What is the first-line treatment for mania?

First-Line Treatment for Mania

For acute mania, initiate treatment with either lithium, valproate, or an atypical antipsychotic (olanzapine, risperidone, quetiapine, aripiprazole, or ziprasidone) as monotherapy, with combination therapy reserved for severe presentations or inadequate response to monotherapy. 1, 2

Medication Selection Algorithm

Start with monotherapy unless the patient presents with severe agitation, psychotic features, or treatment-resistant mania—in these cases, begin with combination therapy (mood stabilizer + atypical antipsychotic) immediately. 1, 3

First-Line Monotherapy Options:

Lithium:

• Target serum level 0.8-1.2 mEq/L for acute treatment 1
• Response rates 38-62% in acute mania 1, 2
• Superior evidence for long-term maintenance and relapse prevention 1, 2
• Reduces suicide attempts 8.6-fold and completed suicides 9-fold 1
• Choose lithium when: Patient has classic euphoric mania, no rapid cycling, and can tolerate regular monitoring 1

Valproate:

• Target therapeutic range 50-125 μg/mL 4
• Higher response rates (53%) compared to lithium (38%) in children/adolescents with mixed episodes 1, 2
• Choose valproate when: Patient has mixed episodes, rapid cycling, or dysphoric mania 1

Atypical Antipsychotics:

• Olanzapine: 10-20 mg/day, provides rapid symptom control, superior when combined with lithium or valproate versus mood stabilizers alone 4, 3
• Risperidone: 2-6 mg/day for adults, 1-2.5 mg/day for adolescents 5, 3
• Quetiapine, aripiprazole, ziprasidone: All FDA-approved and effective for acute mania 1, 6, 3
• Choose atypical antipsychotics when: Rapid symptom control is needed, patient has psychotic features, or previous lithium/valproate failure 1, 3

Combination Therapy Approach

Combine a mood stabilizer (lithium or valproate) with an atypical antipsychotic for:

• Severe mania with marked agitation 1, 7
• Psychotic features 1, 3
• Treatment-resistant mania (failed monotherapy trial) 1, 8
• Mixed episodes with severe symptoms 1

Evidence strongly supports combination therapy superiority in severe presentations: Olanzapine 5-20 mg/day combined with lithium (0.6-1.2 mEq/L) or valproate (50-125 μg/mL) demonstrated superior reduction in manic symptoms versus mood stabilizers alone. 4, 8

Critical Implementation Details

Adequate trial duration: 6-8 weeks at therapeutic doses before concluding treatment failure 1

Monitoring requirements vary by agent:

• Lithium: Serum levels, renal function, thyroid function, urinalysis every 3-6 months 1, 2
• Valproate: Serum levels, liver function, complete blood count every 3-6 months 1
• Atypical antipsychotics: BMI monthly for 3 months then quarterly; blood pressure, fasting glucose, lipids at 3 months then yearly 1, 2

Common Pitfalls to Avoid

Never use antidepressant monotherapy—this triggers manic episodes, rapid cycling, and mood destabilization in 90%+ of cases. 1, 2, 6

Avoid typical antipsychotics (haloperidol, fluphenazine) as first-line—they carry 50% risk of tardive dyskinesia after 2 years in young patients and have inferior tolerability versus atypical agents. 1, 9

Do not discontinue maintenance therapy prematurely—withdrawal (especially lithium) increases relapse risk dramatically, with >90% of noncompliant adolescents relapsing versus 37.5% of compliant patients. 1, 2

Systematic medication trials require adequate dosing—underdosing delays therapeutic response and leads to premature treatment switching. 1

Maintenance Planning

Continue the regimen that successfully treated the acute episode for minimum 12-24 months, with some patients requiring lifelong treatment. 1, 2, 5 Lithium demonstrates superior evidence for preventing both manic and depressive episode recurrence in long-term maintenance. 1, 2