The efficacy of lumateperone on symptoms of depression in bipolar I and bipolar II disorder: Secondary and post hoc analyses

A recent Phase 3, randomized, double-blind, placebo-controlled study established that lumateperone 42-mg monotherapy significantly improved symptoms of depression in patients with bipolar depression. This manuscript reports prespecified secondary and post hoc efficacy analyses. Patients with bipolar I or bipolar II disorder experiencing a major depressive episode were randomized 1:1 to lumateperone 42 mg or placebo, administered orally once daily for 6 weeks. Prespecified analyses evaluated change from baseline to Day 43 in individual Montgomery-Åsberg Depression Rating Scale (MADRS) item scores in the modified intent-to-treat population (mITT) and bipolar I and bipolar II disorder subgroups. Post hoc analyses investigated the MADRS anhedonia factor and categorical shifts in MADRS item scores. In the mITT, there was significant improvement from baseline to Day 43 with lumateperone 42 mg compared with placebo for all 10 MADRS items; most MADRS items significantly improved in subgroups with bipolar I (9 items) and bipolar II disorder (8 items). A significantly higher proportion of patients receiving lumateperone compared with placebo shifted from baseline MADRS item score ≥4 to ≤2 at end of treatment in Reported Sadness, Reduced Sleep, Concentration Difficulties, Lassitude, Inability to Feel, and Pessimistic Thoughts. Lumateperone significantly improved the MADRS anhedonia factor from baseline to Day 43 compared with placebo in the mITT (effect size, -0.47) and subgroups with bipolar I (-0.36) and bipolar II disorder (-0.90). Lumateperone 42 mg treatment significantly improved depression symptoms compared with placebo, with consistent efficacy across a broad range of symptoms in people with bipolar I and bipolar II disorder.


Introduction
Bipolar disorder is a serious mental illness that ranks as the 17th leading source of disability among all diseases worldwide ( Carvalho et al., 2020 ;McIntyre et al., 2020a ;Shah et al., 2017 ). Bipolar I disorder is characterized by overt manic episodes, while bipolar II disorder is defined mainly by episodes of depression and hypomania ( Bahji et al., 2020 ). In both disorders, patients predominantly experience depressive symptoms, which are 3 times more common than manic or hypomanic symptoms ( Berk et al., 2015 ;McIntyre et al., 2020b ). However, patients with bipolar II disorder experience depressive symptoms more often than patients with bipolar I disorder ( Judd et al., 2003( Judd et al., , 2002. Depressive symptoms are particularly debilitating as they diminish quality of life and result in social impairment, decreased productivity, unemployment, and suicidality ( Baldessarini et al., 2020 ;McIntyre et al., 2020b ).
Despite the predominance of depression in bipolar disorder, fewer treatments have been proven effective for the management of depressive symptoms vs manic symptoms in patients with bipolar disorder ( McIntytre et al., 2019 ). Antidepressants, including selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, are of uncertain value and are linked with potential switching to mania in individuals with bipolar I disorder ( Pacchiarotti et al., 2013 ). The only atypical antipsychotics approved by the US Food and Drug Administration (FDA) for treating depression in patients with bipolar disorder are quetiapine (including extended-release quetiapine) ( Seroquel et al., 2022a and2022b ), olanzapinefluoxetine ( Symbyax et al., 2021 ), lurasidone ( Latuda et al., 2019 ), cariprazine ( Vraylar. Prescribing information. Allergan;, and lumateperone ( Baldessarini et al., 2020 ;Caplyta et al., 2022 ;McIntyre et al., 2020a ). Treatment options for depressive episodes associated with bipolar II disorder are further limited, with quetiapine (including extended-release quetiapine) ( Seroquel et al., 2022a and2022b ) and lumateperone ( Caplyta et al., 2022 ) as the only medications currently approved by the FDA ( Carvalho et al., 2020 ).
Lumateperone (lumateperone tosylate, ITI-007) is a mechanistically novel antipsychotic that is FDA approved for the treatment of schizophrenia in adults and for depressive episodes associated with bipolar I or bipolar II disorder (bipolar depression) in adults as monotherapy and as adjunctive therapy with lithium or valproate ( Caplyta et al., 2022 ). Lumateperone simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, the key neurotransmitters implicated in serious mental illness ( Davis and Correll, 2016 ;Li et al., 2014 ;Snyder et al., 2015 ). Lumateperone functions as a potent serotonin 5-HT 2A receptor antagonist, a dopamine D 2 receptor pre-synaptic par-tial agonist and post-synaptic antagonist, a D 1 receptordependent indirect modulator of AMPA ( α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D -aspartate) currents, and a serotonin reuptake inhibitor ( Davis and Correll, 2016 ;Snyder et al., 2015 ;Titulaer et al., 2021 ). The potentiation of both NMDA-and AMPA receptormediated currents by lumateperone may stem from its simultaneous activation of D 1 receptors and inhibition of serotonin reuptake transporter, which is a unique action of lumateperone compared with other antipsychotics ( Titulaer et al., 2021 ). This unique mechanism distinguishes lumateperone as a potential treatment for mood disorders, including bipolar depression.
The Montgomery-Å sberg Depression Rating Scale (MADRS) is used by clinicians to assess the severity of depression while also being sensitive to changes in a patient's depressive symptoms over time ( Thase et al., 2021 ). The MADRS Total score, which can range from 0 to 60 (with a higher score indicating worsening severity), is the sum of 10 individual MADRS item subscores (each ranging from 0 to 6): Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts ( Montgomery and Å sberg, 1979 ). Pharmacotherapy that reduces depressive symptom burden across a wide range of MADRS items may result in fewer residual depressive symptoms, which are a stronger predictor of quality of life and functional ability than symptoms of hypomania or mania in patients with bipolar disorder Michalak et al., 2008 ). Anhedonia, the inability to experience or anticipate pleasure, is a hallmark of major depressive episodes in bipolar disorder and major depressive disorder (American Psychiatric Association, 2013 ;McInytre et al., 2019 ). Recent studies indicate that those with bipolar disorder experience more frequent and more severe anhedonia than those with major depressive disorder ( Fang et al., 2021 ), with approximately half of patients with bipolar disorder reporting anhedonia ( Mazza et al., 2009 ) which is associated with a poorer disease prognosis than depression alone ( Cao et al., 2019 ;McIntyre et al., 2019 ).
In a recent Phase 3, randomized, double-blind, placebocontrolled, multinational study, lumateperone 42-mg monotherapy significantly improved symptoms of depression in patients with bipolar I or bipolar II disorder experiencing an acute major depressive episode (MDE) (Study 404, NCT03249376) . The primary endpoint was met in the modified intent-to-treat (mITT) population, with significantly greater improvement from baseline to Day 43 in MADRS Total score for lumateperone 42-mg treatment compared with placebo ( P < .0001) . The superiority of lumateperone 42 mg compared with placebo in MADRS Total score at Day 43 was observed in both subgroups of patients with bipolar I (effect size, −0.49; P < .0001) and bipolar II disorder (effect size, −0.81; P < .001) . In another Phase 3, randomized, double-blind, placebocontrolled study (Study 402, NCT02600507), lumateperone 42 mg adjunctive to lithium or valproate demonstrated significant improvements compared with placebo adjunctive to lithium or valproate in MADRS Total score (effect size, −0.27; P < .05) and Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S) depression subscore (effect size, −0.31; P < .01) in patients with bipolar I or bipolar II disorder experiencing an acute MDE ( Yatham et al., 2021 ). In both trials, lumateperone was generally well tolerated as monotherapy or adjunctive therapy, with low risk for extrapyramidal symptoms and minimal adverse effects on metabolic parameters, prolactin, or weight Yatham et al., 2021 ).
Prespecified secondary and post hoc analyses of Study 404 were conducted to assess the effects of lumateperone 42mg monotherapy across individual MADRS items in patients with bipolar I or bipolar II disorder experiencing an MDE.

Study design and patients
This analysis investigated the efficacy of lumateperone in a Phase 3, randomized, double-blind, placebo-controlled, multicenter outpatient trial (Study 404, NCT03249376) in patients with bipolar disorder experiencing a current MDE. Detailed study methods for this trial have been previously published . In summary, the study comprised a 2-week screening period, a 6-week on-treatment period, and a 2-week safety follow-up analysis. At baseline, patients were stratified by bipolar I disorder or bipolar II disorder diagnosis and randomized 1:1 to lumateperone 42 mg or placebo, administered via capsule once daily in the evening for 6 weeks with or without food. Efficacy assessments were conducted at weekly clinic visits (Days 8,15,22,29,36,and 43; all visits ±1 day).
Eligible participants were aged 18-75 years, were currently experiencing an MDE, and had a confirmed diagnosis of bipolar I disorder or bipolar II disorder according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition ( First et al., 2014 ). Patients were required to have depression of at least moderate severity, as determined by a MADRS Total score of ≥20 and a CGI-BP-S ( Spearing et al., 1997 ) score of ≥4 for depression and overall bipolar illness subscores at screening and baseline. The duration of the MDE must have been ≥2 weeks but < 6 months prior to screening and must have caused clinically significant distress or functional impairment. Patients were excluded if they had a notable risk for suicidal behavior or had been diagnosed with a psychiatric illness other than bipolar disorder within 12 months of screening. Additional inclusion and exclusion criteria have been previously published . Prior to the study, patients provided written informed consent as approved by the responsible institutional review board/independent ethics committee (IRB/IEC).

Prespecified and post hoc analyses
The primary endpoint was change from baseline to Day 43 in MADRS Total score in the mITT population, defined as all patients who received ≥1 dose of study medication, had a valid baseline assessment, and had ≥1 valid postbaseline MADRS assessment. MADRS Total score was also assessed by visit in subgroups stratified by bipolar I disorder or bipolar II disorder diagnosis. Additional prespecified secondary analyses included the change from baseline to Day 43 in individual MADRS items in the mITT population as well as subgroups with bipolar I disorder or bipolar II disorder.
Treatment effects on the prespecified endpoints (MADRS Total score by visit, individual MADRS items at Day 43) were evaluated using a mixed-effects model for repeated measures (MMRM) in the mITT population. The model included visit, treatment group, site, and bipolar disorder stratification (bipolar I disorder or bipolar II disorder) as factors; the patient ID as a random effect; and baseline score was included as a covariate, with interaction terms for treatment group-by-visit and visit-by-baseline score. An unstructured covariance matrix was used to estimate the correlation of repeated measurements within a patient. To control the overall type I error rate for multiple comparisons of the primary (MADRS Total) and key secondary (CGI-BP-S Total) efficacy parameters, a fixed-sequence hierarchical gatekeeping strategy with a 2-sided significance level of 0.05 was used. Per the statistical analysis plan, other prespecified efficacy analyses, including the analyses of MADRS individual items, were not adjusted for multiple comparisons as the analyses were additional secondary endpoints that were exploratory in nature. MADRS Total score response ( ≥50% decrease from baseline) and remission (MADRS score ≤12) at Day 43 were analyzed using a logistic regression. Statistical analyses were performed with SAS software version 9.4. Descriptive statistics were used to summarize baseline demographics and disease characteristics.
MADRS single-item symptom severity was rated on a numerical continuum corresponding to clinical definitions anchored from 0 (no abnormality), 1 (minimal), 2 (mild), 3 (worsening mild), 4 (moderate), 5 (worsening moderate), or 6 (severe). A post hoc analysis of the mITT population was conducted to investigate the categorical improvements in depression symptom severity by assessing the shifts in single-item MADRS scores from baseline to end of treatment (EOT) in the lumateperone group compared with the placebo group in patients categorized as having moderate-to-severe MADRS single-item symptom severity at baseline (MADRS item score ≥4). Shifts from moderate-to-severe MADRS single-item symptom severity to mild or better (MADRS item score ≤2) at EOT were analyzed using Fisher's exact test. Additionally, the proportions of all patients with a MADRS single-item symptom severity score of mild or better (MADRS item score ≤2) at EOT were also assessed.
A post hoc analysis evaluated the change from baseline in the MADRS anhedonia factor (Apparent Sadness, Reported Sadness, Concentration Difficulties, Lassitude, and Inability to Feel) ( Cao et al., 2019 ) using an MMRM in the mITT population by visit as well as in bipolar I and bipolar II disorder subgroups by visit. The MMRM for bipolar subgroups included study visit, bipolar disorder stratification, treatment group, site, and interaction terms for treatment-by-study visit, treatment-by-type of bipolar disorder, type of bipolar disorder-by-study visit, and treatment-by-type of bipolar disorder-by-study visit as factors, and baseline and interaction term for baseline-by-study visit as the covariates.

Patient population
Of the 546 patients screened for eligibility, 381 were randomized (lumateperone, n = 191; placebo, n = 190). A total of 376 patients were included in the mITT efficacy population, including 300 patients with bipolar I disorder (lumateperone, n = 150; placebo, n = 150) and 76 patients with bipolar II disorder (lumateperone, n = 38; placebo, n = 38). The majority of patients (87.4%) in each treatment group completed the 6-week treatment period (lumateperone, n = 167; placebo, n = 166). Baseline demographics and clinical characteristics were similar between the lumateperone and placebo treatment groups ( Table 1 ). The majority of patients were White (91.2%), and a higher percentage of men were included in the lumateperone 42-mg group (47.3%) compared with the placebo group (36.7%). Mean baseline MADRS Total score and CGI-BP-S depression subscores of 30.5 and 4.6, respectively, indicate that the overall population had moderateto-severe depression symptoms at baseline ( Müller et al., 2003 ). The mean age at first bipolar diagnosis was 32.6 years (range, 5-63 years).

Efficacy
In the mITT population, lumateperone 42-mg treatment was associated with a statistically significant improvement in MADRS Total score from baseline to Day 43 compared with placebo (least squares [LS] mean change, −16.7; least squares mean difference vs placebo [LSMD], −4.6; 95% CI, −6.34 to −2.83; effect size, −0.56; P < .0001) . Significant improvement in MADRS Total score compared with placebo at Day 43 was observed in patients with either bipolar I disorder (LSMD, −4.0; 95% CI, −5.92 to −1.99; effect size, −0.48; P < .0001) or bipolar II disorder (LSMD, −7.0; 95% CI, −10.92 to −3.16; effect size, −0.85; P < .001) ( Fig. 1A and B ). In patients with bipolar I disorder, statistically significant improvements in MADRS Total score were observed as early as Day 22, with continuing improvements throughout the study. In patients with bipolar II disorder, lumateperone significantly improved MADRS Total score compared with placebo as early as Day 8, with continuing significant improvements throughout the study, except at Day 15 ( P = .0586). There was significant MADRS Total score response at Day 43 with lumateperone compared with placebo in the mITT (lumateperone, 51.1%; placebo, 36.7%; Odds Ratio [OR], 2.98; P < .001), the bipolar I subgroup

Individual MADRS items
In the overall mITT population, change from baseline to Day 43 in all 10 MADRS items were significantly improved with lumateperone compared with placebo ( Fig. 2 ). The most prominent MADRS single items at baseline in both the lumateperone and placebo groups were Reported Sadness (lumateperone, 4.2; placebo, 4.1) and Apparent Sadness (lumateperone and placebo, 3.9). Suicidal Thoughts was the least severe item at baseline (lumateperone and placebo, 0.4), likely due to the exclusion of individuals at significant risk for suicidal behavior. The largest placebo-adjusted improvements at Day 43 were observed for Reduced Sleep (LSMD, −0.7; effect size, −0.53), Reported Sadness (LSMD, −0.6; effect size, −0.52), Apparent Sadness (LSMD, −0.5; effect size, −0.40), and Inner Tension (LSMD, −0.5; effect size, −0.42) ( P < .001 for all). In the overall mITT, there were significant improvements vs placebo within the first 2 weeks of treatment that were maintained for the duration of the study for items of reduced sleep (Day 8), apparent sadness (Day 15), and reported sadness (Day 15). Items of inner tension and suicidal thoughts also showed significant improvements by Day 8, which were significant at all but 1 visit (Day 15 and Day 22, respectively).
In the bipolar II subgroup, 8 out of 10 MADRS items significantly improved from baseline to Day 43 with lumateperone compared with placebo ( Fig. 3B ). Similar to the bipolar I population, the most prominent MADRS item at baseline in those with bipolar II disorder was Reported Sadness (lumateperone, 4.0; placebo, 4.1), and the least severe item was Suicidal Thoughts (lumateperone, 0.3; placebo, 0.3). For those with bipolar II disorder, Reduced Sleep and Reduced Appetite had smaller baseline scores compared with the bipolar I population. In those with bipolar II disorder, the largest placebo-adjusted improvement at Day 43 was reported for Reported Sadness (LSMD, −1.2; effect size, −0.97; P < .0001). Non-significant numerical reductions in MADRS items 5 (Reduced Appetite; LSMD, −0.2; effect size, −0.13) and 6 (Concentration Difficulties; LSMD, −0.5; effect size, −0.46) were seen in the bipolar II population.

Shifts in MADRS items
Among individuals with moderate-to-severe symptoms at baseline (MADRS item score ≥4), the percentage of patients who still had a MADRS item score ≥4 at EOT was higher Fig. 4 Shift in the MADRS a Individual Item Score From ≥4 at Baseline to EOT b . a MADRS items are rated on a 0-6 continuum (0 = no abnormality; 6 = severe). b Percentages may not add to 100 due to rounding. No patients had a suicidal thoughts baseline score ≥4 as this was an exclusion criterion for the trial. EOT, end of treatment; LUMA, lumateperone; MADRS, Montgomery-Å sberg Depression Rating Scale; mITT, modified intent-to-treat; PBO, placebo.
in the placebo group than in the lumateperone group for all MADRS single items except Suicidal Thoughts, for which there was not a large enough sample size to evaluate scores at the end of the study due to the exclusion of individuals with significant risk for suicidal behavior ( Fig. 4 ). A significantly higher proportion of the lumateperone group compared with the placebo group shifted from moderateto-severe symptoms (MADRS item score ≥4) at baseline to mild symptoms (score ≤2) at EOT for Reported Sadness ( P < .01), Reduced Sleep ( P < .01), Concentration Difficulties ( P < .05), Lassitude ( P < .01), Inability to Feel ( P < .01), and Pessimistic Thoughts ( P < .05) ( Fig. 5 ).
In addition, in the mITT population, a higher proportion of the lumateperone group compared with the placebo group had mild to no symptoms (MADRS score of ≤2) at EOT for every MADRS single item (Supplemental Fig. 2).

Discussion
Lumateperone demonstrated efficacy in alleviating symptoms of depression in patients with bipolar I or bipolar II disorder in a Phase 3, randomized, double-blind, placebocontrolled study (Study 404) . In the prior prespecified analysis of Study 404, improvement in MADRS Total score with lumateperone 42-mg treatment was statistically significant from placebo at Day 43 in subgroups of patients with either bipolar I (effect size, −0.49; P < .0001) or bipolar II disorder (effect size, −0.81; P < .001) . Additionally, at Day 43, the improvement in MADRS Total score with lumateperone compared with placebo was greater in patients with bipolar II disorder (LSMD, −7.0) than in patients with bipolar I disorder (LSMD, −4.0). Improvements with lumateperone 42 mg compared with placebo in the mITT population (LSMD, −4.6) were similar to improvements with atypical antipsychotics currently FDA approved for treating acute depression in bipolar I disorder (quetiapine [including extended-release quetiapine] ( Seroquel et al 2022a and 2022b ), olanzapine-fluoxetine ( Symbyax et al 2021 ), lurasidone ( Latuda et al., 2019 ), and cariprazine ( Vraylar Prescribing Information. Allergan; 2019 ). MADRS Total response rates at Day 43 were significantly higher with lumateperone compared with placebo in the mITT and in both the bipolar I and bipolar II disorder subgroups.
Lumateperone treatment significantly improved all 10 MADRS single-item symptoms in the overall mITT population compared with placebo. In the overall mITT popula- tion, the MADRS single item with the highest baseline score was Reported Sadness, and the item with the lowest baseline score was Suicidal Thoughts. The low baseline score of Suicidal Thoughts in this trial was due to the procedural exclusion of patients at significant risk for suicidal behavior, as indicated by a score of ≥4 on MADRS item 10 (Suicidal Thoughts) at screening or baseline, suicidal ideation within 6 months prior to screening according to the Columbia Suicide Severity Rating Scale, or suicidal behavior in the last 2 years. As such, the statistically significant improvement in Suicidal Thoughts in both bipolar disorder subpopulations ( P < .01) was particularly interesting, especially considering the boxed warning for suicidal thoughts and behaviors that lumateperone shares with other drugs approved for either major depressive disorder or bipolar depression.
Placebo-controlled studies of other antipsychotics approved for the treatment of acute depression in bipolar disorder have shown significant improvement in the majority of MADRS single items (olanzapine-fluoxetine combination therapy [8 items]; cariprazine [6-9 items], lurasidone [7 items], and quetiapine [7-8 items] monotherapy) ( Calabrese et al., 2005 ;Carvalho et al., 2020 ;Durgam et al., 2016 ;Loebel et al., 2014 ;McElroy et al., 2010 ;Suppes et al., 2014 ;Thase et al., 2006 ;Tohen et al., 2003 ;Young et al., 2010 ); however, this study of lumateperone is the only published study to demonstrate significant improvement for all 10 items. There were significant improvements with lumateperone 42 mg compared with placebo for MADRS single items in subgroups with bipolar I disorder (9 of 10 items) and bipolar II disorder (8 of 10 items). The MADRS items that did not show statistically significant improvement did show numerical improvement with lumateperone compared with placebo.
Depression with anhedonia is common in bipolar disorder and generally associated with poorer outcomes than depression alone ( Cao et al., 2019 ;Mazza et al., 2009 ;. There were significant improvements in anhedonia during this 6-week study, as indicated by the MADRS anhedonia factor, with significant improvements with lumate-perone 42-mg treatment vs placebo at Day 43 in the mITT population (effect size, −0.47, P < .0001) and subgroups with bipolar I disorder (effect size, −0.36, P < .01) and bipolar II disorder (effect size, −0.90, P < .001). This efficacy on anhedonia might therefore be particularly important in patients with bipolar depression.
To explore the clinically meaningful benefit of lumateperone in individual symptoms in addition to statistically significant improvement, we conducted post hoc analyses assessing the categorical shift in MADRS scores from more severe symptoms to less severe symptoms. Compared with patients receiving placebo, a higher proportion of patients treated with lumateperone had mild symptoms or better (MADRS score ≤2) for all MADRS single items at EOT. Among patients with moderate-to-severe symptoms (MADRS item score ≥4) at baseline, the proportion of patients in each group who shifted to a MADRS item score of 0 at EOT was greater in the lumateperone group than in the placebo group for Reduced Sleep and Reduced Appetite. More patients in the placebo group continued to have moderate-to-severe symptoms (MADRS item score ≥4) at EOT compared with the lumateperone group for all MADRS items except for Suicidal Thoughts, which was not included in the analysis due to study exclusion criteria. Among patients with moderateto-severe symptoms (MADRS item score ≥4) at baseline who shifted to mild symptoms or better (MADRS item score ≤2) at EOT, those who received lumateperone had significantly improved symptom scores for Reported Sadness, Reduced Sleep, Concentration Difficulties, Lassitude, Inability to Feel, and Pessimistic Thoughts compared with those who received placebo.
In this analysis, lumateperone treatment demonstrated significant improvements in all 10 items of the MADRS scale, indicating efficacy across a broad range of depression symptoms. While other currently FDA-approved atypical antipsychotics have shown significant improvement in the majority of MADRS items, lumateperone is the only one to have done so in all 10 items. In addition, only lumateperone ( Caplyta et al., 2022 ) and que-tiapine (including extended-release quetiapine) ( Seroquel et al 2022a and2022b ) are FDA approved for major depressive episodes in patients with bipolar II disorder ( Carvalho et al., 2020 ). Other antipsychotics approved for bipolar disorder exhibit a variety of undesirable side effects, such as cardiometabolic disturbances, weight gain, motor impairments, and hyperprolactinemia ( Carvalho et al., 2020 ;Solmi et al., 2017 ). In those with bipolar I disorder or bipolar II disorder, lumateperone displayed a safety profile similar to that of placebo, with low risk for extrapyramidal symptoms and minimal adverse effects on metabolic parameters, prolactin, or weight Yatham et al., 2021 ). With its favorable safety profile and similar efficacy compared with other antipsychotics, lumateperone is a promising treatment option for patients with bipolar I or bipolar II disorder experiencing acute depression.
Limitations of this study include the post hoc nature of the shift analyses, which were not defined a priori. Additionally, the study excluded patients with imminent suicidal risk or serious comorbid psychiatric or medical illnesses, which may not be representative of patients in clinical practice and may limit the generalizability of the findings. Patients experiencing a concurrent episode of mania or hypomania were also excluded from this study, as such, it is unknown how treatment outcomes may differ during mania/hypomania. Also, there were no active comparators in this study, therefore, no direct conclusions can be drawn regarding the effects of lumateperone relative to other antipsychotics, except for historical data in the literature.
These secondary and post hoc analyses of data from a Phase 3, randomized, double-blind, placebo-controlled study in patients with bipolar I or bipolar II disorder experiencing an acute MDE found that lumateperone 42-mg treatment significantly improved depression symptoms compared with placebo on all MADRS efficacy outcome measures, with consistent efficacy across a broad range of symptoms at Day 43. Moreover, compared with placebo, treatment with lumateperone led to a higher proportion of patients exhibiting mild symptoms or better (score ≤2) at EOT for all 10 MADRS single items. For 6 of the MADRS single items, a significantly higher proportion of patients treated with lumateperone 42 mg had reduced severity of symptoms, shifting from moderate-to-severe symptoms at baseline to mild or better symptoms at EOT compared with placebo. Treatment options with broad efficacy across a wide range of symptoms may result in fewer residual symptoms, leading to better quality of life and functional ability. Additionally, lumateperone demonstrated efficacy on measures of anhedonia, which is a particularly important and impairing symptom of bipolar depression. Based on these results, lumateperone may be a promising therapeutic option for treating the broad range of depressive symptoms across all MADRS items in people with bipolar I and bipolar II disorder.

Contributors
SD, SGK, and RED were responsible for the study design, data collection, and data analysis. AJC participated in data collection. RC, JH, and RED were responsible for data analysis. All authors participated in data interpretation and reviewing and editing of the manuscript and approved the final manuscript.

Role of the funding source
Intra-Cellular Therapies, Inc. was the sponsor of this study and was responsible for study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the paper for publication.