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SA114. Lurasidone for the Treatment of Adolescent Patients With Schizophrenia: Effect on PANSS Subscales

ABSTRACT: Abstract Background: Lurasidone is an atypical antipsychotic agent that has demonstrated efficacy in the treatment of adults with schizophrenia in the dose range of 40–160?mg/d. The objective of this randomized, double-blind, placebo-controlled study was to evaluate the acute efficacy and safety of lurasidone in adolescent patients with schizophrenia. Methods: Adolescents (13–17 years old) diagnosed with schizophrenia were randomly assigned to 6 weeks of double-blind treatment with fixed-dose lurasidone 40?mg/d, 80?mg/d, or placebo. Changes from baseline to Week 6 in PANSS total and subscale (positive, negative, general psychopathology, excitability) scores were evaluated using mixed-model, repeated-measures analysis. Treatment response was defined as ?20% reduction from baseline in PANSS total score at Week 6 and was analyzed using a logistic regression model with last observation carried forward (LOCF) approach. Results: A total of 326 patients (mean age, 15.4 years) were randomized and received lurasidone 40?mg/d (N = 108), 80?mg/d (N = 106), or placebo (N = 112). The PANSS total score at Week 6 demonstrated a placebo-adjusted, least-squares (LS) mean improvement of ?8.0 (P < .001; effect size [ES] = 0.51) for the 40?mg/d group and ?7.7 (P < .001; ES = 0.48) for the 80?mg/d group. Placebo-adjusted LS mean change for lurasidone 40?mg/d and 80?mg/d, respectively, was ?3.2 (P < .001; ES = 0.62) and ?3.2 (P < .001; ES = 0.60) on the PANSS positive subscale, ?1.7 (P = .011; ES = 0.41) and ?1.6 (P = .022; ES = 0.35) on the PANSS negative subscale, ?2.8 (P = .012; ES = 0.38) and ?2.8 (P = 0.011; ES = 0.37) on the PANSS general psychopathology subscale, and ?1.1 (P = .016; ES = 0.36) and ?1.8 (P < .001; ES = 0.53) on the PANSS excitability subscale. The proportion of treatment responders at Week 6 (LOCF) was 42.0% in the placebo group, 63.9% in the lurasidone 40?mg/d group (P < .001; NNT = 5), and 65.1% in the lurasidone 80?mg/d group (P < .001; NNT = 5). The most common adverse events (incidence ?5% in either lurasidone group and at least twice the rate of placebo) for lurasidone 40?mg/d, 80?mg/d, and placebo, respectively, were nausea (12.7%, 14.4%, and 2.7%), somnolence (9.1%, 11.5%, and 5.4%), akathisia (9.1%, 8.7%, and 1.8%), vomiting (8.2%, 6.7%, and 1.8%), and sedation (5.5%, 1.9%, and 1.8%). The rate of study discontinuation due to adverse events was higher in placebo-treated versus lurasidone-treated patients (8.0% vs. 3.7%, respectively). Conclusion: In this double-blind, placebo-controlled study of adolescent patients with schizophrenia, lurasidone (40?mg/d and 80?mg/d) demonstrated statistically significant efficacy and clinically meaningful improvement across a range of symptoms associated with this disorder. Lurasidone treatment was generally safe and well tolerated in this study. Sponsored by Sunovion Pharmaceuticals Inc. ClinicalTrials.gov identifier: NCT01911429

SUBMITTER: Correll C

PROVIDER: S-EPMC5476011 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Project description:Lurasidone is a novel benzisothiazole antipsychotic drug for the treatment of schizophrenia. Of the antipsychotic drugs, lurasidone has the highest affinity for the 5-hydroxytryptamine (5-HT)(7) receptor. Lurasidone also has high affinities for the dopamine D(2), 5HT(2A), 5-HT(1A) and α(2C) adrenergic receptors. Moreover, lurasidone has low affinities for the α(1) adrenergic, histamine H(1) and muscarinic M(1) receptors. The involvement of 5-HT(7) receptors in cognitive processes has been suggested by both pharmacological and molecular investigations. Chronic treatment with lurasidone increases neurotrophin BDNF mRNA levels in both the hippocampus (ventral and dorsal) and prefrontal cortex under basal conditions or in response to an acute swim stress. Lurasidone may potentiate N-methyl-D-aspartate receptor (NMDAR) function through antagonistic action on 5-HT(7) receptors without a direct affinity for NMDARs. These results suggest that lurasidone treatment may be a novel approach for the prevention of the development of cognitive impairment in individuals who are at risk for schizophrenia or related disorders involving cognitive impairment. In clinical trials, treatment with lurasidone was associated with significantly greater endpoint improvement versus placebo on the Positive and Negative Syndrome Scale total score after 6 weeks among subjects receiving 80 or 160 mg. The most frequent side effects of lurasidone were akathisia, nausea, parkinsonism, dizziness and somnolence. Once-daily treatment with lurasidone at 160 mg was superior to placebo based on the composite cognitive functioning measure. Lurasidone treatment produced improvements in Montgomery-Asberg Depression Rating Scale scores at 6 weeks that were significantly greater than placebo. A limitation of this review is that the majority of the data were obtained from abstracts and posters. These sources have not been subjected to the peer review processes of medical journals; thus, the results presented in these forums may require further quality review and subsequent revision prior to final publication.

Project description:Abstract Background: Several atypical antipsychotics are approved to treat adolescent patients with schizophrenia. However, risk for antipsychotic-associated weight gain and metabolic dysfunction underscores the need to identify additional evidence-based treatments that are both efficacious and well tolerated in this vulnerable patient population. Lurasidone is an atypical antipsychotic agent that has demonstrated efficacy in the treatment of adults with schizophrenia in the dose range of 40–160?mg/d. The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of lurasidone in adolescent patients with schizophrenia. Methods: Adolescent patients (13–17 years old) who met DSM-IV-TR criteria for schizophrenia were randomized to 6 weeks of double-blind treatment with fixed-dose lurasidone 40?mg/d, 80?mg/d, or placebo. An MMRM analysis was performed to assess change from baseline to Week 6 on the primary (PANSS total score) outcome measure. An ANCOVA using an LOCF approach was performed to assess change from baseline on secondary endpoints: Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) and Children’s Global Assessment Scale (CGAS). Safety and tolerability assessments included adverse event reporting, weight, and laboratory measures. Results: A total of 327 patients (mean age = 15.4 years old) were randomized to receive lurasidone 40?mg/d (N = 108), 80?mg/d (N = 106) or placebo (N = 113). Performance on the PANSS total score at Week 6 demonstrated a placebo-adjusted LS mean improvement of ?8.0 (P < .001) for the 40?mg/d group and ?7.7 (P < .001) for the 80?mg/d group. Placebo-adjusted LS mean improvement at Week 6 on the PQ-LES-Q was 5.3 (P = .001) and 5.8 (P < .001) for the 40?mg/d and 80?mg/d groups, respectively; and, on the CGAS was 4.6 (P = .002) and 4.9 (P < .001) for the 40?mg/d and 80?mg/d groups, respectively. Study discontinuation due to adverse events was 8.0% in the placebo group and 3.7% in lurasidone treated patients. The most common adverse events (?5% in either lurasidone group and at least twice the rate of placebo) were: nausea, somnolence, akathisia, vomiting, and sedation. LS mean change in weight at week 6 for the lurasidone 40?mg/d, 80?mg/d, and placebo groups was 0.17?kg, 0.49?kg, and 0.05?kg, respectively. Median change at Week 6 (LOCF) in total cholesterol was ?4.0?mg/dL, ?2.0?mg/dL, and ?7.0?mg/dL, respectively; in triglycerides was ?2.0?mg/dL, 7.0?mg/dL, and ?2.0?mg/dL, respectively; and in glucose was 0.0?mg/dL, 1.0?mg/dL, and 0.0?mg/dL, respectively. Conclusion: Adolescent patients with schizophrenia treated with lurasidone demonstrated significant improvement in symptoms, quality of life, and function. Lurasidone was generally well tolerated and associated with minimal changes in weight and metabolic parameters. Sponsored by Sunovion Pharmaceuticals Inc. ClinicalTrials.gov identifier: NCT01911429

Project description: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.

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SA114. Lurasidone for the Treatment of Adolescent Patients With Schizophrenia: Effect on PANSS Subscales

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