Pharmacokinetics in children and adolescents
Administering medications to children and adolescents requires special precautions. Younger patients respond differently than adults to psychotropic medications because of differences in pharmacokinetics—how the body handles a drug—and pharmacodynamics—the drug’s effect on the body.
During a child’s growth and development, physiologic changes in absorption, distribution, metabolism, and excretion may affect drug delivery to target tissue (Box 2).12,13 Maturation of brain regions and neurotransmitter systems also may alter a medication’s effect at different ages.
Antipsychotic dosage recommendations and therapeutic ranges for children and adolescents have been published but are extrapolated from adult studies because studies in children are lacking. There is danger, however, in using body weight and proportionately reducing an adult dosage to obtain a pediatric dosage. The plasma concentration may ultimately be subtherapeutic or toxic.14
The liver metabolizes most antipsychotics. The higher rate of hepatic metabolism in children would suggest that on a milligram-to-kilogram basis a child or adolescent would need a higher dose. Children, however, require smaller weight-adjusted doses of antipsychotics than do adults to achieve the same therapeutic effect.15 Children have a greater density of dopamine D-1 and D-2 receptors than do adults, suggesting a greater sensitivity to the beneficial and adverse effects of antipsychotics. To date, dopamine receptor occupancy in children/adolescents with schizophrenia has not been studied with positron emission tomography.
Summary. Compared with adults, children require a reduced milligram-to-kilogram dosage of antipsychotics to achieve the same therapeutic effect and avoid unwanted side effects. Children younger than age 10 or weighing less than 50 kg typically should start with the lowest starting dose, given once or twice a day (Table). The dose should be slowly increased based on the presence of side effects and remission of symptoms.
Maximum daily dosages for children weighing less than 50 kg should rarely exceed one-half of an adult antipsychotic dosage, particularly when used for symptoms of disorders other than primary psychosis. However, dosages closer to those used in adults may be necessary when treating primary psychosis in early-onset schizophrenia, especially in an adolescent (Box 3).
CASE REPORT: ANTIPSYCHOTIC DOSING FOR A TEEN WITH PARANOIA
An adolescent boy, age 13 and weighing 47 kg, presents with the chief complaint of paranoia, which is impairing his academic functioning. On examination, his interaction is guarded, and he exhibits severe emotional withdrawal and a paucity of thought content. His family history is significant for a maternal uncle with early-onset schizophrenia, which is chronic but under reasonable control with olanzapine, 10 mg bid.
The boy’s treatment is started with olanzapine, 2.5 mg once daily. After 2 weeks, the dosage is increased to 2.5 mg in the morning and 5 mg at bedtime, with good symptom resolution.
Childhood/adolescent-onset schizophrenia
Typical antipsychotics appear to have limited efficacy in childhood/adolescent-onset schizophrenia, based on a small number of available case series and relatively short open-label trials.16 In a single-arm, placebo-controlled trial, haloperidol was effective in 16 children ages 5 to 12, but its use was associated with substantial EPS. A similar intolerance was demonstrated in a comparative trial of thioridazine and thiothixene.
Less is known about the incidence of tardive dyskinesia, but there is no reason to believe that the rate is lower in children and adolescents than in adults with schizophrenia (estimated at 5% per year for the first 5 years of treatment).
Clozapine. Information is emerging on the efficacy and tolerability of atypical antipsychotics in childhood/adolescent-onset schizophrenia.16 Clozapine has been studied more than other atypicals, in part because of the severity of early-onset schizophrenia and because clozapine has been used in clinical practice longer than the other agents in that class.
Early case reports and small open-labeled trials confirmed that clozapine was effective for children and adolescents with schizophrenia who had failed prior antipsychotic treatments.17-19 A randomized, double-blind, controlled trial from the childhood schizophrenia division of the National Institute of Mental Health provided the most reliable information.17 In that 6-week treatment study, 21 severely ill adolescents (mean age 14) received clozapine, mean dosage 176 mg/d, or haloperidol, mean dosage 16 mg/d. Response to clozapine was greater for both positive and negative symptoms, and the difference was clinically and statistically significant. In addition, 62% of clozapine-treated patients were rated very much improved on the Clinical Global Impression (CGI) scale.
In the same trial, clozapine treatment was complicated by higher rates of adverse effects than are typically observed in adult studies: