Combining Lithium and Depakote in Bipolar Disorder
Primary Recommendation
For patients with bipolar disorder requiring combination therapy, lithium plus valproate (Depakote) is a safe, effective, and evidence-based treatment strategy that provides superior relapse prevention compared to valproate monotherapy, particularly for patients with severe presentations, rapid cycling, or inadequate response to monotherapy. 1, 2
Evidence-Based Rationale for Combination Therapy
The landmark BALANCE trial demonstrated that lithium plus valproate combination therapy significantly reduces relapse risk compared to valproate monotherapy (hazard ratio 0.59,95% CI 0.42-0.83, p=0.0023), with benefits maintained for up to 2 years. 2 While the trial could not definitively confirm superiority over lithium monotherapy (HR 0.82,95% CI 0.58-1.17, p=0.27), combination therapy remains the most prescribed prophylactic treatment for bipolar I disorder, particularly in patients with multiple previous episodes and lifetime psychotic symptoms. 3
- The American Academy of Child and Adolescent Psychiatry recommends combination therapy with lithium or valproate plus an atypical antipsychotic for severe presentations and treatment-resistant mania. 1
- Combination therapy with valproate plus olanzapine is more effective than valproate alone for acute mania. 1
- Real-world prospective data shows that lithium plus valproate combination significantly reduces annual recurrence frequency compared to valproate monotherapy. 3
Pharmacokinetic Safety Profile
Concomitant administration of lithium and valproate is pharmacokinetically safe, with minimal drug-drug interactions. 4
- Lithium pharmacokinetics remain unchanged by valproate coadministration. 4
- Valproate levels (Cmax, Cmin, AUC) rise only slightly during lithium coadministration, without clinically significant adverse events. 4
- The combination is well-tolerated, with no significant increase in adverse events compared to monotherapy. 4, 5
Clinical Indications for Combination Therapy
Primary Scenarios Requiring Combination Therapy
Initiate combination therapy when a patient has failed a systematic 6-8 week trial of monotherapy at therapeutic doses, particularly in severe presentations, rapid cycling, or treatment-resistant cases. 1
- Rapid cycling bipolar disorder responds particularly well to lithium plus valproate combination, with marked or moderate improvement in 8 of 9 patients in one series. 5
- Patients with bipolar I disorder, high number of previous episodes, and lifetime psychotic symptoms benefit most from combination therapy. 3
- Mixed states and dysphoric mania show superior response to combination therapy. 1, 5
Augmentation Effect in Bipolar Depression
A unique augmentation effect occurs when lithium is added to valproate during the depressed phase of bipolar illness, with significant improvement in depression within 24-48 hours. 5 This rapid antidepressant effect represents a distinct advantage of combination therapy over monotherapy for bipolar depression.
Special Considerations for Patients with Medical Comorbidities
Renal Impairment
For patients with renal impairment, baseline assessment must include BUN, creatinine, and urinalysis before initiating lithium, with ongoing monitoring every 3-6 months. 1
- Lithium is renally excreted and requires dose adjustment in renal dysfunction. 1
- Target lithium levels should be 0.8-1.2 mEq/L for acute treatment, but lower ranges (0.6-1.0 mEq/L) may be appropriate for maintenance or in patients with renal concerns. 1
- Valproate does not require renal dose adjustment and may be preferred as the primary mood stabilizer in severe renal impairment, with lithium added cautiously at lower doses. 1
Thyroid Disease
Lithium therapy requires baseline thyroid function tests and monitoring every 3-6 months, as lithium can cause hypothyroidism and goiter. 1
- Patients with pre-existing thyroid disease can still receive lithium but require more frequent thyroid monitoring (every 2-3 months initially). 1
- Thyroid supplementation with levothyroxine can be added if hypothyroidism develops, allowing continuation of lithium therapy. 1
- Valproate does not affect thyroid function and poses no additional thyroid risk. 1
Previous Adverse Reactions
If a patient experienced adverse reactions to either medication previously, carefully distinguish between dose-related side effects (which can be managed by dose adjustment) versus idiosyncratic reactions (which contraindicate rechallenge). 1
- Common dose-related lithium side effects (tremor, nausea, diarrhea) can be managed by dose reduction or divided dosing. 1
- Valproate-related weight gain, sedation, and tremor are dose-dependent and may improve with dose optimization. 1
- Serious idiosyncratic reactions (Stevens-Johnson syndrome, hepatotoxicity, pancreatitis) absolutely contraindicate rechallenge. 1
Initiation and Monitoring Protocol
Baseline Laboratory Assessment
Before initiating combination therapy, obtain comprehensive baseline labs for both medications:
For lithium: 1
- Complete blood count
- Thyroid function tests (TSH, free T4)
- Urinalysis
- BUN and creatinine
- Serum calcium
- Pregnancy test in females of childbearing age
For valproate: 1
- Liver function tests
- Complete blood count with platelets
- Pregnancy test in females of childbearing age
Dosing Strategy
Initiate valproate at 125 mg twice daily and titrate to therapeutic blood level (50-100 μg/mL), while starting lithium at 300 mg twice or three times daily (depending on weight) and titrating to target level of 0.8-1.2 mEq/L for acute treatment. 1
- Check valproate level after 5-7 days at stable dosing. 1
- Check lithium level after 5 days at steady-state dosing. 1
- Typical therapeutic doses: valproate 750-1500 mg/day divided; lithium 900-1800 mg/day divided. 1
Ongoing Monitoring Schedule
For lithium: 1
- Lithium level, renal function (BUN, creatinine), thyroid function (TSH), and urinalysis every 3-6 months
- More frequent monitoring (monthly) during dose adjustments or if symptoms of toxicity develop
For valproate: 1
- Valproate level, liver function tests, and complete blood count every 3-6 months
- More frequent monitoring if hepatic symptoms develop
For both medications: 1
- Assess mood symptoms weekly for the first month, then monthly once stable
- Monitor for medication adherence at every visit
- Screen for suicidal ideation at every visit
Maintenance Therapy Duration
Continue combination therapy for at least 12-24 months after achieving mood stabilization; many patients will require lifelong treatment. 1, 2
- The BALANCE trial demonstrated sustained benefit for up to 2 years. 2
- Withdrawal of maintenance lithium therapy dramatically increases relapse risk, especially within 6 months of discontinuation, with >90% of noncompliant patients relapsing versus 37.5% of compliant patients. 1, 6
- Patients with multiple severe episodes, rapid cycling, or poor response to alternative agents should be counseled that indefinite treatment is likely necessary. 1
Critical Pitfalls to Avoid
Never discontinue lithium abruptly—taper gradually over 2-4 weeks minimum to prevent rebound mania, which occurs in >90% of patients who stop suddenly. 1
- Abrupt valproate discontinuation also risks rebound mania and withdrawal symptoms; taper by 25% every 1-2 weeks over 4-6 weeks. 1
- Inadequate trial duration is a common error—allow 6-8 weeks at therapeutic doses before concluding ineffectiveness. 1
- Failure to monitor therapeutic drug levels leads to subtherapeutic dosing and apparent treatment failure. 1
- Underdosing either medication compromises the efficacy of combination therapy—ensure both agents are at therapeutic levels. 1
- Premature discontinuation of effective maintenance therapy leads to relapse rates exceeding 90%. 1, 6
When Combination Therapy May Not Be Superior
The BALANCE trial could not definitively confirm superiority of combination therapy over lithium monotherapy (HR 0.82, p=0.27), suggesting that for some patients, lithium monotherapy may be equally effective. 2
- Lithium monotherapy shows superior evidence for long-term efficacy and is the only FDA-approved agent for bipolar disorder in adolescents age 12 and older. 1, 6
- Lithium reduces suicide attempts 8.6-fold and completed suicides 9-fold, an effect independent of mood stabilization. 1
- For patients without rapid cycling, mixed states, or treatment resistance, a trial of lithium monotherapy before advancing to combination therapy is reasonable. 1
Alternative Considerations
If combination therapy with lithium plus valproate fails after an adequate trial, consider adding an atypical antipsychotic (aripiprazole, risperidone, quetiapine, or olanzapine) rather than switching mood stabilizers. 1
- Triple therapy (lithium + valproate + atypical antipsychotic) may be necessary for severe, treatment-resistant cases. 1
- For bipolar depression specifically, olanzapine-fluoxetine combination is first-line, not risperidone. 6
- Lamotrigine may be added for maintenance therapy, particularly for preventing depressive episodes. 1, 6