Lumateperone (ITI−007) in the Treatment of Bipolar Depression: Results from a Randomized Clinical Trial

Abstract

Study ObjectiveApproved treatments for bipolar depression are limited and associated with a spectrum of undesirable side effects. 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. Lumateperone is currently being investigated for the treatment of bipolar depression (major depressive episodes [MDE] associated with bipolar I and bipolar II disorder). This Phase 3 randomized, double-blind, parallel-group, placebo-controlled multinational study (NCT03249376) investigated the efficacy and safety of lumateperone in patients with bipolar I or bipolar II disorder experiencing a MDE.MethodPatients (18 75 years) with a clinical diagnosis of bipolar I or bipolar II disorder who were experiencing a MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score =20 and a Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score =4 at screening and baseline) were randomized to lumateperone 42mg or placebo for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS total score and CGI-BP-S scores, respectively. Secondary efficacy outcomes included response (MADRS improvement = 50%) and remission (MADRS total score =12) at Day 43. Safety assessments included treatment emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms (EPS), and suicidality.ResultsIn this study, 377 patients received treatment (placebo, n=189; lumateperone 42mg, n=188) and 333 completed treatment. Patients in the lumateperone 42-mg group had significantly greater mean improvement on MADRS total score change from baseline to Day 43 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 was associated with significant MADRS improvement in both 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). The lumateperone 42-mg group also had significantly greater mean improvement in CGI-BP-S total score compared with placebo (LSMD=-0.9; 95% CI=-1.37, −0.51; ES=-0.46; P<.001). Lumateperone compared with placebo had significantly greater MADRS response rate (51.1% vs 36.7%; odds ratio=2.98; P<.001) and remission rates (P=.02) at Day 43. Lumateperone treatment was well tolerated, with minimal risk of EPS, metabolic, and prolactin side effects.ConclusionsLumateperone 42 mg significantly improved depression symptoms in both patients with bipolar I and bipolar II depression. Lumateperone was generally well tolerated. These results suggest that lumateperone 42 mg may be a promising new treatment for bipolar depression associated with bipolar I or bipolar II disorder.FundingIntra-Cellular Therapies, Inc.

Bipolar depression: a review of treatment options

“…19 Lumateperone is unique in that it modulates serotonin, dopamine and glutamate simultaneously. 5 In a study of 377 patients, lumateperone had significantly greater MADRS response rate (51.1% vs 36.7%; OR=2.98, p<0.001) and remission rate (p=0.02) at day 43 compared with placebo. 5 Participants in this study reported good tolerability of lumateperone with relatively low risk of EPS, metabolic changes and prolactin elevation.…”

“…In a study of 377 patients, lumateperone had significantly greater MADRS response rate (51.1% vs 36.7%; OR=2.98, p<0.001) and remission rate (p=0.02) at day 43 compared with placebo 5. Participants in this study reported good tolerability of lumateperone with relatively low risk of EPS, metabolic changes and prolactin elevation 5. In the most recent clinical trial, mean changes from baseline in weight, fasting glucose, total cholesterol, triglycerides and low-density cholesterol were similar between lumateperone and placebo 19.…”

“…Lumateperone was recently approved as monotherapy or adjunctive therapy with lithium or valproate for treatment of depression in the context of either BD-I or BD-II disorder 19. Lumateperone is unique in that it modulates serotonin, dopamine and glutamate simultaneously 5. In a study of 377 patients, lumateperone had significantly greater MADRS response rate (51.1% vs 36.7%; OR=2.98, p<0.001) and remission rate (p=0.02) at day 43 compared with placebo 5.…”

“…To date, the US Food and Drug Administration (FDA) has approved several drugs for the treatment of BD-D, including a combination of olanzapine plus fluoxetine (OFC) (approved 2003), quetiapine (2008), lurasidone (2013), cariprazine (2019) and lumateperone (2021) (table 1). 2 5 Although effective in clinical trials, these treatment options are often practically limited by intolerability and adverse effects, particularly for long-term maintenance use, raising the clinical conundrum of weighing the risks associated with long-term antipsychotic use versus the risk of relapsing when patients are off medications. Here, we review the evidence for and adverse effects of currently approved treatment options.…”

Existing and emerging pharmacological approaches to the treatment of mania: A critical overview

“…In pre-approval clinical trials, it demonstrated efficacy in lowering psychotic symptoms during acute schizophrenia and a good short-term safety/tolerability profile with only somnolence/sedation indexes significantly higher than placebo [ 50 ]. Lumateperone’s pharmacodynamic profile suggested its hypothetical efficacy in bipolar depression and the results coming from the first trials tend to confirm the hypothesis [ 51 – 53 ]. No clinical trials of lumateperone in bipolar mania have been performed to our knowledge.…”