250. Efficacy of adjunctive lumateperone 42 mg treatment across patient-reported depression symptoms in major depressive disorder

Abstract

Abstract Background Patient-reported outcomes are increasingly used as endpoints in clinical trials, as they offer a unique perspective about symptoms and ensure comprehensive treatment assessment. Because patients with major depressive disorder (MDD) often experience persistent depression symptoms, a treatment for MDD that improves patient-reported symptoms would be beneficial. Lumateperone is a mechanistically novel FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder, and as adjunctive therapy for MDD. In a previous Phase 3, randomized, double-blind, placebo-controlled trial (Study 502, NCT05061706), adjunctive lumateperone 42 mg met the primary endpoint, significantly improving Montgomery-Asberg Depression Rating Scale (MADRS) Total score vs adjunctive placebo, and was generally well tolerated in patients with MDD with inadequate antidepressant therapy (ADT) response. Aims & Objectives This analysis of Study 502 evaluated the efficacy of adjunctive lumateperone 42 mg across patient-reported depression symptoms measured by symptom domains of the Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score. Method Eligible adults (18-65y) met DSM-5 criteria for MDD with inadequate response to 1-2 ADTs in the current depressive episode (<50% improvement on the Antidepressant Treatment Response Questionnaire) and had MADRS Total score ≥24, Clinical Global Impression-Severity score ≥4, and QIDS-SR-16 score ≥14. Patients were randomized (1:1) to receive 6-week lumateperone 42 mg or placebo adjunctive to ADT. A prespecified analysis measured change from baseline to end of treatment (EOT) in QIDS-SR-16 Total score using an analysis of covariance (ANCOVA) in the intent-to-treat (ITT) population. Post hoc analyses measured changes using an ANCOVA in the ITT population in the 9 symptom domains of the QIDS-SR-16 score: sleep disturbance (highest score of items 1-4), sad mood, appetite/weight change (highest score of items 6-9), concentration, self-criticism, suicidal ideation, interest, energy/fatigue, and psychomotor agitation/retardation (highest score of items 15-16). Results All 480 treated patients were included in the ITT population (lumateperone + ADT, n=242; placebo + ADT, n=238), and 429 (89.4%) completed treatment. Lumateperone + ADT significantly improved QIDS-SR-16 Total score vs placebo + ADT from baseline to EOT (least squares mean difference vs placebo [LSMD], −2.2; effect size [ES], −0.45; P<.0001). The most prominent QIDS-SR-16 symptom domains at baseline in the lumateperone + ADT group were sleep disturbance (mean: lumateperone + ADT, 2.7; placebo + ADT, 2.7), sad mood (lumateperone + ADT, 2.6; placebo + ADT, 2.7) and concentration (lumateperone + ADT, 2.3; placebo + ADT, 2.3). From baseline to EOT, 6 of 9 QIDS-SR-16 symptom domains significantly improved with lumateperone + ADT vs placebo + ADT: sleep disturbance (LSMD, −0.61; ES, −0.65; P<.0001); sad mood (LSMD, −0.35; ES, −0.41; P<.0001); appetite/weight change (LSMD, −0.11; ES, −0.12; P=.179); concentration (LSMD, −0.20; ES, −0.25; P<.01); self-criticism (LSMD, −0.33; ES, −0.37; P<.0001); suicidal ideation (LSMD, −0.04; ES, −0.12; P=.188); interest (LSMD, −0.29; ES, −0.32; P<.001); energy/fatigue (LSMD, −0.21; ES, −0.26; P<.01); and psychomotor agitation/retardation (LSMD, −0.12; ES, −0.17; P=.065). Discussion & Conclusions Lumateperone 42 mg + ADT significantly improved a broad range of patient-reported depression symptoms vs placebo + ADT in patients with MDD with inadequate ADT response.