monoamine oxidase inhibitors,” “an-
tidepressants,” “modafinil,” “‘sleep-wake
disorder,” “agitation,” “depression,” “lev-
odopa,” “bromocriptine,” and “rivastigmine.”
The search was limited to case reports or
series, observational trials, or randomized
controlled trials. Articles published in English
evaluating neurostimulant medications in TBI
were included. Articles regarding nonneu-
rostimulant medications (ie, β-blockers or
antiepileptics) for the management of TBI
sequelae were not included.
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173
PATHOPHYSIOLOGY
Common etiologies of TBI include blunt
head trauma, penetration of the skull, accel-
eration or deceleration forces to the head,
and blast injuries.4 These events can cause
rapid movement of the brain within the skull,
and if rotational movement occurs, it may
result in tearing of the axons within the
white matter.4,7-10 During the acute injury
phase, proinflammatory cytokines cause glio-
sis, demyelination, and apoptosis, resulting in
edema and sustained inflammation.11,12 An
increase in nitric oxide production causes
vasodilation, which reduces cerebral perfu-
sion pressure, and may last from hours to
days.13-17
These effects are associated with a disrup-
tion in the homeostasis between functional
neurotransmitters and receptors. For exam-
ple, glutamate, which binds to N-methyl-D-
aspartate receptors, and γ -aminobutyric acid
are the primary excitatory and inhibitory
neurotransmitters in the brain, respectively.
Directly following TBI, glutamate concen-
trations spike and N-methyl-D-aspartate re-
ceptors downregulate while γ -aminobutyric
acid activity is reduced. This imbalance re-
sults in uninhibited stimulation known as
excitotoxicity. The subsequently powerful
depolarizations can result in loss of ion-
based transmembrane and intracellular po-
tentials, cellular energy crisis, and neuronal
death. These excitotoxic effects are most pro-
nounced during the acute phase (first few
days post-TBI) and self-regulate during the
chronic phase (up to 6 months post-TBI).
Depending on the severity of TBI, these
excitotoxic actions may result in neuronal
dysfunction and long-term neuropsychiatric
sequelae.18 Apart from the brain’s excitatory-
inhibitory balance, key neurotransmitters as-
sociated with neuropsychiatric sequelae in-
clude dopamine, norepinephrine, serotonin,
and acetylcholine. Therefore, pharmacologic
opportunities to enhance these pathways
may be used; however, limited data are avail-
able to support their role.
174 CRITICAL CARE NURSING QUARTERLY/APRIL–JUNE 2020
Table 1. INESSS-ONF Rehabilitation Guidelines for Moderate to Severe Traumatic Brain Injurya,b

Sleep-Wake
Cognitive Disorders Affective Disorders Disorders

Attention Mood/depression Fatigue and sleep

• MPH [B]
• Dextroamphetamine
(second line) [C]
• Amantadine (third line) [B]
Processing speed
• MPH [B]
Arousal/recovery speed
• Amantadine [A]
Memory
• Donepezil [B]
• Rivastigmine [B]
• SSRIs (sertraline or citalopram disorders
preferred) [C] • Melatonin [B]
• MPH (may be used to augment SSRI • Trazodone [C]
effect) [B] • BZDs (<7 d) [C]
• TCAs (third line) [C] • MPH [C]
Anxiety
• SSRIs [C]
• BZDs (not recommended first line) [C]
Agitation/aggression
• Propranolol or pindolol [A]
• SSRIs (sertraline preferred) [B]
• Amantadine or MPH (may be considered
with concomitant arousal/attention
impairment) [B]
• Second-generation neuroleptics [C]c
• VPA and/or CBZ (may be considered
with concomitant seizure disorders) [C]
• TCAs (third line) [C]

Abbreviations: BZD, benzodiazepines; CBZ, carbamazepine; MPH, methylphenidate; SSRIs, selective serotonin reuptake
inhibitors; TCAs, tricyclic antidepressants; VPA, valproic acid.
a
[A] recommendation supported by at least 1 meta-analysis/systematic review or randomized controlled trial; [B] rec-
ommendation supported by at least 1 cohort; and [C] recommendation supported by expert opinion or small reports.
b
From Bayley et al.21 Used with permission.
c
Second-generation neuroleptics: quetiapine, ziprasidone, olanzapine, and risperidone.

AVAILABLE CLINICAL PRACTICE to guide practice today. A summary of those

GUIDELINES
Currently, there is a lack of evidence-based
guidelines on medication use in TBI. The
2016 Guidelines for the Management of Se-
vere Traumatic Brain Injury offer no recom-
mendations for the use of neurostimulants
in TBI.19 The first attempt at formulating an
evidence-based practice consensus occurred
in 2006 by Warden et al20 but was limited by
insufficient evidence to support a true guide-
line recommendation. Over a decade later,
the Institut national d’excellence en santé et
en services sociaux and Ontario Neurotrauma
Foundation (INESSS-ONF) guidelines for reha-
bilitation of persons with moderate to severe
TBI were created to review and summarize
previous guidelines.21 These guidelines are
the most updated recommendations available
recommendations, which include neurostim-
ulants and other classes of medications, can
be found in Table 1 and reflect the support-
ing evidence prior to its publication in 2018.
AMANTADINE
Amantadine was originally developed as
an antiviral agent and is now commonly
used to treat symptoms of Parkinson disease
(see Table 2).33 Similar to what is observed
in Parkinson disease, dopamine release is
impaired in TBI following neuronal inflam-
mation and death. Amantadine is believed
to increase dopamine release and reuptake,
which results in increased dopamine concen-
tration in the synaptic cleft.22 Amantadine
may also have neuroprotective properties
due to possible N-methyl-D-aspartate receptor

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 Table 2. Neurostimulant Dosing Recommendations, Adverse Effects, and Clinical Pearls
Drug/Class Mechanism
Amantadine22 Dopamine agonist
Selective serotonin Increases concentration of
reuptake serotonin in synaptic cleft
inhibitors23,24 by inhibiting serotonin
reuptake
Tricyclic Serotonin and
antidepressants25,26 norepinephrine reuptake
inhibitor. Blockade of
muscarinic, histamine
(H1), and α-adrenergic
receptors
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Dose Adverse Effects Clinical Pearls
100-200 mg twice daily Agitation, irritability, Recommended to
insomnia, vivid dreams, administer doses in the
hyperactivity, seizure, morning and early
and delirium afternoon
May need to taper when
stopping medication
Sertraline: 50-200 mg once Insomnia, dizziness, Alternative SSRI may be
daily drowsiness, nausea, needed if no response
Citalopram: 20-40 mg once constipation, diarrhea, after 6-8 weeks of
daily dry mouth, decreased adequate dose titration
libido Taking SSRIs at bedtime may
Black Box Warning for help reduce daytime
suicidal drowsiness
thinking/behavior
Depression: Sedation, dizziness, Recommended to take at
Amitriptyline: 100-300 mg orthostatic hypotension, bedtime due to sedation
once daily urinary retention, Lowers seizure threshold
Desipramine: 100-300 mg constipation,
once daily arrhythmias, seizure
Agitation/Aggression: Black Box Warning for
Amitriptyline: 150 mg once suicidal
daily thinking/behavior
Desipramine: 150 mg once
daily
(Continues)
Pharmacologic Treatment of Neurobehavioral Sequelae
175
 176

Table 2. Neurostimulant Dosing Recommendations, Adverse Effects, and Clinical Pearls (Continued)

Drug/Class Mechanism Dose Adverse Effects Clinical Pearls

Central stimulants27-29 Increases release of Methylphenidate: 0.3 Insomnia, irritability, MPH dose can be weight
presynaptic mg/kg twice daily agitation, weight loss, based and should be
catecholamines Dextroamphetamine: 10 gastrointestinal upset administered in the
(dopamine and mg once daily morning and early-to-mid
norepinephrine), may also Lisdexamfetamine: 30-70 afternoon
block catecholamine mg once daily Irritability and agitation may
reuptake be medication-limiting
side effects
Possible risk of addiction
and dependence
Controlled substance
Modafinil30 Exact mechanism unknown Modafinil: 200 mg once Headache, nausea, Induces CYP3A4 (potential
Armodafinil31 daily insomnia, anxiety, for drug interactions)
Armodafinil: 250 mg once dizziness, and Controlled substance
CRITICAL CARE NURSING QUARTERLY/APRIL–JUNE 2020

daily palpitations
Donepezil32 Acetylcholinesterase 5-10 mg once daily Insomnia, nausea, diarrhea, May be associated with QT
inhibitor (centrally acting) and weight loss interval prolongation on
electrocardiogram

Abbreviations: MPH, methylphenidate; SSRIs, selective serotonin reuptake inhibitors.

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 Pharmacologic Treatment of Neurobehavioral Sequelae
antagonism.34 By increasing the available
dopamine at the synaptic cleft, amantadine’s
proposed effects include improved cognitive
functioning, concentration, and behavioral
symptoms.35
Amantadine has a favorable safety profile.
Commonly reported side effects are dose de-
pendent and include agitation, irritability, in-
somnia, vivid dreams, and delirium. As pa-
tients with TBIs are at risk for seizures, it
is important to note that rarely, amantadine
has been associated with seizures at higher
doses.34 Amantadine is dosed twice daily, but
because of patient tolerance and insomnia,
it is typically administered in the morning
and in the early afternoon.22 Drug accumu-
lation may occur in renal impairment, neces-
sitating renal function monitoring and dose
adjustments if needed. When amantadine is
abruptly discontinued, patients may experi-
ence a withdrawal syndrome that manifests
similarly to its side effects. In extreme situ-
ations, amantadine withdrawal may present
similarly to neuroleptic malignant syndrome,
which can be fatal. Therefore, it is gener-
ally recommended to taper amantadine when
stopping therapy.22
Amantadine was initially evaluated for pa-
tients with TBI in small case series and trials
in the 1990s.36-38 The first trial to show clin-
ically significant benefit was a randomized,
double-blind, placebo-controlled, crossover,
pilot study in patients with moderate to se-
vere TBI. Thirty-five patients were included
within 6 weeks of their initial injury and were
randomized to receive either amantadine 100
mg twice daily or placebo for 6 weeks. Pa-
tients then crossed over treatments for an ad-
ditional 6-week period. The study found im-
provement in cognition and arousal in the
first 6 weeks in all patients, implying that
some of the improvement was likely spon-
taneous. In patients who initially received
amantadine, this improvement plateaued
once patients crossed over to placebo. In pa-
tients initially randomized to placebo, there
was continued improvement once amanta-
dine was initiated.34 These findings suggest
that initiation of amantadine within the first
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177
12 weeks of injury may result in more rapid
functional improvement. Other observational
trials of amantadine found mixed results, with
a trend toward overall cognitive improvement
and decreased disability.39-41
A 2012 study randomized 184 patients to
amantadine 100 to 200 mg twice daily or
placebo. As in the previous trial, patients had
recently experienced a TBI 4 to 16 weeks
prior. All of these patients were in a vegeta-
tive or minimally conscious state and were re-
ceiving usual inpatient rehabilitation. Aman-
tadine significantly improved recovery speed
assessed by patient disability rating scales
(see Table 3 for further explanation of clini-
cal rating scales).49 Following amantadine dis-
continuation at week 4, the improvement
in disability rating scales significantly slowed
when assessed 2 weeks later. These findings
suggest that patients’ observed accelerated re-
covery pace was directly related to being ad-
ministered amantadine.
Amantadine has also been assessed to im-
prove behavioral symptoms. A single-center,
double-blind, placebo-controlled trial ran-
domized 76 patients (aged 16-65 years) with
chronic TBI symptoms (>6 months post-TBI)
who were referred for irritability manage-
ment. Patients had a history of a moderate,
severe, or complicated mild TBI and were ran-
domized to amantadine 100 mg twice daily or
placebo for 4 weeks.50 The amantadine group
had a significant reduction in overall irritabil-
ity, irritability frequency, and severity. No sig-
nificant difference was found in aggression or
distress scores.
A separate multicenter trial randomized
168 patients to amantadine 100 mg twice
daily or placebo for 60 days with similar char-
acteristics to the previous trial.51 There was
no difference in observer rated irritability,
but a significant reduction in participant self-
rated irritability was found. The patients also
experienced significant improvement in the
Clinical Global Impressions scale for overall
symptoms. From this trial, a cohort of 118
patients who had baseline moderate to se-
vere aggression was further analyzed to assess
amantadine’s impact on anger and aggression
178 CRITICAL CARE NURSING QUARTERLY/APRIL–JUNE 2020

Table 3. Select Clinical Scale Descriptions and Ranges

Score Range and

Scale Description Interpretation

Affect/mood scale42 25-item scale that measures severity
of depression (validated in stroke
patients). Patients are rated by
health care personnel in verbal
communication, observations of
patient behaviors, and
observations of patient mood.
Clinical Global An observer-rated scale applicable
Impressions (CGI) to psychiatric disorders. The CGI
scale43,44 scale is designed to measure
illness severity, as well as illness
improvement or change (CGI-C)
in response to therapy.
Disability Rating Scale Cognitive impairment scale
(DRS)45 designed to rate injury severity
and predict recovery duration in
patients with TBI.
The Hamilton Rating 17-item questionnaire administered
Scale for Depression by a health care professional,
(HAM-D)46 which measures patient rate
severity of depressive symptoms.
Mini-Mental State Cognitive impairment scale
Examination (MMSE)47 designed to measure severity and
cognitive changes over time often
in dementia including orientation,
short-term memory (retention
and recall), attention, and
language
Multiple Sleep Latency A full-day test for excessive daytime
Test (MSLT)48 sleepiness. Measures how quickly
patients fall asleep in a quiet
environment during the day.
25-100; a higher score reflects
more severe depression.
1-7
CGI: a higher score reflects
worse severity of a patient’s
illness
CGI-C: a higher score reflects
worsening of illness
0-29; a higher score reflects
severe disability up to a
vegetative state.
0-52; a higher score reflects
more severe depression.
0-30; lower score reflects
worse cognitive function
Positive MSLT: patient falls
asleep with a mean sleep
latency below 8 min during
naps and patient had no
more than 1 nap or no more
than 2 naps where REM
sleep was reached.

symptoms. Those treated with amantadine
show significant decrease in self-reported ag-
gression compared with placebo at day 60, al-
though there was no difference in observer-
rated aggression. There was no difference in
anger scores.52
Amantadine has shown favorable signals
across a variety of neurobehavioral symp-
toms. The strongest data for amantadine
support its use for recovery speed and overall
symptom management in the acute setting.
In patients with chronic behavioral sequelae,
amantadine may reduce patient self-reported
symptoms, although the results are subjec-
tive, inconsistent, and do not extend to symp-
toms observed by caregivers. Most of the
aforementioned trials excluded patients with
a history of seizures, so caution should be

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 Pharmacologic Treatment of Neurobehavioral Sequelae
exercised when considering prescribing
amantadine to this patient population. It is
reasonable to initiate amantadine at 100 mg
twice daily (dosed in the morning and early
afternoon) and then titrate up to 200 mg
twice daily if needed. Patients were typically
treated for a limited duration of up to 60 days.
Longer courses of therapy may be cautiously
considered because a significant slowing of
recovery was found in one study following
amantadine discontinuation. However, there
is no evidence to support an indefinite
duration of treatment.49
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Patients with traumatic brain injury com-
monly develop neuropsychiatric disorders,
including depression, anxiety, and agitation
caused by disruptions in neurotransmitter
synapses following the insulting event.53-55
Particularly in patients with frontal lobe
damage, an area highly concentrated with
serotonergic projections from the raphe
nuclei, the resulting effect is a decreased pro-
duction of serotonin. One study reported that
severe TBI was associated with a 17% loss
of serotonergic neurons.56 While guidelines
advocate for cognitive behavioral therapy
initially, medications affecting serotonin
concentrations in the synaptic cleft have
also been evaluated as treatment options for
post-TBI affective disorders.
Selective serotonin reuptake inhibitors (SS-
RIs) increase concentrations of serotonin
through the inhibition of presynaptic reup-
take by serotonin transporters. Following
therapy initiation, clinical onset is typically
expected within 1 to 4 weeks. However, due
to the high degree of patient-specific variabil-
ity with these agents, it may take up to 12
weeks to notice a significant difference in
symptoms. Patients failing an initial SSRI trial
may respond to other agents within this med-
ication class. Therefore, it is appropriate to
consider initiating an alternative SSRI if a pa-
tient fails to respond. Selective serotonin re-
uptake inhibitors are usually well tolerated,
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179
but common side effects include drowsiness,
insomnia, headache, nausea, diarrhea, and
sexual dysfunction.23 Current literature sug-
gests that the SSRIs sertraline or citalopram
may have a role in the treatment of post-TBI
affective disorders.
Sertraline is one of the most well-studied
agents for the treatment of agitation, depres-
sion, and anxiety post-TBI. Ashman et al57
performed a 10-week, double-blind, con-
trolled trial to assess the effect of sertra-
line on post-TBI depression. Patients at least
6 months following mild to severe TBI were
randomized to sertraline at a dose of 25 mg
daily (up-titrated to a maximum of 200 mg
per day) or placebo. Fifty-two patients were
evaluated for improvements in depression,
anxiety, and quality of life based on multiple
clinical scales including the Hamilton Rating
Scale for Depression (HAM-D). No improve-
ments were found compared with placebo.
Both groups were found to have nonsignifi-
cant improvements in HAM-D scores (≥50%
reduction from baseline in 59% of the ser-
traline group and 32% of placebo). The im-
provement observed in both groups may have
resulted from a high percentage of patients
from minority background and lower socioe-
conomic status. This may have confounded
the results as these patients likely had lim-
ited access to health care prior to the study
and may explain the improvement in HAM-D
scores in the placebo group.
Lee et al58 compared the effects of
methylphenidate (MPH), sertraline (100 mg
per day), and placebo on various neuropsy-
chiatric sequelae, including depression, in a
4-week double-blind, parallel group trial. Pa-
tients included in this study had experienced
a mild to moderate TBI between 2 weeks
and 1 year prior and were suffering from de-
pression. Thirty patients completed the study
(10 in each treatment arm). Quality of life
and depressive symptoms, as measured by the
HAM-D, significantly improved in all patients
by the end of the study, which suggests
that patients experienced spontaneous recov-
ery. Both sertraline and MPH significantly im-
prove depressive symptoms compared with
180 CRITICAL CARE NURSING QUARTERLY/APRIL–JUNE 2020
placebo. No improvements in cognitive func-
tioning, postconcussive symptoms, or ex-
cessive daytime sleepiness (EDS) were ob-
served in the sertraline group. Compared
with placebo and MPH, sertraline was as-
sociated with more adverse effects such as
nausea, vomiting, diarrhea, and sweating. Be-
cause of the double-blind nature of the study,
all medications were administered in the
morning. As sertraline is known to cause
drowsiness, this may explain why the sertra-
line group had more EDS compared with the
other arms. The limited duration of sertra-
line treatment in this trial (4 weeks) may not
have been long enough for patients to achieve
maximum therapeutic benefit, making it dif-
ficult to fully evaluate its effectiveness. This
trial will be explored further in this article in
the section on central stimulants.
Sertraline has also been evaluated for the
prevention of post-TBI depression. Jorge
et al59 performed a 24-week double-blind,
placebo-controlled trial evaluating patients
with mild to severe TBI. Ninety-four patients
were randomized to either sertraline at a dose
of 100 mg daily or placebo. Patients with on-
going depression were excluded. The major-
ity of patients were enrolled 3 to 4 weeks fol-
lowing TBI. Patients in the sertraline group
were found to have a longer time to onset
of a mood disorder. The number needed to
treat to prevent 1 case of post-TBI depres-
sion was 5.9 (95% confidence interval, 3.1-
71.1). Patients treated with sertraline were
more likely to report dry mouth and diarrhea;
no serious adverse events were attributed to
sertraline. These results are promising, but
given the single-center design and low enroll-
ment, further studies would be needed to rec-
ommend sertraline for post-TBI depression
prophylaxis.
Rapoport et al60 studied the effects of
citalopram on major depression in patients
within 1 year of a mild to moderate TBI. In the
initial 6-week study period, patients received
citalopram at a fixed dose of 20 mg daily.
Because of low response rate, the study’s
duration was extended to 10 weeks, and a
flexible dosing schedule was implemented.
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At week 10, the majority of patients were
receiving 40 mg per day. Among the 54 pa-
tients who completed at least 6 weeks of
the trial, there were significant reductions in
mean HAM-D scores at 6 and 10 weeks, with
26.9% of patients in remission (HAM-D score
<7) at week 10. Dry mouth, nausea, and de-
creased libido were the most commonly re-
ported side effects. Twenty-one patients in re-
mission were then randomized to citalopram
or placebo in a 40-week open-label extension
study.61 The rate of relapse was similar be-
tween the 2 groups, occurring in 50% of the
citalopram group and 54.5% of the placebo.
These studies indicate that citalopram treat-
ment may reduce depressive symptoms ini-
tially; however, there is a high risk of relapse.
Fluoxetine, another SSRI, was investigated
for post-TBI depression in a small, open-label,
pilot study.62 Five patients were administered
fluoxetine at a dose of 20 to 60 mg per day for
8 months. The study reported that fluoxetine
improved mood and working memory; how-
ever, not all patients had depression at base-
line. These results indicate that a randomized
controlled trial evaluating the efficacy of flu-
oxetine may be beneficial. Until further stud-
ies are completed, agents with more robust
evidence, such as sertraline and citalopram,
should be the SSRIs of choice when utilized
for TBI patients.
Selective serotonin reuptake inhibitors
are considered the first-line pharmacologic
treatment for post-TBI depression by some
organization guidelines, such as INESSS-ONF,
because of their effectiveness and mild
side effect profile.21 Most of the evidence
supports the use of sertraline 50 to 200 mg
per day and citalopram 20 to 40 mg per
day. As the treatment of post-TBI depression
may improve cognitive functioning, somatic
symptoms, and quality of life, these agents
should be considered when an adequate
response is not achieved with psychotherapy
alone.53 When initiating therapy with one
of these agents, providers should be aware
that patients may not respond to the initial
antidepressant regimen. It may be necessary
to switch to an alternative SSRI agent after
 Pharmacologic Treatment of Neurobehavioral Sequelae
6 to 8 weeks of treatment if no response is
observed despite adequate dose titration.
The majority of studies had relatively short
trial durations; therefore, a gap in recommen-
dations remains regarding how long patients
should continue treatment. If patients con-
tinue to have significant improvements in
depressive symptoms and wish to continue
treatment, therapy could be continued.
However, as evidenced by Rapoport et al,61
TBI patients may have high rates of treatment
relapse.
TRICYCLIC ANTIDEPRESSANTS
Tricyclic antidepressants (TCAs) in-
hibit the reuptake of both serotonin and
norepinephrine.63 These agents also block
muscarinic, histamine (H1), and α-adrenergic
receptors that results in an increased poten-
tial for adverse effects including sedation,
arrhythmias, and a reduction in the seizure
threshold.63 Because of the potential for
adverse effects, TCAs are infrequently pre-
scribed for indications such as depression,
agitation, and neuropathic pain since the ad-
vent of better tolerated agents such as SSRIs.
Although the clinical utility of TCAs may be
low, there is some evidence to support their
use in post-TBI depression and agitation.
Currently, the best available evidence is for
the TCAs amitriptyline and desipramine.
Wroblewski et al42 conducted a random-
ized, placebo lead-in study of desipramine
150 mg daily (maximum dose 300 mg per
day) in 10 patients with severe TBI who also
had depression for at least 2 months. De-
pressive symptoms were evaluated using the
affect/mood scale. At 1 month, there was
a reduction in the affect/mood scale in pa-
tients started on desipramine (N = 6). Six
of the 7 patients who completed the study
experienced resolution of depression with
desipramine (≥50% reduction in number of
symptoms). Two patients were withdrawn
from the study because of severe seizure ac-
tivity and development of mania. Another
patient experienced mild seizure activity but
continued with the study treatment without
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
181
further occurrences. Although desipramine
appeared to be effective in treating depres-
sion in this small sample of patients, the re-
ported adverse effects are concerning.
Mysiw et al64 evaluated the effect of
amitriptyline on agitation in TBI patients ad-
mitted to a rehabilitation program. All pa-
tients were initially managed with behavioral
psychotherapy. Twenty patients who had re-
mained agitated for more than 7 days were
initiated on amitriptyline 25 mg daily (up-
titrated to a maximum dose of 150 mg per
day). In those patients, 13 patients had a
significant reduction in agitation at 1 week.
One patient experienced more severe agita-
tion after initiating amitriptyline and discon-
tinued therapy; however, no other adverse
events were reported. The majority of respon-
ders were those early in the recovery pro-
cess, who still required maximal assistance,
and were characterized as confused and agi-
tated. This indicates that amitriptyline may be
most effective in treating agitation seen at ear-
lier stages of recovery.
Tricyclic antidepressants have limited ev-
idence to support their use in treating de-
pression and agitation in the TBI population.
This benefit, however, is limited by the risk
of adverse events seen with these agents.
One concern is the increased risk of seizures
with TCAs due to a reduction in the seizure
threshold. Tricyclic antidepressants may be
considered as alternatives after treatment fail-
ure with agents with more favorable side ef-
fect profile (ie, SSRIs). Based on available lit-
erature, amitriptyline 100 to 300 mg per day
and desipramine 100 to 300 mg per day may
be options for the treatment of post-TBI de-
pression and agitation and aggression.
CENTRAL STIMULANTS
Children who are 12 and 24 months post-
TBI have increased rates of attention-deficit/
hyperactivity disorder (ADHD).65 Centrally
acting stimulants, which are Food and
Drug Administration approved for indications
such as ADHD, include MPH, amphetamines
dextroamphetamine, and lisdexamfetamine
182 CRITICAL CARE NURSING QUARTERLY/APRIL–JUNE 2020
(which is a prodrug of dextroamphetamine).
Mechanistically, they may have beneficial ac-
tivity in TBI by increasing dopamine transmis-
sion in the frontostriatal regions, as suggested
by functional magnetic resonance imaging
data.66,67 In addition, stimulants can inhibit
the reuptake of norepinephrine into presy-
naptic neurons, which increases its availabil-
ity in the synaptic cleft. Theoretical effects
of stimulants include enhanced processing
speed, attention, psychomotor and cognitive
recovery, and decreased mental fatigue.68
Common side effects of stimulants include
insomnia, irritability, and weight loss. Be-
cause of the risk of insomnia, stimulants are
dosed in the morning, and if a second dose is
required then in the early-to-mid afternoon.
Rarely, stimulants are associated with psy-
chosis or severe cardiovascular disorders in-
cluding sudden death, stroke, and myocardial
infarction. One retrospective study of greater
than 1 million patients taking stimulants for
ADHD found no significant increase in these
events versus placebo.27 Stimulants also are
controlled substances that carry a black box
warning for abuse and dependence, which
should be accounted for when prescribing or
monitoring these medications.69
Methylphenidate first received Food and
Drug Administration approval in 1955 and is
the most widely studied stimulant in post-TBI
patients.69 Most early studies in the 1990s
were limited by small sample sizes of less
than 20 patients.70-73 In 2004, a 6-week,
double-blind, placebo-controlled, random-
ized, crossover trial published by Whyte
et al74 studied 34 adult patients who expe-
rienced a moderate to severe TBI and had
subjective complaints of difficulties with
attention. Methylphenidate was dosed at 0.3
mg/kg twice daily, which is in contrast to flat
dosing typically seen in ADHD. There was a
large range of time since their TBI in included
patients (median of 3.2 years, range: 4 months
to 34 years). The trial found a significant
benefit in processing speed and caregiver-
rated attention. The results of the study were
limited by a small sample size, yet the
beneficial results were encouraging.
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
A recent meta-analysis reviewed 10 random-
ized controlled trials (261 patients total) in-
vestigating MPH in TBI.68 All trials had at
least 1 primary outcome related to cognitive
ability or attention. Half of the trials used a
weight-based dosing regimen (0.25-0.3 mg/kg
twice daily). Methylphenidate was associated
with a significant improvement in attention.
No differences were found between MPH and
placebo in the studies evaluating memory and
processing speed. Adverse effects primarily
consisted of gastrointestinal upset; 1 study re-
ported irritability and emotional hypersensi-
tivity. Limitations of the meta-analysis were
variations between trial timing, dosing, and
duration of treatment. The included trials also
used inconsistent subjective examinations to
assess each outcome.
A recent randomized trial of 36 patients
who were 2 to 52 weeks from mild to mod-
erate TBI and received 5 to 20 mg per
day of MPH or placebo for 30 weeks was
published.75 Patients who received MPH ex-
perienced significant improvement in the co-
primary outcomes of mental fatigue and cog-
nitive functioning. A secondary outcome also
showed an improvement in depression ac-
cording to the Mini-Mental State Examination.
The previously mentioned trial by Lee et al58
compared the effects of MPH (20 mg per day)
with both sertraline and placebo in 30 pa-
tients. In addition to improving depressive
symptoms and quality of life, MPH was also
found to improve cognitive functioning and
EDS.58 Although further study is warranted,
these trials suggest that in addition to improv-
ing attention, MPH may also have a role in im-
proving depressive symptoms.
The first controlled trial to study an al-
ternative stimulant in TBI was published
in 2014.76 This double-blind, placebo-
controlled, crossover trial studied patients 16
to 42 years of age who were 6 to 34 months
post moderate to severe TBI. Patients were
randomized to receive lisdexamfetamine
dimesylate, titrated from 30 to 70 mg once
daily or placebo for a total of 6 weeks, and
then switched. Twenty-two patients were
enrolled in the study but 9 withdrew (7 loss
 Pharmacologic Treatment of Neurobehavioral Sequelae
to follow-up, and 2 due to blood pressure
elevation). In patients who completed the
study, no differences in the primary outcome
of safety or tolerability were found. Blood
pressure elevation hindered some patients
from reaching the maximum 70-mg dose.
Patients randomized to lisdexamfetamine had
improvements in sustained attention, work-
ing memory, response speed, and executive
functioning. Another randomized trial stud-
ied dextroamphetamine 10 mg once daily
for 3 weeks in 32 patients within 6 months
following a moderate to severe TBI.77
No significant differences were seen for cog-
nitive function and overall functional status.
The largest numerical benefit was seen in
increased processing speed, but patients also
suffered from significantly more agitation.
The evidence suggests that stimulants have
benefits for attention, processing speed,
and cognitive functioning in patients with
TBI. Most of the studies were conducted
with MPH. Methylphenidate may also be
considered as an augmentative agent to
SSRIs in depression.21 Methylphenidate was
commonly dosed on the basis of weight
(0.3 mg/kg) twice daily, lisdexamfetamine
dimesylate 30 to 70 mg per day, and dex-
troamphetamine 10 mg per day. Stimulants
may increase the risk of agitation, irritabil-
ity, and insomnia, which may adversely
affect TBI patients and their functional
improvement.68,69 In addition, patients’
blood pressure should be monitored and
doses adjusted in case of elevation. In these
trials, the stimulants were initiated across
a broad range of time postinjury, both in
the acute (weeks postinjury) and chronic
phases (years postinjury). The treatment
durations studied ranges from 3 to 30 weeks.
Ultimately because stimulant side effects may
be detrimental to TBI recovery, dosing should
be slowly titrated to effect with consideration
of alternative agents if poorly tolerated.
MODAFINIL AND ARMODAFINIL
Modafinil and armodafinil (modafinil’s R-
enantiomer) are nonamphetamine psychos-
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
183
timulants with wake-promoting activity.78
In patients with TBI, excessive sleepiness
is commonly reported and may detrimen-
tally affect cognitive function. Modafinil
and armodafinil’s exact mechanism is un-
known; however, they are not believed to
directly bind catecholamines, serotonin, or
γ -aminobutyric acid receptors.78,79 These
agents have been shown to improve energy
levels, productivity, attention, and social func-
tioning in narcoleptic patients, as well as
cognitive performance in sleep-deprived mili-
tary personnel.80,81 Modafinil and armodafinil
are generally well tolerated; possible adverse
effects include headache, nausea, insomnia,
anxiety, dizziness, and palpitations.30,31 Based
on these characteristics, modafinil and ar-
modafinil seem to be appealing agents to help
increase alertness and reduce EDS and fatigue
in TBI patients.
An initial promising report of modafinil’s
use in TBI patients came from a small,
prospective, open-label trial in 2001.82 Ten
patients with closed-head TBI were given
modafinil 100 to 400 mg per day. Modafinil
was reported to improve EDS in 9 of 10 out-
patients. After 13 months, reported adverse
effects were mild and included overstimula-
tion and gastrointestinal upset.
In a double-blind, placebo-controlled,
crossover trial, Jha et al83 evaluated the
efficacy of modafinil in treating EDS and
fatigue in TBI patients with chronic, self-
reported disabling symptoms. Patients who
were at least 1 year post-TBI were eligible as
long as they did not meet certain exclusion
criteria including cardiovascular disease or
risks, epilepsy, and significant psychiatric or
behavioral disturbances. After randomization,
51 patients received either modafinil, up-
titrated to 400 mg per day, or placebo for 10
weeks (period 1). Subjects then underwent a
4-week washout period before being crossed
over to the alternative treatment group for
the remaining 10 weeks (period 2). In pe-
riod 1, there were no significant differences
between modafinil and placebo in either end
point. In period 2, the modafinil group had
significant improvements in fatigue and EDS
184 CRITICAL CARE NURSING QUARTERLY/APRIL–JUNE 2020
at week 4 but not at week 10 in either end
point. The most commonly reported adverse
events were headache and insomnia. Based
on the inconsistent results, this study does
not support this use of modafinil in treating
post-TBI fatigue or EDS.
Kaiser et al84 performed a double-blind,
placebo-controlled pilot study of 20 patients
with mild to severe TBI. Patients received ei-
ther modafinil, up-titrated to 200 mg per day,
or placebo for 6 weeks. The study found sig-
nificant improvement in measures of EDS but
not fatigue.84 Similar rates of adverse events
occurred in each group and included nausea,
stomach pain, and arthralgia. Based on these
results, modafinil does not appear to be effica-
cious in treating fatigue but may be an option
for EDS.
The effect of armodafinil on EDS was inves-
tigated in a double-blind, placebo-controlled
trial by Menn et al.43 Patients were 1 to 10
years following their injury and the majority
had sustained a mild TBI.
Patients were randomized to armodafinil
50 mg daily (N = 30), armodafinil 150 mg
daily (N = 29), armodafinil 250 mg daily (N
= 29), or placebo (N = 29) for 12 weeks.
Efficacy was assessed by several measures,
including the Clinical Global Impression of
Change scale of excessive sleepiness and
mean sleep latency for 4 different naps sched-
uled throughout the morning and early after-
noon assessed by the Multiple Sleep Latency
Test. At week 12, patients who received ei-
ther armodafinil 150 mg or 250 mg per day
had significant improvements in their Multi-
ple Sleep Latency Test compared with base-
line, with a more significant effect in the 250
mg per day group. The increase in sleep la-
tency, or the time it took patients to fall asleep
for naps, observed in this study suggests
that patients were not as sleepy during the
daytime. There was also a trend toward a
higher percentage of Clinical Global Impres-
sion of Change responders in the 150 mg and
250 mg per day groups. However, this effect
was no longer significant beyond week 4.
Forty-nine patients who completed the ini-
tial 12 weeks of double-blind treatment were
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
enrolled in an additional 12-month open-
label extension of the trial to evaluate the
long-term safety, tolerability, and efficacy of
armodafinil.43 Patients completing the open-
label extension received either armodafinil
150 mg or 250 mg per day. Efficacy was main-
tained throughout the study extension. The
most reported adverse events were mild and
included headache, anxiety, nausea, and dizzi-
ness. Based on the results, there appears to
be a dose-dependent improvement in EDS in
patients treated with armodafinil. However,
as this study was underpowered and enrolled
patients with solely mild-TBI, these results
may not be generalizable to all TBI patients.
The overall literature suggests that these
agents are not effective at improving fatigue
in TBI patients. Doses of modafinil 200 mg
per day and armodafinil 250 mg per day might
improve EDS with minimal adverse effects,
but results have been inconsistent. Although
these agents are not mentioned in the INESSS-
ONF guidelines, they may be considered as a
treatment option for EDS following the acute
phase of TBI. Although Menn et al43 reported
continued efficacy in patients treated with
armodafinil at 12 months, the appropriate
duration of therapy has not yet been deter-
mined. Patients should be periodically evalu-
ated for continued efficacy, as well as adverse
effects. If clinical benefit is not found after ad-
equate dose titration, these agents should be
discontinued.
DONEPEZIL
Donepezil is a centrally acting acetyl-
cholinesterase inhibitor that acts by inhibit-
ing the breakdown of acetylcholine in the
synaptic cleft. It is indicated for the treat-
ment of Alzheimer disease and dementia.32
In TBI, acetylcholine has been found to have
the most prolonged time to normalization
and highest chance of chronic impairments
compared with other neurotransmitters.85,86
Donepezil’s effect on acetylcholine may the-
oretically enhance arousal, attention, learn-
ing, memory, and various other cognitive
functions.85,87-89 Side effects are typically
 Pharmacologic Treatment of Neurobehavioral Sequelae
mild and include insomnia, nausea, diarrhea,
and weight loss.
Several early studies focused on donepezil
in TBI.90-101 These trials consisted of small
sample sizes, nonrandomized designs, and
heterogeneous outcome measures. Improve-
ments in attention, processing speed, mem-
ory, and overall functionality were observed.
The first randomized, placebo-controlled,
crossover study included 20 patients who
were 2 to 24 months after a mild to severe
TBI.102 Patients were treated for 10 weeks
with donepezil 5 to 10 mg daily or placebo,
followed by a 4-week washout period, and
then switched to the other treatment for
the remaining 10 weeks. At week 10, pa-
tients in the group who were treated with
donepezil had significant improvements in
both short-term memory and attention scores
compared with their own baseline and those
given placebo. Patients administered placebo
did not significantly improve compared with
their baseline. After completion of the sec-
ond phase of the trial at week 24, those ini-
tially treated with donepezil maintained their
benefits. The scores of those who crossed
over from placebo to donepezil improved,
and there was no longer any difference be-
tween the groups. The results of this small
study imply that treatment with donepezil
can improve patients’ memory and attention.
A more recent analysis of donepezil was a
retrospective cohort by Campbell et al103 in
2018. This trial included patients who had
sustained a moderate to severe TBI. Fifty-five
subjects who were treated with donepezil 5
to 10 mg daily via physician discretion had
their outcomes compared with 74 patients
who had received standard TBI care and no
donepezil. Donepezil was initiated a mean
17.5 (range: 3-54) days postinjury and dis-
continued after a mean 67.5 (range: 32-120)
days. The prespecified outcomes were pro-
cessing speed, attention, and memory. No
significant differences were found across all
neuropsychological outcomes. A limitation of
this study is the retrospective design and
provider-guided decision for who received
donepezil.
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185
Donepezil is recognized as the primary
agent for memory impairments in the INESSS-
ONF guidelines, but this recommendation is
supported by limited evidence.21 A recent,
larger retrospective trial could not replicate
any previously reported benefits for process-
ing speed, attention, and memory.103 The lack
of reproducible results may be secondary to
small, nonrandomized studies, varying time
to initiation and duration of donepezil. Dos-
ing strategies were consistent at 5 to 10 mg
per day in both trials. Because of acetyl-
choline’s prolonged time to normalization
and higher risk of chronic impairment, future
studies could focus on long-term benefits of
donepezil.85,86
AGENTS WITH LIMITED EVIDENCE
Several other neurostimulants have
been evaluated with limited evidence
to draw conclusions on their benefit in
TBI patients. Milnacipran is a serotonin-
norepinephrine reuptake inhibitor (SNRI).
Serotonin-norepinephrine reuptake in-
hibitors increase concentrations of serotonin
and norepinephrine through inhibition
of presynaptic reuptake by serotonin and
norepinephrine transporters. Although
hypothesized to have similar benefits to
SSRIs, studies evaluating SNRIs in post-TBI
depression are limited. One open label
study of 10 patients evaluated the use of
milnacipran on depression assessed by the
HAM-D and cognitive functioning assessed by
the Mini-Mental State Examination after mild
to moderate TBI.104 Milnacipran was initiated
at a dose of 30 mg twice daily and adjusted
to a maximum dose of 150 mg per day.
After 6 weeks, 44.4% of patients’ depression
was in remission (HAM-D <7). Patients also
had significant improvement in cognitive
functioning based on their Mini-Mental State
Examination. Although the sample size was
low, these results indicate that with further
studies, milnacipran may be effective in
post-TBI depression. A trial evaluating the
SNRI venlafaxine for the treatment of post-
TBI depression has also been completed;
186 CRITICAL CARE NURSING QUARTERLY/APRIL–JUNE 2020
however, the results of this trial have not yet
been published (NCT00205491).
Monoamine oxidase inhibitors (MAOIs) in-
hibit the enzyme monoamine oxidase, result-
ing in increased concentrations of multiple
neurotransmitters including serotonin, nore-
pinephrine, and dopamine.63,105 Although
MAOIs were the first class of antidepres-
sant medications, their use has historically
been limited by drug-drug and drug-food in-
teractions and adverse events. One concern-
ing interaction is with tyramine-containing
foods (ie, cheeses, cured or smoked meats,
and sourdough bread) as MAOIs also in-
hibit monoamine oxidase in the gastroin-
testinal tract. When MAOIs and tyramine are
coingested, this allows unmetabolized tyra-
mine to enter the bloodstream and promotes
a sympathetic effect.105 These agents also
have numerous drug interactions that may in-
crease the risk of serotonin syndrome when
taken concomitantly with other serotonergic
medications (ie, SSRIs or SNRIs). Although
not available in the United States, moclobe-
mide is a novel MAOI with similar therapeutic
properties to other antidepressants. Moclobe-
mide reversibly and selectively inhibits MAO-
A, which results in fewer interactions and ad-
verse effects.106
Newburn et al107 conducted a retrospective
study of TBI patients with a major depres-
sive episode or major depression. Patients
were treated with moclobemide 450 to 600
mg per day. After 3 weeks of treatment, 23
of 26 patients were considered responders
based on their HAM-D scores.107 Five patients
withdrew from the study because of adverse
events including nausea, diarrhea, and ortho-
static hypotension. The results indicate that
with further research, moclobemide might
be an alternative option for the treatment of
depression in TBI patients. However, as this
agent is not available in the United States,
a recommendation for its use cannot be
made.
Levodopa/carbidopa is a combined
dopamine precursor and decarboxylase in-
hibitor that has been evaluated for improving
recovery speed from a persistent vegetative
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
state following severe TBI. In a prospective
case series, 11 patients who remained in a
vegetative state for 1 month following TBI
were given levodopa/carbidopa 100 mg/25
mg twice daily (maximum dose: 375 mg per
day). After 2 to 5 months, 4 patients had
improved to a minimally conscious state.108
No adverse events were reported. As the evi-
dence is limited to case series, further studies
are needed before this agent can be recom-
mended for use in improving recovery speed.
Bromocriptine is a dopamine agonist
with similar therapeutic properties to
amantadine.109 A prospective cohort study
included patients in a minimally conscious
state.110 Adult patients (N = 33) received
bromocriptine 7.5 mg once daily. Patients
exhibited improvements in arousal, cognitive
impairment, and memory after 6 months. As
this study lacked a comparative group, the
6-month time frame may have allowed for
spontaneous improvement and confounds
the results.
Rivastigmine is a centrally acting acetyl-
cholinesterase inhibitor with similar thera-
peutic properties to donepezil.111 A multicen-
ter trial randomized 157 patients with TBI
to rivastigmine 1.5 to 3 mg twice daily or
placebo.112 The primary outcome measured
verbal attention and memory function. No
significant differences were found. Patients
who received rivastigmine experienced sig-
nificantly more nausea. With the limited data
available, the evidence for improvement in
memory in TBI favors donepezil as the agent
of choice.
CONCLUSION
Neurostimulants have been evaluated for
post-TBI conditions including cognitive, af-
fective, and sleep-wake disorders. Benefits
have been reported in both the acute and
chronic phases of recovery, but clinical prac-
tice guidelines are lacking strong recommen-
dations. The available literature is limited by
several factors including small sample sizes,
lack of accountability for spontaneous re-
covery, the use of different and subjective
 Pharmacologic Treatment of Neurobehavioral Sequelae
outcomes scales, and subject heterogeneity
(including variations in TBI severity and time
from injury).
Based on the available literature, there is ev-
idence to support the use of amantadine for
cognitive disorders, particularly in improving
recovery speed. Selective serotonin reuptake
inhibitors may be useful in treating affective
disorders, with the best evidence supporting
sertraline and citalopram for the treatment
of post-TBI depression. For sleep-wake disor-
ders, MPH may be useful in improving mental
fatigue. Modafinil and armodafinil have been
REFERENCES
1. Centers for Disease Control and Prevention,
National Center for Injury Prevention and Con-
trol. Traumatic brain injury in the United States:
epidemiology and rehabilitation. https://www.
cdc.gov/traumaticbraininjury/pdf/tbi_report_to_
congress_epi_and_rehab-a.pdf. Published 2013.
Accessed December 13, 2019.
2. Faul M, Xu L, Wald MM, et al. Traumatic Brain In-
jury in the United States: Emergency Department
Visits, Hospitalizations and Deaths 2002-2006. At-
lanta, GA: Centers for Disease Control and Preven-
tion, National Center for Injury Prevention and Con-
trol; 2010.
3. Bullock R. Mortality rates of placebo groups in se-
vere traumatic brain injury trials. Trauma Care.
1997;7:16-17.
4. Dixon KJ. Pathophysiology of traumatic brain injury.
Phys Med Rehabil Clin N Am. 2017;28(2):215-225.
5. Dikmen S, Machamer J, Fann JR, Temkin NR. Rates
of symptom reporting following traumatic brain in-
jury. J Int Neuropsychol Soc. 2010;16(3):401-411.
6. Sterr A, Herron KA, Hayward C, Montaldi D. Are
mild head injuries as mild as we think? Neurobehav-
ioral concomitants of chronic post-concussion syn-
drome. BMC Neurol. 2006;6:7.
7. Hill CS, Coleman MP, Menon DK. Traumatic axonal
injury: mechanisms and translational opportunities.
Trends Neurosci. 2016;39(5):311-324.
8. Lafrenaye AD, Todani M, Walker SA, Povlishock JT.
Microglia processes associate with diffusely injured
axons following mild traumatic brain injury in the
micro pig. J Neuroinflammation. 2015;12:186.
9. Browne KD, Chen XH, Meaney DF, Smith DH. Mild
traumatic brain injury and diffuse axonal injury in
swine. J Neurotrauma. 2011;28(9):1747-1755.
10. Topal NB, Hakyemez B, Erdogan C, et al. MR
imaging in the detection of diffuse axonal in-
jury with mild traumatic brain injury. Neurol Res.
2008;30(9):974-978.
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
187
shown to improve EDS. When making the de-
cision to initiate a neurostimulant, providers
should work with the patient to identify the
most appropriate agent based on medication
side effect profiles and patient-specific fac-
tors. Patients should be monitored for clinical
improvement and adverse effects. Large ran-
domized controlled trials with homogenous
patient populations are needed to fully deter-
mine the benefit of these agents. In the mean-
time, recommendations such as those pro-
vided by INESSS-ONF are able to offer some
guidance.
11. Lotocki G, de Rivero Vaccari JP, Alonso O, et al.
Oligodendrocyte vulnerability following traumatic
brain injury in rats. Neurosci Lett. 2011;499(3):143-
148.
12. Ghirnikar RS, Lee YL, Eng LF. Inflammation in
traumatic brain injury: role of cytokines and
chemokines. Neurochem Res. 1998;23(3):329-340.
13. Villalba N, Sonkusare SK, Longden TA, et al. Trau-
matic brain injury disrupts cerebrovascular tone
through endothelial inducible nitric oxide synthase
expression and nitric oxide gain of function. J Am
Heart Assoc. 2014;3(6):e001474.
14. DeWitt DS, Prough DS. Traumatic cerebral vas-
cular injury: the effects of concussive brain in-
jury on the cerebral vasculature. J Neurotrauma.
2003;20(9):795-825.
15. McQuire JC, Sutcliffe JC, Coats TJ. Early changes
in middle cerebral artery blood flow velocity after
head injury. J Neurosurg. 1998;89(4):526-532.
16. Golding EM, Robertson CS, Bryan RM Jr. The conse-
quences of traumatic brain injury on cerebral blood
flow and autoregulation: a review. Clin Exp Hyper-
tens. 1999;21(4):299-332.
17. Pasco A, Lemaire L, Franconi F, et al. Perfusional
deficit and the dynamics of cerebral edemas in ex-
perimental traumatic brain injury using perfusion
and diffusion weighted magnetic resonance imag-
ing. J Neurotrauma. 2007;24(8):1321-1330.
18. Guerriero RM, Giza CC, Rotenberg A. Glutamate
and GABA imbalance following traumatic brain in-
jury. Curr Neurol Neurosci Rep. 2015;15(5):27.
19. Carney N, Totten AM, O’Reilly C, et al. Guide-
lines for the management of severe traumatic brain
injury, fourth edition. Neurosurgery. 2017;80(1):
6-15.
20. Warden D, Gordon B, McAllister TW, et al. Guide-
lines for the pharmacological treatment of neurobe-
havioral sequelae of traumatic brain injury. J Neuro-
trauma. 2006;23(10):1468-1501.
188 CRITICAL CARE NURSING QUARTERLY/APRIL–JUNE 2020
21. Bayley MT, Lamontagne ME, Kua A, et al. Unique
features of the INESSS-ONF rehabilitation guidelines
for moderate to severe traumatic brain injury: re-
sponding to users’ needs. J Head Trauma Rehabil.
2018;33(5);296-305.
22. Amantadine hydrochloride [package insert]. Yard-
ley, PA: Vensun Pharmaceuticals, Inc; 2019.
23. Sertraline [package insert]. New York, NY: Pfizer;
2018.
24. Citalopram [package insert]. Madison, NJ: Allergan;
2019.
25. Amitriptyline [package insert]. Wilmington, DE:
Zeneca; 2000.
26. Desipramine [package insert]. Bridgewater, NJ:
Sanofi; 2014.
27. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs
and serious cardiovascular events in children and
young adults. N Engl J Med. 2011;365(20):1896-
1904.
28. Dextroamphetamine [package insert]. Newport,
KY: Independence Pharmaceuticals; 2017.
29. Lisdexamfetamine [package insert]. Toronto, On-
tario, Canada: Shire Pharma Canada ULC; 2019.
30. Modafinil [package insert]. North Wales, PA: Teva;
2018.
31. Armodafinil [package insert]. North Wales, PA: Teva;
2018.
32. Donepezil [package insert]. Basking Ridge, NJ: Tor-
rent Pharma Inc; 2014.
33. Chen JJ, Swope DM. Pharmacotherapy for Parkin-
son’s disease. Pharmacotherapy. 2007;27(12):161-
173.
34. Meythaler JM, Brunner RC, Johnson A, Novack TA.
Amantadine to improve neurorecovery in traumatic
brain injury-associated diffuse axonal injury: a pilot
double-blind randomized trial. J Head Trauma Re-
habil. 2002;17(4):300-313.
35. Stelmaschuk S, Will MC, Meyers T. Amantadine to
treat cognitive dysfunction in moderate to severe
traumatic brain injury. J Neurotrauma Nursing.
2015;22(4):194-203.
36. Kraus MF, Maki P. Effect of amantadine hydrochlo-
ride on symptoms of frontal lobe dysfunction in
brain injury: case studies and review. J Neuropsy-
chiatry Clin Neurosci. 1997;9:222-230.
37. Kraus MF, Maki P. The combined use of amantadine
and L-dopa/carbidopa in treatment of chronic brain
injury. Brain Inj. 1997;11(6):445-460.
38. Schneider WN, Drew-Cates J, Dombovy ML. Cog-
nitive and behavioural efficacy of amantadine in
acute traumatic brain injury: an initial double-
blind placebo controlled study. Brain Inj. 1999;
13(11):863-872.
39. Saniova B, Drobny M, Kneslova L, Minarik M.
The outcome of patients with severe head in-
juries treated with amantadine sulphate. J Neural
Transm. 2004;111:511-514.
40. Hughes S, Colantonio A, Santaguida PL, Paton T.
Amantadine to enhance readiness for rehabilitation
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
following severe traumatic brain injury. Brain Inj.
2005;19:1197-1206.
41. Whyte J, Katz D, Long D, et al. Predictors of
outcome in prolonged posttraumatic disorders of
consciousness and assessment of medication ef-
fects: a multicenter study. Arch Phys Med Rehabil.
2005;86:453-462.
42. Wroblewski BA, Joseph AB, Cornblatt RR. Antide-
pressant pharmacotherapy and the treatment of de-
pression in patients with severe traumatic brain in-
jury: a controlled, prospective study. J Clin Psychi-
atry. 1996;57(12):582-587.
43. Menn SJ, Yang R, Lankford A. Armodafinil for the
treatment of excessive sleepiness associated with
mild or moderate closed traumatic brain injury: a 12-
week, randomized, double-blind study followed by
a 12-month open-label extension. J Clin Sleep Med.
2014;10(11):1181-1191.
44. Busner J, Targum SD. The Clinical Global Im-
pressions Scale. Psychiatry (Edgmont). 2007;4(7):
28-37.
45. Rappaport M, Hall KM, Hopkins K, Belleza T, Cope
DN. Disability rating scale for severe head trauma
patients: coma to community. Arch Phys Med Re-
habil. 1982;63:118-123.
46. Sharp R. The Hamilton Rating Scale for Depression.
Occup Med (Lond). 2015;65(4):340.
47. Pangman VC, Sloan J, Guse L. An examination of
psychometric properties of the Mini-Mental State
Examination and the standardized Mini-Mental State
Examination: implications for clinical practice. Appl
Nurs Res. 2000;13(4):209-213.
48. Carskadon MA, Dement WC, Mitler MM, Roth T,
Westbrook PR, Keenan S. Guidelines for the Multi-
ple Sleep Latency Test (MSLT): a standard measure
of sleepiness. Sleep. 1986;9(4):519-524.
49. Giacino JT, Whyte J, Bagiella E, et al. Placebo-
controlled trial of amantadine for severe traumatic
brain injury. N Engl J Med. 2012;366(9):819-826.
50. Hammond FM, Bickett AK, Norton JH, Pershad M.
Effectiveness of amantadine hydrochloride in reduc-
tion of chronic traumatic brain injury irritability and
aggression. J Head Trauma Rehabil. 2014;29:391-
399.
51. Hammond FM, Sherer M, Malec JF, et al. Amantadine
effect on perceptions of irritability after traumatic
brain injury: results of the amantadine irritability
multisite study. J Neurotrauma. 2015;32(16):1230-
1238.
52. Hammond FM, Malec JF, Zafonte RD, et al. Poten-
tial impact of amantadine on aggression in chronic
traumatic brain injury. J Head Trauma Rehabil.
2017;32(5):308-318.
53. Silverberg ND, Panenka WJ. Antidepressants for
depression after concussion and traumatic brain
injury are still best practice. BMC Psychiatry.
2019;19(1):100.
54. Meythaler JM, Depalma L, Devivo MJ, Guin-Renfroe
S, Novack TA. Sertraline to improve arousal and
 Pharmacologic Treatment of Neurobehavioral Sequelae
alertness in severe traumatic brain injury sec-
ondary to motor vehicle crashes. Brain Inj. 2001;
15(4):321-331.
55. Salter KL, McClure JA, Foley NC, Sequeira K, Teasell
RW. Pharmacotherapy for depression posttraumatic
brain injury: a meta-analysis. J Head Trauma Reha-
bil. 2016;31(4):E21-E32.
56. Yue JK, Burke JF, Upadhyayula PS, et al. Selec-
tive serotonin reuptake inhibitors for treating neu-
rocognitive and neuropsychiatric disorders follow-
ing traumatic brain injury: an evaluation of current
evidence. Brain Sci. 2017;7(8):pii: E93.
57. Ashman TA, Cantor JB, Gordon WA, et al. A random-
ized controlled trial of sertraline for the treatment of
depression in persons with traumatic brain injury.
Arch Phys Med Rehabil. 2009;90(5):733-740.
58. Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon
JS. Comparing effects of methylphenidate, sertra-
line and placebo on neuropsychiatric sequelae in
patients with traumatic brain injury. Hum Psy-
chopharmacol. 2005;20(2):97-104.
59. Jorge RE, Acion L, Burin DI, Robinson RG. Sertraline
for preventing mood disorders following traumatic
brain injury: a randomized clinical trial. JAMA Psy-
chiatry. 2016;73(10):1041-1047.
60. Rapoport MJ, Chan F, Lanctot K, Herrmann N,
McCullagh S, Feinstein A. An open-label study of
citalopram for major depression following traumatic
brain injury. J Psychopharmacol. 2008;22(8):860-
864.
61. Rapoport MJ, Mitchell RA, McCullagh S, et al. A ran-
domized controlled trial of antidepressant continua-
tion for major depression following traumatic brain
injury. J Clin Psychiatry. 2010;71(9):1125-1130.
62. Horsfield SA, Rosse RB, Tomasino V, Schwartz BL,
Mastropaolo J, Deutsch SI. Fluoxetine’s effects on
cognitive performance in patients with traumatic
brain injury. Int J Psychiatry Med. 2002;32(4):337-
344.
63. Feighner JP. Mechanism of action of antidepressant
medications. J Clin Psychiatry. 1999;60(suppl 4):
4-11; discussion 12-13.
64. Mysiw WJ, Jackson RD, Corrigan JD. Amitriptyline
for post-traumatic agitation. Am J Phys Med Reha-
bil. 1988;67(1):29-33.
65. Max JE, Schachar RJ, Levin HS, et al. Predictors
of secondary attention-deficit/hyperactivity disor-
der in children and adolescents 6 to 24 months af-
ter traumatic brain injury. J Am Acad Child Adolesc
Psychiatry. 2005;44(10):1041-1049.
66. Bush G, Spencer TJ, Holmes J, et al. Functional mag-
netic resonance imaging of methylphenidate and
placebo in attention deficit/hyperactivity disorder
during the multisource interference task. Arch Gen
Psychiatry. 2008;65:102-114.
67. Bales JW, Kline AE, Wagner AK, Dixon CE. Target-
ing dopamine in acute traumatic brain injury. Open
Drug Discov J. 2010;2:119-128.
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
189
68. Huang CH, Huang CC, Sun CK, Lin GH, Hou WH.
Methylphenidate on cognitive improvement in pa-
tients with traumatic brain injury: a meta-analysis.
Curr Neuropharmacol. 2016;14(3):272-281.
69. Ritalin/Ritalin SR (methylphenidate) [package in-
sert]. East Hanover, NJ: Novartis Pharmaceuticals;
2019.
70. Williams SE, Ris MD, Ayyangar R, Schefft BK, Berch
D. Recovery in pediatric brain injury: is psychostim-
ulant medication beneficial? J Head Trauma Reha-
bil. 1998;13(3):73-81.
71. Mahalick DM, Carmel PW, Greenberg JP, et al. Psy-
chopharmacologic treatment of acquired attention
disorders in children with brain injury. Pediatr Neu-
rosurg. 1998;29(3):121-126.
72. Whyte J, Hart T, Schuster K, Fleming M, Polansky
M, Coslett HB. Effects of methylphenidate on atten-
tional function after traumatic brain injury. A ran-
domized, placebo-controlled trial. Am J Phys Med
Rehabil. 1997;76(6):440-450.
73. Speech TJ, Rao SM, Osmon DC, Sperry LT. A
double-blind controlled study of methylphenidate
treatment in closed head injury. Brain Inj. 1993,
7(4):333-338.
74. Whyte J, Hart T, Grieb-Neff P, Risser A, Polansky M,
Coslett HB. Effects of methylphenidate on attention
deficits after traumatic brain injury: a multidimen-
sional, randomized, controlled trial. Am J Phys Med
Rehabil. 2004;83:401-420.
75. Zhang WT, Wang YF. Efficacy of methylphenidate
for the treatment of mental sequelae after
traumatic brain injury. Medicine (Baltimore).
2017;96(25):e6960.
76. Tramontana MG, Cowan RL, Zald D, Prokop JW,
Guillamondegui O. Traumatic brain injury-related
attention deficits: treatment outcomes with lis-
dexamfetamine dimesylate (Vyvanse). Brain Inj.
2014;28(11):1461-1472.
77. Hart T, Whyte J, Watanabe T J, Chervoneva I. Ef-
fects of dextroamphetamine in subacute traumatic
brain injury: a randomized, placebo-controlled pilot
study. J Neurosci Res. 2018;96(4):702-710.
78. Gerrard P, Malcolm R. Mechanisms of modafinil:
a review of current research. Neuropsychiatr Dis
Treat. 2007;3(3):349-364.
79. Elovic E. Use of provigil for underarousal follow-
ing TBI. J Head Trauma Rehabil. 2000;15(4):1068-
1071.
80. Batéjat DM, Lagarde DP. Naps and modafinil as
countermeasures for the effects of sleep depriva-
tion on cognitive performance. Aviat Space Envi-
ron Med. 1999;70(5):493-498.
81. Beusterien KM, Rogers AE, Walsleben JA, et al.
Health-related quality of life effects of modafinil
for treatment of narcolepsy. Sleep. 1999;22(6):
757-765.
82. Teitelman E. Off-label uses of modafinil. Am J Psy-
chiatry. 2001;158(8):1341.
190 CRITICAL CARE NURSING QUARTERLY/APRIL–JUNE 2020
83. Jha A, Weintraub A, Allshouse A, et al. A random-
ized trial of modafinil for the treatment of fatigue
and excessive daytime sleepiness in individuals with
chronic traumatic brain injury. J Head Trauma Re-
habil. 2008;23(1):52-63.
84. Kaiser PR, Valko PO, Werth E, et al. Modafinil ame-
liorates excessive daytime sleepiness after traumatic
brain injury. Neurology. 2010;75(20):1780-1785.
85. Arciniegas DB. The cholinergic hypothesis of cog-
nitive impairment caused by traumatic brain injury.
Curr Psychiatry Rep. 2003;5(5):391-399.
86. Whitlock JA Jr. Brain injury, cognitive impair-
ment, and donepezil. J Head Trauma Rehabil.
1999;14(4):424-427.
87. Blokland A. Acetylcholine: a neurotransmitter for
learning and memory? Brain Res Brain Res Rev.
1995;21(3):285-300.
88. Aigner TG. Pharmacology of memory: cholinergic-
glutamatergic interactions. Curr Opin Neurobiol.
1995;5(2):155-160.
89. Sarter M, Bruno JP. Cognitive functions of cortical
acetylcholine: toward a unifying hypothesis. Brain
Res Brain Res Rev. 1997;23(1-2):28-46.
90. Kim YW, Kim DY, Shin JC, Park CI, Lee JD. The
changes of cortical metabolism associated with the
clinical response to donepezil therapy in traumatic
brain injury. Clin Neuropharmacol. 2009;32(2):
63-68.
91. Walker W, Seel R, Gibellato M, et al. The effects of
Donepezil on traumatic brain injury acute rehabili-
tation outcomes. Brain Inj. 2004;18(8):739-750.
92. Masanic CA, Bayley MT, VanReekum R, Simard M.
Open-label study of donepezil in traumatic brain in-
jury. Arch Phys Med Rehabil. 2001;82(7):896-901.
93. Whelan FJ, Walker MS, Schultz SK. Donepezil in
the treatment of cognitive dysfunction associated
with traumatic brain injury. Ann Clin Psychiatry.
2000;12(3):131-135.
94. Kaye NS, Townsend JB III, Ivins R. An open-label
trial of donepezil (Aricept) in the treatment of per-
sons with mild traumatic brain injury. J Neuropsy-
chiatry Clin Neurosci. 2003;15(3):383-384.
95. Morey CE, Cilo M, Berry J, Cusick C. The effect of
Aricept in persons with persistent memory disorder
following traumatic brain injury: a pilot study. Brain
Inj. 2003;17(9):809-815.
96. Khateb A, Ammann J, Annoni JM, Diserens K.
Cognition-enhancing effects of donepezil in trau-
matic brain injury. Eur Neurol. 2005;54(1):39-45.
97. Taverni JP, Seliger G, Lichtman SW. Donepezil med-
icated memory improvement in traumatic brain in-
jury during post acute rehabilitation. Brain Inj.
1998;12(1):77-80.
98. Bourgeois JA, Bahadur N, Minjares S. Donepezil for
cognitive deficits following traumatic brain injury:
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
a case report. J Neuropsychiatry Clin Neurosci.
2002;14(4):463-464.
99. Sugden SG, Kile SJ, Farrimond DD, Hilty DM, Bour-
geois JA. Pharmacological intervention for cognitive
deficits and aggression in frontal lobe injury. Neuro
Rehabil. 2006;21(1):3-7.
100. Trovato M, Slomine B, Pidcock F, Christensen J.
The efficacy of donepezil hydrochloride on memory
functioning in three adolescents with severe trau-
matic brain injury. Brain Inj. 2006;20(3):339-343.
101. Foster M, Spiegel DR. Use of donepezil in the treat-
ment of cognitive impairments of moderate trau-
matic brain injury. J Neuropsychiatry Clin Neu-
rosci. 2008;20(1):106.
102. Zhang L, Plotkin RC, Wang G, SandelME, Lee S.
Cholinergic augmentation with donepezil enhances
recovery in short-term memory and sustained atten-
tion after traumatic brain injury. Arch Phys Med Re-
habil. 2004;85:1050-1055.
103. Campbell KA, Kennedy RE, Brunner RC, Hollis SD,
Lumsden RA, Novack TA. The effect of donepezil
on the cognitive ability early in the course of
recovery from traumatic brain injury. Brain Inj.
2018;32(8):972-979.
104. Kanetani K, Kimura M, Endo S. Therapeutic ef-
fects of milnacipran (serotonin noradrenalin reup-
take inhibitor) on depression following mild and
moderate traumatic brain injury. J Nippon Med Sch.
2003;70(4):313-320.
105. Brown C, Taniguchi G, Yip K. The monoamine oxi-
dase inhibitor-tyramine interaction. J Clin Pharma-
col. 1989;29(6):529-532.
106. Bonnet U. Moclobemide: evolution, pharmacody-
namic, and pharmacokinetic properties. CNS Drug
Rev. 2002;8(3):283-308.
107. Newburn G, Edwards R, Thomas H, Collier J, Fox
K, Collins C. Moclobemide in the treatment of ma-
jor depressive disorder (DSM-3) following traumatic
brain injury. Brain Inj. 1999;13(8):637-642.
108. Ugoya SO, Akinyemi RO. The place of L-
dopa/carbidopa in persistent vegetative state.
Clin Neuropharmacol. 2010;33(6):279-284.
109. Bromocriptine [package insert]. Pennington, NJ: Zy-
dus Pharmaceuticals USA Inc; 2017.
110. Munakomi S, Bhattarai B, Mohan Kumar B. Role
of bromocriptine in multi-spectral manifestations
of traumatic brain injury. Chin J Traumatol.
2017;20(2):84-86.
111. Rivastigmine Tartrate (rivastigmine) [package in-
sert]. East Windsor, NJ: Aurobindo Pharma USA, Inc;
2019.
112. Silver JM, Koumaras B, Chen M, et al. Effects of ri-
vastigmine on cognitive function in patients with
traumatic brain injury. Neurology. 2006;67(5):748-
755.