A Retrospective Review of the Effectiveness of Aripiprazole in the Treatment of Sensory Abnormalities in Autism

Introduction

A utism is characterized by impairment in the development of reciprocal social interactions and communication abilities, and the presence of stereotyped/repetitive behaviors, according to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatric Association 2000). Associated features such as sensory abnormalities and motor deficits are frequently observed in individuals with autism and are currently being proposed to be included in the new fifth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-V) (American Psychiatric Association, in press). The prevalence of sensory processing abnormalities in autism ranges from 30 to 100% (O'Neill and Jones 1997; Dawson and Watling 2000; Baker et al. 2008) and are observed in both children (Liss et al. 2006) and adults (Crane et al. 2009). All sensory modalities appear to be affected in autistic individuals: Visual (Simmons et al. 2009), auditory (Jones et al. 2009), tactile (Ploog and Kim 2007; Cascio et al. 2008), gustatory (Bennetto et al. 2007), and olfactory (Bennetto et al. 2007). A range of abnormalities has been reported in the autistic population: Hypersensitivity, hyposensitivity, sensory overload, sensory distortion, and multichannel receptivity (O'Neill and Jones 1997). These aberrant sensory reactions are thought to reflect abnormal sensory integration and modulation in the central nervous system, resulting in maladaptive emotional and physical responses to environmental stimuli (Iarocci and McDonald 2006). Successful interventions in targeting sensory abnormalities are lacking (Baranek 2002) despite the development of several treatment strategies to alleviate behavioral symptoms such as hyperactivity, repetitive behavior, and irritability (Posey et al. 2008; Marcus et al. 2009; Owen et al. 2009; Stigler et al. 2009).

Aripiprazole has a unique pharmacologic profile that includes partial agonism at dopamine D2 and serotonin (5-HT)1A receptors and antagonism at 5-HT2A receptors (Davies et al. 2004). Aripiprazole has recently been approved by the United States Food and Drug Administration (FDA) for the treatment of irritability associated with autism in children aged 6 to 17 years. The goal of this investigation is to examine the effectiveness of aripiprazole in the treatment of sensory abnormalities observed in children with autism.

Methods

A systematic review of an outpatient clinic research registry for individuals with autistic spectrum disorder was conducted to examine the use of aripiprazole in children and adolescents. This database included clinical and research information on more than 250 children and adults with autism spectrum disorder and/or developmental disabilities. The database was searched for all individuals who had received aripiprazole for disruptive behaviors and met the following criteria: 1) autism diagnosis as based on a clinical interview and a diagnostic instrument such as the autism diagnostic interview-revised (ADI-R); 2) age between 4 and 18 years; 3) availability of the aberrant behavior checklist (ABC) and sensory profile questionnaire (SPQ) as completed by parents or caregivers; and 4) no concomitant medications. Once identified, the following information was obtained: Demographics, dates of visits and completion of behavioral scales, aripiprazole final dosage and duration, vital signs, and side effects. Approval to develop the research registry was obtained from Stanford University Institutional Review Board. Informed consent to be included in the research registry was obtained from all parents or legal guardians and assent was obtained from participants between the ages of 7 and 18 years. Response to treatment was judged using the change in the total ABC.

The ABC is a standardized scale, comprising 58 items, for assessing problem behavior in subjects with mental retardation and developmental disabilities (Aman et al. 1985). The checklist was empirically derived from ratings on ∼1000 subjects, and the items resolve into five subscales: Irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity, and inappropriate speech. High scores indicate more severe behavioral symptoms.

The SPQ is a 125-item parent report questionnaire that evaluates sensory abnormalities and compares to available normative data (Tomchek and Dunn 2007). The items are written such that low scores reflect undesirable and abnormal behaviors. The SPQ is organized in three sections: Sensory processing, sensory modulation, and behavior and emotional responses. The sensory processing section is further subdivided into auditory processing, visual processing, vestibular processing, touch processing, multisensory processing, and oral sensory processing. The modulation section is subdivided into sensory processing related to endurance/tone, modulation related to body position and movement, modulation of movement affecting activity level, modulation of sensory input affecting emotional responses, and modulation of visual input affecting emotional responses and activity level. The behavior and emotional responses section is subdivided into emotional/social responses, behavioral outcomes of sensory processing, and items indicating thresholds for response. The sensory profile is further analyzing by taking predetermined items from the aforementioned subsections and organizing them into nine factors: Sensory seeking, emotionally reactive, low endurance/tone, oral sensory sensitivity, inattention /distractibility, poor registration, sensory sensitivity, sedentary, and fine motor/perceptual.

Paired t tests (two-sided) were used to compare data from all patients between two time points: Baseline (i.e., before initiating aripiprazole) and at the end of treatment. Statistical significance was set at 5%.

Results

The search of the registry identified 177 children and adolescents between the ages of 4 and 18 years who had been diagnosed with autistic disorder. Only 12 male and 1 female subjects with autism were identified from this subgroup as meeting inclusion criteria, and were treated with aripiprazole. The subjects' racial background was reported as Caucasian 7, biracial 3, Asian 2, and African American 1. Their average age at the time of treatment initiation was 10.1 years (SD=3.8; range 6.25–18.0 years). ADI-R scores were available on all these individuals, and the mean score was 48.6 (SD=7.8). None of the participants had serious medical or neurological disorders. Among these subjects, 5 had no prior exposure to psychotropic medications; and 7 had prior medication treatment including risperidone (4 children), quetiapine (1), ziprasidone (1), paroxetine (1), sertraline (1), citalopram (1), phenobarbital (1), valproic acid (1), and guanfacine (1). Patients were not on any other psychotropic medications during the duration of treatment. Aripiprazole was usually initiated at the dose of 2 mg and was increased until improvement was observed in disruptive behaviors. The average total duration of treatment with aripiprazole was 24.4 weeks (SD=16.3; range 8–52 weeks), and the average duration of treatment after the dose was fully escalated was 18.2 weeks (SD=15.8; range 3.2–50.3 weeks). The mean maximum daily dose of aripiprazole was 10.8 mg (SD=4.0 mg; range 5–15 mg).

Discussion

The beneficial effects of aripiprazole in reducing disruptive behaviors in individuals with autism spectrum disorders are well documented (Marcus et al. 2009; Stigler et al. 2009) especially in light of the recent studies that led to the FDA approval of this medication for the treatment of irritability (Marcus et al. 2009; Owen et al., 2009). Whereas the current study is consistent with these findings, it also provides preliminary evidence supporting aripiprazole's potential effectiveness in improving sensory abnormalities observed in children and adolescents with autism, and these benefits do not appear to be related to improvement in disruptive behaviors.

Aripiprazole modulates serotonin and dopamine pathways by partial agonism at dopamine D2 and 5-HT1A receptors and antagonism at 5-HT2A receptor (Davies et al. 2004). Improvements in sensory deficits observed here might be related to this receptor affinity profile, as dopaminergic and serotoninergic transmission have been linked to sensory processing (Mann et al. 2008). Sensory dysfunction has been studied by using models of sensorimotor gating deficits such as prepulse inhibition (PPI) of the startle response (Perry et al. 2007) and P50 suppression of the auditory event-related potential (Kemner et al. 2002) in autistic individuals. In a double-blind, placebo-controlled study, selective depletion of dopamine was shown to have no effect on PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression; however, depletion of both dopamine and serotonin resulted in significant reduction of both PPI and P50 (Mann et al. 2008). These results suggest that optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems result in normal gating function (Mann et al. 2008). These observations support that the serotoninergic and dopaminergic system (Makkonen et al. 2008) might be involved in the pathophysiology of autism, and suggest that modulation of these key pathways might provide a novel avenue in the treatment of sensory abnormalities in neurodevelopmental disorders such as autism.

The current investigation provides preliminary evidence, although limited, on the utility of aripiprazole in improving inattention /distractibility, registration, auditory processing, and modulation of visual input affecting emotional responses and activity level. Results from this retrospective review should be examined with caution in light of several limitations including the small sample size, the retrospective nature, the lack of a control group, and the use of an informant-based questionnaire without the use of an objective or a laboratory-based instrument. Despite these limitations, the current study provides preliminary evidence to support the use of aripiprazole in the pharmacologic treatment of sensory abnormalities in autism. This finding needs be confirmed in a double-blind, placebo-controlled trial with objective measures of sensory functions in this population.