Improvement of Receptive Language but Behavioral Worsening with Combined Donepezil and Choline Treatment

Background:  Social communication impairment is a core feature of autism spectrum disorder (ASD) with no effective pharmacologic treatment. Donepezil treatment was evaluated as such and showed to have a minimal effect on language in children with autism.

Objectives: In order to enhance the effect of Acetyl Choline activity and inhibition, we added the substrate of Choline to Donepezil treatment in a double blind randomized study of 60 children and adolescents with Autism Spectrum Disorder. Efficacy, safety, and tolerability of oral Donepezil + Choline (D&C) combination were assessed.

Methods:

This study was a 9 months randomized, double-blind, placebo-controlled trial of 12 weeks incremental and add- on oral D&C in youth with ASD, preceded by 3 months baseline evaluation and followed by 6 months of wash- out, with subsequent follow up. Study participants were youth between the ages of 5-16 years with ASD, randomized to active drug or placebo in a 1:1 ratio, with the target dose Donepezil 5 mg + Choline as a crushed mixture. Donepezil was administered to the treatment group during the first 12 weeks (2.5 mg/day increased to 5 mg/day after 2 weeks). The Choline dietary supplementation (350mg) was added for the last 4 weeks, both crushed to powder by the pharmacy. Follow up was performed at three months and at nine months (after 6 months wash-out). Placebo powdered tablets were provided at in the same amounts and schedules as the control group. The primary outcome measure of efficacy was language measure. Secondary measures included adaptive functioning as measured by Vineland subscales, executive function measured by BRIEF, and social – behavioral skills measured using ATEC and CGI. Before removing the randomization, both examiner and parent reported his impression about group attendance (placebo vs. D&C). At nine months, the placebo group was notified and continued open- label D&C treatment by same protocol. The one arm crossover follow ups will be reported separately.

Results:

Sixty patients were enrolled (D&C = 29, placebo = 31, age 9.5 years + 3.1, 73% male and IQ 60 + 25). There were no significant differences at baseline between groups in all demographic and clinical variables. Six patients did not continue after initial evaluation due to compliance issues or urgent need for psychotropic medication, 6 did not complete the study (3 due to side effects), 48 completed treatment and 46 completed washout measurements. The frequency of adverse events was high (52%), with no significant difference between groups. However, there were significant differences in the types of side effects with more sleep disturbance, GI side effects, headache and slightly more agitation in the treatment group. 62% of parents correctly guessed group belonging. The daily personal skills, as measured by Vineland subscale, and health/ physical behavior of the treatment group worsened significantly compared to placebo. After wash- out, all differences diminished except significant and persistent improvement in receptive language skills (p= 0.003).

Conclusions: Combined Donepezil- choline treatment may improve language skills in youth with ASD, however, temporary worsening of behavior is a significant side effect of this treatment.