The past decade
has witnessed a steady increase in the incidence of autism spectrum disorder (ASD), with recent study findings of 60–66 per 10,000 affected individuals (Fombonne 2005
; Centers for Disease Control and Prevention 2007
). Symptoms typically include deficits in the area of communication, social reciprocity, and stereotypic interests and behaviors (American Psychiatric Association 2000
). While a range of psychopharmacological interventions has been shown to be efficacious in addressing secondary symptoms of the disorder (e.g., hyperactivity, irritability, and self-injury), no pharmacological treatment has yet been identified to address the core features of ASD (Handen and Lubetsky 2005
One area that has received increasing attention in the ASD treatment literature is deficits in executive functioning (EF). This refers to a set of higher order cognitive processes that provide the foundation for complex problem solving and organized, meaningful behavior. EF includes functions such as set-shifting and cognitive flexibility, verbal and nonverbal working memory, planning and strategy formation, generativity, inhibitory control, and self-reflection/self-monitoring (Welsh and Pennington 1988
). In fact, a number of investigators in the field have suggested that EF deficits are a primary characteristic of ASD and might underlie the expression of the core features (Ozonoff and McEnvoy 1994
; Russell 1997
; Rajendran and Mitchell 2007
). For example, a series of investigations support a multiple primary cognitive deficit model for the cognitive basis of behavior in ASD (Just et al. 2007
; Minshew et al. 1994
). Neuropsychologic functioning in their samples was characterized by intact attention, sensory perception, elementary motor, simple associative memory processes, formal language, and rule-learning aspect of abstraction and by deficits in complex motor (motor apraxia), memory for complex information, higher order interpretative aspects of language, and concept formation abilities. In the reasoning domain, the pattern of performance was characterized by deficits on concept formation tests and intact rule learning abilities. Visual spatial abilities appeared to be spared. Hence, this model of ASD as a selective disorder of complex information processing has significant potential in explaining atypical, idiosyncratic, and problematic behaviors based on this profile of cognitive abilities and deficits.
The desire to address EF deficits in ASD stems from the hypothesis that improvement in this area will enhance learning and academic achievement, as well as promote more successful behavioral and social functioning. Consequently, there has been increased interest in the use of cognitive enhancing drugs, such as cholinesterase inhibitors, as a possible treatment for ASD. The cholinergic system plays a significant regulatory role in neuronal differentiation and synapse formation during early development. Laboratory experiments in rats have demonstrated the importance of cholinergic innervations. For example, delayed cortical neuronal development along with permanent changes in cortical architecture and cognitive functioning was found in rats whose cholinergic innervations were disrupted during early postnatal development (Hohmann and Berger-Sweeney 1998
). Among individuals with ASD, neurochemical abnormalities have also been documented in the cholinergic system. For example, Bauman and Kemper (1994
) noted an increase in the number and size of basal forebrain (septal) cholinergic neurons in children with ASD, but a smaller number and size in adults. Autopsy tissue from individuals with ASD evidenced significantly greater cerebellar nicotinic alpha-4 receptor loss in comparison to tissue from normal controls and non-ASD individuals with intellectual disability (Lee et al. 2002
). Finally, Perry et al. (2001
) found a decrease in the number of cortical M1
receptors in the parietal cortex, a decrease in alpha4
nicotinic receptor subunits in the parietal cortex, and a decrease in nicotinic receptors in the parietal and frontal cortices following autopsy of seven adults with ASD.
A few recent studies have suggested that cholinesterase inhibitors may enhance behavioral functioning, language, social behavior, and core features of ASD. However, there has been limited focus on the effects of such agents on EF measures. In a retrospective study of eight children with ASD who had been prescribed donepezil (mean dose 9.37
mg/day), significant decreases were found on the Irritability and Hyperactivity subscales of the Aberrant Behavior Checklist (Hardan and Handen 2002
). Chez et al. (2003
) also documented gains on measures of expressive and receptive language as well as core ASD features (using the Childhood Autism Rating Scale) in a double-blind study of 43 children who were placed on a 2.5
mg/day dose of donepezil. However, the results were equivocal, as between-group statistical analyses were not conducted and the placebo group evidenced greater improvement on some measures than those on active medication (Yoo et al. 2007
). Niederhofer et al. (2002
) reported the results of a double-blind, placebo-controlled crossover trial of galantamine with 20 children with ASD. Focusing primarily on behavioral measures, slightly lower (but statistically significant) ratings were reported on parent and teacher measures of irritability, hyperactivity, inappropriate speech, and poor eye contact with the use of galantamine versus placebo. A 12-week, open label trial of galantamine (dose range 12–24
mg/day) was conducted among 13 children with ASD (age range 4–17 years) (Nicholson et al. 2006
). Based upon gains on the Inattention subscale of the Conners Parent Rating Scale, the Irritability and Social Withdrawal subscales of a parent-completed Aberrant Behavior Checklist, and “Anger” (from a physician-completed Children's Psychiatric Rating Scale), eight subjects were deemed responders. Chez et al. (2004
) documented significant improvement on behavioral measures, expressive vocabulary, and core features of autism in a 12-week, open label trial of rivastigmine involving 32 children with ASD. Finally, Hertzman (2003
) conducted a case study of galantamine with three adults with ASD (dose range 4–16
mg/day) in which some gains were reported on verbalizations and socially appropriate behavior.
We add to this line of inquiry by reporting the results of a double-blind, placebo-controlled trial to assess the tolerability, safety, and efficacy of donepezil on cognitive functioning in a sample of children and adolescents with ASD. Subjects in the placebo arm of the double-blind trial were offered a 10-week open label trial at the conclusion of their participation. Donepezil was hypothesized to be superior to placebo in improving performance on a range of EF tasks.