Evidence-Based Pharmacologic Treatment of Pediatric Bipolar Disorder

Robert L. Findling, MD, MBA

Pharmacotherapy is an important component of treatment for children and adolescents with bipolar disorder. The body of evidence supporting safe and effective treatments in this population is growing. Available data provide information on the risks and benefits of pharmacologic agents used for acute manic, mixed, and depressive episodes as well as for maintenance treatment. Lithium, anticonvulsants, and antipsychotics comprise the armamentarium for treating pediatric bipolar disorder. When selecting treatment, clinicians must consider the efficacy and side effect profile of potential pharmacotherapies, as well as the patient’s history, including the presence of comorbidities, in order to develop a treatment plan that will ensure optimal outcomes.

(J Clin Psychiatry 2016;77[suppl E1]:e02)

From the Department of Psychiatry, Johns Hopkins University and the Kennedy Krieger Institute, Baltimore, Maryland.

This article is derived from the planning teleconference series "Recognition and Treatment of Pediatric Bipolar Disorder," which was held in August and September 2015 and supported by an educational grant from Forest Laboratories, Inc.

In the last 12 months, Dr Findling has received research support from, acted as a consultant for, and/or served on a speaker’s bureau for Alcobra, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Bracket, Elsevier, Forest, Guilford Press, Ironshore, Johns Hopkins University Press, KemPharm, Lundbeck, Merck, the National Institutes of Health, Neurim, Otsuka, Oxford University Press, Pfizer, Purdue, Rhodes, Roche, SAGE, Shire, Sunovion, Supernus, Tris, Validus, and WebMD.

Corresponding author: Robert L. Findling, MD, MBA, The Johns Hopkins Hospital, Bloomberg Children’s Center, 1800 Orleans St, Ste 12-344A, Baltimore, MD 21287 (RFindli1@jhmi.edu).

dx.doi.org/10.4088/JCP.15017su1c.02

© Copyright 2016 Physicians Postgraduate Press, Inc.

Bipolar disorder is a chronic condition that typically requires lifelong treatment.1 The average age at onset is 18 years,2 but this disorder can emerge in children as young as preschool age.3 Compared with adults with bipolar disorder, children and adolescents with bipolar disorder experience more symptoms and more mood switches and have a poorer prognosis,4 and the experience of bipolar disorder can have a pronounced effect on these individuals’ cognitive, emotional, and social development.5 Effective treatment is needed to mitigate the deleterious effects of this disorder. Treatment for this age group should combine psychosocial and pharmacologic options. The focus of this article is pharmacologic treatment. Although much more evidence is available to guide the selection of pharmacologic treatments for adult patients, some data are available to inform treatment selection for pediatric patients. Treatments should be selected based on the patient’s current mood status and the risks and benefits of prospective pharmacotherapies.

ACUTE TREATMENT

Manic and Mixed States

The majority of clinical trials that have been conducted in pediatric bipolar disorder have investigated treatments for manic and mixed episodes.6 Mood stabilizers, anticonvulsants, and antipsychotics have all been investigated with varying results.

• Carefully evaluate risks and benefits when selecting pharmacotherapy for pediatric patients with bipolar disorder.
• Consider maintenance treatment for pediatric patients who have recovered from an acute bipolar mood episode in order to prevent or delay new mood episodes.
• Avoid antidepressant monotherapy.
• Consider comorbid conditions when treating pediatric patients with bipolar disorder.
• Employ evidence-based pharmacotherapy when considering medication selection and medication dosing.

Lithium. In adults, lithium is considered the benchmark treatment for acute mania and for prevention of bipolar manic and mixed states because of its well-established clinical evidence in this population.7 Lithium is approved by the US Food and Drug Administration (FDA) for the treatment of acute manic episodes in children over 12 years, but when this approval was granted, it was based largely on evidence from trials of lithium in adults.8 In 2008, the National Institute of Child Health and Human Development issued a contract for a series of studies to investigate the safety and efficacy of lithium for bipolar disorder in pediatric patients. In response, my colleagues and I conducted the Collaborative Lithium Trials (CoLT).7 As part of this work, we compared lithium with placebo in 81 pediatric patients aged 7 to 17 years experiencing manic or mixed episodes of bipolar I disorder.9 After 8 weeks, the patients receiving lithium showed significantly greater improvement in manic symptoms and overall clinical global impressions than those receiving placebo (P = .03 for both). Overall, we also found lithium to be well tolerated. The most common side effects were nausea and vomiting, but most adverse events were mild to moderate in severity, and no discontinuations due to intolerability occurred. Notably, significant improvement versus placebo occurred beginning at 6 weeks.

Anticonvulsants. Anticonvulsants are sometimes used to treat acute mania in pediatric patients, but evidence of these agents’ efficacy is weak.6 Divalproex sodium has been studied in several trials. Kowatch and colleagues compared divalproex sodium, lithium, and placebo in 153 children aged 7 to 17 years who were experiencing a manic or mixed episode.10 After 8 weeks of treatment, Kowatch and colleagues found that more patients improved with divalproex sodium treatment than with either lithium or placebo. However, a study by Wagner and colleagues11 failed to find that divalproex sodium was any more effective than placebo.

DelBello and colleagues12 undertook a double-blind, placebo-controlled study of topiramate for mania in pediatric patients, but the study was terminated before completion because studies of topiramate in adults had failed to show efficacy. Although these data cannot be considered conclusive due to the early termination of the study, the data that were generated appeared to indicate a trend toward efficacy.

Oxcarbazepine was investigated in a randomized controlled trial of 116 patients aged 7 to 18 years who were experiencing an acute manic or mixed episode.13 After 7 weeks of treatment, the patients receiving oxcarbazepine did not experience improvement that was significantly greater than that experienced by those receiving placebo.

Open-label studies of carbamazepine14-16 have found some evidence of efficacy for resolving manic or mixed episodes in pediatric bipolar disorder, but randomized controlled trials are needed.

Atypical antipsychotics. The atypical antipsychotics risperidone, olanzapine, quetiapine, aripiprazole, and asenapine all have indications from the FDA for treating manic or mixed states in pediatric bipolar disorder.6,17 These atypical antipsychotics have been investigated in pediatric bipolar disorder in numerous studies, and the results of many of these studies are strikingly similar (AV 1).18-22

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Haas and colleagues18 compared 2 doses of risperidone with placebo in 169 patients aged 10 to 17 years experiencing an acute manic or mixed episode. After 3 weeks, the patients receiving both doses of risperidone experienced significantly greater improvement than those receiving placebo (P < .001). The patients receiving the higher dose of risperidone (3-6 mg/d) did not show significantly greater improvement than those receiving the lower dose (0.5-2.5 mg/d). The patients receiving the higher dose did, however, have a higher rate of discontinuation due to adverse events, with the most common adverse events being somnolence, headache, and fatigue.

Tohen and colleagues19 compared olanzapine and placebo over 3 weeks of treatment in 161 patients aged 13 to 17 years who were experiencing an acute manic or mixed bipolar episode. At the conclusion of the study, the patients who had received olanzapine experienced significantly greater improvement than those receiving placebo as measured by the Young Mania Rating Scale (YMRS; P < .001). However, the olanzapine group reported more somnolence and sedation and greater increases in fasting glucose and cholesterol than the placebo group. Weight gain was also significantly greater in the olanzapine group (P < .001), with the olanzapine group gaining an average of 3.66 kg and the placebo group gaining an average of 0.30 kg.

My colleagues and I20 conducted a study in which we randomly assigned 296 patients aged 10 to 17 years who were experiencing an acute manic or mixed episode to receive placebo, 10 mg/d of aripiprazole, or 30 mg/d of aripiprazole. After 4 weeks of treatment, both aripiprazole groups experienced significantly greater improvement on the YMRS than the placebo group (P < .0001), and the improvement experienced by the group taking the higher dose of aripiprazole was not statistically greater than that experienced by those taking the lower dose. However, most side effects did occur with greater frequency in the 30 mg/d group, with the most common side effects being extrapyramidal symptoms, somnolence, fatigue, nausea, and headache. Weight gain was minimal and comparable between the placebo and active treatment groups. Although the 30 mg/d group gained slightly more weight than the 10 mg/d group (+1.08 kg vs +0.82 kg), this was not a statistically significant difference (P = .35).20

Pathak et al21 conducted a 3-week study comparing quetiapine with placebo in 277 patients aged 10 to 17 years who were experiencing an acute manic episode. The patients who were randomly assigned to the active treatment group received either 400 mg/d or 600 mg/d of quetiapine. At study completion, both quetiapine groups experienced significantly greater improvements in YMRS total score than those receiving placebo (P < .001 for both quetiapine groups). The most common adverse events in the quetiapine-treated group were somnolence, sedation, dizziness, and headache. Somnolence and sedation were slightly more frequent in the group receiving the higher quetiapine dose. Patients receiving either dose of quetiapine gained an average of 1.7 kg, whereas the placebo group gained an average of 0.4 kg.

My colleagues and I22 conducted a study comparing 3 doses of asenapine (2.5 mg bid, 5 mg bid, and 10 mg bid) with placebo in a group of 403 patients aged 10 to 17 years. After 3 weeks, all 3 asenapine groups experienced significantly greater improvement in YMRS scores than the placebo group (P = .0008 for the 2.5 mg bid group; P < .001 for the 5 and 10 mg bid groups). Compared with the placebo group, the asenapine groups more frequently experienced somnolence, sedation, oral hypoesthesia and paresthesia, and increased appetite. The asenapine groups also experienced significantly greater weight gain than the placebo groups (P < .05).

Although ziprasidone is not FDA-approved for pediatric bipolar disorder, my colleagues and I conducted a placebo-controlled study of this drug in 237 patients aged 10 to 17 years who were experiencing a manic or mixed episode.23 After 4 weeks of treatment, the ziprasidone group showed significantly greater improvement on the YMRS total score than those receiving placebo (P = .0005). The ziprasidone group also reported more side effects, with the most frequently reported being sedation, somnolence, headache, fatigue, and nausea, but no clinically significant weight gain was reported. Despite the positive findings of the study, the FDA did not approve an indication for pediatric bipolar disorder for ziprasidone because of deficiencies in the execution of study protocol. An independent audit concluded that the majority of the study data were reliable, so these results should be considered preliminary evidence of efficacy.23

Clozapine has been investigated for pediatric bipolar disorder in a small open-label trial. Clozapine showed significant efficacy (P < .001) in 10 adolescent patients who were experiencing a severe manic or mixed episode and who had not responded to treatment with first-line mood stabilizers and antipsychotics.24 These patients did, however, experience side effects including sedation, increased appetite, and weight gain, indicating that clozapine may have potential benefit in this population but should be reserved for patients who do not respond to first-line treatments.

Cross-class considerations. Some studies have compared different classes of medication for manic or mixed episodes in pediatric patients. Geller and colleagues25 compared risperidone, lithium, and divalproex sodium in the Treatment of Early Age Mania (TEAM) study. They found risperidone to be significantly more effective than lithium or divalproex sodium (P < .001), with the efficacy of lithium and divalproex sodium being comparable. The superior efficacy of risperidone, however, came at the cost of greater side effects, with risperidone being associated with significantly greater increases in weight, body mass index, and prolactin levels than either lithium or divalproex sodium (P < .001 for all measures). A meta-analysis of pharmacologic treatments conducted by Liu and colleagues6 came to a similar conclusion. Their analysis of data from 46 trials of antimanic agents in pediatric bipolar disorder revealed that atypical antipsychotics were more effective than traditional mood stabilizers and anticonvulsants but also carried a greater burden of side effects such as weight gain and other metabolic changes (AV 2).6,12,21,22,25,26 Thus, when clinicians are selecting pharmacologic agents for manic or mixed episodes in pediatric patients, the risks and benefits of potential treatments must be carefully assessed.

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Depressive Episodes

As with adult patients, pediatric patients experiencing an acute episode of bipolar depression must be treated with caution in order to prevent a switch into a manic or mixed episode. The only drug with FDA approval for treating bipolar depression in pediatric populations is olanzapine/fluoxetine combination (OFC). Detke and colleagues26 compared OFC with placebo in 255 patients aged 10 to 17 years who were experiencing an acute episode of bipolar depression. After 8 weeks, the patients receiving OFC had a significantly greater reduction in depressive symptoms than those receiving placebo (P = .003). The OFC group also reported significantly more side effects than the placebo group, including increased appetite, somnolence, tremor, sedation, weight gain, fasting total cholesterol, and increased heart rate (P < .05 for each side effect).

Other agents have also been investigated as treatments for pediatric bipolar depression. In a randomized, controlled trial,27 pediatric patients receiving quetiapine did report improvement in depressive symptoms, but their improvement was not significantly greater than that experienced by the patients receiving placebo. Small, open-label trials of lithium28 and lamotrigine29 in adolescents have reported that these agents may be well tolerated and effective for reducing bipolar depression, but larger, placebo-controlled trials are needed. It is generally recommended that antidepressant monotherapy should be avoided because it may lead to manic switch.30

MAINTENANCE TREATMENT

Because bipolar disorder is a chronic condition, effective maintenance treatment is imperative. Patients who discontinue acute treatment are at an increased risk of relapse.31 Only a few studies have evaluated the safety and efficacy of long-term use of bipolar treatments in pediatric populations.32 My colleagues and I33 compared the efficacy of lithium and divalproex as maintenance treatments. Our study population consisted of 60 patients aged 5 to 17 years who had been stabilized with a combination of lithium and divalproex. Patients were randomly assigned to receive maintenance treatment with either lithium or divalproex for up to 76 weeks, and, at the conclusion of the study, we found that these drugs had comparable efficacy. The median time until mood relapse was 112 days for patients taking divalproex and 114 days for those taking lithium.

My colleagues and I also conducted a study of the safety and efficacy of aripiprazole as a maintenance treatment.34 We randomly assigned 210 patients aged 10 to 17 years to receive 10 mg/d of aripiprazole, 30 mg/d of aripiprazole, or placebo. After 26 weeks, the patients taking either dose of aripiprazole showed significantly greater improvement in YMRS scores than those taking placebo (P < .001). Discontinuation rates for all study arms were high. Only about one third of the patients enrolled completed the study; however, more aripiprazole-treated participants continued the study than placebo-treated children. The most common adverse events were headache, somnolence, and extrapyramidal symptoms. No significant changes in metabolic parameters were observed between the active treatment and placebo groups, but both aripiprazole groups did experience significantly greater weight gain (P < .05). We conducted a maintenance discontinuation study35 in 60 patients aged 4 to 9 years. Our team focused on this population because patients under the age of 10 years are generally considered to be more vulnerable to side effects, and, therefore, the putative risks of ongoing treatment may outweigh the potential benefits. We found a significantly greater length of time until discontinuation for any reason in the aripiprazole group (P = .003) than in the placebo group, and no patients discontinued treatment due to adverse events.

My colleagues and I also investigated lamotrigine as an adjunctive maintenance treatment in pediatric bipolar disorder.36 We randomly assigned 173 patients aged 10 to 17 years to receive add-on lamotrigine or placebo for up to 36 weeks. The study failed to find a significant difference in efficacy between lamotrigine and placebo as measured by time to occurrence of a bipolar event among the overall sample. However, lamotrigine did appear to delay the time to the recurrence of a mood episode in older patients (aged 13 to 17 years). Dermatologic and suicidality-related adverse events were reported among those taking lamotrigine.

TREATMENT FOR PATIENTS WITH COMORBIDITIES

Children with bipolar disorder typically have at least one comorbid psychiatric disorder, with attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorders, substance use disorders, and anxiety disorders being the most common.37 The presence of these comorbidities can affect the course of bipolar disorder. Yen and colleagues38 found that pediatric patients with bipolar disorder and greater severity of any of these comorbid conditions experienced shorter times to recurrence of mood episodes than bipolar patients with less severe comorbidities, and worsening of comorbid conditions may precipitate a new episode or prolong recovery from a mood episode. Comorbidities should, therefore, be considered when making treatment decisions, but comorbid ADHD and substance use are the only conditions for which data from controlled trials are available. In a small study of adolescents, Geller and colleagues39 found that lithium was an effective treatment for both bipolar disorder and comorbid substance use. Other small studies in children and adolescents with bipolar disorder have found stimulants to be safe and effective adjunctive treatments for comorbid ADHD when added to lithium and/or divalproex.40,41

CONCLUSIONS

Pediatric bipolar disorder is a chronic illness, and only in recent years have data with methodological rigor become available regarding the safety and efficacy of treatments in this population. This information provides important guidance for medication selection and dosing, particularly when treating manic and mixed episodes. Clinicians should use this evidence to carefully assess risks and benefits when selecting pharmacotherapy and provide close monitoring for adverse events and symptom recurrence. By including judicious pharmacotherapy as part of a comprehensive treatment plan, clinicians can help mitigate the symptoms of their pediatric patients with bipolar disorder. By doing so, clinicians may help these vulnerable youths enter adulthood as healthy and productive individuals.

Drug names: aripiprazole (Abilify and others), asenapine (Saphris), carbamazepine (Carbatrol, Tegretol, and others), divalproex sodium (Depakote and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), olanzapine (Zyprexa and others), olanzapine/fluoxetine combination (Symbyax and others), oxcarbazepine (Trileptal and others), quetiapine (Seroquel and others), risperidone (Risperdal and others), topiramate (Topamax and others), ziprasidone (Geodon and others)

Disclosure of off-label usage: Dr Findling has determined that carbamazepine, divalproex sodium, lamotrigine, oxcarbazepine, topiramate, and ziprasidone are not approved by the US Food and Drug Administration for the treatment of pediatric bipolar disorder.

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23. Findling RL, Cavuş I, Pappadopulos E, et al. Efficacy, long-term safety, and tolerability of ziprasidone in children and adolescents with bipolar disorder. J Child Adolesc Psychopharmacol. 2013;23(8):545-557. PubMed doi:10.1089/cap.2012.0029

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40. Scheffer RE, Kowatch RA, Carmody T, et al. 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. PubMed doi:10.1176/appi.ajp.162.1.58

41. Findling RL, Short EJ, McNamara NK, et al. Methylphenidate in the treatment of children and adolescents with bipolar disorder and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1445-1453. PubMed doi:10.1097/chi.0b013e31814b8d3b