S5. DOES THE TIME OF DRUG ADMINISTRATION ALTER THE ADVERSE EVENT RISK OF LURASIDONE?

Abstract Background Lurasidone is once a day oral medication, which could be administered any time of the day, but the relationship between the timing of administration and the risk of developing adverse events has not been systematically evaluated. The purpose of this study was to examine whether there is a difference in the risk of adverse events between lurasidone administration in the morning and at night in the treatment of adult schizophrenia. Methods Randomized placebo-controlled trials (RCTs) of lurasidone in adults with acute exacerbation of schizophrenia were analyzed for the incidence of akathisia, somnolence, and nausea. We compared the risk of each adverse event and the risk differences (RDs) for each lurasidone dose versus placebo in patients taking lurasidone in the morning (AM dosing group) and those taking lurasidone at night (PM dosing group). Results Nine RCTs were included in the analysis (six RCTs with AM dosing and three RCTs with PM dosing). In the AM dosing group, lurasidone doses of 20, 40, 80, and 120 mg/day were evaluated, and in the PM dosing group, lurasidone doses of 20, 40, 80, and 160 mg/day were evaluated. The risk of akathisia increased in a dose-dependent manner in AM dosing group, this tendency, however, was not observed in PM dosing group. In addition, RD tended to be larger in AM dosing group than in PM dosing group at the same dose [AM dosing group: 20 mg/day=-4.1%, no significantly different from placebo (ns); 40 mg/day=7.1%, p<0.001; 80 mg/day=9.1%, p<0.001; 120 mg/day=20.3%, p<0.001, PM dosing group: 20 mg/day=3.2%, ns; 40 mg/day=2.3%, ns; 80 mg/day=8,7%, p<0.001; 160 mg/day=6.5%, p<0.01]. Similarly, the risk of somnolence increased in a dose-dependent manner in AM dosing group, however, this tendency was not clearly observed in PM dosing group. RD tended to be larger in AM dosing group than in PM dosing group at the same dose (AM dosing group: 20 mg/day=0.1%, ns; 40 mg/day=3.6%, p<0.05; 80 mg/day=4.9%, p<0.01; 120 mg/day=9.3%, p<0.001, PM dosing group: 20 mg/day=-0.4%, ns; 40 mg/day=2.8%, p<0.05: 80 mg/day=0.2%, ns; 160 mg/day=5.8%, p<0.05). There was no clear dose-dependent trend associated with nausea and RD was similar between AM and PM dosing group (AM dosing group: 20 mg/day=0.2% ns; 40 mg/day=3.8%, p<0.05; 80 mg/day=3.8%, ns; 120 mg/day=6.6%, ns, PM dosing group: 20 mg/day=-1.6%, ns; 40 mg/day=-1.7%, ns; 80 mg/day=5.5%, p<0.01; 160 mg/day=2.8%, ns). Discussion The risk of adverse events in the treatment of schizophrenia with lurasidone can vary depending on the timing of administration. In particular, for akathisia and somnolence, the incidence risks were reduced when lurasidone was administered in PM. Unlike with AM administration, the dose-dependence in the risks of these adverse events were not observed in lurasidone PM administration. The timing of lurasidone administration could be considered in effort to minimize potential adverse events.