An oral compound, SEP-363856, that does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT
) receptors, may ...represent a new class of psychotropic agent for the treatment of psychosis in schizophrenia.
We performed a randomized, controlled trial to evaluate the efficacy and safety of SEP-363856 in adults with an acute exacerbation of schizophrenia. The patients were randomly assigned in a 1:1 ratio to receive once-daily treatment with SEP-363856 (50 mg or 75 mg) or placebo for 4 weeks. The primary end point was the change from baseline in the total score on the Positive and Negative Symptom Scale (PANSS; range, 30 to 210; higher scores indicate more severe psychotic symptoms) at week 4. There were eight secondary end points, including the changes from baseline in the scores on the Clinical Global Impressions Severity (CGI-S) scale and the Brief Negative Symptom Scale (BNSS).
A total of 120 patients were assigned to the SEP-363856 group and 125 to the placebo group. The mean total score on the PANSS at baseline was 101.4 in the SEP-363856 group and 99.7 in the placebo group, and the mean change at week 4 was -17.2 points and -9.7 points, respectively (least-squares mean difference, -7.5 points; 95% confidence interval, -11.9 to -3.0; P = 0.001). The reductions in the CGI-S and BNSS scores at week 4 were generally in the same direction as those for the primary outcome, but the results were not adjusted for multiple comparisons. Adverse events with SEP-363856 included somnolence and gastrointestinal symptoms; one sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin were similar in the trial groups.
In this 4-week trial involving patients with an acute exacerbation of schizophrenia, SEP-363856, a non-D2-receptor-binding antipsychotic drug, resulted in a greater reduction from baseline in the PANSS total score than placebo. Longer and larger trials are necessary to confirm the effects and side effects of SEP-363856, as well as its efficacy relative to existing drug treatments for patients with schizophrenia. (Funded by Sunovion Pharmaceuticals; ClinicalTrials.gov number, NCT02969382.).
The authors evaluated the efficacy and safety of lurasidone in the treatment of patients with major depressive episodes associated with bipolar I disorder.
Patients were randomly assigned to receive ...double-blind treatment with lurasidone (20-60 mg/day N=166 or 80-120 mg/day N=169) or placebo (N=170) for 6 weeks. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively.
Lurasidone treatment significantly reduced mean MADRS total scores at week 6 for both the 20-60 mg/day group (-15.4; effect size=0.51) and the 80-120 mg/day group (-15.4; effect size=0.51) compared with placebo (-10.7). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores for both the 20-60 mg/day group (-1.8; effect size=0.61) and the 80-120 mg/day group (-1.7; effect size=0.50) compared with placebo (-1.1). Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were similar in the 20-60 mg/day (6.6%), 80-120 mg/day (5.9%), and placebo (6.5%) groups. The most frequent adverse events associated with lurasidone were nausea, headache, akathisia, and somnolence. Minimal changes in weight, lipids, and measures of glycemic control were observed with lurasidone.
Monotherapy with lurasidone in the dosage range of 20-120 mg/day significantly reduced depressive symptoms in patients with bipolar I depression. Lurasidone was well tolerated, with few changes in weight or metabolic parameters.
This network meta-analysis assessed the efficacy and tolerability of lurasidone versus other oral atypical antipsychotic monotherapies in adolescent schizophrenia. A systematic literature review ...identified 13 randomized controlled trials of antipsychotics in adolescents with schizophrenia-spectrum disorders. A Bayesian network meta-analysis compared lurasidone to aripiprazole, asenapine, clozapine, olanzapine, paliperidone extended-release (ER), quetiapine, risperidone, and ziprasidone. Outcomes included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), weight gain, all-cause discontinuation, extrapyramidal symptoms (EPS), and akathisia. Results were reported as median differences for continuous outcomes and odds ratios (ORs) for binary outcomes, along with 95% credible intervals (95% CrI). Lurasidone was significantly more efficacious than placebo on the PANSS (− 7.95, 95% CrI − 11.76 to − 4.16) and CGI-S (− 0.44, 95% CrI − 0.67 to − 0.22) scores. Lurasidone was associated with similar weight gain to placebo and statistically significantly less weight gain versus olanzapine (− 3.62 kg, 95% CrI − 4.84 kg to − 2.41 kg), quetiapine (− 2.13 kg, 95% CrI − 3.20 kg to − 1.08 kg), risperidone (− 1.16 kg, 95% CrI − 2.14 kg to − 0.17 kg), asenapine (− 0.98 kg, 95% CrI − 1.71 kg to − 0.24 kg), and paliperidone ER (− 0.85 kg, 95% CrI − 1.57 kg to − 0.14 kg). The odds of all-cause discontinuation were significantly lower for lurasidone than aripiprazole (OR = 0.28, 95% CrI 0.10–0.76) and paliperidone ER (OR = 0.25, 95% CrI 0.08–0.81) and comparable to other antipsychotics. Rates of EPS and akathisia were similar for lurasidone and other atypical antipsychotics. In this network meta-analysis of atypical antipsychotics in adolescent schizophrenia, lurasidone was associated with similar efficacy, less weight gain, and lower risk of all-cause discontinuation compared to other oral atypical antipsychotics.
While clinical trial evidence has firmly established the efficacy of several atypical antipsychotics (AAPs) for treating bipolar depression, no randomized controlled trials (RCT's) comparing AAPs ...have been conducted. This Bayesian network meta-analysis (NMA) compared the relative efficacy and tolerability of AAP monotherapy in adults with bipolar depression.
Efficacy measures included change in Montgomery Åsberg Depression Rating Scale (MADRS), Clinical Global Improvement - Bipolar Disorder (CGI-BP), response, and remission. Multiple tolerability outcomes were examined. Results from random effects models were reported as difference in change from baseline for continuous variables or odds ratios for dichotomous variables. Treatments were ranked using the surface under the curve cumulative ranking probabilities. Number needed to treat (NNT) and harm (NNH) were calculated.
Eighteen RCT's met inclusion criteria of the systematic literature review. On change in MADRS, lurasidone (- 4.71 95% Crl - 6.98, - 2.41), quetiapine (- 4.80 - 5.93, - 3.72), olanzapine (- 4.57 - 5.92, - 3.20), and cariprazine (- 2.29 - 3.47, - 1.09) were more efficacious than placebo. Lurasidone was associated with a significantly greater odds of response (≥50% improvement in MADRS) compared to cariprazine (1.78 95% Crl 1.08, 2.77), aripiprazole (2.38 1.38, 3.85), and ziprasidone (2.47 1.41, 3.98), but was similar to olanzapine (1.68 0.99,2.65) and quetiapine (1.25 0.78, 1.90). For change in CGI-BP-S-overall score, lurasidone was significantly better than cariprazine (- 0.38 95% Crl - 0.66,-0.10) and ziprasidone (- 0.58 - 0.91,-0.26), but similar to quetiapine (- 0.08 - 0.36, 0.19)and olanzapine (- 0.04 - 1.41, 1.46). Lurasidone (0.34 kg 95% Crl - 0.22, 0.89) and aripiprazole (0.20 kg - 0.59, 1.00) had a similar weight change compared to placebo, but olanzapine (2.88 kg 2.40, 3.36), quetiapine (1.17 kg 0.84, 1.49), and cariprazine (0.65 kg 0.34, 0.96) were associated with greater weight gain. The NNT for response was the lowest for lurasidone (NNT = 5) followed by quetiapine (NNT = 6), olanzapine (NNT = 10) and cariprazine (NNT = 12).
In this NMA in adults with bipolar depression, which evaluated change in depressive symptoms (assessed by MADRS) across short-term trials, the largest improvement versus placebo was observed for lurasidone, olanzapine and quetiapine with cariprazine, showing a smaller treatment effect. Aripiprazole and ziprasidone were ineffective for the treatment of bipolar depression. Improvement in CGI-BP-S score for lurasidone was larger than cariprazine and ziprasidone but similar to quetiapine and olanzapine. Based on short term studies lurasidone and aripiprazole had similar weight gain compared to placebo.
The study was designed to evaluate the short-term efficacy and safety of lurasidone in the treatment of acute schizophrenia.
Participants, who were recently admitted inpatients with schizophrenia ...with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of double-blind treatment with 40 mg of lurasidone, 120 mg of lurasidone, 15 mg of olanzapine (included to test for assay sensitivity), or placebo, dosed once daily. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (as the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (as the key secondary efficacy measure).
Treatment with both doses of lurasidone or with olanzapine was associated with significantly greater improvement at week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. There was no statistically significant difference in mean PANSS total or CGI-S change scores for the lurasidone groups compared with the olanzapine group. With responders defined as those with an improvement of at least 20% on the PANSS, endpoint responder rates were significant compared with placebo for olanzapine only. The incidence of akathisia was higher with 120 mg of lurasidone (22.9%) than with 40 mg of lurasidone (11.8%), olanzapine (7.4%), or placebo (0.9%). The proportion of patients experiencing ≥ 7% weight gain was 5.9% for the lurasidone groups combined, 34.4% for the olanzapine group, and 7.0% for the placebo group.
Lurasidone was an effective treatment for patients with acute schizophrenia. Safety assessments indicated a higher frequency of adverse events associated with 120 mg/day of lurasidone compared with 40 mg/day.
Lurasidone is a novel psychotropic agent in development for the treatment of schizophrenia and bipolar disorder.
This paper describes the development of lurasidone, including its receptor binding ...affinities, pharmacokinetics, CNS activity in rodent models and results of early clinical efficacy and safety studies in humans.
The available literature on lurasidone was reviewed, including abstracts from medical congresses supplemented by data on file with the sponsor.
Lurasidone has a high affinity for dopamine D(2) and serotonin 5-HT(2A) receptors as well as for receptors implicated in enhancement of cognitive function (e.g., 5-HT(7,) 5-HT(1A), alpha(2c)). Lurasidone has no affinity for muscarinic M(1) and histamine H(1) receptors and minimal affinity for alpha(1) adrenoceptors, dopamine D(1) and D(3) receptors, serotonin 5-HT(2C) receptors and alpha(2A) adrenoceptors. Phase II efficacy data indicate that lurasidone doses from 40 to 120 mg/day are effective in the treatment of schizophrenia, with positive symptom reduction exceeding that for negative symptoms, as seen with other antipsychotics. Preclinical data indicate that lurasidone reverses MK-801 induced learning and memory impairment in rodents, and active comparator data from a Phase Ib study of lurasidone 120 mg/day versus ziprasidone 160 mg/day also found a signal for effects on cognition. Phase II studies suggest that lurasidone has no significant QTc prolongation and a benign metabolic profile.
ABSTRACT In this study, designed to evaluate the efficacy of lurasidone as adjunctive therapy with lithium or valproate, patients with bipolar I depression were randomized to 6 weeks of double-blind ...treatment with lurasidone (N=180) or placebo (N=176), added to background treatment with lithium or valproate. All patients were treated with lithium or valproate for a minimum of 4 weeks prior to screening. This was confirmed either by prospective treatment after study enrolment (run-in cohort), or retrospectively, with blood levels of lithium and valproate at screening (non-run-in cohort). Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP-S), respectively. Treatment with lurasidone was associated with non-significant improvement at week 6 vs. placebo for the MADRS total score (-11.8 vs -10.4; P=0.176), and the CGI-BP-S score (-1.36 vs -1.13; P=0.095). Significant separation from placebo was observed from weeks 2-5 for the MADRS and weeks 3-5 for the CGI-BP-S. Improvement in the placebo-subtracted MADRS total score was notably larger for the non-run-in cohort compared to the run-in cohort (LS mean difference in endpoint change scores, -4.6; P=0.009). Adverse events most frequently reported for lurasidone were akathisia, somnolence, and extrapyramidal side effects. In conclusion, lurasidone adjunctive with lithium or valproate demonstrated significant improvement in depressive symptoms based on the MADRS from weeks 2-5 but not at the primary week 6 endpoint.
Abstract Objective This study was designed to evaluate the short-term efficacy and safety of once-daily lurasidone (80 mg/day and 160 mg/day) in the treatment of an acute exacerbation of ...schizophrenia. Methods Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of fixed-dose, double-blind treatment with lurasidone 80 mg (n = 125), lurasidone 160 mg (n = 121), quetiapine XR 600 mg (QXR-600 mg; n = 119; active control included to test for assay sensitivity), or placebo (n = 121), all dosed once daily in the evening. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score (the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (the key secondary efficacy measure). Results Treatment with both doses of lurasidone or with QXR-600 mg was associated with significantly greater improvement at Week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. The endpoint responder rate (≥ 20% improvement in PANSS total score) was higher in subjects treated with lurasidone 80 mg (65%; p < 0.001), lurasidone 160 mg (79%; p < 0.001), and QXR-600 mg (79%; p < 0.001) compared with placebo (41%). The proportion of patients experiencing ≥ 7% weight gain was 4% for each lurasidone group, 15% for the QXR-600 mg group, and 3% for the placebo group. Endpoint changes in levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were comparable for both lurasidone groups and placebo, while the QXR-600 mg group showed a significant median increase compared with the placebo group in levels of cholesterol (p < 0.001), LDL cholesterol (p < 0.01), and triglycerides (p < 0.05). Conclusions Lurasidone 80 mg and 160 mg doses administered once-daily in the evening, were safe and effective treatments for subjects with acute schizophrenia, with increased response rates observed at the higher dose. Dose-related adverse effects were limited, and both doses were generally well-tolerated.
To assess the efficacy and tolerability of lurasidone versus other atypical antipsychotic monotherapy agents in patients with bipolar depression, using a Bayesian network meta-analysis.
Fourteen ...randomised clinical trials (6221 patients) of lurasidone, quetiapine (extended release and immediate release), aripiprazole, olanzapine, and ziprasidone for bipolar depression were included. Efficacy assessments included change in the Montgomery-Åsberg Depression Rating Scale (MADRS), rates of response (≥50% improvement in MADRS) and remission (MADRS ≤12 at study endpoint), and change in the Clinical Global Impressions-Bipolar Disorder-Severity (CGI-BP-S) scale. Tolerability outcomes included weight, somnolence, extrapyramidal symptoms (EPS), and all-cause discontinuation. Changes from baseline or odds ratios (OR) with 95% credible intervals (CrI) were evaluated.
Improvement in the MADRS associated with lurasidone treatment was significantly greater than placebo (-4.70, 95%CrI: -7.20, -2.21), aripiprazole (-3.62, 95%CrI: -7.04, -0.20), and ziprasidone (-3.38, 95%CrI: -6.68, -0.11), but not olanzapine (-0.15, 95%CrI: -3.12, 2.74) or quetiapine (0.10, 95%CrI: -2.68, 2.84). Results for improvement in the CGI-BP-S, and for response and remission were similar. Lurasidone was associated with less weight gain than olanzapine (-2.54 kg, 95%CrI: -3.42, -1.67) and quetiapine (-0.83kg, 95%CrI: -1.59, -0.08); and with lower rates of somnolence than quetiapine (OR: 0.33, 95%CrI: 0.11, 0.82) and ziprasidone (OR: 0.34, 95%CrI: 0.09, 0.93). No significant differences among atypical antipsychotic agents were observed in rates of discontinuation or in rates of EPS.
In this network meta-analysis, lurasidone was found to be more efficacious than aripiprazole and ziprasidone, and was associated with less weight gain than quetiapine and olanzapine and less somnolence than quetiapine and ziprasidone.
Abstract Objective The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project produced a battery of tests, the MATRICS Consensus Cognitive Battery (MCCB), designed ...to assess cognitive treatment effects in clinical trials of patients with schizophrenia. In validation studies, the MCCB demonstrated excellent reliability, minimal practice effects and significant correlations with measures of functional capacity. This study addresses whether the MCCB demonstrates these favorable characteristics when administered in the context of the type of large multi-site industry trial for which it was designed. Methods In a clinical trial comparing risperidone and lurasidone, 323 clinically-stable outpatients with schizophrenia at 29 sites were assessed with MCCB at screening and a median of 15 days later at baseline. A measure of functional capacity, the UCSD Performance-based Skills Assessment – Brief (UPSA-B) was administered at baseline. Results All 323 (100%) patients had sufficient data for computing a composite score according to the MCCB criteria. The test–retest reliability of the MCCB composite score was excellent (ICC = 0.88). The severity of cognitive impairment was T = 24.7 (SD = 12.1) at screening and T = 26.7 (SD = 12.4) at baseline. The MCCB composite score demonstrated a large correlation with the UPSA-B composite score ( r = .60, df = 304, p < .001). The practice effect on the composite score was small ( z = 0.18). Discussion In the context of a 29-site antipsychotic trial in stable outpatients with schizophrenia, the MCCB is sensitive to cognitive deficits in all domains, demonstrates excellent test–retest reliability and small practice effects, and is strongly correlated with a leading measure of functional capacity.
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