Lurasidone [(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapirone derivative and a novel antipsychotic candidate. The objective of the current studies was to investigate the in vitro and in vivo pharmacological properties of lurasidone. Receptor binding affinities of lurasidone and several antipsychotic drugs were tested under comparable assay conditions using cloned human receptors or membrane fractions prepared from animal tissue. Lurasidone was found to have potent binding affinity for dopamine D 2 , 5-hydroxytryptamine 2A (5-HT 2A ), 5-HT 7 , 5-HT 1A , and noradrenaline ␣ 2C receptors. Affinity for noradrenaline ␣ 1 , ␣ 2A , and 5-HT 2C receptors was weak, whereas affinity for histamine H 1 and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D 2 and 5-HT 7 receptors and as a partial agonist at the 5-HT 1A receptor subtype. Lurasidone showed potent effects predictive of antipsychotic activity, such as inhibition of methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. Furthermore, lurasidone had only weak extrapyramidal effects in rodent models. In animal models of anxiety disorders and depression, treatment with lurasidone was associated with significant improvement. Lurasidone showed a preferential effect on the frontal cortex (versus striatum) in increasing dopamine turnover. Anti-␣ 1 -noradrenergic, anticholinergic, and central nervous system (CNS) depressant actions of lurasidone were also very weak. These results demonstrate that lurasidone possesses antipsychotic activity and antidepressant-or anxiolytic-like effects with potentially reduced liability for extrapyramidal and CNS depressant side effects.

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.

(ClinicalTrials.gov) Identifier: NCT00088634.

RationaleThere is an unmet need in the treatment of schizophrenia for effective medications with fewer adverse effects.ObjectiveThis study aims to evaluate the efficacy and safety of lurasidone, an atypical antipsychotic, for the treatment of schizophrenia.MethodsPatients with an acute exacerbation of schizophrenia were randomized to 6 weeks of double-blind treatment with once-daily, fixed-dose lurasidone 40 mg (N = 50), lurasidone 120 mg (N = 49), or placebo (N = 50). The primary efficacy measure was mean change from baseline to day 42 (last observation carried forward) in the Brief Psychiatric Rating Scale derived (BPRSd) from the Positive and Negative Syndrome Scale (PANSS).ResultsMean change in BPRSd was significantly greater in patients receiving lurasidone 40 and 120 mg/day versus placebo (−9.4 and −11.0 versus −3.8; p = 0.018 and 0.004, respectively). Treatment with lurasidone 120 mg/day was superior to placebo across all secondary measures, including PANSS total (p = 0.009), PANSS positive (p = 0.005), PANSS negative (p = 0.011), and PANSS general psychopathology (p = 0.023) subscales and Clinical Global Impression of Severity (CGI-S; p = 0.001). Treatment with lurasidone 40 mg/day was superior to placebo on the PANSS positive subscale (p = 0.018) and CGI-S (p = 0.002). The most common adverse events for patients receiving lurasidone were nausea (16.2 versus 4.0 % for placebo) and sedation (16.2 versus 10.0 % for placebo). Minimal changes in weight, cholesterol, triglyceride, and glucose levels were observed.ConclusionsIn this study, which was limited by a relatively high discontinuation rate, lurasidone provided effective treatment for patients with acute exacerbation of chronic schizophrenia and had minimal effects on weight and metabolic parameters.

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We previously reported that treatment with 160mg/d of lurasidone improved cognitive performance in a manner superior to placebo, quetiapine XR 600mg/d, and lurasidone 80mg/d, based on a 6-week randomized trial of patients with an acute exacerbation of schizophrenia. The objective of this post-hoc analysis was to explore the cognitive and functional performance of patients whose final doses of lurasidone were 40/80mg/d, 120mg/d, and 160mg/d compared to quetiapine XR 200-800mg/d (QXR) during a 6-month, double-blind continuation study that followed a short-term trial. Subjects who received final doses of lurasidone 120mg/d (n=77) and 160mg/d (n=49) showed significantly greater improvement in overall cognitive performance compared to QXR (n=85) at week 32 (month 6 of the extension study), while those on last doses of 40/80mg/d (n=25) showed a trend towards significance at week 32. Mean changes in neurocognitive composite z-score from pre-treatment baseline were significant for the 3 lurasidone final dose groups at both weeks 19 and 32, with composite change scores of z=1.53, z=1.43, and z=1.34 for the lurasidone 40/80mg/d, 120mg/d, and 160mg/d, respectively, at week 32. In contrast, the composite change score was not statistically significant in the overall quetiapine group (z=0.46), with none of the individual quetiapine doses showing any significant improvement. Functional capacity scores improved in all treatment groups. Our findings indicate improved cognitive performance in patients treated with each of the flexible doses of lurasidone 40-160mg/d, compared to quetiapine XR 200-800mg/d. All doses of lurasidone were superior to all doses of quetiapine for cognitive performance.

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