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An atypical antipsychotic approved to treat schizophrenia improved depressive episodes for patients with bipolar disorder, according to an industry-supported trial.

In a group of 333 patients with bipolar disorder, 42-mg daily lumateperone (Caplyta) was associated with significantly improved scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) versus placebo at day 43 (least squares mean difference -4.58, P<0.0001), reported Andrew Satlin, MD, of Intra-Cellular Therapies in New York City, and colleagues.

MADRS scores were improved with lumateperone versus placebo for both a cohort of 150 patients with bipolar I disorder (LSMD -3.95, P<0.0001), and a group of 76 patients with bipolar II disorder (LSMD -7.04, P<0.001), they reported in a poster at the virtual Psych Congress.

The treatment was relatively fast acting with improvement beginning at day 8 in the collective group, they noted.

"From a pharmacological standpoint, there were a few things that suggested [lumateperone] would work for depression, and that led us to go down this road," Satlin told 番茄社区. "Some drugs for bipolar disorder are also atypical, but they don't have the same pharmacology as lumateperone does."

The FDA approved lumateperone for the treatment of schizophrenia in 2019 based on positive findings in a trial testing a 42-mg dose. Interestingly, a prior study found that a higher dose of 84 mg and a lower dose of 28 mg did not improve symptoms for patients with schizophrenia, indicating there may be a narrow treatment window in which the drug is effective, at least for schizophrenia.

Like other second-generation antipsychotics, lumateperone works as a 5-HT2A antagonist. It also has downstream effects on glutamate receptors, and blocks serotonin reuptake in a manner similar to selective serotonin reuptake inhibitors (SSRIs), Satlin said.

Second generation antipsychotics often demonstrate improved safety and tolerability at the cost of metabolic side effects like weight gain.

However, there were no significant differences in this study between the placebo and lumateperone groups in terms of weight gain (0.1 kg vs 0.08 kg), BMI (0.03 vs 0.04), and waist circumference (-0.05 cm vs -0.47 cm), the authors reported. No other significant differences occurred in other metabolic parameters like fasting glucose and triglyceride levels, they added.

The most common adverse events for patients on lumateperone were headache (18%), drowsiness (9%), and nausea (6.4%). One patient experienced mania in the treatment group, the authors reported.

Patients with diagnosed bipolar disorder who were currently experiencing a moderate to severe depressive episode (MADRS score of at least 20) were included in the trial.

The cohort was a mean age of roughly 44 and upwards of 90% white. Most had been diagnosed with bipolar disorder at least 30 years prior, typically with anywhere between one and nine prior depressive episodes, and MADRS scores of about 30 at baseline.

Participants on lumateperone also had significantly improved scores on the Clinical Global Impression Scale, Bipolar Version-Severity (CGI-BP-S) versus placebo from baseline to day 43 (LSMD -0.94, P<0.0001), the authors reported. The changes were significant for patients with both bipolar I and bipolar II disorder, they added.

The proportion of patients who responded to treatment, classified as at least a 50% reduction in MADRS scores from baseline, was also higher in the intervention versus placebo arm (51% vs 37%, P<0.001), Satlin and colleagues noted. Remission, defined as an MADRS score of no more than 12 was also slightly but significantly higher (40% vs 34%, P<0.05), they noted.

This was a short-term trial, which is a limitation because most conditions like bipolar disorder or schizophrenia require long-term treatment.

Intra-Cellular Therapies plans to submit an application for the bipolar disorder indication by the end 2020, or early 2021, using the current study, and another that reported positive findings with Satlin said.

Lumateperone is also being investigated for the treatment of dementia and major depressive disorder, according to the company.

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