Can a patient with bipolar disorder be prescribed mirtazapine (Remeron) 15mg and Depakote (valproate) 500mg twice a day (bid)?

Can Mirtazapine and Depakote Be Prescribed Together in Bipolar Disorder?

Yes, a patient with bipolar disorder can be prescribed mirtazapine 15mg with Depakote (valproate) 500mg BID, as this combination represents appropriate treatment when mirtazapine is used adjunctively with a mood stabilizer for specific indications like insomnia or depression. 1, 2, 3

Critical Requirement: Mood Stabilizer Must Be Present

Mirtazapine should never be used as monotherapy in bipolar disorder due to the risk of triggering mania or hypomania. 2 The FDA drug label explicitly requires screening for bipolar disorder prior to initiating mirtazapine and warns against antidepressant monotherapy in this population. 2

• The presence of Depakote 500mg BID (total daily dose 1000mg) provides the necessary mood stabilization to safely use mirtazapine. 1, 3
• Valproate therapeutic levels should be maintained at 40-90 mcg/mL (some sources cite 50-100 mcg/mL) to ensure adequate mood stabilization before adding any antidepressant. 4, 1

Evidence Supporting This Combination

Low-dose mirtazapine (15mg) combined with a mood stabilizer carries minimal risk of inducing mania and is considered safe for treating insomnia or depression in bipolar disorder. 3

• A 2015 systematic review found that low doses of mirtazapine used for hypnotic/sedative effects caused mania only in patients with other risk factors for switching, and there is no evidence that mirtazapine increases switching risk when combined with a mood stabilizer. 3
• Mirtazapine at 7.5-30mg at bedtime is recognized as "potent and well tolerated" and "promotes sleep, appetite, and weight gain." 4

Appropriate Clinical Indications for This Combination

This combination is most appropriate when:

• Treating bipolar depression: Valproate provides mood stabilization while mirtazapine addresses depressive symptoms. 1, 3
• Managing insomnia: Mirtazapine's sedating properties at 15mg make it useful for sleep disturbances common in bipolar disorder. 4, 1
• Addressing anxiety symptoms: Both medications have anxiolytic properties that complement each other. 1

Monitoring Requirements

Regular monitoring is essential when using this combination:

• Check valproate levels, liver function tests, and complete blood count at baseline, then every 3-6 months. 4, 1
• Monitor closely for signs of mood destabilization, particularly manic symptoms, especially in the first 4-8 weeks after adding mirtazapine. 1, 2
• Assess for treatment-emergent mania including decreased need for sleep, racing thoughts, increased energy, or impulsive behavior. 5

Dosing Considerations

The proposed doses are appropriate:

• Mirtazapine 15mg is the FDA-recommended starting dose and falls within the safe range for adjunctive use in bipolar disorder. 2, 3
• Depakote 500mg BID (1000mg total daily) is within the therapeutic range, though levels should be verified to ensure they fall within 40-90 mcg/mL. 4, 1
• Initial valproate dosing typically starts at 125mg twice daily and is titrated to therapeutic levels. 4

Common Pitfalls to Avoid

Never use mirtazapine monotherapy in bipolar disorder—this dramatically increases the risk of mood destabilization and mania induction. 5, 2

• Ensure valproate has reached therapeutic levels before adding mirtazapine, requiring at least 5-7 days at stable dosing. 1
• Do not increase mirtazapine dose above 30mg without careful consideration, as higher doses (used for antidepressant rather than hypnotic effects) carry increased switching risk. 3
• Avoid combining with other serotonergic agents without monitoring for serotonin syndrome. 1

Alternative Considerations

If this combination proves inadequate:

• For persistent depression: Consider switching to FDA-approved options like olanzapine-fluoxetine combination or lurasidone, which have stronger evidence for bipolar depression. 1, 5, 6
• For insomnia alone: Low-dose quetiapine (25-100mg) or trazodone (25-100mg) are alternatives with mood-stabilizing properties. 1
• For anxiety: Buspirone 5mg twice daily (maximum 20mg three times daily) can be added as a non-benzodiazepine anxiolytic. 4, 1

Duration of Treatment

Maintenance therapy with valproate should continue for at least 12-24 months after mood stabilization, with some patients requiring lifelong treatment. 1, 7

• Mirtazapine can be used long-term if beneficial, but should be periodically reassessed (every 9 months) to determine ongoing need. 4
• Withdrawal of maintenance mood stabilizer therapy dramatically increases relapse risk, with over 90% of noncompliant patients relapsing versus 37.5% of compliant patients. 1, 7