The authors of “Adverse Effects of Antipsychotic Medications” in this issue of American Family Physician aptly state that, “The use of antipsychotic medications entails a difficult trade-off between the benefit of alleviating psychotic symptoms and the risk of troubling, sometimes life-shortening adverse effects.”1 The dilemma of how to treat while minimizing medication adverse effects is present especially in the treatment of children and adolescents, in whom the evidence for effectiveness has been limited historically. During a child's physical and mental development, the effects of therapy may be intensified or manifest differently. The use of antipsychotics in children has increased dramatically in recent years, partly fueled by the misperception that second-generation (atypical) antipsychotics might be safer than first-generation (conventional) antipsychotics.2 Here we highlight considerations pertinent to the use of antipsychotics in children within primary care.
Controlled clinical trials support the effectiveness of a number of antipsychotics in the acute treatment of adolescents with schizophrenia, and children and adolescents with bipolar mania (Table 1). In addition, risperidone (Risperdal) is also approved to treat severe aggression and self-injury, in the context of autism. In the United States, antipsychotics do not have approved indications for the treatment of attention-deficit/hyperactivity, conduct, or other disruptive behavioral disorders. The lack of biologic markers for these disorders and the difficulty of identifying conditions such as bipolar disorder during development make a careful diagnostic evaluation critical before treatment is prescribed.
|Drug*||Indicated in children?|
|Acute bipolar I 10 to 17 years||Schizophrenia 13 to 17 years||Irritability in autism 5 to 16 years|
|Olanzapine (Zyprexa)||VOTE–Yes for 13 to 17 years; 2nd tier due to metabolic effects||VOTE–Yes; 2nd tier due to metabolic effects||No|
|Ziprasidone (Geodon)||VOTE–Yes; 2nd tier due to QT prolongation||No||No|
Medication adherence is often poor among adolescents. Skilled questioning and an established rapport can help distinguish between nonadherence and lack of medication effectiveness. Withdrawal dyskinesia from interrupted adherence may appear similar to certain disease manifestations and extrapyramidal effects of medication. Liquid formulations and orally dissolving tablets support adherence and ease of use; however, intramuscular administration has not been studied in children and generally is not indicated.
Weight Gain and Metabolic Effects
Because neurotransmitters alter central satiety and appetite mechanisms, weight gain is a common adverse effect of antipsychotic medication, one to which children and adolescents are more sensitive.3 Weight gain is potentially more serious in childhood because it:
Increases the risk of obesity in adulthood
Contributes to metabolic effects, including liver enzyme elevation
Alters the balance of growth and sex hormones
Complicates the care of children with physical developmental disabilities
Increases the risk of sleep apnea, which may be misinterpreted as medication-related somnolence
May contribute to a shortened life span from accelerated progression of chronic metabolic and cardiovascular diseases among persons with mental illness.4
Attention to caloric intake and establishment of baseline metabolic parameters with frequent monitoring are important strategies for weight management. An overlooked, modifiable metabolic risk factor may be vitamin D deficiency. Although levels of this metabolic pro-hormone have not been studied specifically in children taking atypical antipsychotics, medication-associated weight gain and reduced sun exposure increase the risk of deficiency amidst a high baseline prevalence of vitamin D deficiency.5,6
Certain antipsychotics can elevate prolactin levels, potentially influencing the onset of puberty. Risperidone is especially prone to this effect, whereas aripiprazole (Abilify) may decrease prolactin levels. Gynecomastia should prompt laboratory screening for an elevated prolactin level. Prolactinemia should be included in the differential diagnosis of amenorrhea, along with polycystic ovary syndrome, pregnancy, and delayed onset of menarche.7
Neurologic and Psychiatric Effects
How the sedating effects of medication interfere with childhood learning is not well understood, nor is the extent to which the risk of tardive dyskinesia is cumulative in children. Additionally, there may be unknown effects of medications on the developing brain. The drug labels of atypical antipsychotics approved for the treatment of depression in adults carry a boxed warning for increased risk of suicide in children, adolescents, and young adults—another example of how the illness itself and potential medication effects are entwined.
Recently, clinical trials have been conducted in children, and more studies are forthcoming to better facilitate clinical decision making, including a publicly funded comparative effectiveness trial.3 The Psycho-pharmacologic Drugs Advisory Committee of the U.S. Food and Drug Administration convened in June 2009 to review these clinical trials, which continue to inform the balance between risks and benefits8,9 (Table 1).