Evidence-Based Reviews

Are anticonvulsants safe for pediatric bipolar disorder?

Current Psychiatry. 2005 August;4(8):31-48

References

1. Kowatch R, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44(3):213-35

2. Wang P, Ketter T, Becker O, et al. New anticonvulsant medication uses in bipolar disorder. CNS Spectrums 2003;8(12):930-47.

3. Prescribing information. Physicians’ Desk Reference (59th ed.) Montvale, NJ: Thomson Healthcare, 2005.

4. Kafantaris V, Coletti D, Dicker R, et al. Lithium treatment of acute mania in adolescents: a large open trial. J Am Acad Child Adolesc Psychiatry 2003;42(9):1038-45.

5. Kafantaris V, Coletti D, Dicker R, et al. Lithium treatment of acute mania in adolescents: a placebo-controlled discontinuation study. J Am Acad Child Adolesc Psychiatry 2004;43(8):984-93.

6. Strober M, DeAntonio M, Schmidt-Lackner S, et al. Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania. J Affect Disord 1998;51(2):145-51.

7. Geller B, Cooper T, Zimerman B, et al. Lithium for prepubertal depressed children with family history predictors of future bipolarity: a double-blind, placebo-controlled study. J Affect Disord 1998;51(2):165-75.

8. Weller E, Weller R, Fristad M. Lithium dosage guide for prepubertal children: a preliminary report. J Am Acad Child Adolesc Psychiatry 1986;25(1):92-5.

9. Kowatch R, Suppes T, Carmody T, et al. Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2000;39(6):713-20.

10. Hagino O, Weller E, Weller R, et al. Untoward effects of lithium treatment in children aged four through six years. J Am Acad Child Adolesc Psychiatry 1995;34(12):1584-90.

11. Hagino O, Weller E, Weller R, Fristad M. Comparison of lithium dosage methods for preschool- and early school-age children. J Am Acad Child Adolesc Psychiatry 1995;37(1):60-5.

12. Yonkers K, Wisner K, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161(4):608-20.

13. Holmes L. The North American antiepileptic drug pregnancy registry: a seven-year experience. (paper presentation). New Orleans: American Epilepsy Society annual meeting, 2004.

14. Vajda F, Lander C, Cook M, et al. Antiepileptic medication in pregnancy: the Australian Pregnancy Register: 52 months data (poster presentation). New Orleans: American Epilepsy Society annual meeting, 2004.

15. Messenheimer J, Tennis P, Cunnington M. Eleven-year interim results of an international observational study of pregnancy outcomes following exposure to lamotrigine (poster presentation). New Orleans: American Epilepsy Society annual meeting, 2004.

16. Torbjorn T, Battino D, Bonizzoni E, et al. Eurap: an international registry of antiepileptic drugs and pregnancy (poster presentation). New Orleans: American Epilepsy Society annual meeting, 2004.

17. Wagner K, Weller E, Carlson G, et al. An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2002;41(10):1224-30.

18. Scheffer RE, Kowatch RA, Carmody T, Rush AJ. Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. Am J Psychiatry 2005;162(1):58-64.

19. Findling R, McNamara N, Gracious B, et al. Combination lithium and divalproex sodium in pediatric bipolarity. J Am Acad Child Adolesc Psychiatry 2003;42(8):895-901.

20. DelBello M, Adler C, Strakowski S. Divalproex for the treatment of aggression associated with adolescent mania. J Child Adolesc Psychopharmacol 2004;14(2):325-8.

21. Anderson G. Children versus adults: pharmokinetic and adverseeffect differences. Epilepsia 2002;43(suppl 3):53-9.

22. Yehya N, Saldarini C, Koski M, et al. Valproate-induced hyperammonemic encephalopathy. J Am Acad Child Adolesc Psychiatry 2004;43(8):926-7.

23. Verrotti A, Greco R, Matera V, et al. Platelet count and function in children receiving sodium valproate. Pediatr Neurol 1999;21(3):611-14.

24. Isojarvi J, Tauboll E, Pakarinen A, et al. Altered ovarian function and cardiovascular risk factors in valproate-treated women. Am J Med 2001;111(4):290-6.

25. Bowden C, Calabrese J, McElroy S, et al. A randomized, placebocontrolled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry 2000;57(5):481-9.

26. Findling R, Gracious B, McNamara N, et al. Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disord 2001;3(4):202-10.

27. Davanzo P, Gunderson B, Belin T, et al. Mood stabilizers in hospitalized children with bipolar disorder: a retrospective review. Psychiatry Clin Neurosci 2003;57(5):504-10.

28. Pellock J. Carbamazepine side effects in children and adults. Epilepsia 1987;28(suppl 3):64-70.

29. Sobotka J, Alexander B, Cook B. A review of carbamazepine’s hematologic reactions and monitoring. DICP 1990;24(12):1214-19.

30. Hellewell J. Oxcarbazepine (Trileptal) in the treatment of bipolar disorders: a review of efficacy and tolerability. J Affect Disord 2002;72(supp 1):23-34.

31. Davanzo P, Nikore V, Yehya N, Stevenson L. Oxcarbazepine treatment of juvenile-onset bipolar disorder. J Child Adolesc Psychopharmacol 2004;14(3):344-5.

32. Teitelbaum M. Oxcarbazepine in bipolar disorder. J Am Acad Child Adolesc Psychiatry 2001;40(9):993-4.

33. Dietrich D, Kropp S, Emrich H. Oxcarbazepine in affective and schizoaffective disorders. Pharmacopsychiatry 2001;34(6):242-50.

34. Holtmann M, Krause M, Opp J, et al. Oxcarbazepine-induced hyponatremia and the regulation of serum sodium after replacing carbamazepine with oxcarbazepine in children. Neuropediatrics 2002;33(6):298-300.

35. Prescribing information for oxcarbazepine (Trileptal) Novartis Pharmaceuticals Corp. 2005. Available at: http://www.pharma.us. novartis.com/product/pi/pdf/trileptal.pdf. Accessed June 26, 2005.

36. Asconape J. Some common issues in the use of antiepileptic drugs. Semin Neurol 2002;22(1):27-39.

37. Fattore C, Cipolla G, Gatti G, et al. Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women. Epilepsia 1999;40(6):783-7.

38. Swope G, Hoopes S, Amy L, et al. An open-label study of lamotrigine in adolescents with bipolar mood disorder (poster presentation). New York: American Psychiatric Association annual meeting, 2004.

39. Saxena K, Howe M, Chang K. Lamotrigine adjunct or monotherapy for adolescent bipolar depression or mixed mania (poster presentation). Washington, DC: American Academy of Child and Adolescent Psychiatry annual meeting, 2004.

40. Prescribing information for lamotrigine (Lamictal). GlaxoSmith Kline 2004. Available at: http://us.gsk.com/products/assets/us_ lamictal.pdf. Accessed June 2, 2005.

41. Messenheimer J, Mullens E, Giorgi L, Young F. Safety review of adult clinical trial experience with lamotrigine. Drug Safety 1998;18(4):281-96.

42. DelBello M, Kowatch R, Warner J, et al. Adjunctive topiramate treatment for pediatric bipolar disorder: a retrospective chart review. J Child Adolesc Psychopharmacol 2002;12(4):323-30.

43. DelBello M, Kushner S, Wang D, et al. Topiramate for acute mania in children and adolescents with bipolar I disorder (abstract). New York: American Psychiatric Association annual meeting, 2004.

44. Philippi H, Boor R, Reitter B. Topiramate and metabolic acidosis in infants and toddlers. Epilepsia 2002;43(7):744-7.

45. Arcas J, Ferrer T, Roche M, et al. Hypohidrosis related to the administration of topiramate to children. Epilepsia 2001;42(10):1363-5.

46. Davanzo P, Cantwell E, Kleiner J, et al. Cognitive changes during topiramate therapy. J Am Acad Child Adolesc Psychiatry 2001;40(3):262-3.

47. McIntyre R, Mancini D, McCann S, et al. Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord 2002;4(3):207-13.

VALPROATE: OPEN-LABEL TRIALS ONLY

Efficacy. No double-blind, placebo-controlled study has shown valproate to be effective in treating bipolar disorder in children and adolescents. When used as monotherapy in open-label studies, valproate has produced response rates of:

53% in a 6-week, randomized, open-label trial in which 42 outpatients (mean age 11.4 years) with bipolar disorder type I or II received lithium, divalproex sodium, or carbamazepine⁹
61% in an open-label study of 40 patients ages 7 to 19 with a manic, hypomanic, or mixed episode who received divalproex for 2 to 8 weeks¹⁷
80% in an 8-week open-label trial of 40 patients ages 6 to 17 with bipolar disorder type I (77.5%) or type II (22.5%) and a Young Mania Rating Scale (YMRS)score ≥ 14.¹⁸

In a prospective trial, 90 patients ages 5 to 17 with bipolar disorder type I or II were treated with lithium plus divalproex sodium. After up to 20 weeks, 47% met criteria for depressive and manic symptom remission.¹⁹ A chart review has showed valproate’s efficacy in treating aggression and irritability in adolescent mania.²⁰

Safety: Black-box warnings. Valproate therapy carries risks of hepatic failure, pancreatitis, and birth defects. Monitor blood counts and hepatic enzymes throughout therapy (Table 3).³ Rare yet potentially fatal hepatic toxicity appears to occur most often in children age 21 Other studies suggest:

an association with congenital malformations, including spina bifida and pulmonary atresia, in children exposed to valproate in utero⁶
a link between valproate and hyperammonemic encephalopathy, especially in patients with urea cycle disorders²²
potential for benign thrombocytopenia²³
increased incidence of polycystic ovary syndrome—ovarian cysts, hyperandrogenism, chronic anovulation—in peripubertal mentally retarded women treated with valproate for seizure disorders.²⁴

Because of these risks, use caution when prescribing valproate to bipolar adolescent girls. Monitor menstrual cycle regularity, and collaborate with a gynecologist to watch for potentially dangerous effects.

Table 3

Mood stabilizers’ side effects and recommended monitoring

Medication	Major side effects	Monitoring
Carbamazepine	Allergic skin rash, drowsiness, blood dyscrasias, diplopia	CBC with reticulocytes, iron, LFTs, urinalysis, BUN, TFTs, sodium, serum carbamazepine levels
Lamotrigine	Stevens-Johnson syndrome, headache, dizziness, ataxia, somnolence, nausea, diplopia, blurred vision, rhinitis	No serum monitoring recommended
Lithium	Polyuria, polydipsia, nausea, diarrhea, tininecleatremor, enuresis, fatigue, ataxia, leukocytosis, malaise, cardiac arrhythmias, weight gain	BUN/creatinine, crearance, TFTs, calcium/phosphorus, ECG, serum lithium levels every 1 to 3 months once stabilized
Oxcarbazepine	Dizziness, somnolence/fatigue, ataxia/gait disturbance, vertigo, headache, tremor, rash, hyponatremia, hypersensitivity reaction, GI symptoms, diplopia	Sodium levels (particularly ifirst 3 months)
Topiramate	Hyperchloremic metabolic acidosis, oligohydrosis and hyperthermia, acute myopia, somnolence/fatigue, nausea, anorexia/weight loss, paresthesia, tremor, difficulty concentrating	BUN/creatinine, sodium bicarbonate
Valproate	Irritability/restlessness, ataxia, headache, weight gain, hyperammonemic encephalopathy, alopecia, GI upset, pancreatitis,sedation, thrombocytopenia, liver failure, polycystic ovaries/hyperandrogenism, teratogenic effects,rash	Ammonia, LFTs, bilirubin, CBC with platelets, serum valproate levels
BUN: blood urea nitrogen; CBC: complete blood count; ECG: electrocardiography; LFT: liver function tests; TFTs: thyroid function tests
Note: Bolded items included in black-box warnings
Source: Reference 3

Body weight. Valproate has been associated with weight gain. In a study of 372 bipolar adults, 21% reported a 5% weight-gain during 52 weeks of maintenance therapy, compared with 13% of patients on lithium and 7% on placebo.²⁵ Shortterm studies of adjunctive valproate in pediatric bipolar patients raise similar concerns.²⁶ Thus, monitor for weight gain and serum lipid changes in youths starting valproate therapy.

CARBAMAZEPINE: DRUG INTERACTION RISK

Carbamazepine is used less often than lithium or divalproex for bipolar disorder. It tends to be used adjunctively when lithium alone is ineffective.

Efficacy. In an open-label study,⁹ 42 patients ages 8 to 18 with bipolar disorder type I or II were randomly assigned to lithium, divalproex sodium, or carbamazepine monotherapy for 6 weeks. Response rates—measured as a ≥ 50% change from baseline in YMRS scores—were 53% with divalproex, 38% with lithium, and 38% with carbamazepine.

A retrospective review of 44 hospitalized bipolar patients ages 5 to 12 treated for at least 7 days with lithium, valproate, or carbamazepine reported higher (ie, worse) Clinical Global Impression of Improvement scores with carbamazepine.²⁷ Small sample sizes, particularly in the carbamazepine group, limited this naturalistic study.

Safety: Black-box warnings. Carbamazepine’s hematologic “black box” warns of increased risk of aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Risks associated with carbamazepine have been estimated at:

aplastic anemia: 5.1/million patient years
agranulocytosis: 1.4/million patient years.²⁸

Leukopenia is relatively more common and occurs in approximately 20% of children receiving carbamazepine.²⁹ Consider stopping carbamazepine when the white cell count falls below 3,000/mm³ (or the neutrophil count drops to 3).²⁹ Advise children and parents to watch for leukopenia’s signs and symptoms, including fever, infections, sore throat, and mouth ulcers.³

Body weight. Carbamazepine is not associated with significant weight gain, which could be clinically important for some patients.