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Treatment Options for Children and Adolescents With Bipolar Disorder

Robert L. Findling, MD

Departments of Psychiatry and Pediatrics, Case Western Reserve University, Cleveland, Ohio

Approximately half of adult patients with bipolar disorder experience illness onset during childhood or adolescence,1 and the diagnosis of pediatric bipolar disorder has become increasingly common in recent years.2 Although more data are available about treatment of adults with bipolar disorder than about treatment of young patients, treatment guidelines reached through expert consensus have been proposed to assist in the early diagnosis and effective management of the disorder in children and adolescents.3,4 While recognizing that psychotherapy and psychosocial interventions that focus on academic, social, and family functioning are vital components of treatment for children and adolescents with bipolar disorder, these guidelines focus on evidence-based pharmacotherapy as the primary acute phase treatment.3,4 Medications that have been studied for efficacy in treating children and adolescents with bipolar disorder include lithium, anticonvulsants, and atypical antipsychotics.

Evidence-Based Pharmacotherapies

 

Mood stabilizers. The Pediatric Bipolar Collaborative Mood Stabilizer Trial5 randomly assigned subjects between the ages of 7 and 17 years to receive lithium, divalproex, or placebo for the treatment of acute manic or mixed episodes. Preliminary results showed that, at the end of the 8–week acute period of the 24–week trial, divalproex demonstrated significant efficacy versus placebo on both primary outcome measures (weekly YMRS, P < .01, and CGI–I ratings, P < .05), while lithium trended toward efficacy but did not significantly separate from placebo on either measure (AV 1AV 1). However, a placebo–controlled study6 of patients aged 10 to 17 years did not show divalproex ER to be superior to placebo in the treatment of mania.

Other anticonvulsants. A double-blind placebo-controlled trial7 of topiramate for mania in children and adolescents was terminated early when studies in adults failed to show efficacy for the drug for treating mania. Although the results were inconclusive, preliminary data indicated that topiramate might play a role in treatment for children and adolescents with mania.

Oxcarbazepine was studied in outpatients 7 to 18 years of age in a double-blind, randomized, placebo-controlled study.8 Based on the primary efficacy measure of mean change in YMRS scores from baseline to endpoint, oxcarbazepine was not superior to placebo in treating bipolar disorder in youths.

Atypical antipsychotics. Several 3–week placebo–controlled trials of atypical antipsychotics have been conducted in young patients with manic or mixed episodes, using change in YMRS scores as the primary outcome measure. In one trial,9 adolescents aged 13 to 17 years with manic or mixed episodes who received olanzapine had significantly greater changes in baseline-to-endpoint YMRS scores than those who received placebo (P < .007).

A 3-armed study10 compared outcomes for patients aged 10 to 17 years who received 0.5 to 2.5 mg/d of risperidone, 3.0 to 6.0 mg/d of risperidone, or placebo for mania. Improvement in YMRS total scores was significantly greater in patients in both risperidone arms of the study than among those who took placebo (P < .007).

 

In a study11 of quetiapine for treatment of mania, patients 10 to 17 years of age were randomly assigned to placebo or to quetiapine, either 400 mg/d or 600 mg/d. Patients in both quetiapine groups experienced significant improvement in YMRS scores from baseline to endpoint compared with the placebo group (P < .007; AV 2AV 2).

A placebo–controlled study12 of quetiapine as an adjunct to divalproex for adolescent mania showed a significantly greater reduction in YMRS scores from baseline to endpoint for the active combination compared with divalproex plus placebo (P = .03). However, a double–blind placebo–controlled study13 of quetiapine for pediatric bipolar depression did not show quetiapine to be superior to placebo in reducing symptoms.

More

 

Two double-blind, multicenter, placebo controlled 4-week trials14,15 of atypical antipsychotics have been conducted in young patients (age 10 to 17 years) with bipolar I disorder manic or mixed episodes. In one trial,14 subjects were randomly assigned to receive placebo or flexible doses of ziprasidone (titrated over 1 to 2 weeks to between 80 mg/d and 160 mg/d). Patients treated with ziprasidone experienced a significantly greater mean change from baseline to endpoint in YMRS scores compared with the patients treated with placebo (P = .0005). In the other trial,15 patients were randomly assigned to receive placebo or a fixed dose of aripiprazole (after a titration period) of either 10 mg/d or 30 mg/d. Patients who received either dose of aripiprazole experienced a significantly greater mean change in YMRS scores compared with patients receiving placebo (P <  .0001; AV 3AV 3).

Other agents. Although placebo-controlled data are lacking, findings from an open-label trial16 and a case study17 suggest potential benefit of carbamazepine in juvenile-onset bipolar disorder. Preliminary findings also suggest that clozapine18 might be helpful for young patients with treatment-resistant manic or mixed episodes, and an open-label study19 found lamotrigine to be effective for bipolar depression in adolescents when used either as an adjunctive treatment or as monotherapy.

Future Directions

Although the body of studies on the treatment of acute mania in children and adolescents is growing, more research is needed across the bipolar spectrum, especially regarding depressive episodes and putatively more modest expressions of bipolarity (such as cyclothymia or bipolar disorder not otherwise specified). Additionally, more information is needed on treating the multiple comorbidities common in children and adolescents with bipolar disorder. Studies are also needed to determine how to address the needs of children and adolescents who have a parent with bipolar disorder and are demonstrating early symptoms of a mood disorder (called "cyclotaxia").20 Head-to-head comparative studies are needed to determine which agents may be the most effective in certain populations and to determine the long-term safety profiles of these medications in children and adolescents. Methodologically stringent studies of combination therapies—either combinations of pharmacologic agents or medicine plus psychotherapy—are also needed for young patients who do not achieve full symptom amelioration with monotherapy.

For Clinical Use

  • Placebo-controlled studies with mood stabilizers and atypical antipsychotics have shown efficacy for treating acute manic and mixed episodes in children and adolescents
  • Case reports and open-label trials indicate efficacy for some medications for pediatric bipolar depression and treatment-resistant manic or mixed episodes, but placebo-controlled studies are needed
  • Additional comparative and safety and tolerability studies are needed for medications prescribed to treat pediatric bipolar disorder

Drug Names

aripiprazole (Abilify), carbamazepine (Carbatrol, Equetro, and others), clozapine (FazaClo, Clozaril, and others), divalproex (Depakote and Depakote ER), lamotrigine (Lamictal and others), lithium (Eskalith, Lithobid, and others), olanzapine (Zyprexa), oxcarbazepine (Trileptal and others), quetiapine (Seroquel), risperidone (Risperdal and others), topiramate (Topamax and others), ziprasidone (Geodon)

Abbreviations

CGI-I=Clinical Global Impression–Improvement scale
ER=extended release
LOCF=last observation carried forward
YMRS=Young Mania Rating Scale

Take the online posttest.

References

  1. Leverich GS, Post RM, Keck PE Jr, et al. The poor prognosis of childhood-onset bipolar disorder. J Pediatr. 2007;150(5):485–490.
  2. Moreno C, Laje G, Blanco C, et al. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032–1039.
  3. McClellan J, Kowatch R, Findling RL, et al. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(1):107–125.
  4. Kowatch RA, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(3):213–235.
  5. Kowatch RA, Findling RL, Scheffer RE, et al. Pediatric Bipolar Collaborative Mood Stabilizer Trial [poster]. Presented at the 54th annual meeting of the American Academy of Child and Adolescent Psychiatry (AACAP); October 23–28, 2007; Boston, MA.
  6. 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.
  7. 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.
  8. 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. Am J Psychiatry. 2006;163(7):1179–1186. Correction 2006;163(10):1843.
  9. 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.
  10. Pandina G, DelBello MP, Kushner S, et al. Risperidone for the treatment of acute mania in bipolar youth [poster]. Presented at the 54th annual meeting of the American Academy of Child and Adolescent Psychiatry (AACAP); October 23–28 2007; Boston, MA.
  11. 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 the 46th annual meeting of the American College of Neuropsychopharmacology (ACNP); December 9–13, 2007; Boca Raton, FL.
  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. DelBello MP, Chang K, Howe ME, et al. A double-blind placebo-controlled study of quetiapine for youth with depression associated with bipolar disorder [poster]. Presented at the 55th annual meeting of the American Academy of Child & Adolescent Psychiatry (AACAP); October 28–November 2, 2008; Chicago, IL.
  14. 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.
  15. Chang KD, Nyilas M, Aurang C, et al. Efficacy of aripiprazole in children (10–17 years old) with mania [poster]. Presented at the 54th annual meeting of the American Academy of Child and Adolescent Psychiatry (AACAP); October 23–28, 2007; Boston, MA.
  16. Kowatch RA, Suppes T, Carmody TJ, 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):713–720.
  17. Woolston JL. Case study: carbamazepine treatment of juvenile-onset bipolar disorder. J Am Acad Child Adolesc Psychiatry. 1999;38(3):335–338.
  18. Masi G, Mucci M, Millepiedi S. Clozapine in adolescent inpatients with acute mania. J Child Adolesc Psychopharmacol. 2002;12(2):93–99.
  19. 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.
  20. Findling RL, Youngstrom EA, McNamara NK, et al. Early symptoms of mania and the role of parental risk. Bipolar Disord. 2005;7(6):623–634.