Correll et al19 reported a 10% rate of EPS in patients treated with aripiprazole. Treatment-emergent EPS also was observed in the RCT of risperidone.20 EPS-related adverse events were associated with higher doses of risperidone, although none of the akathisia/EPS measures were thought to be “clinically significant.”
EPS frequency was relatively low and similar to placebo in the 3-week quetiapine trial,21 and no changes in movement disorder scale scores were observed during the olanzapine or ziprasidone RCTs.4,7
Recommendations. If your pediatric patient develops EPS, first try an antipsychotic dose reduction. Because anticholinergics can contribute to antipsychotic-induced weight gain, reserve them until after a dosage reduction has been unsuccessful.
Benztropine (0.25 to 0.5 mg given 2 to 3 times daily, not to exceed 3 mg/d) or diphenhydramine (25 to 50 mg given 3 to 4 times daily; maximum dosage 5 mg/kg/d) can be effective in treating EPS. Avoid anticholinergics in children with narrow-angle glaucoma or age <3.
Akathisia may be managed with propranolol (20 to 120 mg/d in divided doses). Multiple doses (typically 3 times daily) are needed to prevent interdose withdrawal symptoms. Use this beta blocker with caution in children with asthma because of the possibility of bronchospasm.
TD. Short-term trials and a meta-analysis of atypical antipsychotic trials (>11 months’ duration, subject age <18) suggest a low annual risk for TD (0.4%).22 Large, prospective, long-term trials of atypical antipsychotics are necessary to more accurately define the risk of TD in the pediatric population, however. Retrospective analyses of adolescents treated with antipsychotics suggest 3 TD risk factors:
- early age of antipsychotic use
- medication nonadherence
- concomitant use of antiparkinsonian agents.23
Kumra et al24 identified lower premorbid functioning and greater positive symptoms at baseline as factors associated with “withdrawal dyskinesia/tardive dyskinesia” in children and adolescents with early-onset psychotic-spectrum disorders treated with typical or atypical antipsychotics.
Recommendations. To minimize TD risk, use the lowest effective antipsychotic dose, monitor for abnormal involuntary movements with standardized assessments (such as the Abnormal Involuntary Movement Scale), review risks and benefits with parents and patients, and regularly evaluate the indication and need for antipsychotic therapy. It is reasonable to attempt to lower the antipsychotic dose after the patient has attained remission and been stable for 1 year.
Neuroleptic malignant syndrome (NMS). This complication of dopamine-blocking medications:
- is among the most serious adverse effects of antipsychotic treatment
- continues to be associated with a mortality rate of 10%.25
Recommendation. At least 1 recent review of pediatric NMS cases suggests that essential features (hyperthermia and severe muscular rigidity) are retained in children.26 Nonetheless, monitor for variant presentations; hyper thermia or muscle rigidity may be absent or develop slowly over several days in patients treated with atypical antipsychotics.27
Weight gain and glucose metabolism. A major adverse effect of most atypical antipsychotics is increased appetite, weight gain, and possible obesity.28 In children, “obesity” refers to a body mass index (BMI) >95th percentile for age and sex; “over-weight” refers to BMI between the 85th and 95th percentile. Mean weight gain in the 5 atypical antipsychotic pediatric bipolar trials ranged from 0 to 8 lbs across 3 to 4 weeks of treatment (Figure).3-7
Recommendations. Emphasize diet and exercise, with restriction of high-carbohydrate food, “fast foods,” and soft drinks. Another option is a trial of metformin, which decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Klein et al29 studied 39 patients age 10 to 17 with mood and psychotic disorders whose weight increased by >10% during <1 year of olanzapine, risperidone, or quetiapine therapy. In this 16-week, double-blind, placebo-controlled trial, weight was stabilized in subjects receiving metformin, whereas those receiving placebo continued to gain weight (0.31 kg [0.68 lb]/week).
The usual starting metformin dose is 500 mg bid with meals. Increase in increments of 500 mg weekly, up to a maximum of 2,000 mg/d in divided doses. Potential side effects include diarrhea, nausea/vomiting, flatulence, and headache.
Hyperlipidemia. Patients who gain weight with atypical antipsychotics also may develop hyperlipidemia. Fasting serum triglycerides >150 mg/dL (1.70 mmol/L) in obese children are considered to be elevated and an early sign of metabolic syndrome.30 Fasting total cholesterol >200 mg/dL (5.18 mmol/L) or low-density lipoprotein cholesterol >130 mg/dL (3.38 mmol/L) is consistent with hyperlipidemia.