Long-Term Treatment of Bipolar Disorder in Children
Karen Dineen Wagner, MD, PhD
Department of Psychiatry, University of Texas Medical Branch, Galveston
An increasing amount of evidence indicates that bipolar disorder in children has a chronic course. Geller and colleagues1 conducted a prospective 8-year follow-up study of 115 children with first-episode bipolar I disorder; although recovery rates from mania were 88%, the relapse rate was 73%. Of the 54 youths who were young adults by the end of the 8-year follow-up, 44% had a manic episode in adulthood, which demonstrates continuity between childhood and adulthood bipolar disorder. Therefore, children with bipolar disorder are likely to need long-term treatment.
Efficacy of Medication Treatment
Four atypical antipsychotics and lithium have FDA approval for the treatment of bipolar I disorder, mixed or manic, in youths (AV 1AV 1) .2–6 Aripiprazole, quetiapine, and risperidone are approved for youths aged 10 to 17 years, and olanzapine is approved for ages 13 to 17 years. Efficacy of these medications as monotherapy was demonstrated in double-blind, placebo-controlled trials7–10 ranging in duration from 3 to 4 weeks. Another atypical antipsychotic, ziprasidone, also was significantly superior to placebo as monotherapy for pediatric mania in a 4-week, double-blind, placebo-controlled trial.11
To date, the anticonvulsants divalproex ER,12 oxcarbazepine,13 and topiramate14 have not been shown to be significantly superior to placebo in acute treatment studies for youths with bipolar I disorder, mixed or manic. However, divalproex demonstrated significant efficacy compared with placebo in 1 study.15
Limited information exists on the efficacy of treatments for bipolar I disorder, depressed, in youths. A controlled trial16 of quetiapine did not demonstrate superiority to placebo. However, open-label acute studies of lamotrigine17 and lithium18 showed a reduction in depressive symptoms.
Although efficacy of medication treatment has been shown in acute treatment studies, minimal controlled data about long-term medication treatment in youth with bipolar disorder are available. Kowatch and colleagues19 found that 58% of children with bipolar disorder who were treated with 1 medication over 8 weeks required treatment with an additional medication during the 16-week extension phase. The response rate to combination treatment with 2 mood stabilizers was 80% for youths who did not respond to initial mood stabilizer monotherapy. Thus, children with bipolar disorder will often require medication combination treatment over time.
FDA-approved adjunctive treatments for children ages 10 years and older with bipolar I disorder are aripiprazole2 and quetiapine4 added to lithium or valproate. Other combinations have been evaluated as well. In an open-label study,20 the combination of lithium and divalproex sodium was shown to significantly reduce symptoms of mania and depression in youth with bipolar disorder by 8 weeks (P < .0001). In another open-label study,21 risperidone in combination with lithium or divalproex sodium showed significant improvement in manic and depressive symptoms in pediatric bipolar disorder (P < .001).
Lamotrigine monotherapy was shown to be effective in maintaining manic and depressive symptom control for 6 weeks after the discontinuation of the concurrent atypical antipsychotic.22In a maintenance study23 of youths stabilized on combination lithium and divalproex sodium over 20 weeks, relapse occurred within approximately 4 months after discontinuation of either medication. Current guidelines recommend that clinicians consider tapering medication after sustained remission of at least 12 to 24 consecutive months.24
Adverse Event Monitoring
Because children with bipolar disorder will likely receive medication treatment for at least a few years, monitoring for potential adverse events is essential. Atypical antipsychotics have been shown to have cardiometabolic risks in youths treated over a time period as brief as 12 weeks.25 Correll26 suggested a monitoring schedule to assess for cardiometabolic and extrapyramidal symptoms for youths treated with atypical antipsychotics (AV 2AV 2). Additionally, a 12-item list of behaviors to promote healthy lifestyles and prevent and manage weight gain may be useful for youths who have been prescribed psychotropic medication.27 Monitoring for suicidality is also important, particularly given the FDA warning regarding an increased risk of suicidal thoughts and behavior with antiepileptic medications.28 Clinicians should be aware of potential risks of pancreatitis and polycystic ovarian syndrome with divalproex29 and hypothyroidism with lithium.6
Psychoeducational psychotherapy as adjunctive treatment to medication has been shown to improve outcomes for children with bipolar disorder.30 The main goals of this treatment are to provide information about the illness and medications, promote skill building, and facilitate social support. Adjunctive child- and family-focused CBT delivered in a group format demonstrated improvement in children’s manic symptoms and psychosocial functioning.31 Main components of this treatment include establishing a routine, regulating one’s affect, positive thinking, reframing thoughts, problem-solving, exhibiting positive social interaction, and finding social support. Interpersonal and social rhythm therapy as adjunctive treatment has also shown preliminary evidence of decreasing manic and depressive symptoms in adolescents with bipolar disorder.32 The main aims of this treatment are to reduce interpersonal stress, improve social rhythms and sleep/wake cycles, and increase medication compliance.
Support groups, such as the Child and Adolescent Bipolar Foundation (CABF), Depression and Bipolar Support Alliance (DBSA), and National Alliance on Mental Illness (NAMI) Child and Adolescent Action Center may be beneficial resources for youths with bipolar disorder and their parents in the long-term management of this illness.
For Clinical Use
- Be aware that children with bipolar disorder are likely to need long-term treatment
- For pediatric bipolar disorder, 4 atypical antipsychotics and 1 mood stabilizer are FDA-approved for mixed or manic episodes, and 2 atypical antipsychotics are approved for adjunctive treatment
- Vigilantly monitor children and adolescents for adverse events while they are taking psychotropic medications
- Consider using psychosocial interventions in addition to pharmacotherapy to help improve young patients’ symptomatic and functional outcomes
aripiprazole (Abilify), divalproex (Depakote and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), olanzapine (Zyprexa), oxcarbazepine (Trileptal and others), quetiapine (Seroquel), risperidone (Risperdal and others), topiramate (Topamax and others), valproate (Depacon and others), ziprasidone (Geodon)
AIMS = Abnormal Involuntary Movement Scale,BMI = body mass index, CBT = cognitive-behavioral therapy, EKG = electrocardiogram, EPS = extrapyramidal symptoms, ER = extended release, ESRS = Extrapyramidal Symptom Rating Scale, FDA = US Food and Drug Administration, SAS = Simpson Angus Rating Scale
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- Geller B, Tillman R, Bolhofner BS, et al. Child bipolar I disorder: prospective continuity with adult bipolar I disorder; characteristics of second and third episodes; predictors of 8-year outcome. Arch Gen Psychiatry. 2008;65(10):1125–1133.
- Abilify (aripiprazole) [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Company; November 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021436s027lbl.pdf. Accessed April 26, 2010.
- Zyprexa (olanzapine) [package insert]. Indianapolis, IN: Eli Lilly and Company; January 2010. http://pi.lilly.com/us/zyprexa-pi.pdf. Accessed April 26, 2010.
- Seroquel (quetiapine) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; November 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020639s045s046lbl.pdf. Accessed April 26, 2010.
- Risperdal (risperidone) [package insert]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc; June 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020272s056,020588s044,021346s033,
021444s03lbl.pdf. Accessed April 26, 2010.
- Lithobid (lithium carbonate) [package insert]. Miami, FL: Noven Therapeutics; April 2008. http://www.noven.com/Lithobid/LithobidPI.pdf. Accessed April 26, 2010.
- Findling RL, Nyilas M, Forbes RA, et al. Acute treatment of pediatric bipolar disorder, manic or mixed episode, with apripiprazole: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2009;70(10):1441–1451.
- Haas M, DelBello MP, Pandina G, et al. Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 2009;11(7):687–700.
- DelBello MP, Findling RL, Earley WR, et al. Efficacy of quetiapine in children and adolescents with bipolar mania: a 3-week, double blind, randomized, placebo-controlled trial. Poster presented at: 46th annual meeting of the American College of Neuropsychopharmacology; December 9–13, 2007; Boca Raton, FL.
- 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.
- DelBello MP, Findling RL, Wang RP, et al. Safety and efficacy of ziprasidone in pediatric bipolar disorder. Poster presented at the 63rd annual meeting of the Society of Biological Psychiatry; May 1–3, 2008; Washington, DC.
- Wagner KD, Redden L, Kowatch RA, et al. A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2009;48(5):519–532.
- Wagner KD, Kowatch RA, Emslie GJ, et al. A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents [published correction appears in Am J Psychiatry. 2006;163(10):1843]. Am J Psychiatry. 2006;163(7):1179–1186.
- DelBello MP, Findling RL, Kushner S, et al. A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(6):539–547.
- Kowatch RA, Findling RL, Scheffer RE, et al. Pediatric bipolar collaborative mood stabilizer trial. Poster presented at: 54th annual meeting of the American Academy of Child and Adolescent Psychiatry (AACAP); October 23–28, 2007; Boston, MA.
- DelBello MP, Chang K, Walge JA, et al. A double-blind, placebo-controlled pilot study of quetiapine for depressed adolescents with bipolar disorder. Bipolar Disord. 2009;11(5):483–493.
- Chang K, Saxena K, Howe M. An open-label study of lamotrigine adjunct or monotherapy for the treatment of adolescents with bipolar depression. J Am Acad Child Adolesc Psychiatry. 2006;45(3):298–304.
- Patel NC, DelBello MP, Bryan HS, et al. Open-label lithium for the treatment of adolescents with bipolar depression. J Am Acad Child Adolesc Psychiatry. 2006;45(3):289–297.
- Kowatch RA, Sethuraman G, Hume JH, et al. Combination pharmacotherapy in children and adolescents with bipolar disorder. Biol Psychiatry. 2003;53(11):978–984.
- Findling RL, McNamara NK, Gracious BL, et al. Combination lithium and divalproex sodium in pediatric bipolarity. J Am Acad Child Adolesc Psychiatry. 2003;42(8):895–901.
- Pavuluri MN, Henry DB, Carbray JA, et al. Open-label prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. J Affect Disord. 2004;82(suppl 1):S103–S111.
- Pavuluri MN, Henry DB, Mchammed T, et al. Effectiveness of lamotrigine in maintaining symptom control in pediatric bipolar disorder. J Child Adolesc Psychopharmacol. 2009;19(1):75–82.
- Findling RL, McNamara NK, Youngstrom EA, et al. Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(5):409–417.
- Kowatch RA, Fristad M, Birmaher B, et al, for the Child Psychiatric Workgroup on Bipolar Disorder. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(3):213–235.
- Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in primary care. World J Biol Psychiatry. 2007;8(2):67–104 http://www.wfsbp.org/treatment-guidelines/unipolar-depressive-disorder.html. Accessed March 3, 2010.
- 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.
- Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006;45(7):771–791.
- US Food and Drug Administration. FDA requires warnings about risks of suicidal thoughts and behavior for antiepileptic medications. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116991.htm. Published December 16, 2008. Accessed April 26, 2010.
- Depakote (divalproex sodium) [package insert]. North Chicago, IL: Abbott Laboratories; November 2009. http://www.rxabbott.com/pdf/depakote.pdf. Accessed April 26, 2010.
- Fristad MA, Verducci JS, Walters K, et al. Impact of multifamily psychoeducational psychotherapy in treating children aged 8 to 12 years with mood disorders. Arch Gen Psychiatry. 2009;66(9):1013–1021.
- West AE, Jacobs RH, Westerholm R, et al. Child and family-focused cognitive-behavioral therapy for pediatric bipolar disorder: pilot study of group treatment. J Can Acad Child Adolesc Psychiatry. 2009;18(3):239–246.
- Hlastala SA, Kotler JS, McClellan JM, et al. Interpersonal and social rhythm therapy for adolescents with bipolar disorder: treatment development and results from an open trial [published online ahead of print February 23, 2010]. Depress Anxiety. doi:10.1002/da.20668.