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Safety and Tolerability of Bipolar Disorder Treatment in Youth

Robert L. Findling, MD

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

The diagnosis of bipolar disorder in children and adolescents has increased substantially in recent years, and approximately 90% of youths diagnosed with this disorder receive 1 or more psychotropic medications.1 While most studies of mood stabilizers, anticonvulsants, and atypical antipsychotics have been conducted among adults with bipolar disorder, youths are prescribed these medications in about the same proportions as adults.1 Although more controlled trials on pharmacotherapy for bipolar disorder in children and adolescents are needed, recent studies have provided evidence of efficacy and additional information on the safety and tolerability of some of these medications. When prescribing these medications to young patients, baseline screening measures should be obtained and follow-up monitoring for adverse effects should be conducted on a regular basis. Clinicians should work with patients and their families when considering the risk versus benefit of individual treatments; view this brief video to see an example of this scenario (AV 1AV 1). For more information on the efficacy of these agents see “Treatment Options for Children and Adolescents With Bipolar Disorder.”

Mood Stabilizers and Anticonvulsants

A review2 of recent studies has shown lithium to be generally well tolerated in children and adolescents, with the most common side effects reported being polyuria, GI symptoms, headache, tremors, and dizziness. Because lithium has the potential to cause thyroid and renal dysfunction and can be toxic in overdose, blood monitoring is required. Studies are currently underway that will provide evidence-based data on dosing strategies and on the acute as well as long-term efficacy and safety of lithium in treating pediatric bipolar disorder.3

Open-label trials4,5 suggest that divalproex is reasonably well tolerated in children and adolescents for the treatment of acute mixed and manic states, although additional controlled studies are needed. The most common side effects reported were headache and GI effects.

Preliminary data on topiramate from a pilot controlled trial6 for mania in children and adolescents found that nausea and decreased appetite, diarrhea, and paresthesia were the most commonly reported side effects. Carbamazepine for mania in pediatric patients appeared well tolerated in an open-label clinical trial,7 with the most commonly reported side effects being nausea, sedation, rash, and dizziness. An open study8 of lamotrigine for adolescents with bipolar depression found that the most common side effects were headache, fatigue, and nausea, and no one reported a serious rash (N = 20). Randomized, placebo-controlled trials are needed to provide more information on the tolerability and safety of these medications for children and adolescents.

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Atypical Antipsychotics

Placebo-controlled trials of aripiprazole,9 risperidone,10 olanzapine,11 quetiapine,12 and ziprasidone13 have reported adverse effects in children and adolescents. Somnolence is one of the most common side effects across the class of atypical antipsychotics; however, side effect profiles do differ within the class (AV 2AV 2).14 Additionally, children and adolescents appear to be at higher risk than adults for experiencing side effects, such as sedation, weight gain, metabolic effects, prolactin elevation, and EPS.14

Aripiprazole. A study9 compared outcomes of children and adolescents receiving 10 mg/d of aripiprazole, 30 mg/d of aripiprazole, or placebo. Somnolence was a common side effect, followed by EPS, fatigue, and nausea, with a larger percentage of patients experiencing somnolence, EPS, and nausea with the higher dose of aripiprazole. Weight gain for patients treated with aripiprazole was not significantly different from patients treated with placebo.14

Risperidone. A 3-armed study10 compared side effects in youth who received 0.5 to 2.5 mg/d of risperidone, 3 to 6 mg/d of risperidone, or placebo for mania. The most common adverse events were somnolence, headache, fatigue, and abdominal pain. Both risperidone arms were similar in efficacy, but a higher percentage of patients in the group receiving the larger dose of medication experienced somnolence (see AV 2AV 2) and agitation.

Olanzapine. In a 3-week placebo-controlled trial11 of olanzapine in adolescents, the most frequently reported adverse events were increased appetite, weight gain, and somnolence. During this brief study, treatment-emergent weight gain (≥ 7% of baseline) was significantly greater for the olanzapine group than the placebo group (P < .001;
AV 3AV 3). Significantly greater increases from baseline to endpoint also occurred with olanzapine for fasting glucose (P = .002) and cholesterol (P = .010), and a significantly greater incidence of treatment-emergent abnormally high levels of prolactin occurred for both girls (P = .007) and boys (P < .001).

Quetiapine. Another 3-armed study12 compared results in young patients receiving 400 mg/d of quetiapine, 600 mg/d of quetiapine, or placebo for mania. The most frequent side effects reported in this study were somnolence, dizziness, and headache. Both groups receiving an active dose had similar rates of adverse side effects.

Ziprasidone. The most common side effects reported in a pediatric study13 of ziprasidone (flexible dose, 80–160 mg/d) were somnolence, fatigue, and nausea. Ziprasidone has also been associated with possible prolongation of the QTc interval; in this study, 1 patient (0.7% rate) experienced a peak QTc duration of ≥ 460 milliseconds.

Combination Therapy

A 6-week study15 compared divalproex plus quetiapine and divalproex plus placebo in the treatment of adolescents with acute mania (N = 30). The therapy was well tolerated, although 80% of the patients receiving the active combination treatment reported mild-to-moderate sedation, as opposed to 33% of the patients receiving divalproex alone.

A review2 of open-label trials indicated that combination therapies (including lithium plus divalproex, lithium plus an atypical antipsychotic, or divalproex plus an atypical antipsychotic) may be reasonably well tolerated. Controlled studies are needed to determine the comparative safety and efficacy of combination therapies.

For Clinical Use

Recent studies have provided additional information on the safety and tolerability profiles of psychotropic agents for children and adolescents, but more comparative and controlled studies are needed. Studies have shown that, although mood stabilizers, anticonvulsants, and atypical antipsychotics are oftentimes well tolerated in children and adolescents, clinicians should:

  • Monitor their patients for adverse effects, especially for metabolic disturbances, somnolence, GI effects, and sometimes significant weight gain
  • Tailor treatment decisions based on individual patient needs because side effect profiles differ among psychotropic agents

Drug Names

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

Abbreviations

EPS = extrapyramidal symptoms
GI = gastrointestinal
LOCF = last observation carried forward

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References

  1. 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.
  2. Smarty S, Findling RL. Psychopharmacology of pediatric bipolar disorder: a review. Psychopharmacology (Berl). 2007;191(1):39–54.
  3. Findling RL, Frazier JA, Kafantaris V, et al. The Collaborative Lithium Trials (CoLT): specific aims, methods, and implementation. Child Adolesc Psychiatry Ment Health. 2008;2(1):21.
  4. 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.
  5. Redden L, DelBello M, Wagner KD, et al. Long-term safety of divalproex sodium extended-release in children and adolescents with bipolar 1 disorder. J Child Adolesc Psychopharmacol. 2009;10(1):83–89.
  6. 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.
  7. 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.
  8. 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.
  9. Correll CU, Nyilas M, Aurang C, et al. Safety and tolerability of aripiprazole in children (10–17) 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.
  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. 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.
  12. 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; December 9–13, 2007; Boca Raton, FL.
  13. 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.
  14. Correll CU. Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents. J Clin Psychiatry. 2008;69(suppl 4):26–36.
  15. 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.