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Evidence-Based Reviews

Clinical trials support new algorithm for treating pediatric bipolar mania

4 atypical antipsychotics are proposed as first-line therapy, based on current evidence

Vol. 8, No. 11 / November 2009

Discuss this article

Five recent randomized controlled trials (RCTs) have demonstrated the efficacy of atypical antipsychotics for treating bipolar disorder in children and adolescents, but 4 of these 5 trials remain unpublished. The lag time between the completion of these trials and publication of their results—typically 4 to 5 years1—leaves psychiatrists without important evidence to explain to families and critics2 why they might recommend using these powerful medications in children with mental illness.

This article previews the preliminary results of these 5 RCTs of atypical antipsychotics, offers a treatment algorithm supported by this evidence, and discusses how to manage potentially serious risks when using antipsychotics to treat children and adolescents with bipolar disorder (BPD).

Where do atypical antipsychotics fit in?

Details of the 5 industry-sponsored RCTs of atypical antipsychotics in children and adolescents with bipolar I manic or mixed episodes are summarized in Table 1.3-7 Only the olanzapine study4 has been published; data from the other 4 trials were presented at medical meetings in 2007 and 2008.

Change in Young Mania Rating Scale (YMRS) score was the primary outcome measure in these 5 trials, and each compound was more effective than placebo. The trials demonstrated statistically significant and clinically relevant differences between each antipsychotic and placebo. The number needed to treat (NNT)—how many patients need to be treated for 1 to benefit in a controlled clinical trial—ranged from 2 to 4. For comparison, the NNT for statins in the prevention of coronary events is 12 to 22,8 and the NNT in an analysis of trials of selective serotonin reuptake inhibitors for pediatric major depressive disorder was 9.9 Thus, an NNT of ≤4 represents a clinically significant effect.

Risperidone is FDA-approved for short-term treatment of acute bipolar I manic or mixed episodes in patients age 10 to 17. Aripiprazole is approved for acute and maintenance treatment of bipolar I manic or mixed episodes (with or without psychosis) as monotherapy or with lithium or valproate in patients age 10 to 17. In June, an FDA advisory committee recommended pediatric bipolar indications for olanzapine, quetiapine, and ziprasidone.

‘Mood stabilizers’ such as lithium, valproate, and carbamazepine have been used for years to treat bipolar mania in adults, adolescents, and children, despite limited supporting evidence. Preliminary results of a National Institute of Mental Health-funded double-blind RCT provide insights on their efficacy.10

The 153 outpatients age 7 to 17 in a bipolar I manic or mixed episode were randomly assigned to lithium, divalproex, or placebo for 8 weeks. Response rates—based on a Clinical Global Impressions-Improvement score of 1 or 2 (very much or much improved)—were divalproex, 54%; lithium, 42%; and placebo, 29%. Lithium showed a trend toward efficacy but did not clearly separate from placebo on the primary outcome measures. Effect sizes for lithium and divalproex were moderate.10

Only 1 study has compared a mood stabilizer with an atypical antipsychotic for treating mania in adolescents. In a double-blind trial, DelBello et al11 randomly assigned 50 patients age 12 to 18 with a bipolar I manic or mixed episode to quetiapine, 400 to 600 mg/d, or divalproex, serum level 80 to 120 μg/mL, for 28 days. Manic symptoms resolved more rapidly, and remission rates measured by the YMRS were higher with quetiapine than with divalproex. Both medications were well tolerated.

Combination therapy. BPD as it presents in children and adolescents is often difficult to treat because of the disorder’s various phases (manic, depressed, mixed), frequent psychotic symptoms, and high rate of comorbidity. Pediatric BPD patients frequently require several psychotropics, including mood stabilizers and atypical antipsychotics.

In a double-blind, placebo-controlled study, 30 adolescents in a bipolar I manic or mixed episode initially received divalproex, 20 mg/kg/d, then were randomly assigned to 6 weeks of adjunctive quetiapine, titrated to 450 mg/d in 7 days (n=15), or placebo (n=15). Those receiving divalproex plus quetiapine showed a statistically significant greater reduction in manic symptoms (P=.03) and a higher response rate (87% vs 53%, P=.05), compared with those receiving divalproex and placebo. This suggests that a mood stabilizer plus an atypical antipsychotic is more effective than a mood stabilizer alone for adolescent mania. Quetiapine was well tolerated.12

Treatment. The American Psychiatric Association’s outdated 2002 practice guideline for acute bipolar I manic or mixed episodes in adults recommends lithium, valproate, and/or an antipsychotic.13 The more recent Texas Medication Algorithm Project (TMAP) guidelines recommend monotherapy with lithium, valproate, aripiprazole, quetiapine, risperidone, or ziprasidone for adults with euphoric or irritable manic or hypomanic symptoms.14

Based on the TMAP algorithm, recent clinical trial evidence, and our experience in treating pediatric BPD, we offer an approach for treating mania/hypomania in patients age 10 to 17 (see Proposed Algorithm). For dosing and precautions when using atypical antipsychotics in children and adolescents with BPD, see Table 2.15-17

Comorbid psychiatric illnesses (such as anxiety disorders) are prevalent in adolescents with BPD. Evidence in adults and adolescents suggests that some atypical antipsychotics may provide additional benefit for these conditions as well. Thus, consider comorbid conditions and symptoms when choosing antimanic agents.

Attention-deficit/hyperactivity disorder (ADHD) is a common comorbidity in children with BPD, and stimulant medications are most often prescribed to treat inattentiveness and hyperactivity. Caution is imperative when treating bipolar youth with stimulants, which can exacerbate manic symptoms. Treat the patient’s mania before adding or reintroducing stimulant medication. Research and clinical experience suggest that if you first stabilize these patients on a mood stabilizer or atypical antipsychotic, adding a stimulant can be very helpful in treating comorbid ADHD symptoms. Start with low stimulant doses, and increase slowly.

Table 1

RCTs of atypical antipsychotics in patients age 10 to 17
with bipolar I disorder*

Antipsychotic and source

Bipolar I episode (# of subjects)

Trial duration (days)

Dosage (mg/d)

Response rate or YMRS score change


Mean weight gain (kg)

Pandina et al3 AACAP 2007

Manic, mixed (169)


0.5 to 2.5
3 to 6




Tohen et al4

Manic, mixed (161)


10.4 ± 4.5



3.7 ± 2.2

DelBello et al5 AACAP 2007

Manic (284)






Wagner et al6 ACNP 2007

Manic, mixed (296)






DelBello et al7 APA 2008

Manic, mixed (238)


80 to 160

–13.83 with ziprasidone, –8.61 with placebo



*Each trial included a 6-month open extension phase; results are pending

AACAP: American Academy of Child and Adolescent Psychiatry; ACNP: American College of Neuropsychopharmacology; APA: American Psychiatric Association; NNT: number needed to treat; RCT: randomized controlled trial; YMRS: Young Mania Rating Scale

Table 2

Recommended antipsychotic use in pediatric bipolar disorder


Starting dosage (mg)

Target dosage (mg/d)



2.5 to 5 at bedtime

10 to 30

Monitor for CYP 3A4 and 2D6 interactions, weight, BMI, cholesterol, lipids, and glucose


2.5 bid

10 to 20

Monitor for CYP 2D6 interactions, weight, BMI, cholesterol, lipids, glucose, and prolactin levels


50 bid

400 to 1,200

Monitor for weight, BMI, cholesterol, lipids, and glucose


0.25 bid

1 to 2.5

Monitor for EPS, hyperprolactinemia (and associated sexual side effects, including galactorrhea), weight, BMI, cholesterol, lipids, glucose, and prolactin levels


20 bid

80 to 160

Check baseline ECG and as dose increases or with reason for high level of concern; monitor prolactin levels

BMI: body mass index; CYP: cytochrome P450; ECG: electrocardiography; EPS: extrapyramidal symptoms

Source: References 15-17

Proposed Algorithm: Treating a bipolar mixed/manic episode in patients age 10 to 17

Stage 1. Consider patient’s experience with antipsychotics, body weight, and family history when choosing first-line monotherapy (1A). Quetiapine poses low risk for extrapyramidal symptoms and tardive dyskinesia. Aripiprazole and ziprasidone pose relatively low risk of weight gain. Risperidone is potent at low doses but increases prolactin levels (long-term effect unknown).

Second-line choices (1B) are mood stabilizers lithium and valproate (because of lower potency than atypical antipsychotics), and olanzapine (which—although potent—causes substantial weight gain). In case of lack of response or intolerable side effects with initial agent, select an alternate from 1A or 1B. If this is not effective, move to Stage 2.

Stage 2. Consider augmentation for patients who show partial response to monotherapy (in your clinical judgment “mild to moderately improved” but not “much or very much improved”).

Stage 3. Combination therapy could include 2 mood stabilizers (such as lithium and valproate) plus an atypical antipsychotic; 2 atypical antipsychotics; or other combinations based on patient’s past responses. No research has shown these combinations to be efficacious in bipolar children and adolescents, but we find they sometimes help those with treatment-resistant symptoms.

Duration. Maintain psychotropics 12 to 18 months. When patient is euthymic, slowly taper 1 medication across several months. If symptoms recur, reintroduce the mood-stabilizing agent(s).

Source: Adapted and reprinted with permission from Kowatch RA, Fristad MA, Findling R, et al. Clinical manual for the management of bipolar disorder in children and adolescents. Arlington, VA: American Psychiatric Publishing, Inc.; 2008

Managing adverse effects

Although clinically effective, atypical antipsychotics may cause serious side effects that must be recognized and managed. These include extrapyramidal symptoms (EPS), tardive dyskinesia (TD), weight gain and obesity, hyperlipidemia, increased prolactin levels, and QTc changes. Counsel patients and families about the risks and benefits of antipsychotics when you consider them for children and adolescents with BPD (Table 3).

EPS. Drug-induced parkinsonism and akathisia are the most common EPS in children and adolescents with BPD treated with atypical antipsychotics.18

Correll et al19 reported a 10% rate of EPS in patients treated with aripiprazole. Treatment-emergent EPS also was observed in the RCT of risperidone.20 EPS-related adverse events were associated with higher doses of risperidone, although none of the akathisia/EPS measures were thought to be “clinically significant.”

EPS frequency was relatively low and similar to placebo in the 3-week quetiapine trial,21 and no changes in movement disorder scale scores were observed during the olanzapine or ziprasidone RCTs.4,7

Recommendations. If your pediatric patient develops EPS, first try an antipsychotic dose reduction. Because anticholinergics can contribute to antipsychotic-induced weight gain, reserve them until after a dosage reduction has been unsuccessful.

Benztropine (0.25 to 0.5 mg given 2 to 3 times daily, not to exceed 3 mg/d) or diphenhydramine (25 to 50 mg given 3 to 4 times daily; maximum dosage 5 mg/kg/d) can be effective in treating EPS. Avoid anticholinergics in children with narrow-angle glaucoma or age <3.

Akathisia may be managed with propranolol (20 to 120 mg/d in divided doses). Multiple doses (typically 3 times daily) are needed to prevent interdose withdrawal symptoms. Use this beta blocker with caution in children with asthma because of the possibility of bronchospasm.

TD. Short-term trials and a meta-analysis of atypical antipsychotic trials (>11 months’ duration, subject age <18) suggest a low annual risk for TD (0.4%).22 Large, prospective, long-term trials of atypical antipsychotics are necessary to more accurately define the risk of TD in the pediatric population, however. Retrospective analyses of adolescents treated with antipsychotics suggest 3 TD risk factors:

  • early age of antipsychotic use
  • medication nonadherence
  • concomitant use of antiparkinsonian agents.23

Kumra et al24 identified lower premorbid functioning and greater positive symptoms at baseline as factors associated with “withdrawal dyskinesia/tardive dyskinesia” in children and adolescents with early-onset psychotic-spectrum disorders treated with typical or atypical antipsychotics.

Recommendations. To minimize TD risk, use the lowest effective antipsychotic dose, monitor for abnormal involuntary movements with standardized assessments (such as the Abnormal Involuntary Movement Scale), review risks and benefits with parents and patients, and regularly evaluate the indication and need for antipsychotic therapy. It is reasonable to attempt to lower the antipsychotic dose after the patient has attained remission and been stable for 1 year.

Neuroleptic malignant syndrome (NMS). This complication of dopamine-blocking medications:

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