Changes in Metabolic Parameters Associated With Lumateperone in Late-Phase Clinical Trials for 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 the metabolic impact of lumateperone in patients with bipolar depression. Methods: All trials enrolled adults (18-75 years) with bipolar I or bipolar II disorder 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; a 6-month open-label extension (OLE) monotherapy study; and a 6-week, placebo-controlled adjunctive lumateperone study. Changes from baseline to end of treatment in vital signs and cardiometabolic parameters were reported and analyzed in body mass index (BMI) subgroups. Results: The short-term population comprised 746 patients in pooled monotherapy trials and 352 patients in the adjunctive study. Mean changes with lumateperone were similar to placebo for weight, BMI, and waist circumference. With lumateperone, no patients had potentially clinically significant (PCS) weight gain (≥7% increase) and changes in cardiometabolic parameters were similar to placebo. The OLE population comprised 127 patients. There was no mean increase in weight, BMI, or waist circumference with lumateperone. During treatment, 3.4% of patients experienced PCS weight increase and 6.0% had PCS weight loss. There were no clinically significant changes in cardiometabolic parameters. Conclusion: In bipolar depression, lumateperone 42-mg monotherapy or adjunctive therapy had a favorable acute and long-term metabolic profile.