Evidence-Based Reviews

Are anticonvulsants safe for pediatric bipolar disorder?

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

Elizabeth B. Weller, MD

Angelica L. Kloos, DO

Stacie Hitchcock, MD

Ronald A. Weller, MD

Using antiepileptic agents as mood stabilizers requires caution.

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References

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

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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.

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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.

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

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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.

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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.

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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.

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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.

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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.

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Are anticonvulsants safe and effective mood stabilizers for children and adolescents with bipolar disorder? The answer is unclear because most bipolar disorder treatment trials have included adults only, and clinicians are desperate for data.¹

To help you care for young patients, we report what is known about the potential benefits and risks of using mood stabilizers and anticonvulsants in bipolar youth. We base our dosing, target serum level, and monitoring recommendations on clinical experience and the limited published evidence.

AGENTS OF CHOICE?

Bipolar disorder’s “atypical” presentation in children—often more irritability and explosiveness than euphoria—can complicate diagnosis. Bipolar children and adolescents often have comorbid attention-deficit/hyperactivity disorder (ADHD), other disruptive behavior disorders, or anxiety disorders. Thus, comorbidities and presenting symptoms often dictate medication choice.

An expert consensus guideline acknowledges that more evidence on pediatric bipolar disorder is needed. In the meantime, the guideline suggests trying valproate or lithium first to treat nonpsychotic mania in pediatric bipolar patients.¹ It also recommends three atypical antipsychotics— olanzapine, quetiapine, and risperidone—as potential first-line treatments. Valproate and lithium may be preferred because of atypicals’ risk of weight gain and metabolic syndrome.

Trying other anticonvulsants may be justified for bipolar youths who are not functioning well with first-line agents. Lamotrigine, for example, has antidepressant and antimanic effects.² When you try anticonvulsants that lack double-blind, placebo-controlled trials, we recommend that you:

obtain consent from the parents and child
monitor carefully for side effects.

LITHIUM: STRONGEST EVIDENCE

Lithium is one of the most well-studied medications for pediatric bipolar disorder and the only mood stabilizer FDA-approved for children and adolescents (Table 1).³ Although approved for ages 12 and older, lithium has been used in younger children in practice and in clinical trials.

Table 1

FDA-approval status of medications used to treat bipolar disorder

Medication	Indications for adults	Indications for children
Carbamazepine	Acute manic episode and acute mixed episode	Not approved
Lamotrigine	Maintenance therapy	Not approved
Lithium	Acute manic episode and maintenance therapy	Age ≥ 12 years
Oxcarbazepine	Not approved	Not approved
Topiramate	Not approved	Not approved
Valproate	Acute manic episode	Not approved
Source: Reference 3

Efficacy. In an open-label study of 100 adolescents with type I bipolar disorder,⁴ 63% met response criteria after 4 weeks of lithium and 26% showed manic symptom remission. Symptoms worsened in both groups, however, when 40 responders were randomly assigned to continue or discontinue lithium for 2 weeks.⁵ The authors speculated that these conflicting results might indicate that mood stabilization requires longer treatment. Contrary to earlier reports,⁶ manic adolescents with comorbid ADHD did not show poor response to lithium.

In the only double-blind, placebo-controlled trial of lithium in adolescents with bipolar disorder, some subjects had secondary substance dependency disorders.⁷ For 6 weeks, 25 outpatient adolescents received lithium (13 patients) or placebo (12 patients). Lithium was effective in treating bipolar and substance dependency symptoms, with significantly improved clinical global assessment scores and decreased positive urine assays for drugs. Little difference was seen in mood item scores on the Schedule for Affective Disorders and Schizophrenia, child version (KSADS-1986), whether patients were taking lithium or placebo.

Pediatric dosing. For bipolar patients ages 6 to 12, use the child’s weight to determine lithium dosage (Table 2).⁸ Maintain serum levels between 0.8 and 1.2 mEq/L,⁹ and check them frequently when starting therapy.¹⁰ After mood stabilization, check levels every 1 to 3 months or when you suspect noncompliance. Obtain renal and thyroid function values at baseline and every 4 to 6 months.

Table 2

Guide to dosing lithium for prepubertal school-aged children*

	Doses (mg)
Child’s weight (kg)	8 AM	12 PM	6 PM	Total daily
	150	150	300	600
25 to 40	300	300	300	900
40 to 50	300	300	600	1,200
50 to 60	600	300	600	1,500
* Maintain specified dose at least 5 days, drawing serum levels 12 hrs after the last lithium dose until two consecutive levels appear in the therapeutic range (0.6 to 1.2 mEq/L). Dose may then be adjusted based on serum level, side effects, or clinical response. Do not exceed 1.4 mEq/L.
Source: Reference 8

Safety. Common side effects reported in adolescents include weight gain (55%), polydipsia (33%), polyuria (25%), headache (23%), tremor (20%), and GI complaints (up to 18%).⁴ Neurologic side effects are associated with higher serum lithium levels (0.91 to 1.36 mEq/L)¹⁰ and occur more often in younger than in older children.¹¹ The cardiac defect Ebstein’s anomaly occurs in approximately 0.05 to 0.1% of children exposed to lithium in utero (Box).^12-16

Box

Birth-defect risks to consider when prescribing mood stabilizers

Consider teratogenicity when choosing mood stabilizers for bipolar adolescent girls who may be sexually active. Lithium, valproate, and carbamazepine are labeled pregnancy category D because of their potential to cause birth defects.

Lithium treatment has been associated with increased risk of cardiac defects, specifically Ebstein’s anomaly (malformation of the tricuspid valve). Its incidence in children of women who used lithium during pregnancy is estimated to be 1:1,000 (0.10%) to 2:1,000 (0.05%)— 20 to 40 times the rate in the general population.¹²

Valproate.Results from the North American Antiepileptic Drug (AED) Pregnancy Registry showed a 10.7% rate of major congenital malformations (MCM)— including neural tube defects (spina bifida) and cardiac defects (pulmonary atresia)—in children of women who used valproate during pregnancy. The rate of births with MCMs in the general population is 2.9%.¹³

Carbamazepine.Data from the Australian Pregnancy Registry showed no significant increase in malformation rates in infants of carbamazepine users compared with those of women receiving no antiepileptics.¹⁴ Other studies, however, have linked carbamazepine with an increased risk of craniofacial defects (11%), neural tube defects (0.5 to 1%), and cardiac malformations.¹²

Lamotrigine.The teratogenic effects of the newer anticonvulsants are unclear. An 11-year study of lamotrigine¹⁵ found MCM risk after first-trimester exposure to lamotrigine to be similar to the general population’s MCM risk.

Combination therapy.Teratogenic risk appears to increase when multiple antiepileptic drugs are used (9.9% risk in polytherapy vs 6.2% in monotherapy).¹⁶