Dosing in Lurasidone Bipolar Depression Studies
Mark Frye MD1, Joyce Tsai2, PhD, Hans Kroger MS2, Andrei Pikalov MD PhD2, and Antony Loebel MD2
1
2
Mayo Clinic Department of Psychiatry, Rochester MN
Sunovion Pharmaceuticals Inc., Marlborough MA and Fort Lee NJ
Methodological Question Being Addressed: What dosage-specific information can be gleaned from
flexible-dose clinical studies?
Introduction: Studies utilizing flexible dosing are not specifically designed to provide clear doseresponse information. Lurasidone was approved for the treatment of bipolar depression based on a
monotherapy study with fixed-flexible dosing, and an adjunctive therapy study with flexible dosing. This
analysis describes the dose utilization patterns, and explores baseline characteristics potentially
associated with dose changes in these studies.
Methods: Data were from two 6-week placebo-controlled studies and one long-term extension study.
In the acute monotherapy study, patients received lurasidone 20-60mg/day or 80-120mg/day (after
initial dose titration from 20mg to 80mg). In the acute adjunctive therapy study, patients received
lurasidone 20-120mg/day adjunctive to Li or VPA (after initial titration from 20mg/day to 60mg/day). In
the extension study, all patients received lurasidone 20-120mg/day as monotherapy or adjunctive
therapy, starting directly at 60mg/day.
Results: ITT analysis of dosing in the monotherapy study showed that 49% of patients in both the 2060mg and the 80-120mg dose groups had modal doses of 20mg and 80mg, respectively. Smaller
proportions of patients had higher modal doses of 40mg (26%) and 60mg (25%) in the 20-60mg group,
and 100mg (34%) and 120mg (17%) in the 80-120mg group. The distribution of terminal doses was
similar (20mg/40%, 40mg/28%, 60mg/32% in the 20-60mg group; 80mg/44%, 100mg/30%, and
120mg/26% in the 80-120mg group). In this study, comparable proportions (33-38%) of patients had
maximum doses of 20-100mg during study participation; somewhat fewer (27%) had a maximum dose
of 120mg (ITT). In completers, the largest proportions of patients in the 20-60mg group and in the 80120mg group had maximum doses of 60mg (39%) and 80mg (39%), respectively. ITT analysis of dosing
in the adjunctive therapy study showed that the largest proportion (38%) of patients had a modal dose
of 60mg. Successively smaller proportions had higher modal doses (80mg/28%, 100mg/17%,
120mg/10%); very few patients had lower modal doses (20mg/3%, 40mg/5%). Distribution of terminal
and maximum doses showed similar patterns. Baseline psychiatric comorbidity was more frequent in
patients who required dose increase than in patients who stayed at initial target dose. Treatmentemergent adverse events (TEAEs) reported in at least 5% of patients transitioning from acute placebo to
lurasidone 60mg during the 1st 28 days of extension treatment were akathisia (6%, monotherapy),
nausea (8%, adjunctive therapy), and somnolence (5%, adjunctive therapy). The incidence of TEAEs
observed during the 1st 28 days of adjunctive lurasidone treatment during the extension study was
comparable to that seen during the 1st 28 days of acute lurasidone treatment.
Conclusions: Examination of lurasidone dose utilization patterns did not identify specific preferred
doses in monotherapy or adjunctive therapy. A higher proportion of patients who required dose
increase had psychiatric comorbidity. Open-label lurasidone 60mg/day in the extension study was well
tolerated without initial dose titration.