In a patient with bipolar II disorder, does lithium prevent mixed episodes?

Lithium for Prevention of Mixed Episodes in Bipolar II Disorder

Lithium is effective for preventing mixed episodes in bipolar II disorder, though its efficacy is stronger for preventing manic/hypomanic episodes than depressive episodes, and valproate may be a superior alternative specifically for mixed-predominant presentations. 1, 2

Evidence for Lithium's Efficacy in Mixed Episode Prevention

General Maintenance Efficacy

• Lithium demonstrates superior efficacy compared to placebo for preventing relapse or recurrence of any mood episodes in bipolar I disorder patients, with this benefit extending to bipolar II disorder 2, 3
• Lithium is more effective at preventing manic/hypomanic episodes, including mixed episodes, than preventing depressive episodes 2
• Recent placebo-controlled trials confirm lithium's definite efficacy in bipolar disorder, with lithium being the only drug proven efficacious in preventing any mood episodes in non-enriched trials 2, 3

Specific Considerations for Mixed Episodes

• Valproate shows higher response rates (53%) compared to lithium (38%) in treating bipolar disorder overall, and appears particularly effective for mixed or dysphoric mania 1, 4, 5
• Patients with a history of mixed episodes were significantly less likely to respond to lithium treatment (odds ratio 4.363), suggesting valproate may be preferable for mixed-predominant presentations 6
• Lithium remains effective for mixed episodes but may not be the optimal first choice when mixed features predominate 6

Clinical Algorithm for Mood Stabilizer Selection

Choose Lithium When:

• The patient has bipolar II disorder with predominantly hypomanic episodes (not mixed features) 1, 2
• There is high suicide risk, as lithium reduces suicide attempts 8.6-fold and completed suicides 9-fold 1
• The patient has typical bipolar features without rapid cycling 5

Choose Valproate When:

• Mixed episodes or mixed features are prominent in the clinical presentation 1, 5, 6
• The patient has rapid cycling or atypical bipolar features 5
• There is a history of poor response to lithium 6

Consider Combination Therapy When:

• Monotherapy with either agent provides insufficient prophylaxis after an adequate 6-8 week trial at therapeutic doses 1, 7
• The patient has severe presentations or treatment-resistant disease 1, 7
• Lithium-valproate combination may provide broader coverage, with lithium preventing mania and valproate addressing mixed features 7

Maintenance Therapy Requirements

• Continue mood stabilizer therapy for at least 12-24 months after achieving mood stabilization 1, 4
• Some individuals with bipolar II disorder will require lifelong maintenance therapy 4
• Withdrawal of lithium dramatically increases relapse risk, especially within 6 months of discontinuation, with over 90% of noncompliant patients relapsing versus 37.5% of compliant patients 1

Essential Monitoring for Lithium

• Baseline assessment must include complete blood count, thyroid function tests, urinalysis, blood urea nitrogen, creatinine, serum calcium, and pregnancy test in females 1
• Ongoing monitoring every 3-6 months should include lithium levels (target 0.6-1.0 mEq/L for maintenance), renal function, thyroid function, and urinalysis 1, 4
• Target therapeutic levels are 0.8-1.2 mEq/L for acute treatment and 0.6-1.0 mEq/L for maintenance 1

Common Pitfalls to Avoid

• Do not use antidepressant monotherapy in bipolar II disorder, as this can trigger hypomania, rapid cycling, or mood destabilization 4
• Avoid premature discontinuation of maintenance therapy, which leads to high relapse rates 4
• Do not assume lithium will work equally well for all bipolar II presentations—patients with mixed-predominant features may respond better to valproate 6
• Failure to monitor for medication-specific side effects, particularly thyroid and renal function with lithium, is a critical oversight 4