Lurasidone in Combination with Lithium Or Valproate for the Maintenance Treatment of Bipolar I Disorder$

European Neuropsychopharmacology (]]]]) ], ]]]–]]]

www.elsevier.com/locate/euroneuro

Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder$

Joseph R. Calabresea, Andrei Pikalovb,c, Caroline Streicherb,c, Josephine Cucchiarob,c, Yongcai Maob,c, Antony Loebelb,c,n aUniversity Hospitals Case Medical Center, Case Western Reserve University, Cleveland, United States bSunovion Pharmaceuticals Inc., Marlborough, MA, United States cSunovion Pharmaceuticals Inc., Fort Lee, NJ, United States

Received 15 November 2016; received in revised form 7 June 2017; accepted 20 June 2017

KEYWORDS Abstract Bipolar disorder; Lurasidone (DS-RAn) has demonstrated efficacy in the acute treatment of bipolar depression, Recurrence; both as monotherapy, and as combination therapy with lithium or valproate. To evaluate the Atypical antipsycho- recurrence prevention efficacy of lurasidone for the maintenance treatment of bipolar I tic; disorder, patients received up to 20 weeks of open-label lurasidone (20–80 mg/d) combined Lurasidone with lithium or valproate during an initial stabilization phase. A total of 496 patients met stabilization criteria and were randomized to 28 weeks of double-blind treatment with lurasidone (20–80 mg/d) or placebo, in combination with lithium or valproate. Based on a Cox proportional hazard model, treatment with lurasidone reduced the probability of recurrence of any mood episode by 29% (primary endpoint), however, the reduction did not achieve statistical significance. Probability of recurrence on lurasidone was significantly lower in patients with an index episode of depression (HR, 0.57; P=0.039), in patients with any index episode who were not rapid-cycling (HR, 0.69; P=0.046), and when recurrence was based on MADRS, YMRS, or CGI-BP-S severity criteria (HR, 0.53; P=0.025; sensitivity analysis). Long-term treatment with lurasidone combined with lithium or valproate was found to be safe and well- tolerated, with minimal effects on weight or metabolic parameters. & 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY- NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction ☆Clinicaltrials.gov: NCT01358357 Sponsored by Sunovion Pharma- ceuticals Inc. Bipolar disorder is a chronic illness with a high rate of nCorresponding author at: Sunovion Pharmaceuticals Inc., One recurrence that is frequently associated with reduced Bridge Plaza North, Suite 510, Fort Lee, NJ 07024, United States. quality of life and impairment in functioning (Judd et al., http://dx.doi.org/10.1016/j.euroneuro.2017.06.013 0924-977X/& 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013 2 J.R. Calabrese et al.

2005; IsHak et al., 2012; Gitlin et al., 1995). Even with 2.1. Patient population treatment, 40–60% of individuals have been found to experience a relapse within a 2-year period, with depressive Patients who met DSM-IV-TR criteria (APA, 2000) for bipolar I episodes predominant over manic episodes (Perlis et al., disorder were enrolled if they had Z1 manic, mixed manic, or 2006; Tohen et al., 2003). In addition, inter-episode periods depressed episode in the past 2 years (with or without rapid cycling are complicated by residual manic or depressive symptoms or psychotic features), and a current Young Mania Rating Scale in at least one-third of all follow-up days (Perlis et al., 2006; (YMRS; Young et al., 2011) or Montgomery-Åsberg Rating Scale (MADRS; Montgomery and Åsberg, 1979) total score Z14 (if treated Tohen et al., 2003; Judd et al., 2002; Joffe et al., 2004). with lithium or valproate at the time of the screen visit), or Z18 (if Treatment guidelines recommend maintenance therapy not on lithium or valproate). Patients treated with lithium or to prevent recurrence, or reduce the frequency, of acute valproate with YMRS and/or MADRS scores Z14 were judged to episodes. Currently, monotherapy with lithium, olanzapine, be partial responders, and therefore the addition of lurasidone was quetiapine, and aripiprazole are recommended as first-line considered to be warranted. Reasons for exclusion included sub- treatments for prevention of both manic and depressive stance dependence or abuse, clinically significant acute and/or episodes, while lamotrigine is recommended primarily for unstable medical condition, concomitant use of a potent cyto- prevention of depressive episodes associated with bipolar chrome P450 3A4 inhibitor or inducer, history of non-response to disorder, and risperidone long-acting injection (LAI) are Z3 adequate trials of antidepressants, antipsychotics or mood recommended primarily for prevention of mania (National stabilizers, or currently an imminent suicide risk (as judged by the investigator). Collaborative Centre, 2014; Grunze et al., 2013; Goodwin et al., 2016; Ostacher et al., 2016). Since episode recurrence is frequent during monotherapy, 2.2. Study design guidelines typically recommend combination therapy (Perlis et al., 2006; Tohen et al., 2003; National Collaborative Patients first completed 12–20 weeks of open-label treatment with Centre, 2014; Grunze et al., 2013; Goodwin et al., 2016; lurasidone plus lithium or valproate. For patients not currently Ostacher et al., 2016), however, few controlled trials have being treated with lithium or valproate, mood stabilizer treatment was initiated as described below. Patients who met clinical stability been reported that evaluate the maintenance efficacy of criteria after at least 12 weeks of open-label treatment were then combination therapy in preventing episode recurrence in randomized (in a 1:1 ratio) to 28 weeks of double-blind treatment bipolar patients presenting with either mania or depression. with lurasidone or placebo, in combination with lithium or valpro- Use of quetiapine combined with lithium or valproate has ate. The study was conducted at 26 sites in the United States demonstrated maintenance efficacy in preventing recur- (n=468 patients), 10 sites in South America (n=76 patients), 48 rence of both depression and mania in bipolar disorder sites in Europe (n=391 patients), and 10 sites in Asia (n=25 patients regardless of the polarity of the most recent patients) between September 2011 and October 2014. The study episode (Suppes et al., 2009; Vieta et al., 2008). There is was approved by an Institutional Review Board at each investiga- also evidence that adjunctive therapy with risperidone LAI, tional site and was conducted in accordance with the International aripiprazole, and ziprasidone may have benefit, but primar- Conference on Harmonisation Good Clinical Practice guidelines and with the ethical principles of the Declaration of Helsinki. An ily in patients with a recent manic episode, and/or in the independent data and safety monitoring board reviewed and prevention of mania (Quiroz et al., 2010; Macfadden et al., monitored patient data throughout the study. 2009; Vieta et al., 2008a; Marcus et al., 2011; Bowden et al., 2010). Given the relative lack of evidence-based 2.3. Clinical stability criteria combination therapies available, it is clear that additional treatment options would benefit patients. Qualified patients were randomized to the 28-week double-blind Lurasidone (DS-RAn) has demonstrated efficacy in the phase if they achieved clinical stability during open-label treatment acute treatment of bipolar depression, both as monother- with lurasidone, defined as MADRS and YMRS total scores r12 for apy, and as combination therapy with lithium and valproate Z12 weeks. Clinical worsening at up to two visits was permitted (Loebel et al., 2014a, 2014b). In a 6-month extension study, (YMRS Z 13 and/or MADRS Z 14), except during the last 4 weeks treatment with lurasidone was associated with sustained prior to randomization. improvement in depressive symptoms (Ketter et al., 2016). The current study involved a 28-week, double-blind, 2.4. Study medication placebo-controlled, randomized withdrawal design to test whether treatment with lurasidone in combination with Patients who met entry criteria began open-label treatment with either lithium or valproate was effective in preventing lurasidone 20 mg/d on days 1–3, 40 mg/d on days 4–7, and received recurrence of mood episodes in patients with a diagnosis flexible dosing thereafter in the range of 20–80 mg/d, with dose of bipolar I disorder who had demonstrated a stable adjustments permitted in 20 mg increments/decrements per week. response to acute combination therapy with lurasidone Following the 12–20-week open-label phase, patients who met and lithium or valproate. clinical stability criteria were randomly assigned (in a 1:1 ratio) to receive either lurasidone 20–80 mg/day (flexibly dosed) or matching placebo in a double-blind manner; randomization was stratified based on which mood stabilizer was being used. Doses of 2. Experimental procedures lithium and valproate were adjusted throughout the study, as needed, to maintain serum trough concentrations of 0.4–1.2 mEq/ This was a multi-regional, randomized, double-blind, placebo- L and 50–125 μg/mL, respectively. All country-approved formula- controlled study evaluating the efficacy of lurasidone in combina- tions of lithium or valproate (including extended-release and tion with lithium or valproate for the maintenance treatment of controlled-release formulations) were permitted, with the excep- bipolar I disorder. tion of lithium orotate and magnesium valproate. For patients not