Use of donepezil for neurocognitive recovery after brain injury in adult and pediatric populations: a scoping review

Avery L.Miller, Nathan K.Evanson, J.Michael Taylor

Abstract There are few pharmacologic options for the treatment of cognitive deficits associated with traumatic brain injury in pediatric patients.Acetylcholinesterase inhibitors such as donepezil have been evaluated in adult patients after traumatic brain injury, but relatively less is known about the effect in pediatric populations.The goal of this review is to identify knowledge gaps in the efficacy and safety of acetylcholinesterase inhibitors as a potential adjuvant treatment for neurocognitive decline in pediatric patients with traumatic brain injury.Investigators queried PubMed to identify literature published from database inception through June 2023 describing the use of donepezil in young adult traumatic brain injury and pediatric patients with predefined conditions.Based on preselected search criteria, 340 unique papers were selected for title and abstract screening.Thirty-two records were reviewed in full after eliminating preclinical studies and papers outside the scope of the project.In adult traumatic brain injury, we review results from 14 papers detailing 227 subjects where evidence suggests donepezil is well tolerated and shows both objective and patient-reported efficacy for reducing cognitive impairment.In children, 3 papers report on 5 children recovering from traumatic brain injury, showing limited efficacy.An additional 15 pediatric studies conducted in populations at risk for cognitive dysfunction provide a broader look at safety and efficacy in 210 patients in the pediatric age group.Given its promise for efficacy in adults with traumatic brain injury and tolerability in pediatric patients, we believe further study of donepezil for children and adolescents with traumatic brain injury is warranted.

Key Words: acetylcholinesterase inhibitor; adult; cognition; donepezil; pediatrics; traumatic brain injury

Introduction

Over the past two decades, studies have shown that acetylcholine pathways play a major role in cognitive function.In 1997, the FDA approved a series of centrally-acting acetylcholinesterase inhibitors (AChEi) for the treatment of Alzheimer’s disease.Galantamine, rivastigmine, and donepezil remain in routine use, having proven significantly safer and more effective than earlier AChEi (Taverni et al., 1998).Due to the favorable tolerability of modern AChEi,clinicians have considered opportunities for extending the application of these medications to different disease states.

Acquired brain injury (ABI) occurs when a patient is exposed to a discrete injury and receives anatomic and/or physiologic changes to the brain.The most frequently occurring ABI in the general population is traumatic brain injury (TBI), affecting an estimated 2.8 million Americans per year.TBI is a leading cause of morbidity and mortality across all ages (Taylor et al., 2017).The neurocognitive decline after TBI is an important recovery outcome which may require extensive rehabilitative support, increased healthcare utilization,and lost learning and earning potential for years after the inciting injury.A number of small-scale studies and case reports have been published,suggesting the potential for improvement when utilizing AChEi in ABI and other disease processes with cognitive impairment (Ballesteros et al., 2008).Most of these studies were performed in adult populations and showed promising results.Conversely, there has been little exploration of donepezil in children and adolescents with ABI.Recovery from ABI is known to differ dramatically in children compared to adult populations (Hessen et al., 2007;Sariaslan et al., 2016), requiring investigators to verify the applicability and safety of proposed interventions in pediatric patients.The goal of this review is to identify knowledge gaps in the efficacy and safety of AChEi as a potential adjuvant treatment for neurocognitive decline in pediatric patients with TBI.

Methods

For this scoping review, relevant articles listed in PubMed were identified using MeSH terms: donepezil, Aricept, an acetylcholinesterase inhibitor, traumatic brain injury, acquired brain injury, chronic brain injury, and adolescents.To identify studies utilizing donepezil in pediatric disease processes, a search was performed using MeSH terms: pediatric, donepezil, traumatic brain injury,autism, attention deficit hyperactivity disorder, fragile X, Down syndrome,brain tumor, and chemotherapy.We specified inclusion criteria for all studies presenting a clinical trial, case series, or case report describing donepezil as an adjuvant for cognitive recovery after TBI or the defined pediatric disease states; presenting data on a novel patient cohort; and designed to test donepezil’s effect (not other AChEi or pharmacotherapeutics).Studies were excluded from analysis if data represented preclinical animal trials or were not available in review in English.

To avoid sampling patients with cognitive impairment related to adultonset dementias, we selected data on subjects less than 50 years old.When data was available for an individual study subject, we gathered relevant information including age, sex, injury severity, location of injury, age at injury,time since injury, baseline symptoms prior to therapy, dosage of donepezil with titration scheme, duration of treatment, adverse effects, and outcome measures reported.The efficacy of donepezil is reported as described in the primary sources.The authors use a combination of objective measures and patient-reported subjective ratings to determine the effect of treatment.When individual participant data was not published in the manuscript, we summarized the entire cohort, anticipating a distribution of ages above and below the target age range.Adverse effects were recorded without respect to age.Analysis of pediatric studies focused primarily on safety due to limited efficacy data in the published literature.All study data is maintained in a single database utilizing Excel (version 2306, Microsoft, Redmond, WA).

Results

Figure 1 ｜Flow chart demonstrating search criteria and records applicable to this review.

A PubMed query identified 729 records matching the MeSH terms (Figure 1).After eliminating duplicate results, 340 unique articles remained for review.Initial title and abstract screening eliminated 102 records meeting exclusion criteria (94 preclinical studies and 8 not available in English).An additional 206 papers were eliminated for not matching the study inclusion criteria (169 not relevant, 28 topical reviews without novel cases, 9 analyses of AChEi other than donepezil).Thirty-two papers remained for full-text analysis, including 17 articles on TBI (14 adult and 3 adolescent – Table 1) and 15 articles focused on developmental disorders in pediatric/adolescent subjects (Table 2).

All the adult studies focused on TBI.We identified 4 case reports, 3 retrospective case series, 5 open-label trials, and 2 randomized, placebocontrolled, double-blind trials (Figure 2).In 5 papers the age of each subject was reported, 19 of 24 were aged 50 years or less (age data for 5 subjects in the study of Khateb et al.(2005) were not reported due to protocol withdrawal).Eight studies provided general age ranges with median and/or mean age, and one study did not provide age data.These studies included 198 subjects who fell within an overall age range of 17–76 years.Together, the adult data represents 227 subjects treated with donepezil for TBI (Figure 3).

Our query for pediatric studies identified 18 papers for full-text review,including 5 case reports, 1 retrospective study, 7 open-label trials, and 5 randomized, placebo-controlled, double-blind trials (Figure 2).Disease states included 3 TBI studies in adolescents, 1 series of brain tumor survivors, 5 cohorts with attention deficit hyperactivity disorder (ADHD), 2 with Fragile X, 5 with autism spectrum disorders, and 2 with Down syndrome (Figure 4).There were a total of 215 patients that received donepezil (control groups are excluded from this number), of which 191 completed treatment per protocol.Of the 24 subjects who discontinued donepezil, 17 cases were related to side effects, while 7 were due to other reasons.

A summary of all studies included in this analysis is shown in Table 1.

Donepezil in adults

Case reports

There were 4 case reports applicable to this review (Figure 3; Taverni et al.,1998; Bourgeois et al., 2002; Sugden et al., 2006).In the first, a 36-year-old male with severe TBI was treated with donepezil 10 mg daily beginning 2 months after acute injury.He had recently resolved a prolonged interval of delirium and continued with memory consolidation defects.He was treated with a combination of donepezil, risperidone, and venlafaxine over 30 days.His Mini-Mental State Examination (MMSE) score improved from 18 to 29 during combination therapy (Bourgeois et al., 2002).In the second report,two patients in chronic recovery after severe TBI were treated with donepezil 5 mg daily for 3 weeks (Taverni et al., 1998).One patient had improvement in the Functional Independence Measure scores after treatment with persistent memory and problem-solving deficits.The other subject improved in alertness and recall, and showed 60% increase in performance on a modified (nonvalidated) memory test (Table 1).Side effects of gastrointestinal origin were reported but tolerated.In the third report, a 35-year-old male with premorbid antisocial personality disorder, drug and alcohol dependence suffered a severe TBI (Sugden et al., 2006).During his acute post-injury hospitalization,he experienced encephalopathy and delirium requiring stepwise trials of haloperidol, risperidone, amantadine, donepezil, valproic acid, and venlafaxine.Donepezil was titrated to 10 mg daily for a total treatment duration of 43 days.During these multiple medication trials, the patient showed improvement in his MMSE score from 4 to 24 whereupon amantadine and donepezil were discontinued (final MMSE 28).The authors credit the dual treatment with amantadine and donepezil as beneficial in cognitive recovery.In the fourth report, a patient of unspecified age was started on donepezil(dose not specified) to help with word retrieval (Stockhausen and Tower,2016).Donepezil was stopped after 12 days of treatment after the patient developed diarrhea (eventually resolved by redosing statin medication).Within 2 weeks, the patient declined to follow commands, engage in naming tasks, and make more paraphasic errors.Donepezil was restarted with cognition and language symptoms improved.No objective test of function is described in the fourth case report.In each of these four papers, the authors identify an improvement in recovery attributed to donepezil.

Figure 2 ｜Graphic showing details of studies meeting inclusion criteria for the review.

Figure 3 ｜Literature on adult studies divided by study type.

Figure 4 ｜ Literature on pediatric studies divided by disease process.

Table 1 ｜TBI studies reviewed

Table 1 ｜Continued

Retrospective studies

There were three retrospective studies applicable to this review (Whelan et al., 2000; Walker et al., 2004; Campbell et al., 2018).In the first, individuals with a history of ABI from traumatic injury, anoxic encephalopathy, or stroke were given donepezil (Whelan et al., 2000).Fifty-three ambulatory patients were titrated up to 10 mg daily and continued with observation up to 2 years depending on tolerance.The authors note that physician assessment of global functioning showed benefit from treatment, but no significant change was identified on 3 objective measures of cognitive domains (Table 1).No side effects were reported.The second study compares 36 patients with moderate-to-severe TBI at a mean age of 32.2 years in an acute rehabilitation center within 90 days of injury (Walker et al., 2004).Patients were given donepezil up to 10 mg daily with standard rehabilitative therapies (n= 18)and compared to patients treated with standard therapy alone (n= 18).Subjects receiving donepezil showed a nonsignificant increase in cognitive scores on the Functional Independence Measure full and subscales compared to the standard care cohort.Investigators noted subjective improvement in the donepezil-treated cohort, however, no difference was identified in the length of stay in acute rehabilitation.No side effects were observed (Walker et al., 2004).

In a similar study, donepezil was used as an adjuvant to cognitive recovery in an acute hospitalization following moderate-to-severe TBI and compared to standard therapy (Campbell et al., 2018).170 patients were treated with donepezil with 55 patients included in the final analysis for comparison to 74 controls.A substantial fraction of the treatment group (68%) was excluded prior to analysis due to discontinuation of treatment secondary to side effects at low dose (donepezil 5 mg daily), insufficient neuropsychology data,and exclusion as outliers.This compares to an exclusion rate of 6% in the control group.Patients were titrated to donepezil 10 mg daily over 7–10 days.There were no significant differences between the groups on objective measures (Campbell et al., 2018).

Both author groups identified subjective improvements in their cohorts.No test subject showed statistically significant improvement on the objective measures deployed.We have determined an efficacy rate of 56% to reflect the subjective improvements reported (Figure 3).

Open-label trials

Five open-label TBI trials were applicable to this review (Masanic et al., 2001;Kaye et al., 2003; Morey et al., 2003; Khateb et al., 2005; Tenovuo, 2005).Khateb et al.(2005) evaluated the role of donepezil in cognitive recovery in 15 patients with moderate-to-severe TBI at least 6 months after injury(Khateb et al., 2005).Patients were titrated to donepezil 10 mg daily for the duration 12 weeks.The treatment effect was collected by a subjective affective and behavioral assessment and neuropsychological testing.Five subjects failed to complete the protocol (four withdrew due to side effects,one protocol non-adherent).Of the 10 patients that completed the study,7 fit the age criteria for our review with a range of 35–48 years.From this group, 6 of 7 reported subjective improvement in language, memory,attention, emotion, or fatigue after treatment.Objective data is presented for the entire cohort of 10 subjects, showing a significant increase in the Stroop Color Word Interference Test, Test for Attentional Performance,and Rey Auditory Verbal Memory Test with all other measures of executive function, learning, memory, and attention showing no significant change(Khateb et al., 2005).

Table 2 ｜Developmental disorders studies reviewed

Table 2 ｜Continued

In the trial by Masanic et al.(2001), the team evaluated whether donepezil improves memory, behavior, and global function in severe TBI patients aged 24–35 years.Four subjects, recruited from an outpatient ABI treatment program, participated in the protocol.To be eligible, patients were required to have a severe TBI, at least 2 years of recovery, subjective and objective memory deficits as shown on the Rey Auditory Verbal Memory Test.Donepezil titrated to 10 mg was given for 12 weeks followed by a 4-week washout.Data from patients and family members were recorded describing subjective improvements over the study period.Cognitive testing showed specific improvements on the Rey Auditory Verbal Memory Test improvements in learning (0.4 Standard Deviation), short-term memory (1.04 SD), and longterm memory (0.83 SD).The authors highlight these changes as “clinically relevant improvements” which were not statistically significant by analysis of variance.The authors suggest more granular assessments may show the stimulating effect of cholinergic pathways (Masanic et al., 2001).

A third paper is an editorial presenting data on a small series of patients reporting on donepezil’s contribution to global improvement with specific attention to memory (Kaye et al., 2003).Eligible subjects were 10 consecutive chronic TBI patients (mean 1.2 years post-injury) between 28–62 years old presenting to an outpatient clinic for recovery.The paper presents data in aggregate limiting the ability to analyze the 8 subjects less than 50 years old.The study intervention titrated to donepezil 10 mg daily for a total treatment of 8 weeks.Eight subjects completed the study protocol with 2 withdrawing due to side effects and non-adherence.The objective measures failed to demonstrate memory improvement.Patients’ self-reports identified subjective improvements in focus, attention, clarity of thought, processing speed, and multitasking.Family members reported subjectively improved socialization after treatment (Kaye et al., 2003).

Morey details 7 subjects with persistent memory deficits after TBI (Morey et al., 2003).Donepezil dosing was administered in consecutive 6-month blocks in an ABAC trial design to facilitate the patient serving as their control.Treatment began with donepezil titrated to 10 mg daily for 6 months, a 6-week washout period, and donepezil 5 mg daily for a second 6-month treatment.The age range of participants was 19–51 years with a mean age of 30.7 years.Individual data were not included so it was not feasible to pull out participants under 50 years.Multiple domains of cognition were tested objectively and subjectively (Table 1 for details).Subjects were tested 4 times during the study showing significant improvement at donepezil 10 mg daily in immediate and delayed visual memory functioning via Brief Visual Memory Test for 5/7 participants.The authors noted that findings were dose-dependent as there was no significant improvement during the donepezil 5 mg daily 6-month interval.Two subjects discontinued the study due to lethargy and somnolence at the 10 mg dose.The Memory Functioning Questionnaire failed to show statistically significant improvement in subjective memory.Participants and their family members communicated perceived improvement during conversations with clinical evaluators (Morey et al., 2003).

Tenuovo reported on 111 patients, testing the AchEi galantamine,rivastigmine, and 27 subjects on donepezil (Tenovuo, 2005).Subjects in this trial had a mean age of 48 years with a range 17–76 years.Donepezil was dosed at 5 mg daily and increased by study investigators to 10 mg if no effect was noted and medication was tolerated.No objective measures of improvement were employed.Patients reported subjective improvement in cognitive tasks including vigilance, concentration, initiation, general functioning, clearness of thought, mood, cognitive speed, social life, and working ability.However, there were also significant side effects that led some patients to discontinue therapy.No significant difference was identified between the different AchEi (Tenovuo, 2005).

For open-label trials above, 63 subjects received donepezil.Looking only at objective measures, 17 (27%) showed improvement in verbal memory during their trial.Importantly, this includes the 4 subjects reported by Masanic et al.(2001) who showed improvements in verbal memory without statistically significant change.More broadly, the authors identify 36 (57%) subjects with a combination of subjective report and objective test score improvements on treatment (Figure 3).Tolerability of treatment may be of concern as 14 of 63 (22%) discontinued donepezil due to adverse effects.The authors saw promise for donepezil as an adjuvant to cognitive recovery in TBI and advocated for wider-scale randomized controlled trials.

Randomized placebo-controlled studies

Two randomized placebo-controlled trials were applicable to this review(Zhang et al., 2004; Kim et al., 2009).Zhang described 20 subjects between ages 19–57 years with moderate-to-severe TBI at varying stages of recovery(2–24 months) with persistent attention and memory impairment who were randomized to receive donepezil titrated to 10 mg daily or placebo for 10 weeks with a crossover design (Zhang et al., 2004).Patients were assessed using the Auditory and Visual Immediate Indices of the Weschler Memory Scale and the Paced Auditory Serial Addition test at baseline, following the first 10-week intervention, and then after the crossover second 10-week intervention.Subjects who received donepezil first outperformed placeboexposed subjects significantly at the 10-week mark.After crossover, the initial donepezil-treated group sustained improved performance.The authors state that spontaneous recovery must be considered following TBI, but also note that the two groups’ scores differed significantly following the initial 10-week block, likely demonstrating a drug effect.The authors conclude that more study is required to understand the impact of donepezil and the required duration of therapy (Zhang et al., 2004).

In a study by Kim et al.(2009), an assessment of the impact of donepezil on cortical metabolism was undertaken.Participants with cognitive impairment following TBI of unspecified severity were evaluated using positron emission tomography imaging (PET) and neuropsychology assessment tools (Table 1).Twenty-six patients participated in a 6-week study.Patients in the donepezil group (n= 13) were titrated to donepezil 10 mg daily for 6 weeks of treatment.Patients in the donepezil group outperformed the placebo group by a significant margin in the MMSE, Wechsler Memory Scale, and Boston Naming Test indices.The PET studies found metabolic changes with increased glucose uptake in the bilateral frontal, parietal, occipital, and temporal cortices, and decreased uptake in the parahippocampal gyrus.The authors conclude that cholinergic augmentation facilitates improved cognition in cortical territories known to participate in attentional processes (Kim et al.,2009).

The reviewed RCT studies represent 33 patients treated with donepezil in aggregate with an overall efficacy of 94% (Figure 3).In both studies, patients treated with donepezil statistically outperformed the control population on several objective measures.Tolerability in these studies was excellent with 1 subject (3%) discontinuing treatment due to adverse drug effects.Both studies show promising data but have limited study size.

Donepezil in children

Studies that focus on the use of donepezil in pediatric TBI are scarce, with our query identifying three studies that provided relevant data in adolescents(Trovato et al., 2006; Naguy, 2018; Dávila et al., 2020).However, pediatric literature is not silent on donepezil use in children with cognitive and memory impairments.We detail 15 studies where children with developmental and acquired disorders, including ADHD, autism, Down syndrome, brain tumors,and Fragile X have been treated (Table 2).In contrast to the adult studies reported above, there is more variability in the efficacy of donepezil on objective neurocognitive measures in the pediatric studies (Figure 4).The focus of our analysis in this age group is to evaluate cognitive measures used,dosing, and tolerability of donepezil in pediatric trials.

TBI - Adolescents

Trovato and colleagues treated 3 subjects with severe TBI 2 years or more after injury with a 15-week donepezil intervention (Trovato et al., 2006).Patients were given a weekly titration of donepezil, up to 10 mg daily, with assessments measuring verbal memory at 5 intervals during the study.The Buschke Selective Reminding Test, assessing total recall, long-term storage,consistency of long-term retrieval, and delay was used for assessment.All three patients had statistically significant improvements in these subtests (all failed to improve in delayed recall).Patients and their respective caregivers also reported subjective improvements in real-world functioning, and all elected to stay on the medication following the conclusion of the trial.One patient reported mild insomnia and no other adverse effects were recorded(Trovato et al., 2006).

In a single-subject open-label study by Dávila et al.(2020), a 9-year-old subject 6 months recovered after severe TBI affecting the left temporalparietal cortex was treated with donepezil and Intensive Naming Therapy on a 32-week protocol.Treatment targeted anomic aphasia recovery.A control group composed of 7 children, age-matched to the subject, participated in testing.Assessments were performed at 4 intervals to measure language recovery with a battery of standardized tests (Table 1).The TBI patient had lower scores at baseline, which improved during treatment with donepezil alone, and further improved during combined donepezil/Intensive Naming Therapy treatment, leading to scores comparable with the control group in the majority of tests.These improvements remained intact following the washout period (Dávila et al., 2020).

In a case report by Naguy (2018), a 16-year-old patient with a history of TBI requiring ICU admission 6 months prior began exhibiting risk-taking behaviors which were determined to be TBI-related neurocognitive deficits.The patient was treated inpatient for 4 weeks on donepezil 10 mg daily and continued treatment for a total of 7 months.Transient nausea was reported at treatment onset which dissipated and resulted in well-tolerated treatment.The patient had significant improvement in testing via the Wechsler Adult Intelligence Scale – Third Edition, the MMSE, as well as assessments analyzing behaviors related to conduct disorder, disruptive behavior disorder, hyperactivity/impulsivity, and inattentiveness (Naguy, 2018).

The authors of each study concluded that donepezil is an effective adjuvant to recovery as evidenced by objective measures.We identify a treatment efficacy of 100% in the limited adolescent TBI literature with the caveats that sample sizes are limited and higher quality study design is needed.Authors found that donepezil was safe to use in their populations with reasonable tolerability.

Brain tumor survivors treated with cranial radiation

Cognitive dysfunction after cranial radiation for brain tumor treatment is welldescribed.In an open-label trial, Castellino treated 11 patients with a median of 4.7 years after radiosurgery with donepezil for chronic cognitive complaints(Castellino et al., 2012).The subjects ranged in age from 9 and 18 years.Assessments evaluated neurocognitive abilities including executive function,memory, attention, processing speed, and achievement (Table 2).Dosage was determined based on weight with a goal dose of 5 mg for children under 35 kg and 10 mg for larger children.Testing showed significant improvement on the Dellis-Kaplan Executive Function Tower Test and tasks within the Wide Range Assessment of Memory and Learning (2ndedition) – visual memory and number/letter.The National Cancer Institute Common Toxicity Criteria for Adverse Events was utilized at 4 time points to assess adverse events.All subjects reported at least one adverse event prior to the trial.Within two weeks of beginning donepezil therapy, 30% of subjects reported transient gastrointestinal complaints of vomiting and diarrhea (Castellino et al., 2012).

Fragile X

Two studies of donepezil were identified in patients with Fragile X syndrome(Sahu et al., 2013; Bruno et al., 2019).Bruno conducted a randomized control study in subjects 12-29 years old (Bruno et al., 2019).It is noted that this cohort includes pediatric and adult subjects although data is presented across age groups.Donepezil was titrated to 10 mg daily for 12 weeks of treatment.Donepezil did not objectively change cognitive or executive functioning after 12 weeks on the neurocognitive tests (Table 2).Left superior frontal gyrus fMRI activity was altered in the treatment group during an eye gaze task.The authors point to this outcome as a more sensitive measure of change than cognitive and behavioral evaluation.One participant withdrew due to nausea,while all other participants completed the study and were able to tolerate the 10 mg dose (Bruno et al., 2019).

Sahu conducted a 12-week double-blind randomized, placebo-controlled study in males with Fragile X syndrome (Sahu et al., 2013).Patients were between 6–15 years old and were titrated to donepezil 5 mg daily for a total 12 weeks.There was no significant difference between placebo and therapeutic groups in intelligence or behavioral scores after intervention.Adverse effects of somnolence, sluggishness, decreased appetite, and frequent urination were each reported in one participant (Sahu et al., 2013).Overall, studies in the Fragile X population demonstrated high levels of tolerability and safety, but not efficacy (Figure 4).

Down syndrome

Cognitive function in Down syndrome is a significant challenge, and patients are often diagnosed with Alzheimer’s disease at a younger age than the general population.Two studies met our inclusion criteria for Down syndrome(Spiridigliozzi et al., 2007; Kishnani et al., 2010).In the first, Kishnani conducted a randomized double-blind placebo-controlled trial in patients aged 10–17 years (Kishnani et al., 2010).Donepezil doses were gradually titrated up to an average daily dose of 5 mg for 10 weeks.There was no significant difference between the therapeutic and placebo groups on objective measures (Table 2).Four participants failed to complete the study although only one of these participants discontinued treatment due to an unspecified emergent adverse event.The predominant adverse effects were diarrhea and vomiting (Kishnani et al., 2010).

A second study details an open-label case series in 7 children (8–13 years old) (Spiridigliozzi et al., 2007).Patients were titrated to donepezil 5 mg daily for 22 weeks.All patients were able to complete the trial, and most adverse effects (primarily gastrointestinal discomfort and incontinence) were transient and dissipated spontaneously.One patient inadvertently received donepezil 10 mg daily and was excluded from efficacy analysis due to protocol deviation.All reported subjects showed improvement in at least some domains of Vineland Adaptive Behavioral Scales, Connors Parent Rating Scales, and NEPSY subtests for visual attention, memory for names, and narrative memory.However, the authors found a determination of efficacy “unclear” owed to difficulty with the completion of cognitive tasks by some individuals in the cohort.Subjects with higher baseline intelligence quotient (IQ) scores were more compliant with testing and showed improvements.Parent reports on the Connors’ scale found higher scores in patient oppositional behavior– the authors questioned if this is indicative of higher cognitive function or a manifestation of increased irritability (Spiridigliozzi et al., 2007).It is a combination of the parental report of increased assertiveness paired with the differential performance of children with higher baseline IQ which led to our decision to find evidence of subjective efficacy in this study population.The trials by Kishnani et al.(2010) indicate generally tolerable adverse effects of donepezil treatment with low efficacy in Down syndrome patients.

ADHD

Five studies were identified that describe donepezil in ADHD and comorbid disorders (Hoopes, 1999; Wilens et al., 2000, 2005; Doyle et al., 2006; Cubo et al., 2008).In a case series by Hoopes (1999), two patients with Tourette’s syndrome and ADHD were treated with donepezil.The first patient was an 11-year-old boy with severe vocal and motor tics refractory to multiple therapies and exacerbated by ADHD medications.Donepezil was administered at an unspecified dose with reported improvement within a week and persistent effect after 8 months.The second patient was a 13-year-old boy with severe tics and ADHD affecting his day-to-day functioning.He was treated with donepezil 2.5 mg daily with improvement within 1 week and continued treatment for 8 months.Both subjects described subjective improvement in school performance and social function.The authors reported that no adverse effects were seen (Hoopes, 1999).

Doyle reported a retrospective study of patients with pervasive developmental disorder and ADHD treated with open-label donepezil per clinician preference in 10–17-year-old subjects (Doyle et al., 2006).Dosing ranged from donepezil 2.5–30 mg for 1 week.In the reported cases, 7 of 8 treated subjects achieved significant subjective improvement on the Clinical Global Impression Scale in attention symptoms.One patient described tremors and irritability (Doyle et al., 2006).

In an 18-week open-label trial, Cubo studied donepezil in patients with ADHD who have tics (Cubo et al., 2008).The study included 20 individuals aged 8–14 years.Subjects were given a titration of donepezil culminating at 10 mg daily with a total treatment cycle of 14 weeks followed by a 4-week washout period.Participant performance was measured using a standard battery of cognitive and tic assessments (Table 2).Participants experienced a significant reduction in tics as measured on the Yale Global Tic Severity Score, primarily at the 10 mg dose with persistent effect during donepezil washout.No change was noted in scores of memory and attention.Adverse effects of treatment were identified in 65% of participants at both 5 and 10 mg doses with most reporting gastrointestinal symptoms and irritability.Half of the patients withdrew from the trial early.The authors conclude that donepezil was poorly tolerated.They also note that the dropout rate may not necessarily reflect the severity of the side effects due to the age of the participants and heightened concern from parents (Cubo et al., 2008).

In a retrospective case series, 5 subjects with ADHD were treated with Donepezil (Wilens et al., 2000).All patients were male and 8–17 years old.Treatment periods ranged from 8–26 weeks with doses ranging from 5 mg/d to 20 mg/d.All subjects showed improvement via the Clinical Global Impressions scale.One patient experienced gastrointestinal adverse effects that were transient and did not require discontinuation of the protocol.The authors noted that the findings were positive but acknowledged that all subjects were also on additional medications during their treatment, which may have impacted results.A follow-up study from the same first author conducted a 12-week open-label trial where 7 children and 6 adults with ADHD were given donepezil as an adjuvant therapy to improve executive functioning (Wilens et al., 2005).All participants were co-medicated with a stimulant for attention.The study failed to find significant improvements on the Executive Function Checklist, although there was some evidence of subjective improvement measured by the Clinical Global Impression scale.Seven of 13 subjects withdrew early due to side effects, limiting interpretation of outcome data and sustaining concern for tolerability of the intervention(Wilens et al., 2005).

The summary of the ADHD-centered studies indicates substantial attrition due to side effects.Some degree of efficacy was identified in 57% of subjects,although notably the cognitive domain of improvement was inconsistent between trials (Figure 4).

Autism spectrum disorder

Donepezil has been studied in autism spectrum disorders for REM sleep promotion, language, and behavior (Hardan and Handen, 2002; Buckley et al., 2011; Handen et al., 2011; Srivastava et al., 2011; Gabis et al., 2019).In an open-label trial by Buckley, five children between the ages of 2.5 and 6.9 years treated for 10–12 weeks with donepezil 5 mg daily had increases in their relative fraction of sleep demonstrating REM state (Buckley et al., 2011).One subject had behavioral changes which resolved at a reduced dose (Buckley et al., 2011).This study was retained for the review despite no neuropsychiatric assessments due to the importance of sleep maintenance in overall cognitive function.

In a case study, a 5-year-old boy with autism was treated with donepezil 5 mg daily for 6 weeks (Srivastava et al., 2011).He had subjective improvement in communication and an improved score on the Childhood Autism Rating Scale,with no significant side effects (Srivastava et al., 2011).

In a retrospective study, 8 patients with autism were treated with donepezil while on concomitant psychoactive drugs (Hardan and Handen, 2002).Four of the patients showed significant improvement when assessed via the Aberrant Behavior Checklist and Clinical Global Impressions scale.Two subjects experienced limited and transient gastrointestinal distress and mild irritability.The same author group later completed a randomized controlled in 34 children with a diagnosis of autism (Handen et al., 2011).Donepezil wastitrated to 10 mg daily and continued for 10 weeks.Placebo and treatment groups both showed improvement on objective measures, with no significant differences between the groups (Table 2).The authors note that a 10-week observation may be too short an interval to demonstrate change in objective measures.Many subjects reported subjective improvements in baseline sleeping, appetite, and depression complaints.Minor side effects included gastrointestinal distress, headache, and fatigue (Handen et al., 2011).

In a randomized controlled trial by Gabis, 60 children with a diagnosis of autism were randomized to donepezil or control groups (Gabis et al., 2019).Children in the treatment group were titrated to donepezil 5 mg daily and coadministered choline for a portion of the treatment cycle.Observations were made over 10 months.There was an improvement in receptive language skills on the Preschool Language Scale in the younger than 10 years subgroup and a worsening of behavior on the Autism Treatment Evaluation Checklist in the older than 10 years subgroup.Improvements in language skills were sustained following the washout period.Three participants (2 on donepezil)discontinued due to gastrointestinal adverse effects (Gabis et al., 2019).

These five studies suggest that donepezil may have some benefit in treating symptoms of autism spectrum disorder, but the evidence is limited with study endpoints inconsistent.Overall, side effects were minor and well tolerated in most subjects.

Discussion

This review of existing literature on donepezil in adults as an adjuvant to neurocognitive recovery in TBI shows minimal side effects and promising efficacy with much room for further exploration.The pediatric literature on AChEi in TBI is far less developed.In the assessed pediatric studies, the efficacy of donepezil appeared to be high in TBI, brain cancer survivors, ADHD,and autism spectrum disorders, though there remain many open questions regarding the generalizability of these studies.Pediatric literature noted mixed tolerability with high rates of study adverse effects reported in brain tumor survivors and patients with ADHD.In all populations, findings are limited by study designs and small sample groups and often using subjective rather than objective ratings of efficacy.The authors identify a need for further study with rigorous experimental design.Current pediatric literature has more focus on AChEi use as an adjuvant in the static neurocognitive disorders/neurodevelopmental disorders versus acquired disease states.Literature on acquired brain injury and recovery aided by donepezil in children is sparse,with our search identifying only 4 reports; three in TBI (Trovato et al., 2006;Naguy, 2018; Dávila et al., 2020) and one in brain tumor survivors with history of cranial radiation (Castellino et al., 2012).When examining the results of studies focused on developmental versus acquired disorders, there appears to be higher efficacy and safety in children and adolescents with acquired brain injuries.

Efficacy in adults versus pediatrics

In our review, studies of donepezil in adult TBI showed efficacy in each study design.Domains including cognition, language, memory, behavior, attention,mood, clarity of thought, vigilance, concentration, initiation, socialization, and working ability showed gains in the studies reviewed.While the majority of trials had a small number of subjects, results showed promising outcomes in at least one objective domain in many studies (Masanic et al., 2001; Bourgeois et al., 2002; Zhang et al., 2004; Khateb et al., 2005; Sugden et al., 2006; Kim et al., 2009).

When evaluating adult patients, nine studies recorded subjective impressions among participants.All nine studies showed improvement according to subjective reports even in studies that showed no significant or minor changes in objective testing (Taverni et al., 1998; Whelan et al., 2000; Kaye et al., 2003; Walker et al., 2004; Tenovuo, 2005; Stockhausen and Tower, 2016;Campbell et al., 2018).It is challenging to extrapolate meaning from these assessments since objective methods of measuring cognitive improvement varied significantly amongst studies.The Functional Independence Measure,Mini-Mental Status Exam, and Wechsler Adult Intelligence and Memory scales were used most frequently to assess therapeutic improvement (Additional Figure 1).Most studies focused on learning and memory but other trials noted changes in behavior and energy.Evidence of subjective improvement should not be dismissed as it may indicate improvement in cognitive domains that were not measured by specific study design.

In pediatric patients, donepezil treatment for TBI is less rigorously studied than in adults.Interpretation of disparate disease states that include both acquired and developmental disorders is not directly analogous to adult data.Overall, pediatric studies showed less efficacy than in the adult population.However, current evidence in pediatric subjects primarily focuses on populations with developmental disorders, with few studies focusing on TBI.When assessing the pediatric data by disease process, studies on brain cancer survivors and TBI found that donepezil was effective (in aggregate 69% of cases showed efficacy, while studies on developmental disorders including Down Syndrome, ADHD, Fragile X, and autism had mixed results (aggregate 31% efficacy).Certain studies specifically focused on ADHD (Wilens et al.,2005), autism (Handen et al., 2011), Fragile X (Sahu et al., 2013; Bruno et al.,2019), and Down syndrome (Kishnani et al., 2010) concluded that there were no significant changes with donepezil therapy.

The relevance of the acetylcholine pathway likely varies between developmental disorders.For example, the acetylcholine pathway is a relevant intervention for developmental disorders as specific nicotinic receptors play a role in autism spectrum disorder, ADHD, and other neuropsychiatric disease processes (Marotta et al., 2020).However, in a review studying the neurobiology of ADHD, dopamine may play a more significant role in the variation of behavior that classifies this disease process (Tripp and Wickens,2009).Thus, while acetylcholine may play an important role, there are other critical neurotransmitters involved.Modulating acetylcholine alone may not lead to the same efficacy as is seen when treating acquired cognitive impairment.

Variation amongst both pediatric studies and adult studies may also be dependent on the location of brain injury, method of evaluation,neurocognitive endpoints examined, comorbid conditions, and dosing as a fraction of body size.

Safety and side effects

Data on the use of donepezil in the pediatric population remains extremely limited (Figure 5).This literature review placed a heavy emphasis on safety in both the adult and pediatric populations.In adults, donepezil has been well tolerated across many studies.However, since most studies are small, it may not be appropriate to generalize these findings.It is important to note that adult patients, even when analyzing those within the designated age range (< 50 years), tend to have other comorbidities which might exacerbate adverse effects of donepezil therapy.For example, the most frequently reported adverse effects included nausea, diarrhea, and fatigue.In the adult population, diseases such as diabetes, GERD, and cardiovascular disease are common, and subjects are likely to experience some of these symptoms at baseline.These underlying conditions may also lower the threshold for cholinergic side effects making the adult population less tolerant of this medication.

Figure 5 ｜ Side effects reported in the review subjects.

When evaluating pediatric studies, there were other confounding variables from the different disease processes as well as specific characteristics of the patient population.As many of the authors noted, when the population is non-verbal or within a younger age bracket, caretakers play a significant role in reporting side effects.For example, in the Cubo study, which reported more adverse effects than other pediatric studies, parents and caretakers were very sensitive to patients’ needs and were quick to report any complaint that arose (Cubo et al., 2008).Other studies focused on donepezil as an adjuvant therapy in ADHD reported more side effects than studies on other pediatric disease processes.In three of the five studies examined in this review,irritability was a common side effect that may be due in part to patients’baseline behaviors and hyperactivity.Similar to the argument above regarding adults with premorbid disease, a baseline behavioral disturbance in children with a developmental disorder may lower the threshold for medication effect exacerbating behavior.

The most prevalent adverse effects across all age groups involved gastrointestinal symptoms including nausea, vomiting, and diarrhea (Figure 5 – GI upset).This likely represents the anticipated cholinergic effects of this medication class.In the pediatric population, there were additional complaints related to fatigue, insomnia, mood, and urinary incontinence.The majority of studies reported that these side effects were transient and dissipated within a few weeks when patients were able to tolerate them.In studies of shorter duration or smaller population size, it is unclear if the adverse effects would have followed this same pattern or if they would have continued to worsen.In both adult and pediatric studies, adverse effects appeared to be dosedependent.Only 1 study stated dosing goals for donepezil in weight-based dosing – the standard dosing nomenclature in pediatric medicine – at 0.1–0.2 mg/kg per day (Kishnani et al., 2010).Pediatric subjects will in general receive a higher fractional dose per unit of body weight than adults.This difference may account for some of the differential tolerability of dosing in childhood studies.In adults, side effects were fairly well tolerated but the rate of discontinuation was higher.This may have been a result of comorbidities or the severity of acquired brain injury.

Limitations

Many studies included in this review were of lower evidence class, with only seven randomized, placebo-controlled studies identified (two in adults with TBI, and five in pediatrics).To provide a full accounting of clinical use of donepezil in ABI, we included 9 studies drawn from case reports or case series which introduces an important publication bias and asks how many attempts were made at treatment without positive results.The paucity of studies in children with TBI is a significant limitation to the ability to make conclusions about the use of donepezil in this population.The studies included use a broad variety of outcome measures, which increases the difficulty of comparing studies or making broad conclusions on specific endpoints.Finally,many studies cite subjective improvement as a potential endpoint; although subjective outcomes are an important measure of an agent’s success in treating a condition, the rigor of such endpoints is significantly less than for objective measures of outcomes.

Conclusion

Current evidence for the use of donepezil in children and adolescents with acquired brain injury is limited.However, promising clinical data in adults suggests efficacy in multiple behavioral and cognitive domains.In the cohort younger than 50 years old, adverse effects tend to be relatively less common than seen in older patients, and thus we judge donepezil to be well tolerated.Pediatric studies have demonstrated high levels of safety with relatively low side effect rates in patients with acquired disease.It would be beneficial to study donepezil in a chronic pediatric brain injury population to further define the safety, tolerability, and efficacy of this intervention as an adjuvant for neurocognitive recovery.

Authors of several studies in this review reported that treating patients in acute settings may have confounded findings, given that patients often have a degree of spontaneous recovery during this period.For this reason, we propose a population composed of patients in chronic recovery to better understand the value of modulating acetylcholine pathways.

An open-label trial of donepezil in moderate-to-severe pediatric acquired brain injury would be a reasonable next step.Careful consideration of objective assessments, including a standard neurocognitive battery coupled with speech therapy assessments would be beneficial.

Author contributions:Literature review,making figures,writing and revising of manuscript:ALM;writing and revision of the manuscript:NKE and JMT.All authors approved the final manuscript.

Conflicts of interest:None declared.

Author statement:Presentation at a meeting:Organisation:University of CincinnatiResearch and Service Symposium;Place:Cincinnati,OH,USA;Date:March 11,2021.

Data availability statement:All relevant data are within the manuscript and its Additional files.

Open access statement:This is an open access journal,and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License,which allows others to remix,tweak,and build upon the work non-commercially,as long as appropriate credit is given and the new creations are licensed under the identical terms.

Additional file:

Additional Figure 1:Summary of cognitive assessments used in reviewed literature.