Objective: Lumateperone is an atypical antipsychotic to treat schizophrenia, bipolar I or II depression, and major depressive disorder (MDD). Randomized phase 3 Study 502 (NCT05061706) investigated the impact of adjunctive lumateperone 42 mg/day on sexual functioning, per Changes in Sexual Functioning Questionnaire 14-item version (CSFQ-14). Methods: Adults meeting DSM-5 criteria for MDD with inadequate response to 1-2 antidepressant therapies (ADTs) in the current depressive episode, Montgomery-Åsberg Depression Rating Scale Total score ≥24, Clinical Global Impression Scale-Severity score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report-16-item score ≥14 were randomized to 6-week lumateperone 42 mg+ADT or placebo+ADT. Sexual function was assessed by CSFQ-14 Total and domain scores in the intent-to-treat (ITT) population and subgroups. Results: Of 480 patients in the ITT population, 82.5% had sexual dysfunction at baseline (women=284; men=112). Lumateperone+ADT significantly improved CSFQ-14 Total score at Day 43 vs placebo+ADT (least squares mean difference [LSMD]=2.7; effect size [ES]=0.38; P<.0001). Significantly greater improvements were observed in patients with baseline sexual dysfunction (LSMD=3.1; ES=0.42; P<.0001), with no change in those without. Improvements were observed in women (LSMD=3.5; ES=0.47; P<.0001) and in men (LSMD=1.9; ES=0.33; P=.08). Significant improvements in CSFQ-14 Total score at Day 43 were observed across age groups and CSFQ domain scores, with both sexes having significant improvements in pleasure and arousal/ excitement. Improvements in depressive symptoms may be linked to improvement in sexual functioning. Conclusions: Adjunctive lumateperone 42 mg did not worsen sexual functioning and was not associated with treatment-related sexual dysfunction in patients with MDD with inadequate response to ADT. Trial Registration: ClinicalTrials.gov identifier: NCT05061706.

INTRODUCTION:Current treatments for major depressive episodes may not resolve all symptoms, with residual symptoms predicting disease relapse, recurrence, and functional impairment. This post hoc analysis of Study 403 (NCT04285515), a randomized, double-blind, placebo-controlled trial in patients with major depressive disorder (MDD) or bipolar disorder presenting with a major depressive episode with mixed features, evaluated the breadth of efficacy of lumateperone 42 mg across depressive symptoms assessed by Montgomery-Åsberg Depression Rating Scale (MADRS) single item scores. METHODS:Adults aged 18-75 years who met DSM-5 criteria for MDD or bipolar disorder with depressive episode with mixed features were randomized 1:1 to receive 6-week lumateperone 42 mg or placebo treatment. RESULTS:Among 383 patients in the modified intent-to-treat population, lumateperone significantly improved 9 out of 10 MADRS items, except Suicidal Thoughts, versus placebo at Day 43, with earliest significant improvements observed from Days 8-15. A significantly higher proportion of patients had reduced symptom severity with lumateperone versus placebo across a range of individual MADRS items. A smaller percentage of patients with moderate-to-severe baseline symptoms (MADRS score ≥4) continued to have item scores ≥4 at end of treatment with lumateperone compared with placebo across all individual MADRS items, except for the Suicidal Thoughts item. Young Mania Rating Scale Total score improved from baseline to Day 43 versus placebo, with fewer patients experiencing mania worsening. CONCLUSION:Lumateperone 42 mg improved a broad range of depressive symptoms in patients with MDD and bipolar depression with mixed features, supporting its therapeutic potential in these conditions.

Lumateperone, a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission, demonstrated efficacy and safety as adjunctive therapy in two phase III, randomized, double-blind, placebo-controlled trials in patients with major depressive disorder with inadequate antidepressant therapy (ADT) response. The objective of this pooled analysis of Studies 501 and 502 was to investigate the safety and tolerability of lumateperone 42 mg + ADT. Data were pooled from two studies that enrolled adults (aged 18–65 years) with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-defined major depressive disorder with inadequate response to one to two ADTs in the current depressive episode (Montgomery–Åsberg Depression Rating Scale Total score ≥ 24; Clinical Global Impression-Severity score ≥ 4). Patients were randomized to 6 weeks of oral lumateperone 42 mg + ADT or placebo + ADT. Safety measures included adverse events, body morphology, cardiometabolic parameters, prolactin levels, extrapyramidal symptoms (EPS), and suicidality. The pooled population comprised 964 patients (lumateperone + ADT, n = 483; placebo + ADT, n = 481). Treatment-emergent adverse events (TEAEs) occurred in 68.1

This Phase 3 open-label extension study (NCT05061719) investigated long-term safety of lumateperone 42mg (simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission) adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) with inadequate ADT response. Eligible adults (18-65years) completed 6-week double-blind treatment (NCT04985942; NCT05061706) and had DSM-5-defined MDD with inadequate response to 1-2 ADTs in the current depressive episode, Montgomery-Åsberg Depression Rating Scale (MADRS) Total score ≥24, and Clinical Global Impression-Severity (CGI-S) score ≥4 at lead-in study entry. Patients received 26-week, open-label, oral lumateperone 42mg+ADT once-daily. The primary endpoint was safety/tolerability, assessed by adverse events (AEs), vital signs, and laboratory parameters. The secondary endpoint was efficacy, assessed by MADRS Total score and CGI-S score changes from double-blind baseline to open-label Week 26. Of 809 patients treated, 84.5% completed open-label treatment; 67.7% experienced ≥1 treatment-emergent AE (TEAE). Most common TEAEs (≥5%) were headache (16.6%), dizziness (10.6%), dry mouth (8.0%), nausea (7.7%), somnolence (7.2%), diarrhea (6.2%), and nasopharyngitis (5.2%). The majority (98.9%) of TEAEs were mild-to-moderate severity. Rate of extrapyramidal symptom (EPS)-related TEAEs per broad standardized MedDRA query was low (3.8%). No notable changes in EPS scales, body morphology, or cardiometabolic parameters occurred from double-blind baseline to end of open-label treatment. No emergence of suicidal behavior occurred during treatment. Symptoms of depression improved with lumateperone+ADT from double-blind baseline to open-label Week 26 (mean change: MADRS Total score=-22.9, P<.0001; CGI-S score=-2.7, P<.0001). Overall, lumateperone 42mg+ADT was safe and effective during 26-week treatment in patients with MDD with inadequate ADT response.

Purpose:Lumateperone is a mechanistically novel Food and Drug Administration-approved antipsychotic to treat schizophrenia, depressive episodes associated with bipolar I and II disorder, and major depressive disorder (MDD). This analysis of the Phase 3, randomized, double-blind, placebo-controlled, multicenter Study 501 (NCT04985942) evaluated the broad efficacy of lumateperone across depression symptoms assessed by Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonia factor and single-item scores. Patients and Methods:Eligible adults (18-65 years) met DSM-5 criteria for MDD with inadequate response to 1 or 2 ADTs in the current depressive episode and 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 randomized to oral placebo or lumateperone 42 mg adjunctive to ADT for 6 weeks. A post hoc analysis assessed anhedonia symptoms according to MADRS anhedonia factor. MADRS Total score and MADRS anhedonia factor score were analyzed by baseline anhedonia factor score (median value: ≥18). A prospective analysis investigated change in individual MADRS items. Results:Lumateperone+ADT significantly improved anhedonia symptoms versus placebo+ADT at every visit according to MADRS anhedonia factor score (Day 43: least squares mean difference vs adjunctive placebo [LSMD], -2.5; effect size [ES], -0.50; P<0.0001). In patients with baseline anhedonia scores equal to or more than the median, significant improvements in MADRS Total score (LSMD, -5.4; 95% CI, -7.21, -3.59; ES, -0.67; P<0.0001) and anhedonia factor score (LSMD, -2.8; 95% CI, -3.91, -1.65; ES, -0.55; P<0.0001) were observed for lumateperone+ADT versus placebo+ADT at Day 43, with significant between-group differences observed at all study visits. At Day 43, 9 of the 10 MADRS items significantly improved with adjunctive lumateperone compared with adjunctive placebo. Conclusion:Lumateperone 42mg+ADT significantly improved symptoms of anhedonia and a broad range of depression symptoms compared with placebo+ADT in patients with MDD with inadequate response.

BACKGROUND:Antipsychotics with a long-term favorable tolerability profile are needed to improve outcomes in patients with schizophrenia. A 1-year, open-label, Phase 3 study investigated long-term safety and efficacy of lumateperone 42 mg (a simultaneous modulator of serotonin, dopamine, and glutamate) in patients with stable schizophrenia. METHODS:Adult outpatients (≥18 years) with DSM-5-defined schizophrenia with stable pathology received lumateperone 42 mg orally once daily for 368 days. The primary endpoint was safety, assessed by adverse events (AEs) and changes in extrapyramidal symptoms (EPS), cardiometabolic and prolactin parameters, and vital signs. Secondary endpoints included change in Positive and Negative Syndrome Scale (PANSS) Total score and Calgary Depression Scale for Schizophrenia (CDSS). RESULTS:Of 602 patients treated with lumateperone 42 mg, 229 (38.0%) completed 1-year treatment. Treatment-emergent AEs (TEAEs) occurred in 390 patients (64.8%); the most common TEAEs (≥5%) were weight decreased (10.1%), diarrhea (7.6%), dry mouth (7.6%), and headache (7.3%). There were no notable changes in EPS-related scales. Significant improvements occurred for total and low-density lipoprotein cholesterol (P < .001), prolactin (P < .05), and triglycerides (P < .05) at Day 368. Weight, body mass index, and waist circumference significantly decreased throughout the study to Day 368 (P < .001). Lumateperone significantly improved PANSS Total score (mean change = -4.2; 95% CI = -5.6 to -2.8; effect size [ES] = -0.39; P < .001) and CDSS Total score (mean change = -0.6; 95% CI = -0.99 to -0.23; ES = -0.21; P < .01) at Day 368. CONCLUSION:Lumateperone 42 mg demonstrated a favorable safety profile with improvements in cardiometabolic and prolactin parameters and a low EPS risk and maintenance of stable symptoms of schizophrenia over 1-year treatment.

Abstract Background Anxious distress and mixed features are DSM-5 episode specifiers for major depressive episodes (MDE) associated with major depressive disorder (MDD) and bipolar disorder. Patients with depressive episodes with the specifiers have more severe symptoms, more comorbidities, increased suicide risk, and poorer treatment response than patients without the specifiers. Aims & Objectives Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. In a Phase 3, randomized, double-blind, placebo-controlled trial (Study 403; NCT04285515) lumateperone 42mg was efficacious over placebo with a favorable safety profile in patients with MDD or bipolar depression (BPD) with mixed features. This post hoc analysis of Study 403 investigated efficacy of lumateperone 42mg in patients with MDD or BPD with mixed features and anxious distress. Method Eligible adults (18-75 years) met DSM-5 criteria for an MDE with mixed features and had MDD, bipolar I, or bipolar II disorder, with Montgomery-Å sberg Depression Rating Scale [MADRS] Total score>=24 and Clinical Global Impression Scale-Severity [CGI-S] score>=4. Patients were stratified by MDD or bipolar disorder diagnosis and randomized 1:1 to 6-weeks lumateperone 42mg or placebo. This analysis evaluated patients with mixed features and DSM-5 anxious distress in the overall population (combined MDD/BPD) and separately in MDD and BPD individual populations. Assessments included change from baseline in MADRS Total score, CGI-S score, and MADRS inner tension item score. Results Of 383 patients in the combined MDD/BPD modified intent to treat (mITT) population with mixed features, 244 (63.7% of mITT; placebo, 121; lumateperone, 123) had anxious distress. Anxious distress was common in patients with MDD (73.9% of MDD mITT; placebo, 69; lumateperone, 67) and BPD (54.3% of BPD mITT; placebo, 52; lumateperone, 56). Compared with placebo, lumateperone significantly improved change from baseline for MADRS Total score at Day 43 in all 3 populations with anxious distress: combined MDD/BPD population (least squares mean difference vs placebo [LSMD], −6.1; 95% CI −8.52 to −3.71; effect size [ES], −0.67; P<.0001), MDD individual population (LSMD, −6.8; 95% CI −9.82 to −3.77; ES, −0.79; P<.0001), and BPD individual population (LSMD, −5.5; 95% CI −9.34 to −1.62; ES, −0.59; P<.01). In all 3 populations, significantly greater (P <.05) reductions in change from baseline of MADRS Total score occurred by Day 15 and persisted throughout the study in lumateperone-treated patients. Similarly, lumateperone significantly improved change from baseline for CGI-S score at Day 43 vs placebo for patients with anxious distress in the combined MDD/BPD population (LSMD, −0.5; 95% CI −0.78 to −0.26; ES, −0.54; P<.0001), MDD individual population (LSMD, −0.6; 95% CI −0.98 to −0.30; ES, −0.66; P<.001), and BPD individual population (LSMD, −0.4; 95% CI −0.82 to −0.05; ES, −0.48; P<.05). Lumateperone also significantly improved change from baseline for the inner tension MADRS single-item score at Day 43 compared with placebo for all 3 populations (P<.05). Discussion & Conclusion Lumateperone 42mg demonstrated efficacy in improving symptoms of major depression with mixed features and anxious distress, including global disease severity and inner tension, in patients with MDD or bipolar disorder.

Abstract Background This randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifer NCT04285515) evaluated efficacy and safety of lumateperone to treat major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features. Procedures Patients (18–75 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)–defined MDD with mixed features (n = 185) or bipolar disorder with mixed features (n = 200) and experiencing an MDE were randomized 1:1 to 6-week placebo (n = 195) or lumateperone 42 mg (n = 193). Primary and key secondary endpoints were change from baseline to day 43 in Montgomery-Åsberg Depression Rating Scale Total and Clinical Global Impression Scale-Severity (CGI-S) scores in 3 populations with combined MDD/bipolar depression, individual MDD, and individual bipolar depression. Safety included adverse events (AEs), extrapyramidal symptoms, and laboratory parameters. Results Lumateperone met the primary endpoint, significantly improving Montgomery-Åsberg Depression Rating Scale total score at day 43 in populations with combined MDD/bipolar depression (least squares mean difference vs placebo [LSMD], −5.7; 95% confidence interval [CI], −7.60,−3.84; effect size [ES], −0.64; P < 0.0001), MDD (LSMD, −5.9; 95% CI, −8.61,−3.29; ES, −0.67; P < 0.0001), and bipolar depression (LSMD, −5.7; 95% CI, −8.29,−3.05; ES, −0.64; P < 0.0001). Lumateperone significantly improved CGI-S and Young Mania Rating Scale total scores at day 43 in these populations. Lumateperone was well-tolerated. Treatment-emergent AEs (≥5%, twice placebo) in the combined population were somnolence (placebo, 1.6%; lumateperone, 12.5%), dizziness (placebo, 2.1%; lumateperone, 12.0%), and nausea (placebo, 1.6%; lumateperone, 9.9%). There were no mania/hypomania treatment-emergent AEs with lumateperone and minimal extrapyramidal symptoms or metabolic risk. Conclusions Lumateperone 42 mg significantly improved depression symptoms and disease severity and was generally safe and well-tolerated in patients with MDD or bipolar depression with mixed features.

This Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of lumateperone to treat bipolar depression. Patients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode were randomized 1:1:1 to 6-week lumateperone 28 mg ( n = 183), lumateperone 42 mg ( n = 185), or placebo ( n = 186). Primary and key secondary endpoints were change from baseline to Day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total score and time to first sustained response (≥50% reduction from baseline in MADRS Total score), respectively. Safety assessments included adverse events, extrapyramidal symptoms (EPS), laboratory evaluations, and vital signs. Neither dose of lumateperone achieved significant improvement vs. placebo ( P > 0.05) in the primary endpoint (MADRS Total score, least squares mean difference vs. placebo: 28 mg, 0.9; 42 mg, −1.0) or in the key secondary endpoint (MADRS Total time to first sustained response hazard ratio vs. placebo: 28 mg, 1.00; 42 mg, 0.93), likely due to a high placebo response. Both lumateperone doses were well tolerated, with low EPS risk and minimal changes in weight, prolactin, and cardiometabolic or endocrine parameters. While study efficacy objectives were not met, both doses of lumateperone were generally safe and well tolerated in patients with bipolar depression.

OBJECTIVE:This phase 3, randomized, double-blind, placebo-controlled trial evaluated lumateperone 42 mg (a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission) adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) and inadequate ADT response. METHODS:Participants were adults (ages 18-65 years) who had DSM-5-defined MDD and inadequate response to one to two ADTs in the current depressive episode and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥24. Patients were randomized in a 1:1 ratio to 6 weeks of oral placebo plus ADT (N=238) or lumateperone 42 mg plus ADT (N=242), once daily in the evening; the ADT was the latest drug to which they had inadequate response (i.e., <50% improvement). Primary and key secondary outcomes were change from baseline to day 43 in MADRS total score and Clinical Global Impressions Scale severity (CGI-S) score. Safety measures included adverse events, extrapyramidal symptoms, laboratory assessments, and suicidal ideation and behavior. RESULTS:Lumateperone+ADT met primary and key secondary endpoints, significantly improving MADRS total score (least squares mean difference [LSMD] versus placebo=-4.5; effect size=-0.56) and CGI-S score (LSMD=-0.5; effect size=-0.51) versus placebo+ADT at day 43. Patient-reported depression significantly improved with lumateperone+ADT versus placebo+ADT at day 43 (16-item Quick Inventory of Depressive Symptomatology-Self-Report, total score: LSMD=-2.2; effect size=-0.45). Lumateperone+ADT was generally well tolerated. The most common treatment-emergent adverse events (≥5%, twice the rate in the placebo+ADT group) were dizziness, somnolence, dry mouth, nausea, diarrhea, and fatigue; 12.4% versus 0.8% of patients discontinued treatment due to treatment-emergent adverse events in the lumateperone+ADT arm versus the placebo+ADT arm. There was minimal risk of extrapyramidal symptoms. Cardiometabolic abnormalities and weight gain were similar between the lumateperone+ADT arm and the placebo+ADT arm. Emergence of suicidal ideation was low. CONCLUSIONS:Patients receiving lumateperone 42 mg plus ADT had statistically significant and clinically meaningful improvement in depression symptoms and disease severity compared with those receiving placebo+ADT. Lumateperone+ADT was generally safe and well tolerated in patients with MDD with inadequate ADT response.

Abstract Background The DSM-5 and DSM-5-TR define mixed features in major depressive disorder (MDD) or bipolar depression (BPD) as having subsyndromal manic or hypomanic symptoms nearly every day during the majority of days of a major depressive episode (MDE). Mixed features are common in MDD and BPD (25%-35%) and patients with mixed features have more severe symptoms, more comorbidities, increased suicide risk, and poorer treatment response than patients without mixed features. Aims & Objectives Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. This randomized, double-blind, placebo-controlled, multicenter trial (NCT04285515) investigated the efficacy and safety of lumateperone 42mg for the treatment of an MDE in patients with MDD or BPD with mixed features. Method Eligible adults (18-75 years) had DSM-5 diagnosed MDD or bipolar I or II disorder with mixed features and were experiencing an MDE (Montgomery-Asberg Depression Rating Scale [MADRS] Total score>=24, Clinical Global Impression Scale-Severity [CGI-S] score>=4). Patients, stratified by MDD or BPD, were randomized 1:1 to 6-weeks treatment with lumateperone 42mg or placebo. The primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS Total and CGI-S score, respectively, analyzed using a mixed- effects model for repeated measures. Three populations with mixed features were assessed: the overall combined MDD and BPD population, the individual MDD population, and the individual BPD population. Safety assessments included adverse events (AEs), laboratory parameters, vital signs, and extrapyramidal symptoms. Results In this study, 385 patients received treatment (placebo, n=193; lumateperone, n=192) and 344 (89.4%) completed the study. Patients with MDD or BPD and mixed features treated with lumateperone 42mg had significantly greater MADRS Total score improvement compared with placebo as indicated by mean change from baseline to Day 43 (placebo, n=191; lumateperone, n=192; least squares mean difference vs placebo [LSMD]=−5.7; 95% CI, −7.60, −3.84; effect size [ES]=−0.64; P<.0001). Improvements with lumateperone were also significant in individual patient populations with MDD with mixed features (placebo, n=92; lumateperone, n=92; LSMD=−5.9; 95%CI, −8.61, −3.29; ES=−0.67; P<.0001) or BPD with mixed features (placebo, n=99; lumateperone, n=100; LSMD=−5.7; 95%CI, −8.29, −3.05; ES=−0.64; P<.0001). Significant improvements compared with placebo were also observed for CGI-S, the key secondary endpoint, in the combined MDD and BPD population (LSMD=−0.6; 95%CI, −0.81, −0.39; ES=−0.59; P<.0001), individual MDD population (LSMD=− 0.6; 95%CI, −0.89, −0.27; ES=−0.57; P<.001), and individual BPD population (LSMD=−0.6; 95%CI, −0.91, −0.31; ES=−0.61; P<.0001). Lumateperone treatment was generally safe and well tolerated and consistent with prior studies. The most common treatment-emergent AEs with lumateperone (>=5% and twice placebo) were somnolence, dizziness, and nausea. No serious AEs were reported with lumateperone. Discussion & Conclusion Lumateperone 42mg demonstrated robust efficacy over placebo in patients with MDD or BPD with mixed features. Lumateperone was generally safe and well tolerated with no new safety concerns. These results suggest lumateperone 42mg is a promising new treatment for MDEs in MDD with mixed features or BPD with mixed features.

Background This randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifer NCT04285515) evaluated efficacy and safety of lumateperone to treat major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features. Procedures Patients (18-75 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)-defined MDD with mixed features (n = 185) or bipolar disorder with mixed features (n = 200) and experiencing an MDE were randomized 1:1 to 6-week placebo (n = 195) or lumateperone 42 mg (n = 193). Primary and key secondary endpoints were change from baseline to day 43 in Montgomery-& Aring;sberg Depression Rating Scale Total and Clinical Global Impression Scale-Severity (CGI-S) scores in 3 populations with combined MDD/bipolar depression, individual MDD, and individual bipolar depression. Safety included adverse events (AEs), extrapyramidal symptoms, and laboratory parameters. Results Lumateperone met the primary endpoint, significantly improving Montgomery-& Aring;sberg Depression Rating Scale total score at day 43 in populations with combined MDD/bipolar depression (least squares mean difference vs placebo [LSMD], -5.7; 95% confidence interval [CI], -7.60,-3.84; effect size [ES], -0.64; P < 0.0001), MDD (LSMD, -5.9; 95% CI, -8.61,-3.29; ES, -0.67; P < 0.0001), and bipolar depression (LSMD, -5.7; 95% CI, -8.29,-3.05; ES, -0.64; P < 0.0001). Lumateperone significantly improved CGI-S and Young Mania Rating Scale total scores at day 43 in these populations. Lumateperone was well-tolerated. Treatment-emergent AEs (>= 5%, twice placebo) in the combined population were somnolence (placebo, 1.6%; lumateperone, 12.5%), dizziness (placebo, 2.1%; lumateperone, 12.0%), and nausea (placebo, 1.6%; lumateperone, 9.9%). There were no mania/hypomania treatment-emergent AEs with lumateperone and minimal extrapyramidal symptoms or metabolic risk. Conclusions Lumateperone 42 mg significantly improved depression symptoms and disease severity and was generally safe and well-tolerated in patients with MDD or bipolar depression with mixed features.