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Lurasidone as Adjunctive Therapy With Lithium or Valproate for the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study
Antony Loebel, M.D.; Josephine Cucchiaro, Ph.D.; Robert Silva, Ph.D.; Hans Kroger, M.P.H., M.S.; Kaushik Sarma, M.D.; Jane Xu, Ph.D.; Joseph R. Calabrese, M.D.
Am J Psychiatry 2014;171:169-177. doi:10.1176/appi.ajp.2013.13070985
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Dr. Calabrese has provided consultant services to AstraZeneca, Biomedical Development Corp., Convergent Health Solutions, Elan, Eisai, Forest Labs, Health & Wellness, Hoffman LaRoche, Lundbeck, Merck, Otsuka, Pfizer, Scientia, Spirant Communications Private Limitrex, Sunovion, Takeda, and Teva; has received grant support from Cephalon, Elan, NARSAD, Sunovion, and Takeda; and has received payment for lectures from the American Foundation for Suicide Prevention, AstraZeneca, Benecke, Cortex Congress, GlaxoSmithKline, Lundbeck, Medwiz Healthcare, Merck, Pfizer, Promedica, Sunovion, Takeda, Ohio Psychiatry Association, Ohio State University, University of Cincinnati, and the University of Toronto. Drs. Loebel, Cucchiaro, Silva, Kroger, Sarma, and Xu are full-time employees of Sunovion Pharmaceuticals, Inc.

This study was sponsored by Sunovion Pharmaceuticals, Inc.

The authors thank the participants of this study and the members of the Lurasidone Bipolar Disorder Study Group (Czech Republic: J. Drahozal, E. Herman, M. Klabusayova, S. Papezova, Z. Solle; France: M. Abbar, M. Zins Ritter; Germany: J. Thomsen; India: B. Buch, M. Chudgar, H. Gandhi, M. Gowda, V. Indla, S. Mittal, U. Nagapurkar, P. Thatikonda, J. Trivedi, M. Vaishnav; Poland: P. Bogacki, J. Janczewski, A. Kokoszka; Romania: G.M. Badescu, D. Cozman; Russia: V. Kozlovsky, V. Tochilov, V. Vid; South Africa: K. Botha, L. Nel, J. Schronen, R. Verster; Ukraine: V. Abramov, V. Bitenskyy, S. Rymsha, A. Skrypnikov, V. Verbenko; United States: Drs. S. Aaronson, C. Adler, M. Alam, D. Almhana, R. Anderson, J. Aukstuolis, P. Bhatia, J. Booker, G. Dempsey, B. D’Souza, D. Garcia, H. Hassman, T. Ketter, R. Manning, A. Fan, R. Hidalgo, N. Patel, R. Segraves, A. Sfera, T. Tran-Johnson, D. Walling, R. Weisler, K. Yadalam).

Clinicaltrials.gov identifier: NCT00868452

From Sunovion Pharmaceuticals, Inc., Fort Lee, N.J., and Marlborough, Mass.; and University Hospitals Case Medical Center, Case Western Reserve University, Cleveland.

Address correspondence to Dr. Calabrese (joseph.calabrese@UHhospitals.org).

Copyright © 2014 by the American Psychiatric Association

Received July 27, 2013; Revised September 09, 2013; Accepted September 10, 2013.


Objective  Few studies have been reported that support the efficacy of adjunctive therapy for patients with bipolar I depression who have had an insufficient response to monotherapy with mood-stabilizing agents. The authors investigated the efficacy of lurasidone, a novel antipsychotic agent, as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression.

Method  Patients were randomly assigned to receive 6 weeks of double-blind adjunctive treatment with lurasidone (N=183) or placebo (N=165), added to therapeutic levels of either lithium or valproate. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively.

Results  Lurasidone treatment significantly reduced mean MADRS total score at week 6 compared with the placebo group (−17.1 versus −13.5; effect size=0.34). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores compared with placebo (−1.96 versus −1.51; effect size=0.36) as well as significantly greater improvement in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were 6.0% and 7.9% in the lurasidone and placebo groups, respectively. Adverse events most frequently reported for lurasidone were nausea, somnolence, tremor, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone.

Conclusions  In patients with bipolar I depression, treatment with lurasidone adjunctive to lithium or valproate significantly improved depressive symptoms and was generally well tolerated.

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FIGURE 1. Patient Disposition in a Double-Blind, Randomized, Placebo-Controlled Trial of Adjunctive Lurasidone for Bipolar I Depression

FIGURE 2. Change From Baseline in Key Efficacy Measures

aMean scores at baseline were 30.6 (SD=5.3) and 30.8 (SD=4.8) for the lurasidone and placebo groups, respectively.

bMean scores at baseline were 4.47 (SD=0.65) and 4.60 (SD=0.63) for the lurasidone and placebo groups, respectively.

* p<0.05; ** p<0.01; *** p<0.001

Anchor for Jump
TABLE 1.Demographic and Clinical Characteristics at Baseline (intent-to-treat population) of Patients in a Double-Blind, Randomized, Placebo-Controlled Trial of Adjunctive Lurasidone for Bipolar I Depression
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TABLE 2.Adverse Events (incidence ≥5%, with incidence greater for the lurasidone group versus placebo)
Table Footer Note

a Cogwheel rigidity, drooling, dystonia, glabellar reflex abnormal, muscle rigidity, parkinsonism, tremor, and trismus.

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TABLE 3.Baseline to Endpoint Change in Weight and Laboratory Parameters (last observation carried forward)a
Table Footer Note

a Both confirmed and nonconfirmed fasting values are presented for metabolic parameters.



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