Aripiprazole for Irritability Associated With Autistic Disorder

Table 1. Prospective, systematic trials of aripiprazole in individuals with pervasive developmental disorder.
Study type	Sample, n (age in years)	Mean dose (mg/day)	Duration (weeks)	Results	Side effects	Ref.
Open-label	n = 5 (5–18)	10–15	12	5/5 (100%) responded	2/5 reported somnolence, 1/5 gained weight	^[15]
Open-label	n = 25 (5–17)	7.8	14	22/25 (88%) responded	19/25 experienced an increase in BMI, 9/25 reported EPS	^[16]
Double-blind	n = 218 (6–17)	5, 10 and 15 fixed dosing	8	17/49 (35%), 29/52 (56%), 29/59 (49%) and 28/53 (53%) responded to placebo, aripiprazole 5, 10 and 15 mg, respectively; all doses demonstrated significantly greater improvement than placebo on ABC-I and CGI-I	For the placebo, 5, 10 and 15 mg groups, respectively, an increase in BMI was experienced by 1/49, 4/52, 1/59 and 2/53; EPS was reported by 1/49, 2/52, 4/59 and 6/53; and sedation was reported by 3/49, 9/52, 17/59 and 13/53	^[13]
Double-blind	n = 98 (6–17)	8.6	8	Aripiprazole demonstrated significantly greater improvement compared with placebo on the ABC-I and CGI-I (67% were rated as improved or much improved)	For the aripiprazole and placebo groups, respectively, there was an increase in weight (2.0 and 0.8 kg); EPS (7/47 and 4/50); and sedation (5/47 and 1/50)	^[14]

ABC-I: Aberrant Behavior Checklist Irritability subscale; CGI-I: Clinical Global Impressions-Improvement scale; EPS: Extrapyramidal symptoms.

Mechanism of action

Aripiprazole is a partial agonist at the D ₂ (dopamine) and 5-HT _1A (serotonin) receptors.
It also functions as an antagonist at the 5-HT _2A receptor.

Pharmacokinetic properties

Aripiprazole and its active metabolite dehyro-aripiprazole have average elimination half-lives of 75 and 94 h, respectively.
It has a bioavailability of 87%.
Peak plasma concentrations are reported 3–5 h after ingestion.
It is 99% protein bound.
Aripiprazole is metabolized through two primary cytochromes. It is dehydrogenated and hydroxylated by cytochrome P450 3A4 and 2D6. It is N -dealkylated by cytochrome P450 3A4.
Aripiprazole is mainly excreted in the feces with a smaller amount excreted in the urine.

Clinical efficacy

A naturalistic, open-label study of aripiprazole in five male youths with PDDs aged 5–18 years was performed for a mean duration of 12 weeks (range: 8–16 weeks). All five youths were rated as 'much improved' or 'very much improved' on the Clinical Global Impressions-Improvement scale (CGI-I).
In a second open-label study with aripiprazole in 25 children and adolescents (aged 5–17 years) diagnosed with PDDs, 22 (88%) were judged to be responders.
Two large placebo-controlled studies in children and adolescents (aged 6–17 years) with autistic disorder found aripiprazole to be superior to placebo for the treatment of irritability, as judged by the Aberrant Behavior Checklist Irritability subscale and CGI-I.

Safety & tolerability

There is the possibility of clinically significant weight gain and an increase in trigylcerides.
Prolactin levels are reduced.
Sedation is a frequent side effect reported with this medication.
Extrapyramidal symptoms can occur in those treated with this medication.
There is no clinically significant increase in blood pressure or heart rate.

Drug interactions