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Calabrese JR, et al. Am J Psychiatry. 2021;[Epub ahead of print].
This randomized, double-blind, parallel-group, placebo-controlled multinational phase III study investigated the efficacy and safety of lumateperone in patients with bipolar I or bipolar II disorder experiencing a major depressive episode.
Patients aged 18-75 years with a clinical diagnosis of bipolar I or bipolar II disorder who were experiencing an major depressive episode (MADRS total score of 20 and CGI-BP-S score of 4 at screening and baseline) were randomized to lumateperone 42 mg or placebo for 6 weeks. The primary and key secondary efficacy endpoints were changed from baseline to Day 43 in MADRS total score and CGI-BP-S score, respectively. Secondary efficacy outcomes included response (MADRS improvement of 50%) and remission (MADRS total score of 12) at Day 43.
In this study, 377 patients received treatment (188 patients received lumateperone 42 mg and 189 received placebo) and 333 completed treatment. Patients in the lumateperone 42 mg group had statistically significantly greater mean improvement on MADRS total score change from baseline to Day 43 compared with placebo (effect size: -0.56). The advantages of lumateperone were apparent at Week 1. Lumateperone treatment was associated with statistically significant MADRS improvement in both patients with bipolar I (effect size: 0.49) and bipolar II (effect size: -0.81) disorders. The lumateperone 42 mg group also had a statistically significantly greater mean improvement in CGI-BP-S score as well as MADRS-measured response and remission rates. Lumateperone treatment was well tolerated, with minimal risk of EPS, metabolic, and prolactin adverse events.
Lumateperone 42 mg significantly improved depression symptoms in patients with bipolar I and bipolar II disorders. 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. Somnolence and nausea were the 2 most common adverse events but were not associated with a significant dropout from the study.
Clinical Commentary by Roger McIntyre MD, FRCPC
Bipolar depressive symptoms and episodes dominate the longitudinal course of bipolar disorder and are the principal detractors of quality of life and function for persons affected. Suicidality is also highly associated with depressive symptoms in adults with bipolar disorder. Currently, only 4 treatments are approved by the FDA for bipolar depression (quetiapine, lurasidone, cariprazine, combination olanzapine/fluoxetine ). Only quetiapine has been evaluated in adults with bipolar II depression. Bipolar II depression may be more prevalent than bipolar I and recent evidence indicate it has higher suicidal completion rates than bipolar I disorder.
A strength, yet possible limitation, of the study, is the use of a fixed dose (ie, lumateperone 42 mg). The fact that this study used monotherapy demonstrates unequivocal efficacy but does not sufficiently address the question of the optimal combination of lumateperone with other drugs. Unfortunately, as with all studies in bipolar disorder, persons with suicidality were excluded. Other lines of evidence indicate that lumateperone can improve patient-reported outcomes (eg, quality of life and function).
Lumateperone is a second-generation antipsychotic with a unique mechanism of action characterized by high affinity for the 5-HT2 receptor, moderate affinity for the D2 receptor, and serotonin transporter (SERT). Of interest, lumateperone has indirect effects on glutamate hypothesized to be mediated to the D1 receptor.
The strengths of this study are the wide age range of patients who were enrolled (ie, 18-75 years) and the inclusion of adults with either bipolar I or bipolar II depression. Investigators reported statistically significant improvement in depression severity in both patients with bipolar I disorder and bipolar II disorder.
Of interest, evidence of statistical significance on the secondary outcome measures (ie, CGI-BPS) as well as response and remission rates were also noted. Individuals with bipolar disorder are differentially affected by obesity, type 2 diabetes mellitus, and metabolic syndrome and have a greater susceptibility to EPS from antipsychotics. Lumateperone treatment was well tolerated with no evidence of EPS, metabolic, or prolactin adverse events.
Lumateperone did not induce hypomania, nor did it worsen depression. The lack of worsening depression should not be taken for granted as first-generation antipsychotics have been reported to increase depression symptom morbidity in adults with bipolar disorder.
The simple dosing strategy of lumateperone (ie, 42 mg) and separation from placebo at Week 1 provides a very simple, practical, and reasonable timeline for symptomatic improvement in bipolar depression without the burden of commonly encountered treatment-limiting adverse events (eg, weight gain, EPS).
It would be interesting to compare lumateperone with lurasidone in adults with bipolar depression as both agents have a minimal propensity to weight gain and metabolic disruption. It would also be relevant to determine whether lumateperone may improve mixed features in bipolar disorder, cognitive symptoms in adults with grandiose delusions and reset hedonic tone as evidenced by the decrease in drug and alcohol misuse.
Clinical Commentary by Sanjay Gupta, MD
This is a well-designed, randomized, multicenter, placebo-controlled trial that included patients with bipolar I and bipolar II disorders. Both these trials (lumateperone and quetiapine) excluded suicidal patients as is the standard for such studies using placebo. New agents demonstrating efficacy and excellent tolerability are needed, as treatment is lifelong for this disease state.
Healthcare professionals should continue to focus on accurate diagnosis of both bipolar I and II disorders through exhaustive longitudinal assessment and collateral information. This study indicates that, because of its demonstrated efficacy and excellent tolerability, lumateperone offers an attractive choice for bipolar I and bipolar II disorder–related depressive episodes upon FDA approval, prior to which it may not be covered by insurance.