Aripiprazole Use in Children Diagnosed with Down Syndrome and Comorbid Autism Spectrum Disorders

Case Report

The patient was a 6-year-old male. He was born by normal delivery at the 37th gestational week, weighing 2.8 kg following an uneventful pregnancy and an uncomplicated vaginal delivery. He was taken to the department of pediatrics, Gaziantep Child Hospital at 8 months of age because of developmental retardation. Down's syndrome was diagnosed based on the patient's facial features, and was later confirmed by a chromosomal analysis (caryotype: 47, XY, +21). As an infant, the patient showed little affection and did not smile or laugh while playing. Compared with his siblings, his eye-to-eye contact was poor. Review of early milestones showed global developmental delays with unsupported sitting at 2 years, beginning to talk independently at 3 years and 6 months, and saying his first recognizable words at 4 years. He began attending a school for children with learning difficulties at the age of 5 years. At the end of the school year, his teacher recommended that family see a child psychiatrist, because the patient was not able to adapt to the individualized education program in school. Also he was referred for assessment and treatment of his behavioral problems.

During the interview with the parents and children, the parents said that the patient responded to his name being called, but only on the third or fourth repetition; he was markedly limited in his use of facial expressions and abnormalities in eye contact, did not attempt to share his enjoyment of things with others and preferred to be alone, and had a great difficulty in accepting changes in routine. His verbal communication was delayed, and his speech could be understood by people who knew him only with difficulty. Behavioral problems involved hyperactivity, unprovoked aggression, and self-injurious behaviors such as hand biting when angry. On mental status examination, details about his behavior as given in the history were confirmed. He was having trouble paying attention and exhibited hyperactivity. Also, his eye contact was very limited. He did not make any attempts to initiate conversation and did not respond to his name. The Ankara Developmental Screening Test (AGTE in Turkish) (Savasir et al.1998) was performed, and the patient was shown as having moderate developmental delay. As a result of the psychiatric and psychometric examination, he was diagnosed with DS+ASD. Routine physical examination and biochemical, hematological, and thyroid function tests excluded any underlying physical disorder. Also the results of neurological evaluations including electroencephalogram and magnetic resonance imaging were normal.

First, the patient was referred to individual education programs for ASD (not only for DS), and family education about ASD was provided to the parents. Three months later, despite individual education programs, because of the continuation of behavioral problems aripiprazole was added to the treatment. Before starting treatment, the Aberrant Behavior Checklist (ABC) was given to his parents, and the patient's score was 69 (Table 1). Aripiprazole treatment was started at 2.5 mg/day, and 1 week later, the dose was increased to 5 mg/day. Because of a remarkable improvement in the patient's behavioral symptoms after 2 weeks, 5 mg/day dose was continued. Eight weeks after aripiprazole treatment initiation, improvement could be observed in ABC irritability, hyperactivity, and lethargy subscales (Table 1), as well as in self-injurious behaviors in our patient. The medication was well tolerated, and except for daytime somnolence, no significant side effects were observed. The patient's weight was obtained at the beginning and the end of the treatment. At the end of the 8 weeks of treatment, a 0.2 kg increase was observed in weight. (before treatment the patient weight 20.1 kg; after treatment he weighed 20.3 kg) Routine serum metabolic testing was not performed after the treatment.

Discussion

ASD is an infrequently diagnosed psychiatric comorbidity in children with DS. To our knowledge, there have been no trials of aripiprazole treatment in children with this dual diagnosis.

Aripiprazole is a partial agonist at the D2 and 5-HT1A receptors and an antagonist at the 5-HT2A receptors. Whittle at al. found serotonin and dopamine level reduction in the frontal cortex of fetal DS brains that may indicate potential mechanisms for the observed dysfunctional neuronal development (Whittle et al. 2007). Although the pathophysiology of ASD is not completely understood, both serotonergic and dopaminergic dysregulation have been postulated to exist in ASD (Israngkun et al. 1986; Anderson et al. 2002). This research suggests that dysfunctions of these neurotransmitters contribute to maladaptive behaviors in DS+ASD. Therefore, serotonin and dopamine may be a potential targets for pharmacotherapy, which is why aripiprazole appears to be an effective treatment option in subjects with a dual diagnosis of DS and ASD.

Some patients with ASD and/or DS also experience irritability, which may be manifested as aggression and self-injurious behaviors. Aripiprazole was previously shown to be effective at reducing irritability in children and adolescents with ASD (no comorbid DS) (Marcus et al. 2009; Owen et al. 2009). Similarly, the improvement in these studies in ABC irritability and hyperactivity subscale scores was seen in our case. Additionally, impairments in sociability (as captured on the lethargy subscale) showed improvement in response to treatment with aripiprazole. This positive result in sociability may be the result of 1) a personality trait of DS; Dressler et al. reported the DS+ASD subjects showed a better social performance than subjects with only ASD (Dressler et al. 2011); 2) aripiprazole's mechanism of action as a partial 5-HT1A agonist, which is associated with improvements of anxiety, depression, and negative symptoms of schizophrenia (Millan 2000); 3) decreasing irritability; and 4) reorganization of individual education programs for ASD. For these reasons, social functioning may be increased.

Capone et al., in an open-label study, found that low dose risperidone had a positive effect on symptoms of irritability, disruptive behaviors, and social withdrawal in children with DS+ASD. Although they suggested that low dose risperidone appears to be well tolerated in children with DS+ASD, they also reported weight gain (Capone et al. 2008). Compared with a study that used risperidone treatment in DS+ASD cases, aripiprazole treatment led to less weight gain in our case. Less weight gain with aripiprazole treatment may be the result of a low affinity for histamine H1 receptors and that it is a partial agonist of serotonin 5-HT2C receptors, which are associated with weight gain (Davies et al. 2004). Also, in the nonrandomized “Second-Generation Antipsychotic Treatment Indications, Effectiveness, and Tolerability in Youth” cohort study that evaluated the effects of olanzapine, quetiapine, risperidone, and aripiprazole on cardiometabolic parameters in children and adolescent patients, aripiprazole caused the least weight gain (Correll et al. 2009). Unfortunately, we did not observe other metabolic parameters, and this is important limitation of our study. Aripiprazole was generally well tolerated, and no extrapyramidal side effects (EPS) were experienced in our case. Reduced risk for EPS with aripiprazole may be caused by antagonism at the 5-HT2A receptor and partial agonism at 5-HT1A (DeLeon et al. 2004).

In conclusion, identification of children with DS+ASD is important, so that appropriate individualized education programs and pharmacological treatments can be implemented for these dually diagnosed children. Aripiprazole has the potential to be an effective and well-tolerated treatment for irritability and disruptive behaviors in DS+ASD cases. In addition, the improvement in socialization observed with aripiprazole treatment is intriguing, and further study studies are needed to provide more evidence in support of these observations.