Safety & Tolerability
Although aripiprazole has been noted to be safe and generally well tolerated in most of the studies in PDDs, some concern remains over its propensity to cause weight gain, EPS and sedation (Table 1). The increased incidence of weight gain and sedation are in contrast to the limited incidence of these found in adult aripiprazole studies in schizophrenia and bipolar disorder.[19,20]
Weight Gain, Fasting Glucose & Hyperlipidemia
Weight gain is a noted side effect of atypical antipsychotics particularly when prescribed for children and adolescents. Available research suggests that of the atypical antipsychotics, aripiprazole has a lower propensity to cause weight gain than the majority of others in the same class. Of note is its lower propensity to cause weight gain compared with risperidone, the only other FDA-approved medication to treat irritability related to autistic disorder. However, this conclusion is based on average weight gain. Some children can gain a large amount of weight on atypical antipsychotics that are considered to be 'weight-neutral'. Weight gain and its associated comorbid medical conditions are of significant concern in children and adolescents. Weight gain in this population can be associated with diabetes, hyperlipidemia and cardiovascular disease. Among each of the trials discussed above, with the exception of the Stigler et al. 2004 open-label study, weight gain was described as a side effect of the medication.
In the open-label naturalistic study by Stigler et al., one of the five subjects (20%) gained weight (1 lb). Two of the subjects lost weight; however, this was hypothesized to be secondary to the discontinuation of a different atypical antipsychotic that had originally caused significant weight gain.
In the second open-label study performed by Stigler et al., 19 of the 25 participants gained weight. The average BMI of participants increased from 20.3 to 21.1 with an average weight gain of 2.7 kg over the 14 weeks of the study. Although the majority of the subjects did gain weight, it was within what would be expected for normal growing youths. Fasting blood glucose did not increase above the normal range in any subjects during this study. However, the average value for blood glucose did increase over the 14 weeks of the study. Three subjects had a clinically significant increase in lipid values during the study.
In the retrospective study performed by Valicenti-McDermott and Demb, the mean BMI increased from 23.3 to 24. The change was clinically significant for those under 12 years of age who experienced an increase in mean BMI from 21.3 to 23. In adolescents, the mean increase was not clinically significant (26.7 to 27).
In the fixed dose placebo-controlled study by Marcus et al., mean changes in weight were +0.3, +1.3, +1.3 and +1.5 kg for placebo, and aripiprazole 5, 10 and 15 mg/day, respectively. Aripiprazole and 15 mg/day was associated with clinically significant weight gain when compared with placebo. One individual treated with aripiprazole 15 mg/day and one receiving 10 mg/day had an increase in fasting blood glucose to 115 mg/dl or greater. At the end of the study, the incidence of individuals with fasting triglycerides of 120 mg/dl or more (female subjects) and 160 mg/dl or more (male subjects) was 11.5, 3.1 and 10% for aripiprazole 5, 10 and 15 mg/day, respectively, and 3.6% for placebo.
In the flexibly dosed, placebo-controlled study by Owen et al., mean changes in weight were significantly greater for aripiprazole (2 kg) than for placebo (0.8 kg). A greater increase in BMI was noted in the aripiprazole group (0.7 kg/m2) compared with the placebo group (0.1 kg/m2) in the observed case analysis. One individual receiving aripiprazole discontinued the study owing to weight gain. In this study there was no statistically significant change in fasting triglycerides, total cholesterol, low-density lipoprotein, high-density lipoprotein or serum glucose levels.
Change in Prolactin
Prolactin elevation has been reported frequently in studies involving antipsychotics. In three of the studies discussed above, the prolactin levels were recorded at baseline and at the end of the study.[13,14,16] Stigler et al. reported a decrease from a mean value of 9.3 ng/ml at the beginning to 2.9 ng/ml serum prolactin at the end of the 14-week study. Owen et al. noted a decrease from a mean value of 9.8 ng/ml at the onset of the study to 3.5 ng/ml at the end of the 8-week study. Marcus et al. reported a decrease in mean serum prolactin levels of 5.4 ng/ml in the aripiprazole 5-mg/day group, 5.2 ng/ml in the aripiprazole 10-mg/day group and 5.8 ng/ml in the aripiprazole 15-mg/day group. At study end point, the aripiprazole groups in each of the controlled studies noted a significant decrease in serum prolactin levels when compared with the placebo group.
Sedation is exhibited in a dose–response relationship in those prescribed aripiprazole. In the studies discussed above, two of the five patients in the Stigler et al. study experienced mild somnolence. In the Valicenti-McDermott and Demb study, six of the 32 patients reported sedation. In this study, the sedation caused four of the children to discontinue treatment. In the Stigler et al. open-label study, 14 of the 25 participants acknowledged mild tiredness and one acknowledged moderate tiredness owing to aripiprazole; however, none of the 14 individuals discontinued the study owing to tiredness. Owen et al. reported sedation and/or somnolence as the most common side effect. A total of five of the 47 aripiprazole-treated individuals reported sedation while only one out of 50 individuals in the placebo group complained of sedation. Eight individuals in the aripiprazole group and two in the placebo group reported somnolence. One individual receiving aripiprazole discontinued the study owing to fatigue. Marcus et al. reported seven individuals discontinuing the study owing to sedation. One child was receiving aripiprazole 5 mg/day, four were receiving 10 mg/day and two were receiving 15 mg/day. Over the entire study, three of the 51 participants in the placebo group reported sedation, while nine of the 52 in the aripiprazole 5 mg/day, 17 of the 59 in the 10 mg/day and 13 of the 54 in the 15-mg/day group complained of sedation.
Abnormal movements in individuals with autism have been reported when pharmacotherapy with aripiprazole has been initiated. Stigler et al. noted that mild EPS was reported in nine of the 25 participants in their study. Clinician assessment revealed no EPS during the study; however, mild sialorrhea was reported by four participants, mild tremor in two, mild sialorrhea and mild tremor in one, mild sialorrhea and muscle stiffness in one and moderate neck stiffness and mild tremor in one. Owen et al. reported an EPS event in seven of the 47 (a total of eight EPS events) participants receiving aripiprazole and four of the 50 participants receiving placebo. In the aripiprazole group, of the eight EPS events reported, three were considered possibly related to the study, four were recorded as probably related to the study and one was recorded as certainly related to the study medication. One of the individuals received treatment with benztropine. Marcus et al. reported that six of the 51 individuals in the placebo group, 12 of 52 (23%) in the aripiprazole 5-mg/day group, 13 of 59 (22%) in the 10-mg/day group and 12 of 54 (22.2%) in the 15-mg/day group complained of EPS. A total of eleven individuals, one in the placebo group and ten in one of the active treatment groups, received medication for treatment of possible EPS.
Other Adverse Effects
Other atypical antipsychotics have been associated with increased blood pressure and pulse rate. In the three systematic aripiprazole studies mentioned above, none reported a clinically significant change in heart rate or blood pressure.
Pediatr Health. 2010;4(4):375-381. © 2010 Future Medicine Ltd.
Cite this: Aripiprazole for Irritability Associated with Autistic Disorder in Children and Adolescents Aged 6–17 Years - Medscape - Aug 01, 2010.