Medical treatment of autism spectrum disorder in children: Current evidence, controversies, and clinical challenges

Table 3 Comparison between risperidone vs aripiprazole in pediatric autism spectrum disorder

Feature	Risperidone	Aripiprazole
FDA approval	Approved in 2006 for irritability (aggression, self-injury, tantrums) in children with autistic disorder aged 5-16 years	Approved in 2009 for the same indication in children and adolescents aged 6-17 years
Mechanism of action	Dopamine D2 and serotonin 5-HT2A receptor antagonist	Dopamine D2 and serotonin 5-HT1A partial agonist, 5-HT2A antagonist
Core clinical target	Severe behavioral symptoms - irritability, aggression, self-injury, tantrums	Same behavioral symptoms; sometimes preferred for milder irritability or when metabolic risk is a concern
Efficacy (ABC-I)	Robust reduction (approximately 50%-60%) vs placebo in multiple RCTs (RUPP 2002, Shea 2004). Effects sustained up to 21 months	Similar magnitude of improvement (approximately 40%-60%) vs placebo; benefits evident within 1-2 weeks and maintained up to 52 weeks
Effects on other ABC subscales	Significant improvements in hyperactivity, stereotypy, and inappropriate speech; modest gains in social withdrawal	Moderate improvement in hyperactivity and stereotypy; inconsistent effects on social withdrawal
Effect on core ASD symptoms	Minimal or inconsistent improvement in social and communication domains; benefits, mainly indirect via behavior control	Similar - limited impact on core ASD features, though better adaptive engagement may follow behavioral improvement
Weight gain	Significant, often rapid (mean +2.7 to +5.4 kg in 8-24 weeks); linked to increased appetite and metabolic changes	Milder (mean +1.3 kg in 8-12 weeks); generally, not associated with metabolic syndrome
Metabolic effects	Marked rise in insulin, glucose, HOMA-IR, leptin, and fall in adiponectin; increased risk of metabolic syndrome	Minimal changes in glucose or lipid parameters; low metabolic liability overall
Prolactin	Increases prolactin (dose-dependent); may cause galactorrhea, gynecomastia	Usually reduces or normalizes prolactin due to partial D2 agonism
Sedation/somnolence	Common (40%-60%); often transient but dose-related	Mild to moderate; usually transient; less sedation than risperidone
EPS	Low-moderate risk; tremor approximately 8%-9%, dose-related	Low risk overall; akathisia slightly more frequent than with risperidone
Cognitive effects	No cognitive decline; some studies show mild improvement in attention/recognition	Neutral cognitive profile; no significant impairment reported
Pharmacokinetics	Metabolized by CYP2D6 → active metabolite 9-hydroxyrisperidone-risperidone; TDM useful (target sum trough 3.5-7 μg/L)	Metabolized by CYP2D6 and CYP3A4 → active dehydro-aripiprazole; TDM not routinely required
Pharmacogenetics	CYP2D6 poor metabolizers have higher active moiety levels; BDNF Val66Met linked to insulin resistance	CYP2D6 poor metabolizers show higher exposure; limited evidence of clinical impact from DRD2/HTR variants
Duration of benefit	Sustained efficacy with continued use; relapse on discontinuation	Sustained up to 1 year; relapse possible on abrupt discontinuation
Overall clinical impression	Highest efficacy for irritability and aggression, but greater metabolic and endocrine burden	Comparable efficacy, better metabolic profile, slightly higher akathisia risk; favorable long-term tolerability

This table provides a critical head-to-head comparison of the two Food and Drug Administration-approved atypical antipsychotics for pediatric autism spectrum disorder: Risperidone and aripiprazole. Both drugs are highly effective, demonstrating robust, comparable efficacy in reducing severe, challenging behaviors such as irritability, aggression, and tantrums (the primary target of Food and Drug Administration approval), with effects maintained over time. Their contrasting tolerability profiles primarily drive the choice between them. Risperidone is associated with a greater metabolic and endocrine burden, specifically significant weight gain and marked increases in prolactin (leading to potential side effects like gynecomastia). Aripiprazole, while showing comparable efficacy, has a significantly better metabolic profile (less weight gain, minimal change in glucose/Lipids) and tends to reduce prolactin levels. The trade-off is that aripiprazole carries a slightly higher risk of akathisia (a type of extrapyramidal symptom or extrapyramidal symptoms). Clinically, risperidone is often chosen for patients requiring the highest reduction in severe aggression. At the same time, aripiprazole is preferred for patients with pre-existing metabolic risk factors or those with milder symptoms, where the priority is to minimize metabolic side effects.

FDA: Food and Drug Administration; 5-HT₂A: Serotonin 5-hydroxytryptamine receptor type 2A; 5-HT₁A: Serotonin 5-hydroxytryptamine receptor type 1A; ABC-I: Aberrant Behavior Checklist-Irritability subscale; RCTs: Randomized controlled trials; RUPP: Research Units on Pediatric Psychopharmacology (a study group); ABC: Aberrant Behavior Checklist; ASD: Autism spectrum disorder; HOMA-IR: Homeostasis model assessment of insulin resistance; EPS: Extrapyramidal symptoms (motor side effects like tremor or dystonia); CYP2D6: Cytochrome P450 2D6 (a liver enzyme involved in drug metabolism); TDM: Therapeutic drug monitoring (measuring drug levels in blood); CYP3A4: Cytochrome P450 3A4 (a liver enzyme involved in drug metabolism); BDNF: Brain-derived neurotrophic factor; Val66Met: Valine to Methionine substitution at position 66 (a polymorphism in the brain-derived neurotrophic factor gene); DRD2: Dopamine D2 receptor; HTR: 5-hydroxytryptamine receptor (serotonin receptor).