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Update on the development of lurasidone as a treatment for patients with acute schizophrenia.

ABSTRACT: 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 ?(2C) adrenergic receptors. Moreover, lurasidone has low affinities for the ?(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.

SUBMITTER: Yasui-Furukori N

PROVIDER: S-EPMC3367402 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Update on the development of lurasidone as a treatment for patients with acute schizophrenia.

Yasui-Furukori Norio N

Drug design, development and therapy 20120508

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 sugges ...[more]

PMID: 22675261

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Project description: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

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Update on the development of lurasidone as a treatment for patients with acute schizophrenia.

Publications

Update on the development of lurasidone as a treatment for patients with acute schizophrenia.

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