LUMATEPERONE IN THE TREATMENT OF PATIENTS WITH MAJOR DEPRESSIVE DISORDER AND BIPOLAR DISORDER WITH ANXIOUS DISTRESS AND MIXED FEATURES

Abstract Background Anxious distress and mixed features are DSM-5 episode specifiers for major depressive episodes (MDE) associated with major depressive disorder (MDD) and bipolar disorder. Patients with depressive episodes with the specifiers have more severe symptoms, more comorbidities, increased suicide risk, and poorer treatment response than patients without the specifiers. Aims & Objectives Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. In a Phase 3, randomized, double-blind, placebo-controlled trial (Study 403; NCT04285515) lumateperone 42mg was efficacious over placebo with a favorable safety profile in patients with MDD or bipolar depression (BPD) with mixed features. This post hoc analysis of Study 403 investigated efficacy of lumateperone 42mg in patients with MDD or BPD with mixed features and anxious distress. Method Eligible adults (18-75 years) met DSM-5 criteria for an MDE with mixed features and had MDD, bipolar I, or bipolar II disorder, with Montgomery-Å sberg Depression Rating Scale [MADRS] Total score>=24 and Clinical Global Impression Scale-Severity [CGI-S] score>=4. Patients were stratified by MDD or bipolar disorder diagnosis and randomized 1:1 to 6-weeks lumateperone 42mg or placebo. This analysis evaluated patients with mixed features and DSM-5 anxious distress in the overall population (combined MDD/BPD) and separately in MDD and BPD individual populations. Assessments included change from baseline in MADRS Total score, CGI-S score, and MADRS inner tension item score. Results Of 383 patients in the combined MDD/BPD modified intent to treat (mITT) population with mixed features, 244 (63.7% of mITT; placebo, 121; lumateperone, 123) had anxious distress. Anxious distress was common in patients with MDD (73.9% of MDD mITT; placebo, 69; lumateperone, 67) and BPD (54.3% of BPD mITT; placebo, 52; lumateperone, 56). Compared with placebo, lumateperone significantly improved change from baseline for MADRS Total score at Day 43 in all 3 populations with anxious distress: combined MDD/BPD population (least squares mean difference vs placebo [LSMD], −6.1; 95% CI −8.52 to −3.71; effect size [ES], −0.67; P<.0001), MDD individual population (LSMD, −6.8; 95% CI −9.82 to −3.77; ES, −0.79; P<.0001), and BPD individual population (LSMD, −5.5; 95% CI −9.34 to −1.62; ES, −0.59; P<.01). In all 3 populations, significantly greater (P <.05) reductions in change from baseline of MADRS Total score occurred by Day 15 and persisted throughout the study in lumateperone-treated patients. Similarly, lumateperone significantly improved change from baseline for CGI-S score at Day 43 vs placebo for patients with anxious distress in the combined MDD/BPD population (LSMD, −0.5; 95% CI −0.78 to −0.26; ES, −0.54; P<.0001), MDD individual population (LSMD, −0.6; 95% CI −0.98 to −0.30; ES, −0.66; P<.001), and BPD individual population (LSMD, −0.4; 95% CI −0.82 to −0.05; ES, −0.48; P<.05). Lumateperone also significantly improved change from baseline for the inner tension MADRS single-item score at Day 43 compared with placebo for all 3 populations (P<.05). Discussion & Conclusion Lumateperone 42mg demonstrated efficacy in improving symptoms of major depression with mixed features and anxious distress, including global disease severity and inner tension, in patients with MDD or bipolar disorder.