Latuda (Lurasidone) for Major Depressive Disorder with Mixed Features
Direct Recommendation
Lurasidone is FDA-approved and effective for bipolar I depression, NOT for unipolar major depressive disorder (MDD) with mixed features. The FDA indication is specifically limited to "major depressive episode associated with bipolar I disorder" as monotherapy (20-120 mg/day) or adjunctive to lithium/valproate 1.
Critical Distinction: Bipolar Depression vs. Unipolar MDD with Mixed Features
FDA-Approved Indication
- Lurasidone is approved ONLY for bipolar I depression, not unipolar MDD with mixed features 1
- The approved dose range is 20-120 mg/day for adults, taken with food (at least 350 calories) 1
- For pediatric patients (10-17 years) with bipolar depression, the dose range is 20-80 mg/day 1
Off-Label Research in Unipolar MDD with Mixed Features
While not FDA-approved for this indication, research studies have evaluated lurasidone in unipolar MDD with DSM-5 mixed features (≥2-3 manic symptoms):
- Lurasidone 20-60 mg/day demonstrated efficacy in reducing depressive symptoms in patients with unipolar MDD plus 2-3 manic symptoms, with effect sizes of 0.59-0.95 depending on baseline anxiety severity 2
- Recovery rates (symptomatic + functional remission) were significantly higher with lurasidone (31.3%) versus placebo (12.2%) at 6 weeks 3
- The presence of specific manic symptoms moderated treatment response: patients with "elevated mood" and "increased motor activity-energy" showed less improvement, while "rapid/pressured speech" predicted better response 4
Dosing Algorithm (If Used Off-Label for Unipolar MDD with Mixed Features)
Starting dose: 20 mg once daily with food (≥350 calories) 1, 3
Titration: Flexible dosing 20-60 mg/day based on response and tolerability 3, 2
Key caveat: Higher doses (80-120 mg/day) did not provide additional efficacy in bipolar depression studies and may increase adverse effects 1
Safety Profile and Monitoring
Common Adverse Effects
- Akathisia, extrapyramidal symptoms, and somnolence are most frequent 5
- Favorable metabolic profile: Minimal weight gain and metabolic disturbances compared to other atypical antipsychotics 5, 6
Critical Warnings
- Black box warning for suicidal thoughts/behaviors in antidepressant use, requiring close monitoring 1
- Must be taken with food; absorption increases 2-fold (AUC) and 3-fold (Cmax) when administered with at least 350 calories 1
Dose Adjustments
- Moderate renal impairment (CrCl 30-50 mL/min): Start 20 mg/day, maximum 80 mg/day 1
- Severe renal impairment (CrCl <30 mL/min): Start 20 mg/day, maximum 80 mg/day 1
Clinical Context: Standard MDD Treatment
The American College of Physicians guidelines for MDD do not include atypical antipsychotics as first-line monotherapy 7. Standard first-line options include:
- Second-generation antidepressants (SSRIs, SNRIs) with or without psychotherapy 7, 8
- Cognitive behavioral therapy (CBT) shows equivalent efficacy to antidepressants 7, 8
Atypical antipsychotics like lurasidone are only FDA-approved as adjunctive treatment in treatment-resistant unipolar MDD (quetiapine, aripiprazole, olanzapine), not as monotherapy 6.
Bottom Line Algorithm
Confirm diagnosis: Is this bipolar I depression or unipolar MDD with mixed features?
If considering off-label use for unipolar MDD with mixed features:
Administration: Always with ≥350 calories to ensure adequate absorption 1
Monitor: Suicidality, extrapyramidal symptoms, akathisia, and metabolic parameters 1, 5