What is the first‑line treatment for an adult with bipolar disorder, including preferred medication, dosing, monitoring, and alternative options?

First-Line Treatment for Bipolar Disorder in Adults

Lithium or valproate combined with an atypical antipsychotic represents the first-line treatment for acute mania in adults with bipolar disorder, with lithium showing superior long-term efficacy for maintenance therapy. 1

Acute Mania Treatment Algorithm

Initial Medication Selection

For acute manic or mixed episodes, start with:

• Lithium at 300 mg three times daily (900 mg/day total), titrating weekly by 300 mg increments to achieve therapeutic levels of 0.8-1.2 mEq/L 1
• OR Valproate starting at 125 mg twice daily, titrating to therapeutic blood levels of 40-90 mcg/mL (or 50-100 mcg/mL for acute treatment) 2, 1
• Combined with an atypical antipsychotic for severe presentations: aripiprazole (5-15 mg/day), olanzapine (10-20 mg/day), risperidone (2 mg/day), quetiapine (400-800 mg/day), or ziprasidone 2, 1, 3

Combination therapy with a mood stabilizer plus atypical antipsychotic is superior to monotherapy for severe mania and provides faster symptom control. 1, 4

Choosing Between Lithium and Valproate

• Lithium is preferred when: the patient has classic euphoric mania, strong family history of bipolar disorder, or high suicide risk (lithium reduces suicide attempts 8.6-fold and completed suicides 9-fold) 2, 1
• Valproate is preferred when: the patient presents with mixed episodes, rapid cycling, irritability, or dysphoric mania (valproate shows 53% response rates versus 38% for lithium in mixed states) 2, 1

Baseline Laboratory Monitoring

Before Starting Lithium:

• Complete blood count, thyroid function tests (TSH, free T4), urinalysis, BUN, creatinine, serum calcium, pregnancy test in females 1
• Check lithium level after 5 days at steady-state dosing, then every 3-6 months 1

Before Starting Valproate:

• Liver function tests (AST, ALT), complete blood count with platelets, pregnancy test in females 1
• Check valproate level after 5-7 days at stable dosing, then every 3-6 months 1

Before Starting Atypical Antipsychotics:

• Body mass index, waist circumference, blood pressure, fasting glucose, fasting lipid panel 1
• Monitor BMI monthly for 3 months, then quarterly; blood pressure, glucose, lipids at 3 months, then annually 1

Bipolar Depression Treatment

For moderate to severe depressive episodes, use a mood stabilizer (lithium, valproate, or lamotrigine) ALWAYS combined with an antidepressant—never antidepressant monotherapy. 5, 1

Preferred Antidepressant Options:

• SSRIs (fluoxetine, sertraline, escitalopram) are preferred over tricyclic antidepressants due to lower risk of mood destabilization 5, 6
• Bupropion (150-300 mg/day) is associated with weight loss rather than gain and has lower risk of manic switch 2, 7
• Olanzapine-fluoxetine combination is FDA-approved as first-line for bipolar depression 1
• Lurasidone demonstrates efficacy for bipolar depression with minimal weight gain 2, 6

Antidepressants should be tapered 2-6 months after remission to prevent mood destabilization. 7

Maintenance Therapy

Continue the regimen that successfully treated the acute episode for at least 12-24 months; some patients require lifelong treatment. 5, 1

Maintenance Medication Options:

• Lithium (0.6-1.0 mEq/L for maintenance) shows superior evidence for preventing both manic and depressive episodes 1, 6
• Lamotrigine is particularly effective for preventing depressive episodes 1, 6
• Valproate is effective for maintenance, especially in mixed states 5, 8
• Atypical antipsychotics (aripiprazole, olanzapine, quetiapine) as monotherapy or combined with mood stabilizers 1, 6

Withdrawal of maintenance lithium dramatically increases relapse risk, with >90% of noncompliant patients relapsing versus 37.5% of compliant patients. 1

Dosing Specifics

Lithium:

• Acute: 0.8-1.2 mEq/L 1
• Maintenance: 0.6-1.0 mEq/L 1
• Check levels twice weekly during acute phase until stable, then every 3-6 months 1

Valproate:

• Acute: 50-100 mcg/mL 1
• Maintenance: 40-90 mcg/mL 2, 1
• Typical dose: 750-1500 mg daily in divided doses 1

Atypical Antipsychotics:

• Aripiprazole: 5-15 mg/day 1
• Olanzapine: 10-20 mg/day 1, 4
• Risperidone: 2 mg/day 1
• Quetiapine: 400-800 mg/day 1
• Ziprasidone: 40-80 mg twice daily with food 3

Critical Pitfalls to Avoid

• Never use antidepressant monotherapy in bipolar disorder—this triggers manic episodes, rapid cycling, and mood destabilization in up to 58% of patients 1
• Avoid premature discontinuation of maintenance therapy—relapse rates exceed 90% in noncompliant patients 1
• Do not underdose or conduct inadequate trials—allow 6-8 weeks at therapeutic doses before concluding treatment failure 1
• Monitor metabolic side effects aggressively, particularly with olanzapine (highest weight gain risk) and quetiapine 2, 1
• Avoid typical antipsychotics (haloperidol) due to 50% risk of tardive dyskinesia after 2 years in young patients 2

Psychosocial Interventions (Essential Adjunct)

Psychoeducation, cognitive-behavioral therapy, and family-focused therapy should accompany all pharmacotherapy to improve outcomes. 5, 1

• Educate patients and families about symptoms, course, treatment options, medication adherence, recognition of early relapse signs, and factors that precipitate relapse (sleep deprivation, substance abuse) 9, 5
• Family-focused therapy enhances medication supervision, problem-solving, communication skills, and reduces access to lethal means 5, 1
• Cognitive-behavioral therapy addresses depressive and anxiety components 5, 1

Alternative Options for Treatment-Resistant Cases

• Combination of lithium plus valproate serves as foundation for treatment-resistant mania 7, 4
• Carbamazepine is the leading alternative mood stabilizer if lithium and valproate fail 7
• Clozapine for treatment-resistant cases (requires weekly CBC monitoring for agranulocytosis) 1
• Electroconvulsive therapy (ECT) for severely impaired patients when medications are ineffective or cannot be tolerated 1

Special Considerations

For patients with metabolic syndrome or obesity: prioritize aripiprazole or lurasidone over olanzapine or quetiapine due to lower metabolic risk 2, 6

For patients with high suicide risk: lithium is strongly preferred due to its unique anti-suicide effects independent of mood stabilization 2, 1

For rapid cycling: valproate monotherapy is recommended initially 7