What mood stabilizer can I start for a patient with a depressive episode?

Mood Stabilizer Selection for Depressive Episode in Bipolar Disorder

Lithium should be your first-line mood stabilizer for a patient with a depressive episode in the context of bipolar disorder, particularly if there is any history of suicidal ideation or attempts. 1, 2, 3

Primary Recommendation: Lithium

Lithium is the only mood stabilizer with robust evidence for preventing both manic and depressive episodes in bipolar disorder, and it uniquely reduces suicide attempts by 8.6-fold and completed suicides by 9-fold—an effect independent of its mood-stabilizing properties. 1, 2, 3, 4

Evidence Supporting Lithium as First-Line

• Lithium demonstrates superior efficacy compared to placebo and other mood stabilizers for preventing relapse or recurrence of any mood episodes in bipolar I disorder 3, 5
• Recent systematic reviews confirm lithium is the only drug proven efficacious in preventing manic, mixed, and depressive episodes in trials not enriched for prior lithium response 5
• Lithium shows a median survival time of 81 months before relapse, compared to 42 months for carbamazepine and 36 months for valproate 6
• The hazard of relapse is 66% higher with valproate compared to lithium after controlling for symptom covariates 6

Lithium Initiation Protocol

• Target therapeutic level: 0.8-1.2 mEq/L for acute treatment; 0.6-1.0 mEq/L for maintenance 1
• Baseline laboratory assessment required: Complete blood count, thyroid function tests, urinalysis, BUN, creatinine, serum calcium, and pregnancy test in females 1, 2
• Ongoing monitoring: Lithium levels, renal and thyroid function, and urinalysis every 3-6 months 1, 2
• Starting dose: 300 mg three times daily (900 mg/day) for patients ≥30 kg, with weekly increases of 300 mg until therapeutic levels achieved 1

Alternative Option: Lamotrigine

If lithium is contraindicated or not tolerated, lamotrigine is the preferred alternative specifically for bipolar depression, as it is particularly effective for preventing depressive episodes. 1, 2

When to Choose Lamotrigine

• Patient has predominantly depressive episodes rather than manic episodes 1, 2
• Lithium is contraindicated due to renal disease or thyroid dysfunction 1
• Patient cannot tolerate lithium's side effects (tremor, polyuria, weight gain) 1
• Patient has concerns about the metabolic effects of other mood stabilizers 1

Critical Lamotrigine Safety Requirement

• Slow titration is mandatory to minimize risk of Stevens-Johnson syndrome and serious rash 1
• Never rapid-load lamotrigine—this dramatically increases risk of potentially fatal rash 1
• If lamotrigine was discontinued for more than 5 days, restart with the full titration schedule rather than resuming the previous dose 1

Valproate: Third-Line Option

Valproate may be considered if both lithium and lamotrigine are unsuitable, but it has weaker evidence for preventing depressive episodes specifically 1, 7, 6

• Valproate shows higher response rates (53%) compared to lithium (38%) in children and adolescents with mania and mixed episodes, but this advantage does not extend to depression prevention 1
• Valproate is particularly effective for mixed or dysphoric mania and irritability, but less effective for pure depressive episodes 1, 7
• Baseline monitoring requires liver function tests, complete blood count, and pregnancy test in females 1, 2

Critical Clinical Algorithm for Decision-Making

1. First, assess suicide risk: If any history of suicidal ideation or attempts exists, lithium is strongly preferred due to its unique anti-suicide effects 2, 3, 4

2. Second, evaluate episode pattern: If depressive episodes predominate over manic episodes, consider lamotrigine as an alternative to lithium 1, 2

3. Third, check for contraindications: Obtain baseline renal and thyroid function before initiating lithium 1, 2

4. Fourth, plan for combination therapy if needed: If monotherapy with a mood stabilizer proves insufficient after 6-8 weeks at therapeutic levels, consider adding an SSRI (fluoxetine preferred) or bupropion, but never use antidepressants as monotherapy in bipolar disorder 1, 2

Common Pitfalls to Avoid

• Never start an antidepressant without a mood stabilizer in place first—this can trigger manic episodes or rapid cycling 1, 2
• Inadequate trial duration: Allow 6-8 weeks at therapeutic doses before concluding a mood stabilizer is ineffective 1
• Premature discontinuation: Maintain therapy for at least 12-24 months after mood stabilization, with some patients requiring lifelong treatment 1, 2
• Failure to monitor therapeutic levels: Subtherapeutic levels are a common cause of apparent treatment failure 1
• Neglecting psychosocial interventions: Combine pharmacotherapy with psychoeducation and cognitive-behavioral therapy for optimal outcomes 1, 2

Maintenance Therapy Duration

• Continue mood stabilizer for at least 12-24 months after achieving mood stabilization 1, 2
• For patients with two or more depressive episodes, longer duration (potentially lifelong) may be necessary 8, 1
• Withdrawal of lithium dramatically increases relapse risk, especially within 6 months of discontinuation, with >90% of noncompliant patients relapsing versus 37.5% of compliant patients 1, 2