Lumateperone in the Treatment of Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: Evaluation of Extrapyramidal and Motor Symptoms in Late-Phase Clinical Trials

This work was sponsored by Intra-Cellular Therapies, Inc. Background: Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder as monotherapy and as adjunctive therapy with lithium or valproate. This analysis evaluated extrapyramidal symptoms (EPS) across studies of lumateperone for bipolar depression. Methods: All trials enrolled adults (18-75 years) with bipolar I or bipolar II disorder who were experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale Total score≥20, Clinical Global Impression Scale-Bipolar Version-Severity score≥4). Lumateperone 42-mg was administered once-daily. This analysis included 3 groups: 2 pooled, 6-week, placebo-controlled monotherapy studies (NCT02600494, NCT03249376); a 6-month open-label extension (OLE) monotherapy study; and a 6-week, placebo-controlled adjunctive lumateperone study (NCT02600507). EPS-related treatment-emergent adverse events (TEAEs) and clinician-rated motor scales were reported. Results: The short-term population comprised 746 patients in pooled monotherapy trials (placebo, 374; lumateperone, 372) and 352 patients in the adjunctive study (adjunctive placebo, 175; adjunctive lumateperone, 177). Reported EPS-related TEAEs were 1 patient (0.3%) with mild dyskinesia (lumateperone monotherapy), 1 (0.6%) with mild akathisia (adjunctive lumateperone), and 1 (0.3%) with severe akathisia (placebo monotherapy). Benztropine and propranolol use was rare (