Efficacy of adjunctive lumateperone 42 mg treatment across a broad range of depression symptoms in patients with major depressive disorder

Background

Major depressive disorder (MDD) is a heterogeneous condition characterised by a wide range of emotional, cognitive, and physical symptoms. Despite effective antidepressant therapy (ADT), many patients experience residual symptoms, which predict higher relapse and recurrence rates, as well as posttreatment functional impairment. Lumateperone is an atypical antipsychotic indicated for schizophrenia, depressive episodes associated with bipolar I or bipolar II disorder, and as adjunctive therapy to ADT in MDD. The efficacy and safety of lumateperone 42mg adjunctive to ADT were demonstrated in 2 Phase 3, randomised, double-blind, placebo-controlled studies (Study 501 [NCT04985942], Study 502 [NCT05061706]) in patients with MDD with inadequate ADT response.

This pooled analysis of Studies 501 and 502 assessed the efficacy of lumateperone 42mg+ADT on individual depression symptoms using Montgomery-Asberg Depression Rating Scale (MADRS) individual item scores.

Methods

Pooled data were analysed from these 2 studies in adults (18-65 years) with DSM-5-defined MDD with inadequate response to 1-2 ADT in the current depressive episode who had MADRS Total score ≥24, Clinical Global Impression–Severity score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report-16 item score ≥14. Patients were randomised to 6-week lumateperone 42mg+ADT or placebo+ADT. Change from baseline in MADRS Total score was analysed using a mixed-effects model for repeated measures. A prospective analysis investigated change in individual MADRS items using analysis of covariance models in the modified intent-to-treat (mITT) population. The proportion of patients with ≥2-point improvement from baseline within each individual MADRS item was also assessed.

Results

A total of 950 patients were included in the mITT population (lumateperone+ADT, 471; placebo+ADT, 479). At Day 43, lumateperone+ADT met the primary endpoint, significantly improving depression symptoms according to MADRS Total score versus placebo+ADT (least squares mean difference vs placebo+ADT [LSMD], −4.7; effect size, −0.59; P<.0001).

Baseline scores on individual MADRS items ranged from a mean score of 4.1 (reported sadness) to 0.4 (suicidal thoughts) in the lumateperone+ADT group. At Day 43, all 10 MADRS items significantly improved with lumateperone+ADT versus placebo+ADT: apparent sadness (LSMD, 0.55; P<.001), reported sadness (LSMD, 0.60; P<.001), inner tension (LSMD, 0.46; P<.001), reduced sleep (LSMD, 0.90; P<.001), reduced appetite (LSMD, 0.40; P<.001), concentration difficulties (LSMD, 0.38; P<.001), lassitude (LSMD, 0.47; P<.001), inability to feel (LSMD, 0.41; P<.001), pessimistic thoughts (LSMD, 0.44; P<.001), and suicidal thoughts (LSMD, 0.06; P<.05). With lumateperone+ADT, 9 of 10 MADRS individual items improved by ≥2 points in ≥42% of patients at Day 43: apparent sadness (64%), reported sadness (60%), inner tension (42%), reduced sleep (63%), reduced appetite (45%), concentration difficulties (48%), lassitude (53%), inability to feel (50%), and pessimistic thoughts (43%). Improvements with lumateperone+ADT were significant at every visit for apparent sadness, reported sadness, and reduced sleep, and improvements were significant at Day 15 onward for lassitude and inability to feel. Lumateperone+ADT significantly improved inner tension, reduced appetite, concentration difficulties, and pessimistic thoughts from Day 22 onward, and suicidal thoughts at Day 43.

Conclusions

Lumateperone 42mg+ADT demonstrated superior efficacy in improving a broad range of depression symptoms compared with placebo+ADT in patients with MDD with inadequate ADT response.

References

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