Clinical implications
The approval of lumateperone for both BD I and BD II depression, and for its use as monotherapy and for adjunctive use with lithium or VPA, satisfies several unmet needs for the management of acute major depressive episodes in patients with BD. Clinicians now have both safety and tolerability data to present to their bipolar spectrum patients regardless of subtype, and regardless of whether the patient requires mood stabilizer therapy. The tolerability advantages for lumateperone seen in schizophrenia trials were replicated in a diagnostic group that is very sensitive to D2-related adverse effects, and for whom any signal of clinically significant weight gain or sedation often represents an insuperable barrier to patient acceptance.23
Efficacy in adults with BD I or II depression.
The efficacy of lumateperone for major depressive episodes has been established in 2 pivotal, double-blind, placebo-controlled trials in BD I or II patients: 1 monotherapy study,17 and 1 study when used adjunctively to lithium or VPA.18 The first study was a 6-week, double-blind, placebo-controlled monotherapy trial (study 404) in which 377 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode were randomized in a 1:1 manner to lumateperone 42 mg/d or placebo given once daily in the evening. Symptom entry criteria included a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥20, and scores ≥4 on the depression and overall BD illness subscales of the Clinical Global Impressions Scale–Bipolar Version Severity scale (CGI-BP-S) at screening and at baseline.17 Study entry also required a score ≤12 on the Young Mania Rating Scale (YMRS) at screening and at baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS. Several secondary efficacy measures were examined, including the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS), or remission (MADRS score ≤12), and differential changes in MADRS scores from baseline for BD I and BD II subgroups.17
The patient population was 58% female and 91% White, with 79.9% diagnosed as BD I and 20.1% as BD II. The least squares mean changes on the MADRS total score from baseline to Day 43 were lumateperone 42 mg/d: -16.7 points; placebo: -12.1 points (P < .0001), and the effect size for this difference was moderate: 0.56. Secondary analyses indicated that 51.1% of those taking lumateperone 42 mg/d and 36.7% taking placebo met response criteria (P < .001), while 39.9% of those taking lumateperone 42 mg/d and 33.5% taking placebo met remission criteria (P = .018). Importantly, depression improvement was observed both in patients with BD I (effect size 0.49, P < .0001) and in those with BD II (effect size 0.81, P < .001).
The second pivotal trial (study 402) was a 6-week, double-blind, placebo-controlled adjunctive trial in which 528 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode despite treatment with lithium or VPA were randomized in a 1:1:1 manner to lumateperone 28 mg/d, lumateperone 42 mg/d, or placebo given once daily in the evening.18 Like the monotherapy trial, symptom entry criteria included a MADRS total score ≥20, and scores ≥4 on the depression and overall illness CGI-BP-S subscales at screening and baseline.18 Study entry also required a score ≤12 on the YMRS at screening and baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS for lumateperone 42 mg/d compared to placebo. Secondary efficacy measures included MADRS changes for lumateperone 28 mg/d and the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS) or remission (MADRS score ≤12).
The patient population was 58% female and 88% White, with 83.3% diagnosed as BD I, 16.7% diagnosed as BD II, and 28.6% treated with lithium vs 71.4% on VPA. The effect size for the difference in MADRS total score from baseline to Day 43 for lumateperone 42 mg/d was 0.27 (P < .05), while that for the lumateperone 28 mg/d dose did not reach statistical significance. Secondary analyses indicated that response rates for lumateperone 28 mg/d and lumateperone 42 mg/d were significantly higher than for placebo (both P < .05). Response rates were placebo: 39%; lumateperone 28 mg/d: 50%; and lumateperone 42 mg/d: 45%. Remission rates were similar at Day 43 in both lumateperone groups compared with placebo: placebo: 31%, lumateperone 28 mg/d: 31%, and lumateperone 42 mg/d: 28%.18 As of this writing, a secondary analysis by BD subtype has not yet been presented.
A third study examining lumateperone monotherapy failed to establish superiority of lumateperone over placebo (NCT02600494). The data regarding tolerability from that study were incorporated in product labeling describing adverse reactions.
Continue on to: Adverse reactions...