Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: Results from a randomized placebo-controlled clinical trial.

OBJECTIVE: This phase 3, randomized, double-blind, placebo-controlled study (NCT02600507) evaluated the efficacy and safety of lumateperone adjunctive therapy to lithium or valproate in patients with bipolar depression. METHODS: Patients (18-75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (MDE), with inadequate therapeutic response to lithium or valproate, were randomized 1:1:1 to 6 weeks adjunctive therapy with lumateperone 28 mg (n = 176), lumateperone 42 mg (n = 177), or placebo (n = 176). The primary and key secondary efficacy endpoints were change from baseline to Day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score and the Clinical Global Impression Scale-Bipolar Version-Severity Scale (CGI-BP-S) depression subscore. Safety assessments included adverse events, laboratory evaluations, vital signs, extrapyramidal symptoms (EPS), and suicidality. RESULTS: Patients treated with adjunctive lumateperone 42 mg showed significantly greater improvement compared with adjunctive placebo in MADRS Total score (LS mean difference vs placebo [LSMD], -2.4; p = 0.02) and CGI-BP-S depression subscore (LSMD, -0.3; p = 0.01), while adjunctive lumateperone 28 mg showed numerical improvement in MADRS Total score (LSMD, -1.7; p = 0.10) and improvement in the CGI-BP-S depression subscore (LSMD, -0.3; p = 0.04). Adjunctive lumateperone treatment was well tolerated; treatment-emergent adverse events reported at rates >5% and twice placebo for lumateperone 42 mg were somnolence (11.3%), dizziness (10.7%), and nausea (8.5%), with minimal risk of EPS, metabolic abnormalities, or increased prolactin. CONCLUSIONS: Lumateperone 42-mg treatment adjunctive to lithium or valproate significantly improved depression symptoms and was generally well tolerated in patients with MDEs associated with either bipolar I or bipolar II disorder.

Relapse prevention with levomilnacipran ER in adults with major depressive disorder: A multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Levomilnacipran extended release (ER) is a serotonin and norepinephrine reuptake inhibitor approved for major depressive disorder (MDD) in adults. This study was designed to evaluate relapse prevention with levomilnacipran ER in patients with MDD. METHODS: Patients (≥18 years) with MDD (N = 644) received 20 weeks of open-label treatment with levomilnacipran ER 40, 80, or 120 mg/d (8 weeks flexible dosing; 12 weeks fixed dosing). Patients with a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤12 from the end of week 8 to week 20 were randomized to 26 weeks of double-blind treatment with levomilnacipran ER (same dosage; n = 165) or placebo (n = 159). The primary efficacy endpoint was time to relapse, defined as insufficient therapeutic response (≥2-point increase from randomization in Clinical Global Impression of Severity score, risk of suicide, need for hospitalization due to worsening of depression, or need for alternative antidepressant treatment as determined by the investigator) or an MADRS total score ≥18 at 2 consecutive visits. RESULTS: In the double-blind intent-to-treat population, levomilnacipran ER-treated patients had a significantly longer time to relapse compared with placebo (hazard ratio = 0.56; 95% CI, 0.33-0.92; P = 0.0212). Crude relapse rates were 14.5% (levomilnacipran ER) and 24.5% (placebo). Double-blind treatment-emergent adverse events (AEs) were reported for 58.8% and 56.0% of levomilnacipran ER and placebo patients, respectively; 3.0% and 1.3% discontinued due to AEs, and 1.2% and 0.6% had serious AEs, respectively. CONCLUSION: Levomilnacipran ER (40-120 mg/d) was effective in preventing relapse in patients with MDD. Safety and tolerability results were consistent with levomilnacipran ER acute studies.

Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial.

BACKGROUND: Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms. METHODS: In this randomised, double-blind, phase 3b trial, we enrolled adults aged 18-65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4·5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) analysed in a modified intention-to-treat population of patients who had follow-up assessments within 5 days after last receipt of study drugs with a mixed-effects model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, number 2012-005485-36. FINDINGS: Between May 27, 2013, and Nov 17, 2014, 533 patients were screened and 461 (86%) patients were randomised to treatment (230 for cariprazine and 231 for risperidone); 460 were included in the safety population (one patient discontinued before study drug intake). 227 (99%) of 230 patients in the cariprazine group and 229 (99%) of 230 patients in the risperidone group were included in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). Mean daily doses were 4·2 mg (SD 0·6) for cariprazine and 3·8 mg (0·4) for risperidone. Treatment-emergent adverse events (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 123 (54%) patients treated with cariprazine and 131 (57%) patients treated with risperidone. Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (-8·90 points for cariprazine vs -7·44 points for risperidone; least squares mean difference -1·46, 95% CI -2·39 to -0·53; p=0·0022; effect size 0·31). One patient in the risperidone group died of a cause regarded as unrelated to treatment. INTERPRETATION: Our results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia. FUNDING: Gedeon Richter Plc.

Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-year open-label study.

OBJECTIVE: Cariprazine, a dopamine D3/D2 partial agonist atypical antipsychotic with preferential binding to D3 receptors, is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of cariprazine was established in three randomized, double-blind, placebo-controlled, 6-week trials in patients with acute exacerbation of schizophrenia. This 53-week study evaluated the long-term safety and tolerability of cariprazine in patients with schizophrenia. METHODS: This was a multicenter, open-label, flexible-dose study of cariprazine 3-9 mg/d in adults with schizophrenia. Participants included new patients and patients who had completed one of two phase III lead-in studies (NCT01104766, NCT01104779). Eligible patients entered a no-drug screening period of up to 1 week followed by 48 weeks of flexibly dosed, open-label cariprazine treatment (3-9 mg/d) and 4 weeks of safety follow-up. RESULTS: A total of 586 patients received open-label cariprazine treatment, ~39% of whom completed the study. No unexpected safety issues or deaths were reported. The most common (≥10%) adverse events (AEs) observed were akathisia (16%), headache (13%), insomnia (13%), and weight gain (10%). Serious AEs occurred in 59 (10.1%) patients, and 73 (12.5%) patients discontinued the study due to AEs during open-label treatment. Mean changes in metabolic, hepatic, and cardiovascular parameters were not considered clinically relevant. Mean body weight increased by 1.5 kg during the study, prolactin levels decreased slightly, and measures of efficacy remained stable. CONCLUSIONS: Long-term cariprazine treatment at doses up to 9 mg/d appeared to be generally safe and well tolerated in patients with schizophrenia.

Measures of suicidality in phase 3 clinical trials of levomilnacipran ER in adults with major depressive disorder.

OBJECTIVE: To evaluate the effects of levomilnacipran extended-release (ER) on suicidal ideation and behavior in adults with major depressive disorder (MDD). METHODS: Post hoc analyses were conducted in patients from 4 randomized, double-blind, placebo-controlled trials and a long-term, open-label extension study of levomilnacipran ER (40-120 mg/d) in adults with MDD. Analyses included incidence of suicide-related treatment-emergent adverse events (TEAEs); incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation (score=1-5) and behavior (score=6-10); percent of patients who shifted from no C-SSRS suicidal ideation/behavior at baseline to suicidal ideation during treatment (worsened from score=0 to score=1-5), or vice-versa (improved from score=1-5 to score=0). RESULTS: Suicide-related TEAEs occurred in<1% of patients in the levomilnacipran ER studies. The incidence of C-SSRS suicidal ideation was 22.2%, 23.9%, and 21.7% for placebo, short-term levomilnacipran ER, and long-term levomilnacipran ER, respectively; C-SSRS suicidal behavior was<1% in all of these groups. In the short-term studies, the percentage of patients with C-SSRS shifts were as follows: worsening from score=0 to score=1-5 (placebo, 8.6%; levomilnacipran ER, 11.0%); improvement from score=1-5 to score=0 (placebo, 24.0%; levomilnacipran ER, 27.7%). CONCLUSION: In adult MDD patients, the incidence of suicidal ideation and behavior was similar between placebo and short-term levomilnacipran ER as indicated by TEAE reports and C-SSRS scores. Worsening in C-SSRS scores was also similar between placebo and levomilnacipran ER. There was no indication of increased suicidality during longer courses of continued therapy. Together, these findings suggest that this medication is not associated with increased risks of suicidal ideation or behavior.

The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis.

BACKGROUND: Schizophrenia is a chronic and debilitating neuropsychiatric disorder that often requires long-term pharmacotherapy to manage symptoms and prevent relapse. Cariprazine is a potent dopamine D3 and D2 receptor partial agonist that is FDA-approved in the US for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults; the recommended dose range is 1.5-6 mg/d. METHODS: To further characterize the long-term safety of cariprazine, data from two 48-week open-label, flexible-dose extension studies were pooled for post hoc analyses. Outcomes were evaluated in the pooled safety population (patients who received ≥1 dose of cariprazine during an open-label extension period); findings were summarized using descriptive statistics for the overall cariprazine group and in modal daily dose groups (1.5-3, 4.5-6, and 9 mg/d). RESULTS: Of the 679 patients in the overall cariprazine safety population, 40.1% completed the study. The only adverse events (AEs) leading to discontinuation of ≥2% of patients in any dose group were akathisia, worsening of schizophrenia, and psychotic disorder. Treatment-emergent AEs (TEAEs) of akathisia, insomnia, weight increased, and headache were reported in ≥10% of the overall population. Mean prolactin levels decreased in all dose groups (overall, -15.4 ng/mL). Clinically insignificant changes in aminotransferase levels and alkaline phosphatase were observed; no dose-response relationship was observed across groups. Mean total (-5.3 mg/dL), low-density lipoprotein (-3.5 mg/dL), and high-density lipoprotein (-0.8 mg/dL) cholesterol levels decreased; no dose-response relationship was observed for metabolic parameters. Mean change in body weight was 1.58 kg; body weight increase and decrease ≥7% occurred in 27% and 11% of patients, respectively. Mean changes in cardiovascular parameters, including blood pressure and pulse, were generally not considered clinically significant. EPS-related TEAEs that occurred in ≥5% of patients were akathisia, tremor, restlessness, and extrapyramidal disorder. CONCLUSION: In these post hoc pooled analyses of data from 2 long-term open-label studies, treatment with cariprazine was generally safe and well tolerated. Results support the safety and tolerability of cariprazine within the FDA-recommended dose range of 1.5-6 mg/d for schizophrenia. CLINICAL TRIALS REGISTRATION: NCT01104792, NCT00839852.

Global improvement with cariprazine in the treatment of bipolar I disorder and schizophrenia: A pooled post hoc analysis.

INTRODUCTION: Global rating scale measures are useful for assessing the clinical relevance of patient change. Cariprazine, a dopamine D3 and D2 receptor partial agonist, is FDA-approved for the adult treatment of acute manic/mixed episodes of bipolar I disorder and schizophrenia. Post hoc evaluations of Clinical Global Impressions-Severity (CGI-S) scores from the cariprazine pivotal trials in both indications were conducted. METHODS: Data from 3 bipolar mania and 3 schizophrenia trials were pooled by indication (bipolar disorder = 1033; schizophrenia = 1466). Cariprazine- and placebo-treated patients were categorised by baseline CGI-S scores; the proportion of patients who improved from more severe categories at baseline to less severe categories at end-point was evaluated using a logistic regression model. Correlations between Young Mania Rating Scale and Positive and Negative Syndrome Scale total score changes and category shifts were also evaluated. RESULTS: In both disease states, more cariprazine- than placebo-treated patients had improved CGI-S scores at end-point; more placebo-treated patients had worse end-point scores. More cariprazine- vs placebo-treated patients shifted from the extremely/severely ill to mildly ill/better category (bipolar disorder = 55% vs 36%, odds ratio [OR] = 2.1; P = .09; schizophrenia = 42% vs 18%, OR = 3.4, P<.01). ORs was statistically significant in favour of cariprazine in shifts from marked and moderate illness to borderline/normal in both indications (P < .05). Correlations between rating scale improvement and category shift were greatest in patients with extreme/severe baseline illness for bipolar disorder (-0.853) and schizophrenia (-0.677). CONCLUSIONS: Post hoc analyses showed that more cariprazine- than placebo-treated patients with bipolar mania or schizophrenia had statistically significant and clinically meaningful CGI-S improvement.

Efficacy and Safety of Cariprazine in Acute Exacerbation of Schizophrenia: Results From an International, Phase III Clinical Trial.

This phase III study evaluated the efficacy and safety of cariprazine, a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors, in patients with acute exacerbation of schizophrenia. Patients were randomized to 6-week double-blind treatment with placebo, cariprazine 3 to 6 mg/d, or cariprazine 6 to 9 mg/d. Primary and secondary efficacy: change from baseline to week 6 in Positive and Negative Syndrome Scale total and Clinical Global Impressions-Severity scores, respectively, analyzed using a mixed-effects model for repeated measures adjusting for multiple comparisons. Safety included treatment-emergent adverse events, clinical laboratory values, vital signs, electrocardiograms, ophthalmologic examination, Columbia-Suicide Severity Rating Scale, and extrapyramidal symptom scales. In the Safety Population (placebo, n = 147; cariprazine 3-6 mg/d, n = 151; cariprazine 6-9 mg/d, n = 148), 60.5% of patients completed the study. At week 6, statistically significant least squares mean differences in favor of cariprazine versus placebo were observed for Positive and Negative Syndrome Scale total score (3-6 mg/d: -6.8, P = 0.003; 6-9 mg/d: -9.9, P < 0.001) and Clinical Global Impressions-Severity (3-6 mg/d: -0.3, P = 0.012; 6-9 mg/d: -0.5, P < 0.001). Common treatment-emergent adverse events (≥5% and twice the rate of placebo) in both cariprazine groups were akathisia, extrapyramidal disorder, and tremor; most were mild to moderate in severity. Mean changes in metabolic parameters were generally small and similar between groups. Prolactin levels decreased in all groups. In conclusion, cariprazine 3 to 6 and 6 to 9 mg/d versus placebo demonstrated significant improvement on primary and secondary efficacy parameters. Cariprazine was generally well tolerated. These results suggest that cariprazine may be a new and effective treatment for schizophrenia.

The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial.

OBJECTIVES: Cariprazine, an orally active and potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors, is being developed for the treatment of schizophrenia and bipolar mania. This Phase II trial evaluated the efficacy, safety, and tolerability of cariprazine versus placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder. METHODS: This was a multinational, randomized, double-blind, placebo-controlled, flexible-dose study of cariprazine 3-12 mg/day in patients with acute manic or mixed episodes associated with bipolar I disorder. Following washout, patients received three weeks of double-blind treatment. The primary and secondary efficacy parameters were change from baseline to Week 3 in Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity (CGI-S) scores, respectively. Post-hoc analysis evaluated changes on YMRS single items. RESULTS: In each group, 118 patients received double-blind treatment; 61.9% of placebo and 63.6% of cariprazine patients completed the study. The overall mean daily dose of cariprazine was 8.8 mg/day. At Week 3, cariprazine significantly reduced YMRS and CGI-S scores versus placebo, with least square mean differences of -6.1 (p < 0.001) and -0.6 (p < 0.001), respectively. On each YMRS item, change from baseline to Week 3 was significantly greater for cariprazine versus placebo (all, p < 0.05). A significantly greater percentage of cariprazine patients than placebo patients met YMRS response (48% versus 25%; p < 0.001) and remission (42% versus 23%; p = 0.002) criteria at Week 3. Adverse events (AEs) led to discontinuation of 12 (10%) placebo and 17 (14%) cariprazine patients. The most common AEs (> 10% for cariprazine) were extrapyramidal disorder, headache, akathisia, constipation, nausea, and dyspepsia. Changes in metabolic parameters were similar between groups, with the exception of fasting glucose; increases in glucose were significantly greater for cariprazine versus placebo (p < 0.05). Based on Barnes Akathisia Rating Scale and Simpson-Angus Scale scores, more cariprazine than placebo patients experienced treatment-emergent akathisia (cariprazine: 22%; placebo: 6%) or extrapyramidal symptoms (parkinsonism) (cariprazine: 16%; placebo: 1%). CONCLUSION: Cariprazine demonstrated superior efficacy versus placebo and was generally well tolerated in patients experiencing acute manic or mixed episodes associated with bipolar I disorder.

A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder.

BACKGROUND: Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is approved for treating major depressive disorder in adults. This study (NCT01629966 ClinicalTrials.gov) evaluated the efficacy and safety of vilazodone in adults with generalized anxiety disorder (GAD). METHODS: A multicenter, double-blind, parallel-group, placebo-controlled, fixed-dose study in patients with GAD randomized (1:1:1) to placebo (n = 223), or vilazodone 20 mg/day (n = 230) or 40 mg/day (n = 227). Primary and secondary efficacy parameters were total score change from baseline to week 8 on the Hamilton Rating Scale for Anxiety (HAMA) and Sheehan Disability Scale (SDS), respectively, analyzed using a predefined mixed-effect model for repeated measures (MMRM). Safety outcomes were presented by descriptive statistics. RESULTS: The least squares mean difference (95% confidence interval) in HAMA total score change from baseline (MMRM) was statistically significant for vilazodone 40 mg/day versus placebo (-1.80 [-3.26, -0.34]; P = .0312 [adjusted for multiple comparisons]), but not for vilazodone 20 mg/day versus placebo. Mean change from baseline in SDS total score was not significantly different for either dose of vilazodone versus placebo when adjusted for multiplicity; significant improvement versus placebo was noted for vilazodone 40 mg/day without adjustment for multiplicity (P = .0349). The incidence of adverse events was similar for vilazodone 20 and 40 mg/day (∼71%) and slightly lower for placebo (62%). Nausea, diarrhea, dizziness, vomiting, and fatigue were reported in ≥5% of patients in either vilazodone group and at least twice the rate of placebo. CONCLUSIONS: Vilazodone was effective in treating anxiety symptoms of GAD. No new safety concerns were identified.

Lumateperone for the Treatment of Schizophrenia: Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed.

Objective: To describe lumateperone for the treatment of schizophrenia in adults using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).Methods: Data were obtained from the 3 phase 2/3 lumateperone trials, conducted between 2011 and 2016, in patients with schizophrenia diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, or Fifth Edition. Efficacy was assessed using various response criteria; tolerability was principally assessed using rates of adverse events (AEs).Results: Pooled data of the 2 informative studies showed statistically significant estimates of NNT versus placebo for lumateperone 42 mg/d for the responder thresholds of ≥ 20% and ≥ 30% improvement on Positive and Negative Syndrome Scale (PANSS) total scores, with NNT for response versus placebo at 4 weeks and endpoint of 9 (95% confidence interval [CI], 5-36) and 8 (95% CI, 5-21), respectively. Pooling all studies, discontinuation because of AEs was uncommon, and the NNH versus placebo was 389 (not statistically significant from placebo [NS]). Rates of individual AEs resulted in NNH versus placebo > 10 except for somnolence/sedation (NNH of 8; 95% CI, 6-12). The occurrence of weight gain ≥ 7% from baseline yielded a NNH estimate of 122 (NS). Rates of akathisia were lower for patients receiving lumateperone compared with placebo. LHH for response versus somnolence/sedation was ~ 1 for lumateperone (similar to the risperidone active control group); otherwise, lumateperone exhibited LHH ratios that were much greater than 1 for all other AEs and that ranged from 13.6 to 48.6 for these other benefit-risk calculations.Conclusions: In 3 phase 2/3 trials, the benefit-risk assessment of lumateperone was favorable as measured by NNT, NNH, and LHH.Trial Registration: ClinicalTrials.gov identifiers: NCT01499563, NCT02282761, NCT02469155.

The Efficacy of Lumateperone in Patients With Bipolar Depression With Mixed Features.

Objective: A post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled outpatient study investigated efficacy of lumateperone 42 mg in patients with bipolar I or bipolar II disorder and experiencing a major depressive episode (MDE) stratified by the presence of mixed features.Methods: Adults (18-75 years) with bipolar I or bipolar II disorder experiencing an MDE, defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria, were randomized 1:1 to 6-week oral lumateperone 42 mg/d or placebo (conducted November 2017-March 2019). Montgomery-Asberg Depression Rating Scale (MADRS) total score, Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S) total score, and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) were analyzed in patients (N = 376) categorized as having mixed features (Young Mania Rating Scale [YMRS] score ≥ 4 and ≤ 12, 41.5%) or not having mixed features (YMRS < 4, 58.5%) at baseline. Treatment-emergent adverse events (TEAEs) including mania/hypomania were assessed.Results: At day 43, lumateperone significantly improved MADRS and CGI-BP-S total scores change from baseline compared with placebo for patients with mixed features (MADRS least squares mean difference [LSMD] = -4.4, P < .01; CGI-BP-S LSMD = -0.7, P < .05) and without mixed features (MADRS LSMD = -4.2, P < .001, CGI-BP-S LSMD = -1.0, P < .001). Q-LES-Q-SF percent score significantly improved at day 43 with lumateperone vs placebo in patients with mixed features (LSMD = 5.9, P < .05), with numerical improvements in patients without mixed features (LSMD = 2.6, P = .27). TEAEs of mania/hypomania were rare.Conclusions: Lumateperone 42 mg significantly improved symptoms of depression and disease severity in patients with an MDE associated with bipolar I or bipolar II disorder, with or without mixed features.Trial Registration: ClinicalTrials.gov identifier: NCT03249376.

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.

Safety and tolerability of lumateperone for the treatment of schizophrenia: a pooled analysis of late-phase placebo- and active-controlled clinical trials.

Lumateperone, an antipsychotic that is US Food and Drug Administration-approved for the treatment of schizophrenia, has a novel mechanism of action that may confer beneficial effects with improved tolerability. This pooled analysis of three randomized, double-blind, placebo-controlled trials was conducted to evaluate the safety and tolerability of lumateperone 42 mg. The pooled population comprised 1073 patients with an acute exacerbation of schizophrenia randomized to placebo (n = 412), lumateperone 42 mg (n = 406) or risperidone 4 mg (n = 255). Treatment-emergent adverse events (TEAEs) were predominantly mild and rates of discontinuation due to TEAEs with lumateperone 42 mg (0.5%) were similar to placebo (0.5%) and lower than risperidone (4.7%). The only TEAEs that occurred at a rate of ≥5% and twice placebo for lumateperone were somnolence/sedation and dry mouth. Mean change from baseline in metabolic parameters and prolactin were similar to or reduced in lumateperone 42 mg relative to placebo-treated patients and were smaller than risperidone. Mean change in weight and rates of extrapyramidal symptoms-related TEAEs were similar for lumateperone 42 mg and placebo-treated patients and less than for risperidone-treated patients. This pooled analysis demonstrates the safety and favorable tolerability profile of lumateperone 42 mg.

Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial.

OBJECTIVE: In a phase 3 randomized double-blind placebo-controlled study, the authors investigated the efficacy and safety of 42 mg/day of lumateperone in patients with bipolar I or bipolar II disorder experiencing a major depressive episode. METHODS: Patients 18-75 years old with a clinical diagnosis of bipolar I or bipolar II disorder and experiencing a major depressive episode were eligible for the study. Patients were randomized in a 1:1 ratio to receive 42 mg/day of lumateperone (N=188) or placebo (N=189), administered orally once daily in the evening for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to day 43 in score on the Montgomery-Åsberg Depression Rating Scale (MADRS) and total score on the Clinical Global Impressions Scale-Bipolar Version severity scale (CGI-BP-S), respectively. Safety assessments included treatment-emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms, and suicidality. RESULTS: At day 43, lumateperone treatment was associated with significantly greater improvement from baseline in MADRS score compared with placebo (least squares mean difference compared with placebo, -4.6 points; effect size=-0.56) and CGI-BP-S total score (least squares mean difference compared with placebo, -0.9; effect size=-0.46). Significant MADRS superiority for lumateperone over placebo was observed both in patients with bipolar I and bipolar II disorders. Somnolence and nausea were the only treatment-emergent adverse events that occurred with lumateperone at a clinically meaningful greater rate than placebo. The incidence of extrapyramidal symptom-related treatment-emergent adverse events was low and similar to that for placebo. Minimal changes were observed in weight, vital signs, or metabolic or endocrine assessments. CONCLUSIONS: Lumateperone at 42 mg/day significantly improved depression symptoms and was generally well tolerated in patients with major depressive episodes associated with both bipolar I and bipolar II disorders.

Relationship Between Plasma Concentrations and Clinical Effects of Cariprazine in Patients With Schizophrenia or Bipolar Mania.

Population pharmacokinetic/pharmacodynamic modeling (via NONMEM) was used to describe longitudinal exposure-response relationships for total cariprazine (sum of cariprazine and its major active metabolites) in 2,558 patients with schizophrenia or bipolar mania. Drug exposure metrics were explored for potential relationships with efficacy and safety end points. Total cariprazine exposures were significantly related to reductions in Positive and Negative Syndrome Scale (PANSS) or Young Mania Rating Scale (YMRS) total scores in schizophrenia or bipolar mania, respectively, via a maximum effect (Emax )-type relationship. Typical steady-state plasma concentrations after 3 and 4.5 mg/day were associated with 50% of maximum typical reductions in PANSS and YMRS total scores, respectively. Time-weighted cariprazine exposures had significant relationships with the probability of common adverse events (AEs). Dose increase was associated with increased efficacy but was also associated with an increase in AEs. Results of these pharmacokinetic/pharmacodynamic analyses support that the recommended dose range (1.5-6 mg/day for schizophrenia and 3-6 mg/day for bipolar mania) provides an appropriate benefit-risk balance between cariprazine efficacy and safety.

OnabotulinumtoxinA for the treatment of major depressive disorder: a phase 2 randomized, double-blind, placebo-controlled trial in adult females.

This 24-week double-blind placebo-controlled multicenter randomized phase 2 trial evaluated efficacy and safety of onabotulinumtoxinA (onabotA; BOTOX) vs. placebo for major depressive disorder (MDD) [NCT02116361]. Primary endpoint was the change in Montgomery-Åsberg Depression Rating Scale (MADRS); secondary endpoints were Clinical Global Impressions-Severity and 17-item Hamilton Depression Rating Scale at week 6. A total of 255 adult females were treated. OnabotA 30 U approached significance compared to placebo on MADRS (mixed-effect model repeated measures least-squares mean difference: -3.7; P = 0.053) and reached significance [least-squares mean differences: -3.6 to -4.2; P < 0.05 (two-sided)] at weeks 3 and 9. Secondary endpoints were also significant at several time points. At week 6, onabotA 50 U did not separate from placebo in any parameters. OnabotA was generally well-tolerated: the only treatment-emergent adverse events reported in ≥5% in either onabotA group, and more than matching placebo were headache, upper respiratory infection, and eyelid ptosis. OnabotA 30 U, administered in a standardized injection pattern in a single session, had a consistent efficacy signal across multiple depression symptom scales for 12 or more weeks. OnabotA 30 U/placebo MADRS differences of (observed ANCOVA) ≥4.0 points (up to week 15) and ≥2.0 points (weeks 18-24) agree with the 2-point change threshold considered clinically relevant in MDD. OnabotA is a local therapy and is not commonly associated with systemic effects of conventional antidepressants and may represent a novel treatment option for MDD.

Efficacy of cariprazine on negative symptoms in patients with acute schizophrenia: A post hoc analysis of pooled data.

Although currently approved antipsychotics exert efficacy on positive symptoms of schizophrenia, treatments for negative symptoms remain a major unmet need. Post hoc analyses were used to investigate the possible efficacy of cariprazine in patients with moderate/severe negative symptoms of schizophrenia and no predominance of positive symptoms. Data were pooled from 2 randomized, double-blind, placebo- and active-controlled cariprazine studies in patients with acute schizophrenia (NCT00694707, NCT01104766). Analyses included data from a subset of patients with a Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) ≥24, PANSS factor score for positive symptoms (PANSS-FSPS) ≤19, and scores of ≥4 on ≥2 of 3 PANSS items (blunted affect [N1], passive/apathetic social withdrawal [N4], lack of spontaneity/flow of conversation [N6]). Changes from baseline to week 6 in PANSS-FSNS were evaluated in the following treatment groups: placebo (n = 79), cariprazine 1.5-3 (n = 94) and 4.5-6 mg/d (n = 66), risperidone 4 mg/d (n = 34), or aripiprazole 10 mg/d (n = 44). Significant differences were observed versus placebo for cariprazine (1.5-3 mg/d, P = .0179; 4.5-6 mg/d, P = .0002) and risperidone (P = .0149), but not aripiprazole (P = .3265), and versus aripiprazole for cariprazine 4.5-6 mg/d (P = .0197). After adjusting for positive symptom changes, differences versus placebo remained statistically significant for cariprazine (1.5-3 mg/d, P = .0322; 4.5-6 mg/d, P = .0038) but not for risperidone (P = .2204). PANSS-FSNS response (≥20% reduction from baseline) rates were significantly higher with cariprazine (1.5-3 mg/d = 54.3%, P = .0194; 4.5-6 mg/d = 69.7%, P = .0001) than placebo (35.4%). In patients with acute schizophrenia and moderate/severe negative symptoms, cariprazine was associated with significantly greater improvement in negative symptoms compared with placebo and aripiprazole, warranting further exploration of the efficacy of cariprazine on negative symptoms.

Efficacy of cariprazine across symptom domains in patients with acute exacerbation of schizophrenia: Pooled analyses from 3 phase II/III studies.

Schizophrenia affects various symptom domains, including positive and negative symptoms, mood, and cognition. Cariprazine, a dopamine D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, with preferential binding to D3 receptors, is approved for the treatment of adult patients with schizophrenia (US, Europe) and mania associated with bipolar I disorder (US). For these investigations, data were pooled from 3 positive, 6-week, double-blind, placebo-controlled, phase II/III trials of cariprazine in patients with acute exacerbation of schizophrenia (NCT00694707, NCT01104766, NCT01104779); 2 trials were fixed-dose and 1 trial was flexible-dose. Post hoc analyses evaluated mean change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) -derived symptom factors (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression) and PANSS single items for cariprazine (1.5-9.0 mg/d) versus placebo. P values were not adjusted for multiple comparisons. At week 6, statistically significant differences versus placebo were seen for cariprazine on all 5 PANSS factors (P < 0.01 all). Effects sizes ranged from 0.21 (anxiety/depression) to 0.47 (disorganized thought). Dose-response analysis from the fixed-dose studies found significant differences for all cariprazine doses (1.5, 3.0, 4.5, and 6.0 mg/d) versus placebo in PANSS total score, and in negative symptom and disorganized thought factor scores (P < 0.001). Differences between cariprazine and placebo were also statistically significant on 26 of 30 PANSS single items (P < 0.05). In these post hoc analyses, cariprazine was effective versus placebo in improving all 5 PANSS factor domains, suggesting that it may have broad-spectrum efficacy in patients with acute schizophrenia.

Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder.

Lack of treatment response is a critical problem in major depressive disorder (MDD). Cariprazine is a D3-preferring dopamine D3/D2 receptor partial agonist and 5-HT1A partial agonist. This phase 3, multicenter, open-label, long-term (26-week), flexible-dose (1.5-4.5 mg/day) study assessed the long-term safety and tolerability of cariprazine used adjunctively with antidepressant therapy in adult patients with MDD who had either completed a lead-in study (n=311) or had been newly recruited (n=131). A higher percentage of continuing patients (66.2%) than new patients (35.9%) completed the study. The most common reason for discontinuation was adverse events (AEs; 13.9%); 79% of patients experienced a treatment-emergent AE [most common: akathisia (15.9%,) headache (11.6%)]. Serious AEs occurred in 2% of patients; two deaths occurred (one traffic accident, one completed suicide, both considered unrelated to treatment). The mean changes in clinical laboratory, cardiovascular, and ophthalmologic parameters were generally not clinically relevant. The mean (SD) changes from the open-label baseline in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity score at week 26 were -7.3 (9.5) and -1.0 (1.2), respectively. By week 26, 53.3% of patients were in remission (Montgomery-Åsberg Depression Rating Scale total score≤10). The results suggest that cariprazine was generally safe and well tolerated as adjunctive therapy to treat MDD.