Evaluation of Mania and Hypomania in Late-Phase Clinical Trials of Lumateperone in the Treatment of Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder

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 mania/hypomania across studies of lumateperone for bipolar depression. Methods: Trials enrolled adults (18-75 years) with bipolar I or II disorder experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale Total score≥20, Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score≥4). Lumateperone 42mg 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; a 6-week, placebo-controlled adjunctive lumateperone study (NCT02600507). Mania/hypomania treatment-emergent adverse events (TEAEs) were monitored. Results: The short-term safety population comprised 746 patients in monotherapy trials (placebo, 374; lumateperone, 372) and 352 patients in the adjunctive study (adjunctive placebo, 175; adjunctive lumateperone, 177). Mania/hypomania TEAEs were reported in 11 patients (placebo, 5 [1.3%]; lumateperone, 6 [1.6%]) in the monotherapy groups and in 2 patients (adjunctive placebo, 1 [0.6%]; adjunctive lumateperone, 1 [0.6%]) who received adjunctive treatment. Mania/hypomania TEAEs were mild or moderate in severity. There was 1 serious mania TEAE (lumateperone monotherapy) and no serious hypomania TEAEs. The long-term OLE safety population comprised 127 patients. One patient (0.8%) had a mild mania TEAE which was not serious. No patients had hypomania TEAEs. Conclusion: In patients with bipolar depression, lumateperone 42-mg monotherapy or adjunctive therapy was associated with low rates of treatment-emergent mania and hypomania that were similar to placebo in acute and long-term treatment.