Is it acceptable to prescribe two mood stabilizers, such as lithium (lithium) and valproate (valproic acid), together for a patient with a history of bipolar disorder who has not responded adequately to a single mood stabilizer?

Combining Two Mood Stabilizers in Bipolar Disorder

Yes, it is acceptable and often clinically necessary to prescribe two mood stabilizers together, particularly lithium plus valproate, for patients with bipolar disorder who have failed monotherapy after an adequate 6-8 week trial at therapeutic doses. 1, 2

Evidence-Based Rationale for Combination Therapy

The American Academy of Child and Adolescent Psychiatry explicitly supports the use of two mood stabilizers in adults with bipolar disorder, with preliminary support for similar strategies in children and adolescents. 1, 2 This approach is particularly indicated for:

• Severe presentations requiring rapid control 2
• Treatment-resistant cases after failed monotherapy 2, 3
• Rapid cycling bipolar disorder 4, 5
• Patients with mixed episodes or psychotic features 5

The combination of lithium plus valproate represents the most extensively studied dual mood stabilizer regimen, with evidence demonstrating superior efficacy compared to monotherapy in preventing relapses. 4, 5, 6

Clinical Algorithm for Initiating Combination Therapy

Step 1: Verify Adequate Monotherapy Trial

• Confirm the patient completed a systematic 6-8 week trial at therapeutic doses before concluding monotherapy failure 2
• Document therapeutic drug levels: lithium 0.8-1.2 mEq/L for acute treatment, valproate 50-100 μg/mL 2
• Assess medication adherence through therapeutic drug monitoring, as noncompliance is a common cause of apparent treatment failure 2

Step 2: Select the Second Mood Stabilizer

Lithium plus valproate is the preferred combination based on:

• Strongest evidence base for efficacy and safety 4, 7, 6
• No clinically significant pharmacokinetic interactions—lithium does not alter valproate levels, and valproate causes only statistically insignificant changes in lithium pharmacokinetics 8, 6
• Complementary mechanisms of action without pharmacodynamic opposition 6
• Well-tolerated combination with manageable side effect profile 4, 6

Step 3: Baseline Assessment Before Adding Second Agent

For adding valproate to existing lithium:

• Liver function tests, complete blood count with platelets, pregnancy test in females 2

For adding lithium to existing valproate:

• Complete blood count, thyroid function tests, urinalysis, BUN, creatinine, serum calcium, pregnancy test in females 2

Step 4: Initiation and Titration

• Start valproate at 125 mg twice daily, titrate to therapeutic blood level (50-100 μg/mL) 2
• For lithium, typical starting dose is 300 mg three times daily for patients ≥30 kg, titrating to 0.8-1.2 mEq/L 2
• Check drug levels after 5-7 days at stable dosing 2

Step 5: Ongoing Monitoring

• For lithium: Monitor lithium levels, renal and thyroid function, urinalysis every 3-6 months 2
• For valproate: Monitor serum drug levels, hepatic function, hematological indices every 3-6 months 2
• Assess mood symptoms weekly for the first month, then monthly once stable 2

Expected Outcomes and Timeline

• The annual frequency of recurrences decreases significantly with lithium plus valproate combination compared to valproate monotherapy 5
• Dramatic responses can occur within 24-48 hours, particularly for depressive symptoms, suggesting potential augmentation effects between the two agents 4
• Maintenance therapy must continue for at least 12-24 months after achieving stability, with some patients requiring lifelong treatment 2
• Withdrawal of maintenance therapy dramatically increases relapse risk, with over 90% of noncompliant patients relapsing versus 37.5% of compliant patients 2

Critical Safety Considerations

Drug Interactions

• No clinically significant interaction between lithium and valproate—concomitant administration does not significantly alter lithium pharmacokinetics 8, 6
• Valproate inhibits metabolism of phenobarbital, phenytoin, and other medications—review all concomitant medications 8
• Monitor coagulation tests if patient is taking anticoagulants, as valproate increases unbound warfarin fraction 8

Specific Populations

• Patients with mixed episodes may have higher recurrence rates on combination therapy 5
• Combination therapy is prescribed mainly to patients with bipolar I disorder, high number of previous episodes, and lifetime psychotic symptoms 5

Common Pitfalls to Avoid

• Inadequate duration of monotherapy trial before adding second agent—always complete 6-8 weeks at therapeutic doses 2
• Premature discontinuation of effective combination therapy—maintain for minimum 12-24 months 2
• Failure to monitor therapeutic drug levels—both agents require regular monitoring to ensure efficacy and prevent toxicity 2
• Attributing all symptoms to bipolar disorder—distinguish between medication-responsive mood symptoms versus psychosocial stressors requiring non-pharmacological interventions 1
• Unnecessary expansion to three or more mood stabilizers—optimize the two-drug combination before considering additional agents 1, 3

When Combination Therapy May Not Be First-Line

The American Academy of Child and Adolescent Psychiatry emphasizes that combination therapy should follow optimization of individual medications, not replace adequate monotherapy trials. 3 However, for severe presentations, rapid cycling, or treatment-resistant cases, initiating combination therapy earlier is justified. 2, 5

Agents should be added carefully with continued monitoring of adverse effects, giving patients only as much medication as needed. 3