Efficacy and Safety of Lumateperone (ITI-007) in the Treatment of Depressive Episodes Associated With Bipolar I and II Disorders

Background: Treatments for bipolar depression are limited. Lumateperone (lumateperone tosylate, ITI-007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia. This phase 3 randomized, double-blind, placebo-controlled study (NCT03249376) investigated the efficacy and safety of lumateperone in patients with bipolar I or bipolar II disorder experiencing a major depressive episode (MDE). 

Methods: Patients (18─75 years) with a clinical diagnosis of bipolar I or II disorder experiencing a MDE were randomized to lumateperone 42 mg or placebo and treated for 6 weeks. The primary efficacy endpoint was change from baseline to Day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score. Safety assessments included treatment emergent adverse events (TEAEs), laboratory parameters, vital signs, extrapyramidal symptoms (EPS). 

Results: There were 377 patients randomized (placebo, 189; lumateperone, 188) and 333 completed treatment. Lumateperone treatment significantly improved MADRS Total score compared with placebo (least squares mean difference [LSMD]=−4.6; 95% confidence interval [CI]=−6.34, −2.83; effect size vs placebo [ES]=−0.56; P < .0001). Lumateperone treatment significantly improved MADRS scores in patients with bipolar I (LSMD=−4.0; 95% CI=−5.92, −1.99; ES=−0.49; P < .0001) and bipolar II (LSMD=−7.0; 95% CI=−10.92, −3.16; ES=−0.81; P=.0004) disorder. Lumateperone treatment was well tolerated, with minimal risk of metabolic, EPS, and prolactin side effects.

Conclusion: Lumateperone 42 mg significantly improved depression symptoms in patients with bipolar I and bipolar II depression and was generally well tolerated, suggesting lumateperone 42 mg may be a promising new treatment for bipolar depression associated with bipolar I or bipolar II disorder.