Frequently Asked Questions

Yes. In this exploratory post hoc analysis of a phase 3 randomized, double-blind, placebo-controlled trial, adjunctive lumateperone 42 mg plus antidepressant therapy significantly improved depressive symptoms, anxiety symptoms, and global illness severity versus placebo plus antidepressant therapy in patients with major depressive disorder who met DSM-5 criteria for anxious distress at baseline.

At Day 43, lumateperone+ADT significantly improved MADRS Total score and CGI-S score versus placebo+ADT, both with P<.0001. It also significantly improved QIDS-SR-16 Total score (effect size 0.80; P<.0001), MADRS item 3 inner tension (P<.001), and GAD-7 Total score (P<.0001) in the anxious distress subgroup.

The antidepressant effect was larger in patients with anxious distress than in those without anxious distress. At Day 43, the effect size for MADRS Total score was 0.85 in patients with anxious distress versus 0.44 in patients without anxious distress.

A similar pattern was seen for global severity: the CGI-S effect size at Day 43 was 0.91 in patients with anxious distress versus 0.50 in patients without anxious distress. In the discussion, the authors also reported a least squares mean difference in MADRS Total score versus placebo of −6.8 in the anxious distress subgroup and −3.5 in the subgroup without anxious distress.

Improvement in depressive symptoms emerged by Day 15 in patients with anxious distress. Lumateperone+ADT produced a significant improvement in MADRS Total score versus placebo+ADT by Day 15 in the anxious distress subgroup, and that benefit persisted through the 6-week study.

For global severity, CGI-S improvement became significant by Day 22 in patients with anxious distress. In patients without anxious distress, both MADRS and CGI-S separated from placebo earlier, by Day 8.

Patients with anxious distress had higher response and remission outcomes with adjunctive lumateperone than with adjunctive placebo at Day 43. In the discussion, the authors reported that 52% of lumateperone-treated patients with anxious distress achieved MADRS response and 27% achieved remission.

The number needed to treat was 3 for MADRS response and 7 for remission in the anxious distress subgroup. In patients without anxious distress, the corresponding lumateperone-treated rates were 40% for response and 25% for remission, with NNTs of 9 and 10.

Yes. In patients who met DSM-5 anxious distress criteria, adjunctive lumateperone significantly improved anxiety-related outcomes as well as depression outcomes.

At Day 43, lumateperone+ADT significantly improved GAD-7 Total score versus placebo+ADT in the anxious distress subgroup (P<.0001), and the discussion reports a least squares mean difference of −3.2. It also significantly improved MADRS item 3 inner tension, a proxy measure for anxious distress, with P<.001.

No significant GAD-7 benefit was shown in patients without anxious distress. Although lumateperone+ADT significantly improved depressive symptoms and other outcomes in that subgroup, the change in GAD-7 Total score at Day 43 was not statistically significant versus placebo+ADT (P=.379).

By contrast, GAD-7 improvement was significant in patients with anxious distress (P<.0001). The placebo group without anxious distress also had a larger GAD-7 reduction than the placebo group with anxious distress (−3.6 versus −2.3), which the authors noted in the results.

Anxious distress was defined using DSM-5 criteria and confirmed with the MINI anxious distress module at screening. Patients were considered to have anxious distress if they had 2 or more anxiety symptoms during most days of the major depressive episode.

• feeling keyed up or tense
• feeling unusually restless
• difficulty concentrating because of worry
• fear that something awful might happen
• feeling that one might lose control of oneself

In this analysis, 207 of 481 patients in the modified intent-to-treat population, or 43.0%, met DSM-5 criteria for anxious distress at baseline.

This was an exploratory post hoc analysis of Study 501, a phase 3, randomized, double-blind, placebo-controlled trial. The parent trial enrolled 481 patients with major depressive disorder, inadequate response to 1 to 2 antidepressant monotherapies in the current episode, and a current major depressive episode; patients were randomized 1:1 to oral once-daily lumateperone 42 mg plus antidepressant therapy or placebo plus antidepressant therapy for 6 weeks.

Because this subgroup analysis was post hoc and was not adjusted for multiplicity, the findings are hypothesis-generating rather than definitive. The original randomized, blinded design supports internal validity, but the subgroup results should be interpreted with appropriate caution.

Adjunctive lumateperone was generally well tolerated in both subgroups, with minimal changes in metabolic parameters and prolactin levels. Among lumateperone-treated patients, 62.7% of those with anxious distress and 54.2% of those without anxious distress experienced at least 1 treatment-emergent adverse event.

Discontinuation due to adverse events was 4.5% in patients with anxious distress and 6.9% in those without anxious distress. EPS-related treatment-emergent adverse events occurred in 9.1% and 3.8%, respectively.

The main limitations are that this was a post hoc analysis, it was not adjusted for multiplicity, and it inherited the eligibility restrictions of the parent trial. Those features mean the results are exploratory and may not generalize to all patients seen in routine practice.

Patients with a primary anxiety disorder or anxiety symptoms requiring concurrent treatment were excluded, and benzodiazepines and nonbenzodiazepine anxiolytics were not allowed. The authors noted that these exclusions may reduce generalizability in patients whose anxiety symptoms exceed those required for the DSM-5 anxious distress specifier.