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.

Drug interactions. Carbamazepine activates the cytochrome P-450 liver enzyme system, increasing the metabolism of many medications and decreasing their blood levels. Consider monitoring serum levels when using carbamazepine with valproate, imipramine, corticosteroids, warfarin, oral contraceptives, and some antibiotics. Because carbamazepine induces its own metabolism, you might need to increase its dosage if its effects appear to be waning.³

Carbamazepine and tricyclic antidepressants may show cross-sensitivity because of structural similarity. Do not use monoamine oxidase inhibitors with carbamazepine; discontinue them at least 14 days before starting carbamazepine.³

OXCARBAZEPINE: FEWER INTERACTIONS

Oxcarbazepine has similar efficacy to carbamazepine but less side effect risk and does not require plasma level monitoring. A weaker inducer of CYP-450, it causes fewer clinically important drug-drug interactions and may be useful for patients who respond to carbamazepine but cannot tolerate its side effects.³⁰

Efficacy. Case studies^31,32 have been encouraging, but no published, double-blind, placebo-controlled studies support using oxcarbazepine in bipolar children and adolescents.

Safety. Oxcarbazepine appears to be generally well-tolerated but can cause potentially serious reactions—including hyponatremia.³³ Somnolence, emesis, and ataxia are the most common side effects in pediatric patients.³

Hyponatremia —plasma sodium 125 mEq/L—occurs in 2.5% of adults taking oxcarbazepine³ and has been reported in a similar percentage of children.³⁴ This potentially severe reaction—characterized by nausea, lethargy, malaise, headache, confusion, decreased seizure threshold, or simply decreased serum sodium³⁵—is usually noted within the first 12 weeks of therapy. The risk increases with concomitant use of other sodium-altering drugs, such as antidepressants or antipsychotics.³⁶

Evaluate serum sodium when starting oxcarbazepine, periodically in the first 3 months, and if symptoms occur.^34,36 For sodium levels of 125 to 130 mEq/L, obtain repeat measurements to confirm that hyponatremia is not worsening. Intervention is often required when levels fall below 125 mEq/L.³⁶

Other serious adverse reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions; 25% to 30% of patients with hypersensitivity to carbamazepine also will react to oxcarbazepine.³³

Contraceptive concerns. Oxcarbazepine may reduce contraceptive efficacy by altering estrogen and progesterone plasma concentrations.³⁷ Consider other birth control methods for sexuallyactive bipolar adolescent girls.

LAMOTRIGINE

Neurologists often use lamotrigine for children with atypical seizure disorders, but no controlled data exist on the drug’s efficacy and safety in youths with bipolar disorder.

Efficacy. In a prospective, open-label study,³⁸ 13 adolescents with type I bipolar disorder received lamotrigine, 200 to 400 mg/d. After 12 weeks (mean dosage 241 mg/d), their symptoms had improved as shown by these mean scores:

Montgomery-Asberg Depression Rating Scale: from 21 at baseline to 4 at endpoint
Clinical Global Impressions–Severity of Illness scale: from 4 to 1
Children’s Depression Rating Scale (CDRS-R): from 74 to 40
YMRS: from 20 to 6.

In another open-label study,³⁹ 16 of 18 youths (88%) with bipolar depression or mixed mania improved with lamotrigine alone or as adjunctive therapy, as shown by Clinical Global Impression of Change scores. CDRS-R scores also decreased by ≥50% in 11 of 17 who finished the study.

Safety: Severe rash. An age-related association with Stevens-Johnson syndrome may limit pediatric use of lamotrigine. Severe and potentially life-threatening rashes have been reported in 0.8% of children treated with lamotrigine.⁴⁰ Discontinue lamotrigine if a rash develops, unless it clearly is not drug-related. Three factors that increase rash risk include:

co-administering lamotrigine with valproate
higher-than-recommended initial dosages
rapid dose titration.⁴¹

Most rashes appear in the first 8 weeks,⁴¹ though cases can occur after prolonged treatment.

Pediatric dosing. We find no published studies of efficacious dosages and plasma levels of lamotrigine in pediatric bipolar disorder (Table 4).^3,9,17 Based on our clinical experience, we recommend starting lamotrigine at 1 to 5 mg/kg/day (1 to 3 mg/kg/day if given with valproate) divided into two daily doses. Watch for rash or skin disorders. Do not exceed the recommended daily dosage by 200 mg in children age

Table 4

Using anticonvulsants in pediatric bipolar disorder patients

Drug	Recommended dosage	Target serum level
Carbamazepine	Age 6 to 12: 20 to 30 mg/kg/d	≥ 7.0 μg/L
Carbamazepine	Age >12: 400 to 1,200 mg/d	≥ 7.0 μg/L
Lamotrigine*	Unknown	Unknown
Oxcarbazepine	11 to 16 mg/kg/d (as adjunct)	Unknown
Topiramate*	Unknown	Unknown
Valproate	15 to 20 mg/kg/d	45 to 125 μg/mL (trough)
Valproate	15 to 20 mg/kg/d	85 to 110 μg/mL (target)
* No published studies found for efficacious dosage and plasma levels in pediatric bipolar disorder.
Dosage supported by case reports only; no studies found examining efficacious plasma levels.
Source: References 3,9, and 17.

TOPIRAMATE: LIMITED INFORMATION

Efficacy. Little is known about using topiramate in children and adolescents. A retrospective chart review⁴² of 26 patients with bipolar disorder type I (n=23) or II (n=3) showed adjunctive topiramate to be effective, with response rates of 73% for mania and 62% overall. Topiramate was well tolerated, and no serious events were reported.