Is lithium an effective treatment for bipolar II disorder?

Is Lithium Effective for Bipolar II?

Lithium demonstrates clear efficacy for bipolar I disorder but has limited and inconsistent evidence for bipolar II disorder, with recent mirror-image studies showing no significant reduction in hospital admissions for severe depressive episodes in bipolar II patients after lithium discontinuation. 1

Evidence Quality and Limitations

The evidence base for lithium in bipolar II is substantially weaker than for bipolar I disorder. Most clinical guidelines extrapolate recommendations for bipolar II from bipolar I data, rather than relying on direct evidence in the bipolar II population. 1

• Lithium is FDA-approved only for bipolar disorder in patients age 12 and older, without specific distinction for bipolar II subtype. 2
• Recent guidelines recommend lithium as a first-line mood stabilizer for bipolar disorder broadly, but this recommendation is primarily based on bipolar I evidence. 2, 3
• The American Academy of Child and Adolescent Psychiatry recognizes lithium as showing superior evidence for long-term efficacy in maintenance therapy, though this applies predominantly to bipolar I patients. 2

Critical Evidence from Bipolar II-Specific Research

A 2019 mirror-image study directly comparing lithium discontinuation effects in bipolar I/schizoaffective disorder versus bipolar II/other bipolar disorder revealed striking differences:

• In bipolar I/schizoaffective patients, mean hospital admissions doubled from 0.44 to 0.95 per patient after lithium discontinuation (P<0.001), and bed days doubled from 11 to 22 (P=0.025). 1
• In bipolar II/other bipolar disorder patients, lithium discontinuation did NOT lead to increased hospital admissions for severe depressive episodes, suggesting lithium may not prevent the most clinically significant relapses in this population. 1
• The higher relapse risk in bipolar I patients suggests a higher threshold should be applied before discontinuing lithium in bipolar I compared to bipolar II. 1

Efficacy Profile Across Mood Episodes

When lithium does demonstrate efficacy in bipolar disorder, its effects are not uniform across episode types:

• Lithium is more effective in preventing manic/hypomanic episodes (including mixed episodes) than preventing depressive episodes. 3
• Lithium's efficacy as monotherapy for acute bipolar depression remains controversial, though it is recognized as a therapeutic option. 3
• For maintenance therapy, lithium is superior to placebo for preventing relapse in bipolar I patients with recent manic or hypomanic episodes. 3

Comparative Effectiveness

Recent head-to-head trials provide context for lithium's relative position:

• Lithium was superior to aripiprazole, valproic acid, and quetiapine in improving manic symptoms. 4
• Lithium resulted in lower relapse rates compared to valproic acid. 4
• Lithium appears less effective than lamotrigine in preventing depression, which is particularly relevant given that bipolar II is characterized by predominant depressive episodes. 5

Unique Anti-Suicidal Properties

One area where lithium maintains clear superiority across all bipolar subtypes:

• Lithium reduces suicide attempts 8.6-fold and completed suicides 9-fold, an effect independent of its mood-stabilizing properties. 2, 6, 7
• Lithium is the only drug effective in the prophylaxis of suicidal symptoms in bipolar disorder. 4
• Discontinuation of lithium is associated with a 7-fold increase in suicide attempts and 9-fold increase in completed suicides. 6

Clinical Decision Algorithm for Bipolar II

For bipolar II patients with prominent hypomanic episodes and suicide risk: Lithium remains a rational first-line choice given its anti-suicidal properties and efficacy against hypomania. 2, 6

For bipolar II patients with predominant depressive episodes: Consider lamotrigine as first-line instead, as it demonstrates superior efficacy for preventing depressive episodes compared to lithium. 5

For bipolar II patients requiring acute depression treatment: The olanzapine-fluoxetine combination or a mood stabilizer with careful addition of an antidepressant is preferred over lithium monotherapy. 2

Monitoring Requirements

If lithium is prescribed for bipolar II:

• Baseline laboratory assessment must include complete blood count, thyroid function tests, urinalysis, BUN, creatinine, serum calcium, and pregnancy test in females. 2
• Ongoing monitoring requires lithium levels, renal and thyroid function, and urinalysis every 3-6 months. 2
• Target therapeutic levels are 0.8-1.2 mEq/L for acute treatment and 0.6-1.0 mEq/L for maintenance. 2, 8

Common Pitfalls

• Extrapolating bipolar I efficacy data to bipolar II without recognizing the different clinical course and treatment response patterns. 1
• Failing to recognize that bipolar II patients may not experience the same degree of relapse prevention from lithium, particularly for depressive episodes. 1
• Abrupt lithium discontinuation, which increases rebound risk even in bipolar II patients who may not have shown robust initial response. 6
• Inadequate trial duration—lithium requires 6-8 weeks at therapeutic doses before concluding ineffectiveness. 2