New uses for atypicals in pediatric patients: How to offer the benefits while minimizing side effects
Using antipsychotics in children can improve intractable symptoms, but the drugs’ long-term health effects are unknown. These authors scour the literature to help you safely treat young patients with schizophrenia, bipolar disorder, and psychotic depression.
Prescribing of atypical antipsychotics for children and adolescents is increasing, despite a lack of randomized controlled clinical trials. Like many psychiatrists, you may be treating pediatric patients with these medications for a variety of indications beyond psychosis.
Three factors are driving the use of atypical antipsychotics for broader indications:
- substantial evidence that these newer agents are safer and more effective than typical antipsychotics 1
- inadequate response of childhood and adolescent psychiatric disorders to their primary treatments
- evidence that atypical antipsychotics have potential thymoleptic, antiaggressive, and anxiolytic properties.
These attributes already have expanded atypical antipsychotic use in adult patients. In fact, atypicals are being used more extensively in adults for affective and nonpsychotic conditions than for schizophrenia. 2
In preparing the following two-part article for Current Psychiatry, we scoured the available literature—Medline, abstracts from scientific meetings, and American Academy of Child and Adolescent Psychiatry (AACAP) practice parameters—to examine the evolving role of atypical antipsychotics in children and adolescents. In part 1 of this article, we discuss using atypicals in childhood/adolescent-onset schizophrenia, bipolar disorder, and psychotic depression. In part 2, we look at evidence for using atypicals in children with autism and developmental disorders, Tourette’s and other tic disorders, disruptive behavior disorders, anorexia nervosa, anxiety disorders, and stuttering.
RECOMMENDED WORK-UP BEFORE PRESCRIBING ANTIPSYCHOTICS
Before prescribing antipsychotic medications for children and adolescents, always conduct a comprehensive history and complete physical examination.
History. Include information about:
- seizures, head trauma, and cardiac or endocrine problems (often elicited with questions about fatigue, temperature intolerance, or weight concerns)
- perinatal history (apnea, Apgar scores, days in hospital)
- family history (e.g., significant medical problems).
Physical exam. Obtain baseline blood pressure, pulse, body weight and habitus, and laboratory tests—complete blood count, comprehensive metabolic profile with liver function tests, and cholesterol/triglyceride levels.
Educate the parent and child about possible side effects, whether they are likely to be transient or persistent, and ways to minimize them (e.g., bedtime dosing to prevent daytime sedation, dietary recommendations to lessen potential weight gain).
Monitor lab values and weight throughout treatment (compared with normal growth curves). Use words the child understands when asking about side effects (e.g., “Have you had leakage from your breasts?”). Continually weigh the benefits versus the risks of antipsychotics, and discuss this balance with the parent and child.
Shift in pharmacotherapy of schizophrenia.
One-quarter of patients with schizophrenia develop the disorder before age 15, and subtle psychotic manifestations are often observed in early childhood. 3 In general, schizophrenia’s presenting symptoms are comparable in adults and children, but the childhood/adolescent-onset form is more severe. 4,5
During the past 5 years, pharmacotherapy of adult schizophrenia has shifted dramatically away from typical antipsychotics. Atypical agents have shown greater efficacy and tolerability, especially with respect to extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). 1
In a recent survey, most general and specialist psychiatrists (86%) said they prefer using atypical antipsychotics as first-line treatment for new-onset schizophrenia and as maintenance therapy. They also reported using atypicals to treat patients with dementia (80%), personality disorders (69%), developmental delay/mental retardation (65%), and autism (40%). 6
Translating adult findings to children. Most evidence of atypical antipsychotics’ efficacy and tolerability is derived from adult studies, which likely will continue to influence clinical practice more than the limited number of child and adolescent studies. In 1998, a thorough review of atypical antipsychotic use in child and adolescent psychiatry found only five blinded placebo-controlled clinical trials, 24 open-label trials, and 33 case series. 7 A follow-up review in 1999 again found mainly case reports and case series, with a handful of controlled studies. 8
Available atypical antipsychotics include clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. An investigational agent—aripiprazole—is likely to be available soon for clinical use.
Issues in pediatric use of atypicals
When prescribing atypical antipsychotics, it is important to balance the benefit of treatment with the risk of exposing children to possible adverse effects. Side effects associated with atypicals include weight gain, secondary metabolic disturbances such as hyperglycemia, hyperprolactinemia, and cardiac conduction abnormalities. These side effects are health concerns for all patients but particularly for children and adolescents, who may require years of exposure to antipsychotics.
Weight gain. Younger patients may be particularly susceptible to weight gain with the use of the atypicals. In a state hospital adult population, Buckley et al found a strong inverse relationship between patient age and weight gain associated with atypical antipsychotic use. 9 Key issues for pediatric populations are:
- Will children have difficulties losing weight over time?
- Will they stop their medications over time?
- Will they stop their medications because of this effect?
- Will they be further stigmatized at school because of obesity?
- Are they at increased risk to develop diabetes mellitus?
- What are the long-term consequences of antipsychotic-induced obesity and metabolic disturbances for this patient population?
Hyperprolactinemia in children and adolescents may lead to breast enlargement and galactorrhea, which are particularly distressing in this age group. Sustained elevation of prolactin may affect the regulation of other hormones, resulting in low estrogen and testosterone levels. The long-term impact of these changes on adolescent growth and development is unknown. Antipsychotic-induced hyperprolactinemia also may be associated with reduced bone density. 10
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
Younger 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
FDA-approved dosages for psychosis in adults
For psychosis in children and adolescents
For bipolar disorder in children and adolescents
Initial: 25 mg bid; increase gradually to 300 to 800 mg/d in divided doses
Not recommended for children under age 16
Psychosis. Initial: 5 to 10 mg qd or 5 mg bid; increase to 20 mg qd or 10 mg bid
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
Clinically beneficial at dosages comparable to those used in psychosis
Initial: 25 mg bid; increase to 300 to 800 mg/d divided in two to three doses
Initial: 12.5 mg bid (<50 kg) to 25 mg bid (>50 kg)
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
Clinically beneficial at dosages comparable to those used in psychosis
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
* 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.
Special care is required to decrease the risks associated with using antipsychotics in children and adolescents and to increase compliance with medication recommendations (Box 1).
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.