Lumateperone (Caplyta) just hit the pharmacy shelves with FDA approval in schizophrenia (see TCPR March 2020), and its manufacturer is pursuing further approval for bipolar depression. So far they’ve completed two phase III trials—one negative and one positive—and the positive one was presented in poster form by Suresh Durgam and colleagues at the International Society for Bipolar Disorders in June 2020.

The positive study was a controlled trial that randomized 377 patients to placebo or lumateperone 42 mg/day without titration (the same dose used in schizophrenia). Lumateperone began to separate from placebo after 1 week on the primary outcome measure (the Montgomery-Åsberg Depression Rating Scale), and those improvements continued throughout the 6-week trial (p < 0.0001 with intent-to-treat analysis). The main side effects were nausea and fatigue, but sleep also improved on this sedating antipsychotic. Consistent with the schizophrenia studies, the rates of akathisia and weight gain were low and not significantly different from placebo.

A strength of the study was the inclusion of bipolar II patients, who represented 20% of the sample. Although depression is more common in bipolar II than I, most antipsychotics have only been tested in bipolar I depression. Exceptions are quetiapine, which worked in bipolar II patients, and cariprazine (Vraylar), which did not. Lumateperone worked in the subset with bipolar II, but its effects were more pronounced in the bipolar I group.

Details on the negative trial were not available, but it was a smaller study (178 patients) with a similar design. Joseph Calabrese, one of the principal authors, reported that lumateperone still upheld a moderate effect size (0.56) when the results of the two studies were combined.

TCPR’s Take
Lumateperone is worth trying when other options for bipolar depression have failed, but insurance coverage will be difficult without FDA approval for that indication.

 

To learn more, listen to our 8/31/20 podcast, “Existential Despair in Bipolar Depression: An Interview with Nassir Ghaemi.” Search for “Carlat” on your podcast store.