What mood stabilizer should be added?

Mood Stabilizer Selection for Bipolar Disorder

Direct Recommendation

For first-line mood stabilization in bipolar disorder, lithium or valproate should be added, with lithium being the superior choice when long-term efficacy and suicide prevention are priorities, and valproate preferred when rapid control of mixed/dysphoric mania is needed. 1, 2

Evidence-Based Selection Algorithm

First-Line Options

Lithium remains the gold standard mood stabilizer with the most comprehensive evidence base across all phases of bipolar disorder treatment 1, 3:

• Lithium is the only FDA-approved agent for bipolar disorder in patients age 12 and older and demonstrates response rates of 38-62% in acute mania 1
• Lithium reduces suicide attempts 8.6-fold and completed suicides 9-fold, an effect independent of its mood-stabilizing properties 1, 2
• Lithium shows superior evidence for long-term efficacy in preventing both manic and depressive episodes in maintenance therapy 1
• Target serum level is 0.8-1.2 mEq/L for acute treatment 1, 2

Valproate represents an equally valid first-line alternative with specific advantages 1, 4:

• Valproate shows higher response rates (53%) compared to lithium (38%) in children and adolescents with mania and mixed episodes 1
• Valproate is particularly effective for mixed or dysphoric mania 1
• Valproate has been shown to be as effective as lithium for maintenance therapy 1
• Therapeutic blood level target is 40-90 mcg/mL 1

Choosing Between Lithium and Valproate

Select lithium when:

• Long-term maintenance and suicide prevention are primary concerns 1, 2
• Patient can tolerate regular monitoring (lithium levels, renal and thyroid function every 3-6 months) 1, 2
• Sedation is a major concern (lithium is NOT associated with significant sedation) 1

Select valproate when:

• Mixed or dysphoric mania is present 1
• Rapid symptom control is needed 1
• Patient is a child or adolescent (higher response rates) 1
• Lithium is contraindicated or not tolerated 4

Alternative and Adjunctive Options

Lamotrigine should be considered for:

• Maintenance therapy, particularly for preventing depressive episodes 1, 2, 5
• Lamotrigine significantly delays time to intervention for any mood episode in bipolar I disorder 2
• Must be titrated slowly to minimize risk of Stevens-Johnson syndrome - if discontinued for more than 5 days, restart with full titration schedule 1, 2

Atypical antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) are recommended:

• For acute mania, particularly with psychotic features or severe agitation 1
• When more rapid symptom control is needed than mood stabilizers alone provide 1
• Combination therapy with lithium or valproate plus an atypical antipsychotic is considered for severe presentations 1

Combination Therapy Considerations

Combination therapy is more effective than monotherapy in specific situations 1, 6:

• Lithium plus valproate combination prevents relapse more effectively than valproate monotherapy (RR 0.78,95% CI 0.63 to 0.96) 1
• Quetiapine plus valproate is more effective than valproate alone for adolescent mania 1
• The safest and most efficacious mood stabilizer combinations are mixtures of anticonvulsants and lithium, particularly valproate plus lithium 6

Critical Monitoring Requirements

For lithium 1, 2:

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

For valproate 1, 7:

• Baseline: liver function tests, complete blood count, pregnancy test in females
• Ongoing: serum drug levels, hepatic function, hematological indices every 3-6 months
• Valproate is associated with polycystic ovary disease in females 1

For lamotrigine 2:

• Monitor weekly for rash, particularly during first 8 weeks of titration
• Serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration 7

Duration of Treatment

Maintenance therapy must continue for at least 12-24 months after the acute episode 1, 2:

• Some individuals will require lifelong treatment when benefits outweigh risks 1, 2
• Withdrawal of maintenance lithium therapy increases relapse risk, especially within 6 months following discontinuation 1
• More than 90% of adolescents who were noncompliant with lithium treatment relapsed, compared to 37.5% of those who were compliant 1

Common Pitfalls to Avoid

Critical errors in mood stabilizer management 1, 2:

• Antidepressant monotherapy can trigger manic episodes or rapid cycling - always combine with a mood stabilizer 1
• Inadequate duration of maintenance therapy leads to relapse rates exceeding 90% in noncompliant patients 1
• Systematic medication trials require 6-8 weeks at adequate doses before concluding an agent is ineffective 1
• Premature discontinuation of effective medications dramatically increases relapse risk 1
• Failure to monitor for metabolic side effects of atypical antipsychotics, particularly weight gain 1

Special Drug Interactions

When valproate is used concurrently 7:

• Valproate increases lamotrigine half-life from 26 to 70 hours (165% increase) - lamotrigine dose must be reduced 7
• Valproate increases phenobarbital half-life by 50% and decreases clearance by 30% 7
• Valproate increases free fraction of phenytoin by 60% 7
• Concomitant valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy 7