The U.S. Food and Drug Administration (FDA) has expanded approval of lumateperone (Caplyta) to include treatment of adults with depressive episodes associated with bipolar I and II disorder, as monotherapy or adjunctive therapy with lithium or valproate. Lumateperone was approved in 2019 for the treatment of schizophrenia and has numerous actions, including acting as an antagonist at the 5-HT2A receptor, binding to D1, D2, and D4 receptors, and some serotonin transporter inhibition (Figure).
The FDA approval for lumateperone additional indications is based on two positive Phase 3 placebo-controlled bipolar depression studies, which evaluated the effects of lumateperone on depression in adult patients with bipolar I or bipolar II disorder both as monotherapy and as adjunctive therapy with lithium or valproate. In both studies, the efficacy of lumateperone 42 mg was established by demonstrating statistically significant improvements over placebo for the change from baseline in the Montgomery-Asberg Depression Rating scale (MADRS) total score at week 6. Lumateperone 42 mg also showed a statistically significant improvement in the key secondary endpoint, Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S).
The efficacy of lumateperone, as monotherapy, was established in a 6-week, randomized, double-blind, placebo-controlled, multi-center study in adult patients who met DSM-5 criteria for depressive episodes associated with bipolar I or bipolar II disorder. The primary efficacy measure was the change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 6. The secondary endpoint was the change from baseline in Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S) total score at Week 6. The CGI-BP-S total score is a clinician-rated scale that measures the patient’s current illness state on a 21-point scale that assesses depression, mania, and overall illness, where a higher score is associated with greater illness severity. A total of 381 patients were randomized to receive lumateperone 42 mg or placebo. Compared to the placebo group, patients randomized to lumateperone 42 mg showed a statistically significant improvement from baseline to Day 43 in the MADRS total score and CGI-BP-S total score. The efficacy of lumateperone, as adjunctive therapy with lithium or valproate, was established in a 6-week, randomized, double-blind, placebo-controlled, multi-center study in adult patients who met DSM-5 criteria for depressive episodes associated with bipolar I or bipolar II disorder. A total of 529 patients were randomized to receive lumateperone 28 mg (two-thirds the recommended daily dose), lumateperone 42 mg, or placebo. Compared to the placebo group, patients randomized to lumateperone 42 mg showed a statistically significant improvement from baseline to Day 43 in the MADRS total score and CGI-BP-S depression score. The treatment effect in the lumateperone 28 mg group (vs. placebo) was not statistically significant.
In both studies, The most common adverse reactions (incidence of at least 5% of patients exposed to lumateperone and greater than twice the rate of placebo) are somnolence/sedation, dizziness, nausea, and dry mouth. Lumateperone is the only FDA-approved treatment for depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults as monotherapy and as adjunctive therapy with lithium or valproate.
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References:
Calabrese JR et al. Am J Psychiatry 2021; 178:1098–110. Abstract.
D’Souza I et al. CNS Spectr. 2021;26(2):150. Abstract.