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Use of Atypical Antipsychotics in Children: Balancing Safety and Effectiveness



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Am Fam Physician. 2010 Mar 1;81(5):585-589.

  Related Article

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.

Effectiveness

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.

Table 1.

Current and Proposed FDA Indications for Atypical Antipsychotics in Children, August 2009

Drug* Indicated in children?
Acute bipolar I 10 to 17 years Schizophrenia 13 to 17 years Irritability in autism 5 to 16 years

Aripiprazole (Abilify)

Yes

Yes

No

Olanzapine (Zyprexa)

VOTE–Yes for 13 to 17 years; 2nd tier due to metabolic effects

VOTE–Yes; 2nd tier due to metabolic effects

No

Quetiapine (Seroquel)

VOTE–Yes

VOTE–Yes

No

Risperidone (Risperdal)

Yes

Yes

Yes

Ziprasidone (Geodon)

VOTE–Yes; 2nd tier due to QT prolongation

No

No


note: VOTE–Yes means that the FDA is considering approval for these therapeutic options for the childhood age group. Irrespective of which action the FDA takes (approval or not for the indication for children), the product labeling will be revised to incorporate new information resulting from clinical trials in children.

FDA = U.S. Food and Drug Administration.

*— The drugs listed are administered orally.

Table 1.   Current and Proposed FDA Indications for Atypical Antipsychotics in Children, August 2009

View Table

Table 1.

Current and Proposed FDA Indications for Atypical Antipsychotics in Children, August 2009

Drug* Indicated in children?
Acute bipolar I 10 to 17 years Schizophrenia 13 to 17 years Irritability in autism 5 to 16 years

Aripiprazole (Abilify)

Yes

Yes

No

Olanzapine (Zyprexa)

VOTE–Yes for 13 to 17 years; 2nd tier due to metabolic effects

VOTE–Yes; 2nd tier due to metabolic effects

No

Quetiapine (Seroquel)

VOTE–Yes

VOTE–Yes

No

Risperidone (Risperdal)

Yes

Yes

Yes

Ziprasidone (Geodon)

VOTE–Yes; 2nd tier due to QT prolongation

No

No


note: VOTE–Yes means that the FDA is considering approval for these therapeutic options for the childhood age group. Irrespective of which action the FDA takes (approval or not for the indication for children), the product labeling will be revised to incorporate new information resulting from clinical trials in children.

FDA = U.S. Food and Drug Administration.

*— The drugs listed are administered orally.

Adherence

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

Prolactin Elevation

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).

The views expressed herein are those of the authors; no endorsement by the U.S. Food and Drug Administration is intended or should be inferred.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the National Institutes of Mental Health, the National Institutes of Health, or the U.S. Department of Health and Human Services.

Address correspondence to Ingrid Kohlstadt, MD, MPH, at ingrid.kohlstadt@fda.hhs.gov. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. Muench J, Hamer AM. Adverse effects of antipsychotic medications. Am Fam Physician. 2010;81(5):617–622.

2. Vitiello B, Correll C, van Zwieten-Boot B, Zuddas A, Parellada M, Arango C. Antipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns. Eur Neuropsychopharmacol. 2009;19(9):629–635.

3. Sikich L, Frazier JA, McClellan J, et al. Double-blind comparison of first-and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study [published correction appears in Am J Psychiatry. 2008;165(11):1495]. Am J Psychiatry. 2008;165(11):1420–1431.

4. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42.

5. Kohlstadt I. Scientific Evidence for Musculoskeletal, Bariatric, and Sports Nutrition. Boca Raton, Fla.: Taylor & Francis; 2006:621.

6. Kumar J, Muntner P, Kaskel FJ, Hailpern SM, Melamed ML. Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES 2001–2004. Pediatrics. 2009;124(3):e362–e370.

7. Correll CU. Effect of hyperprolactinemia during development in children and adolescents. J Clin Psychiatry. 2008;69(8):e24.

8. U.S. Food and Drug Administration. July 20, 2009 meeting of the Psychopharmacologic Drugs Advisory Committee. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Psycho-pharmacologicDrugsAdvisoryCommittee/ucm126199.htm. Accessed October 19, 2009.

9. Kohlstadt I, Rappley M, Robb A, Vitiello B. Atypical antipsychotics in children and adolescents: Balancing safety and efficacy. Audio-Digest Pediatrics. 2009;55(16):1–4.


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