Abnormal cardiac conduction. Thioridazine recently received a “black box” label warning from the FDA because of sudden deaths and a prolonged QTc interval seen on electrocardiogram (ECG) readings. Several other antipsychotics also show ECG evidence of QTc prolongation.11 However, the clinical significance of this finding is unclear.
HOW ANTIPSYCHOTICS ARE METABOLIZED IN CHILDREN AND ADOLESCENTS
TableYounger patients respond differently than do adults to antipsychotic medications because of developmental differences in pharmacokinetics: absorption, distribution, metabolism, and excretion.
Absorption. Stomach contents tend to be less acidic in younger persons than in adults, potentially slowing absorption of weakly acidic drugs. In theory, the absorption of antidepressants and psychostimulants is more likely to be altered than that of antipsychotics. Children may also have fewer and less diverse intestinal microflora, which may explain why phenothiazines (absorbed or metabolized in the intestinal wall) must be given at higher-than-adult oral dosages for clinical effect.12
Children may absorb certain psychotropic medications (e.g., imipramine) more rapidly than adults. This contributes to greater fluctuations in blood levels and possible cardiac toxicity—often a function of peak plasma concentrations.
Distribution. Drug distribution patterns in infants, children, and adolescents—especially those going through puberty—are not homogenous.13 Fat stores and the relative proportion of total body water to extracellular water affect distribution and change with development.
The proportion of fat to body weight is highest in the first year of life, declines steadily during childhood, increases prior to puberty, then declines thereafter. Thus, although individuals have variable degrees of fat stores, children in general have a lower proportion of body fat than adults and therefore a smaller volume of distribution. This becomes significant when prescribing antipsychotics, which are lipid-soluble.
If one considers only a drug’s distribution, one would expect to find a higher plasma concentration in a child if a child and an adult were given the same weight-adjusted dose of a lipophilic drug. Children, however, exhibit a lowerplasma concentration of lipophilic drugs than do adults because of differences in metabolism.13
Metabolism. Children’s increased metabolic rate is directly related to age-related changes in hepatic enzymes. In general, metabolic pathways for many drugs function at a low level during the perinatal period, mature by 6 months, peak between ages 1 and 5, and decline gradually to adult values by about age 15. Liver mass is also greater in children than in adults. Therefore, higher ratios of milligrams of drug to kilograms of body weight may be needed in children to achieve steady-state plasma levels comparable to those seen in adults.
Excretion. Infant and adult renal functioning are approximately the same. With the exception of lithium, developmental changes in renal function do not contribute substantially to age-related differences in psychotropic drug excretion.13
Summary. When compared with adults, children require a higher milligram-to-kilogram dosage of antipsychotics to achieve the same plasma concentration but clinically require a lower milligram-to-kilogram dosage—starting dosages usually less than one-half of an adult dose—to avoid unwanted side effects.
SUGGESTED DOSAGES OF ATYPICAL ANTIPSYCHOTICS
| Drug | FDA-approved dosages for psychosis in adults | For psychosis in children and adolescents | For bipolar disorder in children and adolescents |
|---|---|---|---|
| Clozapine | Initial: 25 mg bid; increase gradually to 300 to 800 mg/d in divided doses | Not recommended for children under age 16 Initial: 12.5 to 25 mg bid; increase gradually to 300 to 450 mg/d (divided) Increased risk of seizures; potential for agranulocytosis | Limited research |
| Olanzapine | Psychosis. Initial: 5 to 10 mg qd or 5 mg bid; increase to 20 mg qd or 10 mg bid Bipolar disorder. Similar initial; lower maintenance (10 to 20 mg qd or 10 mg bid can often be obtained) | Clinical benefit in children age 10 at 2.5 to 10 mg/d; For age >10, 5 to 20 mg qd or 10 mg bid may be used Sedation and weight gain are common side effects | Clinically beneficial at dosages comparable to those used in psychosis Maintenance dosage may be lower than that required in a primary psychotic disorder |
| Quetiapine | Initial: 25 mg bid; increase to 300 to 800 mg/d divided in two to three doses | Initial: 12.5 mg bid (50 kg) Maintenance: 50 mg bid (50 kg) Few controlled trials in children | Limited research |
| Risperidone | Initial: 2 mg/d; may be increased to 4 to 6 mg/d in divided doses | Clinical trials indicate benefit at 0.25 to 0.5 mg qd or bid May be increased as needed to 0.5 to 1.5 mg/d in single or divided doses | Clinically beneficial at dosages comparable to those used in psychosis |
| Ziprasidone | Initial: 20 to 40 mg bid; may be increased to 40 to 80 mg bid | Preliminary studies suggest benefit at 10 to 20 mg bid, increasing to 20 to 60 mg bid Not recommended as first-line therapy in this population | Limited research |
| * The FDA has not approved a specific indication for these agents for use in children and adolescents. In adult patients, atypical antipsychotics have been approved for psychosis, and olanzapine is FDA-approved for psychosis and mood disorders. | |||