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.

(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.

4SEASONS is a Fermi chopper spectrometer in operation at the Materials and Life Science Experimental Facility (MLF) in the Japan Proton Accelerator Research Complex (J-PARC). 4SEASONS is expected to facilitate highefficiency measurements of weak inelastic signals on novel spin and lattice dynamics using thermal neutrons. The spectrometer is equipped with a coupled moderator and sophisticated components such as an elliptical converging neutron guide with high-critical-angle supermirrors, long (2.5 m) position-sensitive detectors, and a Fermi chopper appropriate for multiple-incident-energy (multi-E i ) measurements by the repetition-rate multiplication technique. Herein, we discuss in detail the design and performance of the spectrometer, and present some examples of the measurements obtained using this spectrometer.

We succeeded in experimentally demonstrating that a series of two-dimensional maps of a dynamical structure factor in momentum-energy space with multiple incident energies can be simultaneously obtained by one measurement. This method reduces the dead time of time-of-flight measurement, and thus, it markedly increases the measurement efficiency. Our achievement realized using the Fermi chopper spectrometer 4SEASONS in J-PARC is expected to open up new possibilities of inelastic neutron scattering measurements.KEYWORDS: pulsed neutron source, Fermi chopper spectrometer, inelastic neutron scattering, multi-E i measurement, J-PARC DOI: 10.1143/JPSJ.78.093002A ''Fermi chopper'' spectrometer is a typical instrument for inelastic neutron scattering (INS) measurement at a pulsed neutron source. The Fermi chopper is used for monochromating the incident neutron beam. Inelastic scattering from a sample is measured by a time-of-flight (TOF) technique over a neutron source period. The accumulated TOF data can be converted to a dynamical structure factor. In fact, the INS measurements conducted using Fermi chopper spectrometers have revealed various mysteries of materials science, and thus, a Fermi chopper spectrometer should remain to be a flagship instrument in new-generation pulsed neutron sources such as the Japan Proton Accelerator Research Complex (J-PARC), which is one of the world's highest intensity pulsed neutron sources.A conventional Fermi chopper has a set of curved slits. The curvature is adjusted to the passage of neutrons with a selected velocity, which means that neutron transmission is optimized for a specific single incident energy (E i ). From another point of view, the curved slits would bring about the inefficiency of an INS measurement. Chopper rotation frequency (100 -600 Hz) is typically much higher than the frequency of the pulsed source (25 Hz in J-PARC), and the utilized TOF region of INS measurement with single E i is approximately less than 10% of the source period (40 ms in J-PARC). To reduce the dead time of TOF measurement, we have proposed the method of utilizing multiple E i beams. 1,2)We apply a set of straight and wide slits to a Fermi chopper, and consequently, a high transmission of neutrons can be achieved over a wide E i range, though the energy resolution is relaxed. Thus, this type of Fermi chopper can select multiple E i beams within the source period, and the simultaneous INS measurements with multiple E i 's can be realized. We refer to this method as Multi-E i measurement.Another technique, the so-called ''repetition rate multiplication (RRM) method'', for reducing the dead time of TOF measurement has also been developed, 3,4) and recently its first implementation has been reported. 5) The RRM method is mainly applied to measurements with cold neutrons, such as those involving quasi-elastic neutron scattering. It requires several disk choppers to suppress the contamination of slow neutrons and produce the symmetric pulse shape of incident neutrons. On the other hand, Multi-E i m...