Evidence-Based Reviews

Clinical trials support new algorithm for treating pediatric bipolar mania

Current Psychiatry. 2009 November;8(11):19-34

References

1. Hopewell S, Clarke M, Stewart L, et al. Time to publication for results of clinical trials. Cochrane Database Syst Rev. 2007;(2):MR000011.-

2. Carey B. Risks found for youths in new antipsychotics. The New York Times. September 15, 2008:A17.

3. Pandina G, DelBello M, Kushner S, et al. Risperidone for the treatment of acute mania in bipolar youth. Paper presented at: Annual Meeting of the American Academy of Child and Adolescent Psychiatry, October 23-28, 2007; Boston, MA.

4. Tohen M, Kryzhanovskaya L, Carlson G, et al. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. Am J Psychiatry. 2007;164(10):1547-1556.

5. DelBello M, Findling RL, Earley W, et al. Efficacy of quetiapine in children and adolescents with bipolar mania: a 3-week, double-blind, randomized, placebo-controlled trial. Paper presented at: Annual Meeting of the American Academy of Child and Adolescent Psychiatry, October 23-28, 2007; Boston, MA.

6. Wagner K, Nyilas M, Forbes R, et al. Acute efficacy of aripiprazole for the treatment of bipolar I disorder, mixed or manic, in pediatric patients. Paper presented at: Annual Meeting of the American College of Neuropsychopharmacology, December 9-13, 2007; Boca Raton, FL.

7. DelBello M, Findling RL, Wang P, et al. Safety and efficacy of ziprasidone in pediatric bipolar disorder. Paper presented at: Annual Meeting of the American Psychiatric Association, May 3-8, 2008; Washington, DC.

8. McElduff P, Jaefarnezhad M, Durrington PN. American, British and European recommendations for statins in the primary prevention of cardiovascular disease applied to British men studied prospectively. Heart. 2006;92(9):1213-1218.

9. Tsapakis EM, Soldani F, Tondo L, et al. Efficacy of antidepressants in juvenile depression: meta-analysis. Br J Psychiatry. 2008;193(1):10-17.

10. Kowatch R, Findling R, Scheffer R, et al. Placebo controlled trial of divalproex versus lithium for bipolar disorder. Paper presented at: Annual Meeting of the American Academy of Child and Adolescent Psychiatry; October 23-28, 2007; Boston, MA.

11. DelBello MP, Kowatch RA, Adler CM, et al. A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. J Am Acad Child Adolesc Psychiatry. 2006;45(3):305-313.

12. DelBello MP, Schwiers ML, Rosenberg HL, et al. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry. 2002;41(10):1216-1223.

13. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.

14. Suppes T, Dennehy EB, Hirschfeld RM, et al. The Texas implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66(7):870-886.

15. Becker AL, Epperson CN. Female puberty: clinical implications for the use of prolactin-modulating psychotropics. Child Adolesc Psychiatr Clin N Am. 2006;15(1):207-220.

16. Correll CU, Penzner JB, Parikh UH, et al. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2006;15(1):177-206.

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

18. Correll CU. Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry. 2008;47(1):9-20.

19. Correll CU, Nyilas M, Ashfaque S, et al. Long-term safety and tolerability of aripiprazole in children (10-17 years) with bipolar disorder. Paper presented at: Annual Meeting of the American College of Neuropsychopharmacology; December 9-13, 2007; Boca Raton, FL.

20. Pandina GJ, Bossie CA, Youssef E, et al. Risperidone improves behavioral symptoms in children with autism in a improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord. 2007;37(2):367-373.

21. DelBello M, Findling RL, Earley W, et al. Efficacy of quetiapine in children and adolescent with bipolar mania; a 3-week, double-blind, randomized, placebo-controlled trial. Paper presented at: Annual Meeting of the American College of Neuropsychopharmacology; December 9-13, 2007; Boca Raton, FL.

22. Correll CU, Kane JM. One-year incidence rates of tardive dyskinesia in children and adolescents treated with second-generation antipsychotics: a systematic review. J Child Adolesc Psychopharmacol. 2007;17(5):647-656.

23. McDermid SA, Hood J, Bockus S, et al. Adolescents on neuroleptic medication: is this population at risk for tardive dyskinesia? Can J Psychiatry. 1998;43(6):629-631.

24. Kumra S, Jacobsen LK, Lenane M, et al. Case series: spectrum of neuroleptic-induced movement disorders and extrapyramidal side effects in childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry. 1998;37(2):221-227.

25. Strawn JR, Keck PE, Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876.

26. Croarkin PE, Emslie GJ, Mayes TL. Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases. J Clin Psychiatry. 2008;69(7):1157-1165.

27. Picard LS, Lindsay S, Strawn JR, et al. Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations. Pharmacotherapy. 2008;28(4):530-535.

28. Correll CU. Metabolic side effects of second-generation antipsychotics in children and adolescents: a different story? J Clin Psychiatry. 2005;66(10):1331-1332.

29. Klein DJ, Cottingham EM, Sorter M, et al. A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry. 2006;163(12):2072-2079.

30. Kavey RE, Allada V, Daniels SR, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research. J Cardiovasc Nurs. 2007;22(3):218-253.

31. O’Grady MJ, Brown AM, O’Neill MB. Cholesterol screening in an at-risk pediatric population. Pediatr Cardiol. 2008;29(3):609-613.

32. Ali J, Khemka M. Hyperprolactinemia: monitoring children on long-term risperidone. Current Psychiatry. 2008;7(11):64-72.

33. Blair J, Scahill L, State M, et al. Electrocardiographic changes in children and adolescents treated with ziprasidone: a prospective study. J Am Acad Child Adolesc Psychiatry. 2005;44(1):73-79.

34. Malone RP, Delaney MA, Hyman SB, et al. Ziprasidone in adolescents with autism: an open-label pilot study. J Child Adolesc Psychopharmacol. 2007;17(6):779-790.

Recommendation. Monitor and treat hyperlipidemia, which increases the risk of atherosclerosis as obese children grow older.³¹

Prolactin. Elevated prolactin concentrations may have deleterious effects in the developing child or adolescent, including gynecomastia, oligomenorrhea, and amenorrhea.¹⁷ Long-term effects on growth and sexual maturation have not been fully evaluated.

Clinical Point

If a patient develops elevated prolactin symptoms, switch to a different atypical antipsychotic that does not increase serum prolactin

The relative tendency of atypical antipsychotics to cause hyperprolactinemia is roughly: risperidone/paliperidone > olanzapine > ziprasidone > quetiapine > clozapine > aripiprazole.¹⁸ In the risperidone RCT, mean changes in baseline prolactin levels were 41 ng/mL for boys and 59 ng/mL in girls.³ Results of the olanzapine RCT suggest a high incidence of hyperprolactinemia (26% of girls, 63% of boys).⁴ Decreases in serum prolactin were observed in bipolar children and adolescents treated with aripiprazole for 30 weeks.¹⁹

Recommendations. For any pediatric patient treated with an atypical antipsychotic that increases prolactin levels:

Obtain a baseline prolactin level.
Repeat after 6 months of treatment or with the emergence of elevated prolactin symptoms, such as gynecomastia in boys. Ask about increases in breast size, galactorrhea, changes in menstruation, sexual functioning, and pubertal development.

Switch patients who develop any of these side effects to another atypical agent that does not increase serum prolactin.³²

QTc interval prolongation. All atypical antipsychotics can cause QTc prolongation. Several cases of significant QTc prolongation have been reported in children and adolescents treated with ziprasidone.^33,34 In the RCT of ziprasidone, QTc prolongation was not clinically significant in most of the patients in which it was reported, and it did not lead to adverse events.³⁴ Mean QTc change was 8.1 msec at study termination.⁷

Patients enrolled in clinical trails are screened very carefully, however, and those with preexisting medical abnormalities typically are excluded. Thus, these findings may have limited usefulness for “real-world” patients.

Recommendations. Until additional information is known about the cardiac effects of atypical antipsychotics in children and adolescents:

Perform a careful history, review of symptoms, and physical exam looking for any history of palpitations, shortness of breath, or syncope.
Query specifically about any family history of sudden cardiac death.
Perform a baseline resting ECG for patients starting ziprasidone or clozapine, or for other atypicals if indicated by history, review of systems, physical exam, etc.
For patients treated with ziprasidone or clozapine, repeat ECG as the dose increases or if the patient has cardiac symptoms (unexplained shortness of breath, palpitations, skipped beats, etc.).

Table 3

Talking to families about using antipsychotics
in children with bipolar disorder

Effectiveness. Large, placebo-controlled studies have shown that atypical antipsychotics can significantly reduce manic symptoms in children and adolescents with bipolar disorder
Safety data. Additional 6-month safety data indicate that atypical antipsychotics continue to be effective in children and adolescents, without dramatic changes in side effects
Precautions. Antipsychotics are powerful medications and must be used carefully in pediatric patients
Potential side effects. All antipsychotics have serious potential side effects that must be recognized, monitored, and managed
Potential benefits from using atypical antipsychotics include mood stabilization, treatment of psychotic symptoms, and lower risk of extrapyramidal symptoms compared with typical antipsychotics
Risk vs benefit. On balance, the potential benefit of these agents outweighs the potential risk for children and adolescents with bipolar disorder

Figure: Mean weight gain with atypical antipsychotics in pediatric bipolar trials

Weight gain in children and adolescents with bipolar disorder varied among atypical antipsychotics used in 5 recent randomized controlled trials. Treatment duration was 3 weeks with olanzapine, risperidone, and quetiapine and 4 weeks with aripiprazole and ziprasidone. Dosages were olanzapine, 10.4 ± 4.5 mg/d; risperidone, 0.5 to 2.5 mg/d or 3 to 6 mg/d; aripiprazole, 10 or 30 mg/d; quetiapine, 400 or 600 mg/d; and ziprasidone, 80 to 160 mg/d.
Source: References 3-7Related resources

Child and Adolescent Bipolar Foundation. www.bpkids.org.
University of Illinois at Chicago Pediatric Mood Disorders Clinic. www.psych.uic.edu/pmdc.
Ryan Licht Sang Bipolar Foundation. www.ryanlichtsangbipolarfoundation.org.

Drug brand names

Aripiprazole • Abilify
Benztropine • Cogentin
Carbamazepine • Carbatrol
Clozapine • Clozaril
Diphenhydramine • Benadryl
Divalproex sodium • Depakote
Lithium • Lithobid, others
Metformin • Glucophage
Olanzapine • Zyprexa
Paliperidone • Invega
Propranolol • Inderal
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate • Depacon
Ziprasidone • Geodon

Disclosures

Dr. Kowatch is a consultant to and speaker for AstraZeneca and a consultant to Forest Pharmaceuticals. He receives research support from the National Alliance for Research on Schizophrenia and Depression, the National Institute of Child Health and Human Development, the National Institute of Mental Health, and the Stanley Foundation.

Dr. Strawn has received research support from the American Academy of Child and Adolescent Psychiatry (Lilly Pilot Research Award).