Which FDA‑approved agents are indicated as first‑line treatment for mixed or manic episodes in children and adolescents with bipolar I disorder, including their age limits, typical starting doses, and required monitoring?

FDA-Approved Medications for Pediatric Bipolar Mixed/Manic Episodes

For children and adolescents with bipolar I disorder experiencing mixed or manic episodes, five FDA-approved atypical antipsychotics are available as first-line options: aripiprazole (age 10+), asenapine (age 10+), olanzapine (age 13+), quetiapine (age 10+), and risperidone (age 10+), alongside lithium (age 12+). 1

FDA-Approved First-Line Agents by Age

Atypical Antipsychotics

Aripiprazole (Age 10 and older):

• Approved dose: 10 mg once daily for 12 weeks for moderate to severe manic episodes 2
• Starting dose: 2 mg daily, titrate to 5-10 mg daily over 1 week 1
• Maximum dose: 30 mg/day, though 10 mg/day shows better benefit-risk profile than higher doses 2
• Favorable metabolic profile compared to olanzapine, with lower weight gain risk 3
• Monitor: BMI monthly for 3 months then quarterly; blood pressure, fasting glucose, and lipids at 3 months then yearly 3

Risperidone (Age 10 and older):

• Effective dose range: 0.5-2.5 mg/day shows superior benefit-risk profile compared to 3-6 mg/day 4
• Starting dose: 0.5 mg daily, titrate by 0.5-1 mg every 24-48 hours 1
• Target dose: 2 mg/day for acute treatment 3
• Mean improvement: -18.5 points on YMRS at 0.5-2.5 mg/day versus -9.1 for placebo 4
• Common adverse effects: somnolence, headache, fatigue, and mean weight gain of 1.9 kg over 3 weeks 4
• Monitor: Same metabolic parameters as aripiprazole 3

Quetiapine (Age 10 and older):

• Starting dose: 50 mg twice daily on day 1, increase to 100 mg twice daily on day 2 1
• Target dose: 400-600 mg/day divided doses 1
• Quetiapine plus valproate is more effective than valproate alone for adolescent mania 3
• Higher metabolic risk than aripiprazole, including weight gain and dyslipidemia 3

Olanzapine (Age 13 and older):

• Starting dose: 2.5-5 mg daily 1
• Target dose: 10-15 mg/day for acute mania 3, 5
• Therapeutic range: 5-20 mg/day 3
• Provides rapid symptom control within 1-2 weeks 5
• Major limitation: significant metabolic side effects including weight gain, diabetes risk, and hyperprolactinemia 5
• Best reserved for acute treatment rather than maintenance due to side-effect profile 5

Asenapine (Age 10 and older):

• FDA-approved for pediatric bipolar mania 1
• Sublingual administration required 1

Mood Stabilizers

Lithium (Age 12 and older):

• The only FDA-approved mood stabilizer for pediatric bipolar disorder 3, 1
• Starting dose: 300 mg three times daily (900 mg/day) for patients ≥30 kg, or 300 mg twice daily (600 mg/day) for patients <30 kg 3
• Target level: 0.8-1.2 mEq/L for acute treatment 3
• Response rate: 38-62% in acute mania 3
• Unique advantage: reduces suicide attempts 8.6-fold and completed suicides 9-fold 3
• Baseline labs required: CBC, thyroid function (TSH, free T4), urinalysis, BUN, creatinine, serum calcium, pregnancy test in females 3
• Ongoing monitoring: Lithium level, renal and thyroid function, urinalysis every 3-6 months 3

Non-FDA-Approved Options (Lower Priority)

Valproate/Divalproex:

• NOT FDA-approved for pediatric bipolar disorder 1
• Failed to separate from placebo in pediatric RCTs 1
• Historical data showed 53% response rate versus 38% for lithium and carbamazepine in open-label trials 6
• Effect size: 1.63 for divalproex versus 1.06 for lithium in children ages 8-18 6
• Despite lack of FDA approval, AACAP guidelines still recommend as first-line option 3
• If used: Starting dose 125 mg twice daily, target level 50-100 μg/mL 3
• Baseline labs: LFTs, CBC with platelets, pregnancy test 3

Treatment Algorithm for Acute Mania/Mixed Episodes

Step 1: Monotherapy Selection

• Choose aripiprazole 10 mg daily OR risperidone 0.5-2.5 mg/day as first-line for most patients due to FDA approval and favorable benefit-risk profiles 1, 2, 4
• Consider lithium for patients age 12+ with high suicide risk given its unique anti-suicide effects 3
• Avoid olanzapine as first-line unless rapid control is critical, due to metabolic risks 5

Step 2: Combination Therapy for Severe Presentations

• Add lithium or valproate to atypical antipsychotic for severe mania, psychotic features, or inadequate monotherapy response after 6-8 weeks 3
• Combination therapy provides superior efficacy versus monotherapy 3

Step 3: Maintenance Duration

• Continue successful acute regimen for minimum 12-24 months 3
• >90% of noncompliant adolescents relapsed versus 37.5% of compliant patients 3

Critical Monitoring Requirements

All Atypical Antipsychotics:

• Baseline: BMI, waist circumference, blood pressure, fasting glucose, fasting lipid panel 3
• Follow-up: BMI monthly for 3 months then quarterly; blood pressure, glucose, lipids at 3 months then yearly 3

Lithium:

• Check level after 5 days at steady-state dosing, then every 3-6 months 3
• Monitor renal function (BUN, creatinine) and thyroid function (TSH) every 3-6 months 3

Common Pitfalls to Avoid

• Never use antidepressant monotherapy—triggers mania, rapid cycling, and mood destabilization 3
• Do not conclude treatment failure before completing 6-8 week trial at therapeutic doses 3
• Avoid premature discontinuation—withdrawal dramatically increases relapse risk, especially within 6 months 3
• Do not overlook metabolic monitoring with atypical antipsychotics—failure to monitor is a common error 3

FDA-Approved Options for Pediatric Bipolar Depression

Lurasidone (Age 10 and older):

• FDA-approved for bipolar depression in children/adolescents 1
• Dose: 20-80 mg/day 3

Olanzapine-Fluoxetine Combination:

• FDA-approved for bipolar depression 3, 1
• First-line option for depressive episodes 3