New ECNP Poster Data on Adjunctive Lumateperone for Major Depressive Disorder

CONFERENCE REPORTER

Investigators presented new data on adjunctive lumateperone for the treatment of major depressive disorder (MDD) and potential comorbidities via poster presentations at the 38th European College of Neuropsychopharmacology (ECNP) Annual Congress, on October 11-14, 2025, in Amsterdam. Results show that treatment with antidepressants plus lumateperone led to significant improvements in symptoms of anhedonia, sexual dysfunction, and a broad range of other depressive symptoms.^1-3

Anhedonia occurs in approximately 70% of individuals with MDD and is associated with severe and recurrent illness, reduced quality of life, and impaired functioning.^4,5 Meanwhile, sexual dysfunction occurs in approximately 68% of individuals with MDD, with patients who take antidepressants experiencing everything from new or worsening sexual dysfunction, to decreased sexual desire, sexual excitement, and orgasmic function—all of which negatively impacts quality of life and reduces treatment adherence.^6,7 Novel, effective treatments with minimal adverse effects are needed for patients with MDD.

Lumateperone—a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission—is a mechanistically novel antipsychotic that is approved by the US Food and Drug Administration to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder as monotherapy and as adjunctive therapy with lithium or valproate.

Two phase 3, randomized, double-blind, placebo-controlled, multicenter studies sought to better understand the effect of lumateperone 42 mg adjunctive to antidepressant therapy (ADT): Study 501 (NCT04985942) and Study 502 (NCT05061706).

Study 501

In Study 501, lumateperone 42 mg + ADT significantly improved depressive symptoms and disease severity in patients with MDD with inadequate response to ADT. As to safety profile, lumateperone 42 mg + ADT was generally safe and well tolerated. Investigators analyzed the broad efficacy of lumateperone 42 mg + ADT across depression symptoms, as assessed by Montgomery-Åsberg Depression Rating Scale (MADRS) single item and anhedonia factor scores. Patients were randomly assigned 1:1 to 6-week treatment with oral lumateperone 42 mg + ADT or placebo + ADT. The primary endpoint was change in MADRS Total score from baseline to day 43. The MADRS Total score and the MADRS anhedonia factor score were analyzed in patients with an anhedonia baseline higher than the median, defined as baseline MADRS anhedonia greater than or equal to 18.

Lumateperone +ADT met the primary endpoint, with significant improvement in MADRS total score at day 43 compared with placebo + ADT (P<.0001). Investigators noted that the most prominent MADRS single items at baseline were reported sadness and apparent sadness. Then, at day 43, lumateperone + ADT significantly improved all MADRS single items, except suicidal thoughts, compared with placebo + ADT, with the largest improvement in reduced sleep. The earliest significant (P<.05) reductions from baseline occurred at day 8 for reported sadness, apparent sadness, and reduced sleep; these improvements continued throughout the study. There were significant improvements in inability to feel and pessimistic thoughts observed at day 15, persisting up to day 43. There were also consistent significant improvements for inner tension and concentration difficulties beginning at day 22, and for reduced appetite and lassitude beginning at day 29. In patients with anhedonia baseline higher than the median, lumateperone 42 mg + ADT significantly improved both depression and anhedonia symptoms compared with placebo + ADT.

Study 502

In Study 502, lumateperone 42 mg/day adjunctive to antidepressants significantly improved depressive symptoms compared with placebo adjunctive to antidepressants, as measured by both clinician-rated and patient-rated outcomes, in patients with MDD with inadequate ADT response. Lumateperone 42 mg/day + ADT demonstrated no notable changes in cardiometabolic parameters or body morphology and a low risk of extrapyramidal symptoms. Investigators sought to understand the impact of lumateperone 42 mg/day + ADT on sexual functioning, assessed by the Changes in Sexual Functioning Questionnaire 14-item version (CSFQ-14), in patients with MDD with inadequate ADT response. The primary endpoint was the change from baseline to Day 43 in MADRS total score, analyzed using a mixed-effects model for repeated measures. Lumateperone 42 mg/day + ADT significantly improved sexual function compared with placebo + ADT.

Concluding Thoughts

These results support lumateperone 42 mg/day as a promising adjunctive treatment option in patients with MDD with inadequate ADT response.

References

1. Earley WR, Durgam S, Kozauer SG, et al. Efficacy of adjunctive lumateperone 42 mg treatment across depression and anhedonia symptoms in major depressive disorder. Poster presented at: 38th European College of Neuropsychopharmacology Annual Congress; October 11-14, 2025; Amsterdam, The Netherlands. Accessed October 10, 2025.

2. Thase ME, Earley WR, Kozauer SG, et al. Adjunctive lumateperone 42 mg treatment in major depressive disorder: efficacy in anhedonia and across broad range of depressive symptoms. Poster presented at: 38th European College of Neuropsychopharmacology Annual Congress; October 11-14, 2025; Amsterdam, The Netherlands. Accessed October 10, 2025.

3. Clayton AH, Earley WR, Kozauer SG, et al. Evaluation of sexual function with adjunctive lumateperone in patients with major depressive disorder. Poster presented at: 38th European College of Neuropsychopharmacology Annual Congress; October 11-14, 2025; Amsterdam, The Netherlands. Accessed October 10, 2025.

4. Whitton AE, Pizzagalli DA. Anhedonia in depression and bipolar disorder. Curr Topics Behav Neurosci. 2022;58:111-128.

5. Serretti A. Anhedonia: current and future treatments. Psychiatry Clin Neurosci Rep. 2025;4(1):e70088.

6. Jacobsen P, Zhong W, Nomikos G, Clayton A. Paroxetine, but not vortioxetine, impairs sexual functioning compared with placebo in healthy adults: a randomized, controlled trial. J Sex Med. 2019;16(10):1638-1649.

7. Rothmore J. Antidepressant-induced sexual dysfunction. Med J Aust. 2020;212(7):329-334.