REVIEW OF: Calabrese JR et al, Am J Psychiatry 2021. Epub ahead of print

STUDY TYPE: Randomized, placebo-controlled trial

In 2019, lumateperone (Caplyta) became the 13th atypical antipsychotic with FDA approval in schizophrenia. Compared to other atypicals, it is relatively well tolerated, with low rates of akathisia and metabolic side effects. On December 20, 2021, the FDA approved the drug for bipolar I and II depression, and here we report on one of the trials that led to that approval.

This large, randomized, placebo-controlled, multi-center trial involved 377 patients with both bipolar I (n = 301) and bipolar II (n = 76) depression. The study was “quadruple blind,” meaning the subjects, providers, investigators, and people administering the rating scales were all blinded to the assigned treatment. The primary outcome measure was the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS). Lumateperone was started and maintained at 42 mg/day and used as monotherapy.

After six weeks, lumateperone outperformed placebo with a medium effect size (0.56) on the primary outcome of change on MADRS. Response (51.1% vs 36.7%, p < 0.001) and remission rates (39.9% vs 33.5%, p < 0.018) were also significantly greater with lumateperone. It was well tolerated, with minimal risk of metabolic, EPS, and prolactin side effects. A post-hoc analysis found greater benefits in bipolar II vs bipolar I depression (effect size of 0.81 vs 0.49) and revealed that a subgroup of patients with mixed features benefited from the medication.

The FDA reviewed two other trials that tested lumateperone in bipolar I and bipolar II depression with a similar design. These have not been published but were made available as a press release. One study was negative (study 401) and the other positive (study 402). Both were large, six-week trials, enrolling 554 and 529 patients. Unlike the Calabrese study, they tested three arms: lumateperone 28 mg, lumateperone 42 mg, and placebo. The positive study tested lumateperone as an adjunct to lithium or valproate and arrived at a small effect size (0.27) for the 42 mg dose and a nonsignificant effect with the 28 mg dose. A fourth trial is underway for unipolar depression with mixed features, a new disorder in DSM-5 that recognizes manic features in depressed patients who do not meet criteria for a bipolar diagnosis.

These trials are unique in their inclusion of bipolar II patients. Among the antipsychotics, only quetiapine and cariprazine have large studies in bipolar II depression, and only quetiapine’s studies were positive.

TCPR’S TAKE
Lumateperone joins quetiapine as the only atypical antipsychotic with evidence in both bipolar I and bipolar II depression. Its main advantage is its favorable tolerability, while disadvantages include cost and the lack of research in the manic and maintenance phases of bipolar disorder.