Bipolar disorder is a serious and chronic disorder with lifetime prevalence worldwide estimated to range from 0.2 to 1.0 % (Merikangas et al., 2011; Nishi et al., 2019; Kato et al., 2021). Within developed countries, bipolar disorder was ranked among the top 10 causes of disability in 2010 (Vos et al., 2012). The overall prevalence of bipolar disorder and the associated burden of the disorder has been relatively unchanged from 1990 to 2019 (GBD 2019 Mental Disorders Collaborators, 2022). The rapid cycling subtype of bipolar disorder, defined as having 4 or more episodes in a 12-month period, has received particular attention as this subtype is associated with an earlier age of onset, a longer course of illness, female gender, and increased suicidality compared to non-rapid cycling bipolar disorder (Carvalho et al., 2014; M. Kato et al., 2020). Among individuals diagnosed with bipolar disorder, the prevalence of rapid cycling has been found to vary between about 5 % and 33 % in different studies (Coryell et al., 2003; Cruz et al., 2008; Nierenberg et al., 2010; Carvalho et al., 2014; M. Kato et al., 2020). However, in The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, the rate in the follow up year was much lower (5 %) than in the year before entry into the study (32 %), indicating the rapid cycling is a transitory phenomenon (Schneck et al., 2008).
There is no clear consensus regarding optimal pharmacological management of rapid cycling bipolar disorder (Fountoulakis et al., 2013; Yatham et al., 2018). For patients treated with the combination of lithium and divalproex, a lack of efficacy and high rates of early discontinuation have been reported for the majority of patient with rapid cycling bipolar disorder (Kemp et al., 2012). Response to lithium alone has been found to be superior in non-rapid cycling patients compared to patients with rapid cycling (Hui et al., 2019). In STEP-BD study, continuation treatment with antidepressants was associated with worsened maintenance outcomes compared to antidepressant discontinuation for those with rapid cycling bipolar disorder (El-Mallakh et al., 2015).
Studies examining use of atypical antipsychotics for patients with rapid cycling bipolar disorder have yielded mixed results. In a comparison of adjunctive long-acting injectable risperidone plus treatment-as-usual versus treatment-as-usual alone, no significant differences were evident in the total number or duration of relapse events or in the number of manic or depressive relapses among patients with rapid cycling bipolar disorder (Bobo et al., 2011). A study comparing rapid-cycling and non-rapid-cycling bipolar I manic patients treated with olanzapine found less favorable long-term outcomes for rapid cycling compared to non-rapid cycling patients (Vieta et al., 2004). In a pooled analysis of patients with bipolar depression type II, 8 weeks of treatment with quetiapine was found to be superior to placebo for patients with rapid cycling (Suppes et al., 2008). Subgroup analyses in an 8-week study of extended-release quetiapine for bipolar depression (type I or II) found significant superiority to placebo for both rapid cycling and non-rapid cycling patients (Suppes et al., 2010). In contrast, the EMBOLDEN I trial failed to find a significant difference between quetiapine (either 300 or 600 mg/d) and placebo on improvement in depressive symptoms over the course of 8 weeks in a subgroup analysis of rapid cycling patients (Young et al., 2010). A subgroup analysis also failed to find significant clinical improvement among patients with rapid cycling treated with the extended-release formulation of quetiapine, though this analysis was limited in part by the small sample size (see review report by the Japan Pharmaceuticals and Medical Devices Agency (PMDA), 2017).
Lurasidone is an atypical antipsychotic with potent binding affinity for D2 and 5-HT2A and 5-HT7 receptors as antagonist as well as partial agonist activity at 5-HT1A receptors. Antagonistic activity at 5-HT7 receptors and partial agonist activity at 5-HT1A receptors has been implicated in antidepressant-like effects observed in animal models of depression (Ishibashi et al., 2010).
Three 6-week, randomized, placebo-controlled studies have established the efficacy of lurasidone as a monotherapy or adjunctive (to lithium or valproate) therapy for the acute treatment of bipolar I depression (Loebel et al., 2014a; Loebel et al., 2014b; T. Kato et al., 2020). Minimal changes in body weight or metabolic parameters were evident for lurasidone in all three studies. Open-label extension trials of 24, 28, and 52 weeks have indicated that the improvements found in the short-term trials were maintained over time (Ketter et al., 2016; Ishigooka et al., 2021; Higuchi et al., 2021). Descriptively, lurasidone with lithium or valproate worked better in non-rapid cycling patients compared to rapid cycling patients for relapse prevention of bipolar disorder (Calabrese et al., 2017), Despite these positive trials, the efficacy of lurasidone compared to placebo for rapid cycling and non-rapid cycling patients has not been explored to date.
The goal of the current report was to conduct post-hoc analyses of the efficacy and safety, relative to placebo, of lurasidone monotherapy in patients with bipolar I depression with, and separately those without, rapid cycling.
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