What are the treatment options for bipolar disorder?

Treatment of Bipolar Disorder

First-Line Pharmacotherapy by Phase

For acute mania or mixed episodes, start with lithium, valproate, or an atypical antipsychotic (aripiprazole, olanzapine, risperidone, quetiapine) as monotherapy, with lithium showing the strongest long-term prophylactic evidence. 1

Acute Mania/Mixed Episodes

• Lithium (ages 12+) is the only FDA-approved mood stabilizer for adolescents and remains first-line for adults, with response rates of 38-62% in acute mania 1
• Valproate demonstrates higher response rates (53%) compared to lithium (38%) in children and adolescents with mania and mixed episodes 1
• Atypical antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone) are FDA-approved for acute mania in adults and provide rapid symptom control 1, 2, 3
• Haloperidol is recommended in resource-limited settings where second-generation antipsychotics are unavailable or cost-prohibitive 4
• Combination therapy (lithium or valproate plus an atypical antipsychotic) should be used for severe presentations or inadequate monotherapy response 1

Maintenance Therapy

Continue the regimen that successfully treated the acute episode for at least 12-24 months, with lithium showing superior evidence for preventing both manic and depressive episodes. 1

• Lithium has the most robust evidence for long-term prophylaxis of both manic and depressive episodes 1, 5
• Valproate is equally effective as lithium for maintenance therapy 1
• Lamotrigine is approved for maintenance therapy and is particularly effective for preventing depressive episodes 1
• Withdrawal of maintenance lithium increases relapse risk dramatically, with >90% of noncompliant adolescents relapsing versus 37.5% of compliant patients 1
• Some patients require lifelong treatment when benefits outweigh risks 1

Bipolar Depression

Use olanzapine-fluoxetine combination as first-line treatment for bipolar depression; never use antidepressant monotherapy due to risk of mood destabilization. 1

• Olanzapine-fluoxetine combination is the first-line FDA-approved option for bipolar depression 1, 2
• Antidepressants must always be combined with a mood stabilizer (lithium or valproate) to prevent switching to mania or rapid cycling 4, 1
• SSRIs (fluoxetine) are preferred over tricyclic antidepressants when antidepressants are used 4
• Lamotrigine has the most robust effect among mood stabilizers for treating and preventing depressive episodes 5
• Antidepressants should be tapered 2-6 months after remission 6

Medication Selection Algorithm

Step 1: Determine Current Phase

• Acute mania/mixed: Lithium, valproate, or atypical antipsychotic 1
• Bipolar depression: Olanzapine-fluoxetine combination or mood stabilizer plus SSRI 1
• Maintenance: Continue acute treatment regimen 1

Step 2: Consider Patient-Specific Factors

• Adolescents (13-17 years): Lithium is the only FDA-approved option; start at 2.5-5 mg daily for atypical antipsychotics if used 1, 3
• Sedation concerns: Choose lithium over valproate (lithium causes no sedation) 1
• Weight gain concerns: Both lithium and valproate cause weight gain; aripiprazole has the most favorable metabolic profile among atypical antipsychotics 1
• Mixed/dysphoric mania: Valproate may be superior to lithium 6
• Rapid cycling: Valproate monotherapy initially; lamotrigine reduces cycling in bipolar II 6, 5

Step 3: Dosing Strategy

• Lithium: Start 5-10 mg daily in adults, 2.5-5 mg in adolescents; target 10 mg/day 1
• Valproate: Conduct 6-8 week trial at adequate doses before adding or switching 1
• Atypical antipsychotics: Start low (2.5-5 mg for adolescents, 5-10 mg for adults) and titrate based on response 1

Step 4: Combination Therapy if Monotherapy Fails

• Lithium plus valproate serves as the foundation for treatment-resistant cases 6, 5
• Mood stabilizer plus atypical antipsychotic for severe or psychotic presentations 1
• Lithium plus lamotrigine provides effective prevention of both mania and depression 5

Mandatory Monitoring Requirements

Lithium

• Baseline: Complete blood count, thyroid function tests, urinalysis, BUN, creatinine, serum calcium, pregnancy test in females 1
• Ongoing: Lithium levels, renal and thyroid function, urinalysis every 3-6 months 1

Valproate

• Baseline: Liver function tests, complete blood count, pregnancy test 1
• Ongoing: Serum drug levels, hepatic function, hematological indices every 3-6 months 1

Atypical Antipsychotics

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

Essential Psychosocial Interventions

Combine pharmacotherapy with psychoeducation for all patients with bipolar disorder to improve medication adherence and outcomes. 4, 1

• Psychoeducation should be routinely offered to patients and family members regarding symptoms, course, treatment options, and medication adherence 4, 1
• Cognitive behavioral therapy has strong evidence for both acute and maintenance phases 1
• Family interventions improve outcomes and should be considered when trained professionals are available 4

Critical Pitfalls to Avoid

• Antidepressant monotherapy triggers manic episodes or rapid cycling in 15-20% of patients 1
• Premature discontinuation of maintenance therapy leads to >90% relapse rates versus 37.5% in compliant patients 1
• Inadequate trial duration: Conduct 6-8 week trials at adequate doses before concluding ineffectiveness 1
• Failure to monitor metabolic effects of atypical antipsychotics, particularly weight gain and metabolic syndrome 1
• Rapid lamotrigine titration increases risk of Stevens-Johnson syndrome; always use slow titration schedule 1
• Overlooking comorbidities such as substance use disorders, anxiety, or ADHD that complicate treatment 1
• Using anticholinergics routinely for extrapyramidal symptoms; reserve for acute/severe cases only 4