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.

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.

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.

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.

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.

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.

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.

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.

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.

Efficacy of adjunctive low-dose cariprazine in major depressive disorder: a randomized, double-blind, placebo-controlled trial.

This 19-week, double-blind, placebo-controlled, randomized phase 2 study evaluated the efficacy, safety, and tolerability of adjunctive cariprazine (0.1-0.3 and 1.0-2.0 mg/day) as an antidepressant treatment for adults with treatment-resistant major depressive disorder (MDD) (NCT00854100). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and the secondary was change in the Clinical Global Impression-Intensity score. Additional efficacy parameters were also assessed. A total of 231 patients were randomized. None of the predefined parameters reached significance for either cariprazine doses, but higher doses yielded numerically greater mean changes in MADRS and Clinical Global Impression-Intensity scores, and MADRS response and remission rates, compared with placebo. No differences were seen on any measures between cariprazine 0.1-0.3 mg/day and placebo. Cariprazine was relatively well tolerated, and common treatment-emergent adverse events (incidence ≥5% and twice the placebo group rate) in both dosage groups included headache, arthralgia, restlessness, fatigue, increased appetite, insomnia, dry mouth, and constipation. In conclusion, both cariprazine doses were relatively well tolerated; although differences were not statistically significant, patients treated with cariprazine 1.0-2.0 mg/day had greater mean decreases in measures of depression symptoms compared with placebo, which is consistent with another adjunctive cariprazine MDD study, and thus warrants further investigation.

Relapse prevention in adults with major depressive disorder treated with vilazodone: a randomized, double-blind, placebo-controlled trial.

This randomized withdrawal study assessed relapse prevention with vilazodone in adults with major depressive disorder. After 20 weeks of open-label treatment with vilazodone 40 mg/day, responders were randomized (1 : 1 : 1) to 28 weeks of double-blind, fixed-dose treatment with vilazodone 20 mg/day, vilazodone 40 mg/day, or placebo. The primary efficacy endpoint was time to first relapse, defined as Montgomery-Åsberg Depression Rating Scale total score of at least 18 and meeting major depressive episode criteria, Montgomery-Åsberg Depression Rating Scale total score of at least 18 at two consecutive visits, or discontinuation for an insufficient therapeutic response. Of 1204 patients who received open-label treatment, 564 completed treatment and were randomized (placebo=192, vilazodone 20 mg/day=185, vilazodone 40 mg/day=187). No significant difference was detected in time to relapse during the double-blind period (P>0.05). The crude percentage of patients that relapsed was similar between treatment groups (placebo=12.6%; vilazodone 20 mg/day=11.4%; vilazodone 40 mg/day=13.4%). The most common treatment-emergent adverse events were diarrhea (29.6%), nausea (24.0%), and headache (14.0%) during open-label treatment and headache (8.9%), nasopharyngitis (8.4%), and diarrhea (7.5%) during double-blind treatment in the combined vilazodone groups (20 and 40 mg/day). In conclusion, time to relapse with vilazodone was not statistically different from placebo. Vilazodone was generally well tolerated in adults with major depressive disorder.

A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Vilazodone in Adolescents with Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is a serious illness in children and adolescents. Vilazodone is a selective serotonin reuptake inhibitor approved for MDD in adults. This study evaluated the efficacy, safety, and tolerability of vilazodone in adolescent patients, ages 12-17 years, with MDD (NCT01878292). METHODS: This double-blind, randomized, placebo-controlled, parallel-group, fixed-dose study was conducted at 56 study centers in the United States and was 10 weeks in duration (a 1-week screening period, an 8-week double-blind treatment period, and a 1-week double-blind down-taper period). Outpatients with an MDD diagnosis based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria were included in the study. Clinical inclusion criteria required a Children's Depression Rating Scale-Revised (CDRS-R) total score of ≥ 40 and Clinical Global Impressions-Severity (CGI-S) score of ≥ 4. Patients were randomized 1:1:1 to 8 weeks of double-blind treatment with placebo (n = 174), vilazodone 15 mg/day (n = 175), or vilazodone 30 mg/day (n = 180). The primary and secondary efficacy parameters were change from baseline to week 8 in CDRS-R total score and CGI-S score, respectively. Safety parameters included adverse events (AEs); clinical laboratory, vital sign, and electrocardiogram parameters; and the Columbia-Suicide Severity Rating Scale. RESULTS: Approximately 86% of patients completed double-blind treatment. There was no statistically significant difference between vilazodone 15 mg/day or 30 mg/day and placebo in change from baseline in CDRS-R score. Change in CGI-S score was not significant after adjustment for multiple comparisons. The most common treatment-emergent AEs were nausea, upper abdominal pain, vomiting, diarrhea, nasopharyngitis, headache, and dizziness. Reports of suicidal ideation (placebo, 33.3%; vilazodone 15 mg/day, 36.0%; vilazodone 30 mg/day, 31.1%) and suicidal behavior (placebo, 1.8%; vilazodone 15 mg/day, 1.1%; vilazodone 30 mg/day, 1.1%) were similar between treatment groups. There were no deaths in the study. CONCLUSIONS: The efficacy of vilazodone for the treatment of MDD in adolescent patients could not be confirmed in this study. Vilazodone was generally safe and well tolerated, with treatment-emergent AEs similar to those in adult patients. CLINICAL TRIAL REGISTRATION: NCT01878292.

The safety and tolerability of cariprazine in patients with manic or mixed episodes associated with bipolar I disorder: A 16-week open-label study.

BACKGROUND: We evaluated the safety/tolerability of longer-term open-label treatment with cariprazine in patients who had responded to cariprazine for acute bipolar mania. METHODS: In this multinational, multicenter study, open-label, flexible-dose, cariprazine 3-12mg/d was administered for up to 16 weeks to patients (18-65 years) with bipolar mania. Safety evaluations included adverse events (AEs), laboratory values, vital signs, and extrapyramidal symptom (EPS) scales. Symptom change was evaluated by Young Mania Rating Scale (YMRS) total score change from baseline using the last observation carried forward approach. RESULTS: Of the 402 patients taking cariprazine, 33% completed the trial; the most frequent reasons for discontinuation were withdrawal of consent (20%), AEs (16%), and protocol violation (14%). Most common AEs leading to discontinuation were akathisia (4.7%) and depression (1.5%). Mean treatment duration was 57.7 days; mean cariprazine dose was 6.2mg/d. The incidence of serious AEs was 7.5% (most common: mania [2.2%], depression [1.2%]); 83.3% had treatment-emergent AEs, including akathisia (32.6%), headache (16.7%), constipation (10.7%), and nausea (10.4%). Mean body weight increased <1kg; 9.3% had ≥7% weight gain; 5.7% had sedation; 3% had somnolence. Mean changes in laboratory values, vital signs, ECGs, and ophthalmology parameters were not clinically significant. Mean YMRS total score decreased by -15.2 at week 16. LIMITATIONS: Uncontrolled, open-label design. CONCLUSIONS: Open-label cariprazine 3-12 (mean 6.2) mg/d for up to 16 weeks was generally well tolerated, with low (<10%) rates of sedation and ≥7% weight gain. Although akathisia occurred in 33%, it yielded discontinuation in <5%.

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.

Randomized, Double-Blind, Placebo-Controlled Trial of Asenapine Maintenance Therapy in Adults With an Acute Manic or Mixed Episode Associated With Bipolar I Disorder.

OBJECTIVE: The authors determined the efficacy and safety of asenapine in preventing recurrence of any mood episode in adults with bipolar I disorder. METHOD: Adults with an acute manic or mixed episode per DSM-IV-TR criteria were enrolled in this randomized, placebo-controlled trial consisting of an initial 12- to 16-week open-label period and a 26-week double-blind randomized withdrawal period. The target asenapine dosage was 10 mg b.i.d. in the open-label period but could be titrated down to 5 mg b.i.d. After completing the open-label period, subjects meeting stabilization/stable-responder criteria were randomized to asenapine or placebo treatment in the double-blind period. The primary efficacy endpoint was time to recurrence of any mood event during the double-blind period. Kaplan-Meier estimation was performed, and 95% confidence intervals were determined. Safety was assessed throughout. RESULTS: A total of 549 subjects entered the open-label period, of whom 253 enrolled in the double-blind randomized withdrawal period (127 in the placebo group; 126 in the asenapine group). Time to recurrence of any mood episode was statistically significantly longer for asenapine- than placebo-treated subjects. In post hoc analyses, significant differences in favor of asenapine over placebo were seen in time to recurrence of manic and depressive episodes. The most common treatment-emergent adverse events were somnolence (10.0%), akathisia (7.7%), and sedation (7.7%) in the open-label period and mania (11.9% of the placebo group compared with 4.0% of the asenapine group) and bipolar I disorder (6.3% compared with 1.6%) in the double-blind period. CONCLUSIONS: Long-term treatment with asenapine was more effective than placebo in preventing recurrence of mood events in adults with bipolar I disorder and was generally well-tolerated.