Combining Latuda (Lurasidone) and Mirtazapine
Direct Recommendation
The combination of lurasidone and mirtazapine is pharmacologically rational and generally safe for patients with bipolar depression, particularly when depressive symptoms persist despite mood stabilizer therapy, though this combination lacks specific clinical trial data and requires careful monitoring for sedation and metabolic effects. 1, 2
Evidence-Based Rationale
Lurasidone's Role in Bipolar Depression
Lurasidone is FDA-approved for bipolar I depression both as monotherapy (20-120 mg/day) and as adjunctive therapy with lithium or valproate (20-120 mg/day), with demonstrated efficacy (NNT 5-7 for response) and favorable metabolic profile compared to other atypical antipsychotics 1, 2, 3
Lurasidone must be taken with food (at least 350 calories) as administration with food increases absorption approximately 2-fold for AUC and 3-fold for Cmax 1
Common adverse events with lurasidone include akathisia, extrapyramidal symptoms, and somnolence (incidence ≥5% and at least twice placebo rate), with minimal metabolic or electrocardiogram abnormalities 3, 4
Mirtazapine's Pharmacological Profile
Mirtazapine is a sedating antidepressant with faster onset of action than SSRIs (fluoxetine, paroxetine, sertraline), though it is associated with weight gain as a notable side effect 5
Mirtazapine may be considered as a low-dose sedating antidepressant for insomnia when accompanied by comorbid depression, though evidence for efficacy when used alone is relatively weak 5
The American College of Physicians emphasizes that antidepressants in bipolar disorder should never be used as monotherapy and must always be combined with mood stabilizers to prevent mood destabilization 5
Clinical Algorithm for Combination Use
When to Consider This Combination
Primary indication: Persistent depressive symptoms in bipolar I disorder despite adequate trial of lurasidone monotherapy or adjunctive therapy with lithium/valproate 1, 2
Secondary consideration: Comorbid insomnia requiring pharmacological intervention beyond lurasidone's sedating effects 5
Patient has failed or cannot tolerate SSRI augmentation strategies due to activation, sexual dysfunction, or other adverse effects 5
Dosing Strategy
Start lurasidone at 20 mg daily with food, titrating based on response up to 120 mg/day maximum (most patients respond in the 20-80 mg/day range) 1, 4
Add low-dose mirtazapine 7.5-15 mg at bedtime initially, with potential titration to 30-45 mg if depressive symptoms persist and tolerability allows 5
Always ensure concurrent mood stabilizer therapy (lithium or valproate at therapeutic levels) when combining any antidepressant with lurasidone in bipolar disorder 6, 1, 7
Critical Monitoring Requirements
Baseline metabolic assessment: BMI, waist circumference, blood pressure, fasting glucose, and fasting lipid panel before initiating combination therapy 6
Follow-up monitoring: BMI monthly for 3 months then quarterly; blood pressure, fasting glucose, and lipids at 3 months then yearly 6
Weekly assessment for mood destabilization, emergence of manic symptoms, akathisia, or excessive sedation during the first 4-8 weeks 5, 1
Monitor for additive sedation risk, particularly during initial titration, as both agents can cause somnolence 1, 3
Important Safety Considerations
Drug Interaction Profile
Lurasidone dose adjustment is required with moderate CYP3A4 inhibitors or inducers, and in patients with moderate-to-severe renal impairment (maximum 80 mg/day for creatinine clearance <50 mL/min) 1, 3
Mirtazapine has minimal anticholinergic activity compared to tricyclic antidepressants but carries significant weight gain risk 5
No major pharmacokinetic interactions are expected between lurasidone and mirtazapine, though pharmacodynamic effects (sedation, weight gain) may be additive 1, 3
Metabolic Risk Management
The combination carries cumulative weight gain risk: NNH for ≥7% weight gain is 58 for lurasidone monotherapy and 36 for lurasidone adjunctive to mood stabilizers, while mirtazapine independently causes weight gain 2
Proactive weight management counseling, dietary guidance, and exercise recommendations are essential at treatment initiation 6
Consider adjunctive metformin (starting 500 mg daily, titrating to 1000 mg twice daily) if significant weight gain occurs or baseline metabolic syndrome is present 6
Mood Destabilization Risk
Antidepressant-induced mood destabilization, including mania induction and rapid cycling, remains a concern even with concurrent mood stabilizer therapy 6, 2
Schedule follow-up within 1-2 weeks of adding mirtazapine to assess for agitation, decreased need for sleep, increased goal-directed activity, or other manic symptoms 5
If mood destabilization occurs, immediately discontinue mirtazapine and optimize mood stabilizer dosing before considering alternative augmentation strategies 6
Common Pitfalls to Avoid
Never use mirtazapine (or any antidepressant) as monotherapy in bipolar disorder—this dramatically increases risk of mood destabilization and treatment-emergent mania 5, 6
Avoid rapid titration of either agent; lurasidone requires no initial titration but mirtazapine should be increased gradually to assess tolerability 1
Do not overlook food requirement for lurasidone administration—inadequate caloric intake with dosing substantially reduces absorption and efficacy 1, 3
Failure to monitor metabolic parameters leads to missed opportunities for early intervention when weight gain or metabolic syndrome develops 6
Inadequate duration of maintenance therapy (minimum 12-24 months after mood stabilization) leads to high relapse rates exceeding 90% in noncompliant patients 6
Alternative Considerations
If this combination fails after 6-8 weeks at adequate doses, consider switching mirtazapine to bupropion (150-300 mg/day), which has lower mood destabilization risk and may address motivational symptoms through dopaminergic effects 6
For treatment-resistant bipolar depression, olanzapine-fluoxetine combination or quetiapine monotherapy represent alternative FDA-approved options with similar efficacy (NNT 4-7) but different tolerability profiles 2, 8
Psychoeducation and cognitive-behavioral therapy should accompany all pharmacotherapy to improve long-term outcomes and medication adherence 6