Table 2.

Developmental disorders studies reviewed

Study	Study design	Disease process	Study population	Age (yr)	Donepezil dosing	Outcome measure	Result	Conclusion
Bruno et al. (2019)	Randomized placebo-controlled trial	Fragile X	Pediatric – Young adult 20 subjects (13 male, 7 female) treated with donepezil (42 enrolled)	12–29	2.5–5 mg daily × 1 wk, 5–10 mg daily Duration: 12 wk	Contingency Naming Test Aberrant Behavior Checklist fMRI	No objective measure of change was identified in cognition or behavior. Functional MRI showed evidence of change.	The authors suggest further studies on donepezil in Fragile X syndrome. Findings on fMRI may help inform future studies that combine pharmacological and behavioral therapies.
Buckley et al. (2011)	Open-label study	Autism	Pediatric/adolescent 5 subjects	2.5–6.9	1.25 mg daily × 2-4 wk titrating to 5 mg daily (based on trial criteria) Duration 10-12 wk	Polysomnogram	There was no significant difference in TST, stage 1, stage 2, stage 3, sleep onset time, sleep latency, or sleep efficiency on 1.25 mg. There was a significant change in REM% at latency to REM sleep on 1.25 mg.	Authors note cholinergic signals likely contribute to REM sleep and specific symptoms of autism. It would be reasonable to consider using this donepezil therapy combined with other therapy.
Castellino et al. (2012)	Open-label study	Brain tumor survivors	Pediatric/adolescent 11 subjects	9.3–17.3	Weight under 35 kg 5 mg every other day × 5 wk, 5 mg daily × 19 wk, washout 12 wk Weight over 35 kg 5 mg daily × 5 wk, 10 mg daily × 19 wk, washout 12 wk Duration 24 wk on therapy, 36 wk total	Dellis-Kaplan Executive Function Test Wide Range Assessment of Memory and Learning Conners Continuous Performance Test Wechsler Intelligence Scale for Children -IV Woodcock Reading Mastery Test; Woodcock-Johnson III Calculations Behavior Rating Inventory on Executive Function Behavior Assessment System for Children, 2nd Edition Health-Related Quality of Life - child and parent proxy report	There was an improvement in tests evaluating executive function and memory. Donepezil was well tolerated without weight loss or adverse neurological symptoms. There were transient gastrointestinal symptoms in the first 2 weeks of administration.	The authors note donepezil was well tolerated and showed improvements in neurocognitive function. Larger trials should be considered in this population.
Cubo et al. (2008)	Open-label study	ADHD	Pediatric/Adolescent 20 subjects 17 male 3 female	8–14	2.5 mg daily × 2 wk, 5 mg daily × 6 wk, 10 mg daily × 6 wk, washout × 4 wk. Duration: 18 wk	Children's Global Assessment Scale Yale Global Tic Severity Scale Revised Conners' Parent Rating Scale Wisconsin Card Sorting Test Stroop Color Interference Test Rey Complex Figure Test Children’s Yale-Brown Obsessive Compulsive Scale	Donepezil led to a significant decrease in tics on the Yale Global Tic Severity Scale. There were no significant changes in ADHD symptoms. The analysis is per protocol in 10 subjects (50% of the enrolled population withdrew and are not included in the analysis).	Authors found in subjects adherent to the protocol that donepezil significantly reduced tics but did not change ADHD burden. The study drug was poorly tolerated in this population.
Doyle et al. (2006)	Case report/case series	ADHD	Pediatric/Adolescent 8 subjects (a male)	10–17	Non-standard dosing. 2.5–30 mg daily Duration: 1 wk	Clinical Global Impression Scale – ADHD, Pervasive Developmental Disorder	Lower symptom burden in the ADHD severity scale and symptoms of pervasive developmental disorders were observed in 7 of 8 subjects. Donepezil was well tolerated with one participant discontinuing due to adverse effects.	The authors concluded that the series showed the need for further investigation of the efficacy and tolerability of donepezil in ADHD and pervasive developmental disorders.
Gabis et al. (2019)	Randomized placebo-controlled trial	Autism	Pediatric/Adolescent 24 subjects treated with donepezil (60 enrolled)	5–16	2.5 mg daily × 2 wk 5 mg daily × 6 wk, 5 mg daily and choline 350 mg × 4 wk, washout × 6 mon. Repeat the cycle above over 12 wk. Duration: ~10 mon	Autism Diagnostic Observation Schedule Clinical Global Impressions scale Kaufman Brief Intelligence Test 2nd Edition Preschool Language Scale, 4th edition, Wechsler Intelligence Scale for Children 4th Edition Vineland Adaptive Behavior Scales, 2nd Edition Children’s Sleep Habits Questionnaire Autism Treatment Evaluation Checklist	A significant improvement in receptive language skills and significant worsening in the Autism Treatment Evaluation Checklist health/physical behavior scale was observed over the study interval. Patients reported few adverse effects in the treatment and placebo group.	The authors suggested that donepezil was tolerable and showed significant improvement in language function for children with autism.
Handen et al. (2011)	Randomized placebo-controlled trial	Autism	Pediatric/Adolescent 18 subjects (17 male, 1 female) treated with donepezil (34 enrolled)	8.6–16.8	2.5 mg daily titrating to goal dose 10 mg daily Duration: 10 wk with optional 10 wk open-label treatment per titration scheme above	Autism Diagnostic Interview-Revised Autism Diagnostic Observation Schedule Wechsler Abbreviated Scale of Intelligence The Diagnostic Interview for Children and Adolescents – Revised Delis-Kaplan Battery of Executive Function System Trail Making Test Verbal Fluency Design Fluency Test Color-word-interference Test Sorting Test Twenty Questions Test Tower Test Word context Test Executive Functions Rating Scale Expressive One-Word Vocabulary Test California Verbal Learning Test Paired-Associate Learning Test	Non-significant improvements in neuropsychological measures employed were seen in both the therapy and control groups.	The authors note findings are inconsistent with prior studies. Donepezil failed to demonstrate change on any neuropsychology measure. Noted limitations of investigating cognitive endpoints in a static developmental disorder over a 10-wk study. A longer period of observation may be necessary.
Hardan and Handen (2002)	Retrospective study	Autism	Pediatric/adolescent 8 subjects (6 male, 2 female)	7–19	2.5 mg daily, titrating weekly to goal 10 mg daily (dose arrest for report of adverse effects). Duration: variable	Aberrant Behavior Checklist Clinical Global Impression Scale	Subjects were found to show significant improvement in Clinical Global Impression Severity of Illness. Irritability and hyperactive symptoms improved in 50% of patients. No changes were noted in inappropriate speech, lethargy, or stereotypies. Adverse effects were transient and tolerable; 1 subject reported GI symptoms, 1 mild irritability.	Authors conclude donepezil is safe and potentially efficacious in the treatment of autism. Call for further investigation with more rigorous study design.
Hoopes (1999)	Case report/case series	ADHD	Pediatric/adolescent 2 subjects (both male)	11–13	Subject 1: no dosing provided Subject 2: 2.5 mg daily Duration: 8 mon	Subjective	Summary of 2 patients with ADHD and tic disorder – both of which experienced relief in symptoms on donepezil. Both subjects improved in educational and social endpoints.	The author suggests that further studies are warranted. No objective measures were employed to corroborate patient reports.
Kishnani et al. (2010)	Randomized placebo-controlled trial	Down syndrome	Pediatric/adolescent 62 subjects (36 male, 26 female) treated with donepezil and completed protocol (129 enrolled)	10–17	2.5 mg daily titrated every 2 wk to goal dose 0.1-0.2 mg/kg/day (max 10 mg daily) × 4 wk Duration: 10 wk	Vineland-II Adaptive Behavior Scales-II Test of Verbal Expression and Reasoning	There were no significant differences between the donepezil and control groups per objective assessments. Secondary analyses failed to show any significant difference between the two groups. Mild adverse effects were identified in greater proportion in the donepezil group (48.4% vs. 30.8%).	The authors conclude the study provides no support for the use of donepezil in Down syndrome. The study interval of 10 weeks is too brief to adequately observe for change and further study is warranted.
Sahu et al. (2013)	Randomized placebo-controlled trial	Fragile X	Pediatric/Adolescent 10 subjects treated with donepezil (20 enrolled) 10 male	6–15	2.5 mg daily × 4 wk, 5 mg daily × 8 wk Duration: 12 wk	Stanford-Binet Intelligence Scale Conners 3 (Parent Rating Scale (short)) Childhood Autism Rating Scale	In this population, there were no significant changes in objective measures. Treatment appeared to be safe and well tolerated with mild, transient adverse effects.	The authors note no evidence of efficacy in their objective measures of IQ and behavior.
Spiridigliozzi et al. (2007)	Open-label study	Down syndrome	Pediatric/adolescent 6 subjects (7 enrolled [2 male, 5 female]) 1 subject (male)	8–13.8	2.5 mg daily × 8 wk, 5 mg daily × 8 wk, washout × 6 wk Duration: 22 wk Duration: 6 wk	NEPSY subtests Visual Attention, Memory for Names, Narrative Memory Conners Parent Rating Scales-Revised Vineland Adaptive Behavior Scales	Donepezil showed improvement in subjects with higher baseline IQ on tests of memory, attention, and mood. Subjects with lower baseline IQ did not show improvement. Overall efficacy is “unclear.” Increased irritability and assertiveness deemed related to improved expressive language were identified. Adverse effects were mild and transient.	The authors note that the safety of donepezil treatment has been established and careful titration is required when studying pediatric patients. Larger, double-blind studies are needed to explore efficacy.
Wilens et al. (2005)	Open-label study	ADHD	All ages 13 subjects	Ages not provided 7 children 6 adults	2.5 mg daily titrated to 10 mg daily Duration: 12 wk	ADHD Rating Scale Executive Function Checklist	There were no statistically significant improvements in primary outcome measures. The majority of subjects experienced adverse effects. 6 of 13 subjects completed the trial per protocol.	The authors noted donepezil was not well-tolerated and did not appear to be a useful intervention.
Wilens et al. (2000)	Case report/case series	ADHD	Pediatric/adolescent 5 subjects (all male)	8–17	2.5 mg daily titrated to 20 mg daily Duration 8–26 wk	Clinical Global Impressions scale	Subjects showed improvement on objective evaluation while parents and patients reported subjective improvement in organization and attention. One patient reported transient gastrointestinal adverse effects.	The authors conclude that the findings are positive. All subjects were on additional medications which may confound results. Further study should be pursued.

ADHD: Attention deficit hyperactivity disorder; IQ: intelligence quotient; REM: rapid eye movement.