Adverse reactions
In the positive monotherapy trial, there were 376 patients in the modified intent-to-treat efficacy population to receive lumateperone (N = 188) or placebo (N = 188) with nearly identical completion rates in the active treatment and placebo cohorts: lumateperone, 88.8%; placebo, 88.3%.17 The proportion experiencing mania was low in both cohorts (lumateperone, 1.1%; placebo, 2.1%), and there was 1 case of hypomania in each group. One participant in the lumateperone group and 1 in the placebo group discontinued the study due to a serious adverse event of mania. There was no worsening of mania in either group as measured by mean change in the YMRS score. There was also no suicidal behavior in either cohort during the study. Pooling the 2 monotherapy trials, the adverse events that occurred at ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone 42 mg/d: 13%, placebo: 3%), dizziness (lumateperone 42 mg/d: 8%, placebo: 4%), and nausea (lumateperone 42 mg/d: 8%, placebo: 3%).13 Rates of EPS were low for both groups: lumateperone 42 mg/d: 1.3%, placebo: 1.1%.13 Mean weight change at Day 43 was +0.11 kg for lumateperone and +0.03 kg for placebo in the positive monotherapy trial.17 Moreover, compared to placebo, lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant. No patient exhibited a corrected QT interval >500 ms at any time, and increases ≥60 ms from baseline were similar between the lumateperone (n = 1, 0.6%) and placebo (n = 3, 1.8%) cohorts.
Complete safety and tolerability data for the adjunctive trial has not yet been published, but discontinuation rates due to treatment-emergent adverse effects for the 3 arms were: lumateperone 42 mg/d: 5.6%; lumateperone 28 mg/d: 1.7%; and placebo: 1.7%. Overall, 81.4% of patients completed the trial, with only 1 serious adverse event (lithium toxicity) occurring in a patient taking lumateperone 42 mg/d. While this led to study discontinuation, it was not considered related to lumateperone exposure by the investigator. There was no worsening of mania in either lumateperone dosage group or the placebo cohort as measured by mean change in YMRS score: -1.2 for placebo, -1.4 for lumateperone 28 mg/d, and -1.6 for lumateperone 42 mg/d. Suicidal behavior was not observed in any group during treatment. The adverse events that occurred at rates ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone, 13%; placebo, 3%), dizziness (lumateperone, 11%; placebo, 2%), and nausea (lumateperone, 9%; placebo, 4%).13 Rates of EPS were low for both groups: lumateperone, 4.0%, placebo, 2.3%.13 Mean weight changes at Day 43 were +0.23 kg for placebo, +0.02 kg for lumateperone 28 mg/d, and 0.00 kg for lumateperone 42 mg/d.18 Compared to placebo, both doses of lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant.18
Lastly, the package insert notes that in an uncontrolled, open-label trial of lumateperone for up to 6 months in patients with BD depression, the mean weight change was -0.01 ± 3.1 kg at Day 175.13
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