Research report
Long-term efficacy of quetiapine in combination with lithium or divalproex on mixed symptoms in bipolar I disorder

https://doi.org/10.1016/j.jad.2012.04.014Get rights and content

Abstract

Background

To evaluate quetiapine in patients with bipolar I disorder with mixed symptoms.

Methods: Data from 2 studies (D1447C00126, D1447C00127) were pooled and mixed events analyzed separately. Patients received quetiapine (400–800 mg/day) plus lithium/divalproex to achieve ≥12 weeks of clinical stability, followed by double-blind quetiapine (400–800 mg/day) or placebo, plus lithium/divalproex, for up to 104 weeks. Primary endpoint was time to first mood event post-randomization.

Results: The ITT population included 1326 patients, of whom 445 had a mixed episode at study entry, 219 received quetiapine plus lithium/divalproex, and 226 received placebo plus lithium/divalproex. Mood events were reported by fewer quetiapine-plus-lithium/divalproex than placebo-plus-lithium/divalproex–treated patients (21.0% vs 54.0%), and included mixed (6.4% vs 22.1%), pure manic (5.0% vs 13.3%), and pure depressed events (9.6% vs 18.6%). Hazard ratios (HR) for time to recurrence were longer for quetiapine plus lithium/divalproex than placebo plus lithium/divalproex for mixed (HR=0.23; 95% CI: 0.13–0.42; p<0.0001), pure manic (HR=0.30; 95% CI: 0.15–0.60; p=0.0007), and pure depressed events (HR=0.38; 95% CI: 0.22–0.64; p=0.0003). No new safety concerns were noted.

Limitations

The post hoc nature of the analyses as patients were not randomized according to index symptom status.

Conclusions

In stable patients with bipolar I disorder, quetiapine plus lithium/divalproex significantly increased time to recurrence of mood events versus placebo in patients with mixed symptoms at study entry and time to occurrence of mixed-mood events in patients with any mood episode at study entry.

Introduction

The chronic and episodic nature of bipolar disorder imposes a substantial patient burden in terms of impairments in functioning and quality of life (Goldberg et al., 2005, Rosa et al., 2009). Thus, lifelong treatment of the condition is a prerequisite to minimize relapse and symptom recurrence. Among bipolar subtypes, mania and depression episodes typify the clinical features of bipolar I disorder (American Psychiatric Association, 2000). Concurrent symptoms of mania and depression (mixed states) are common among patients with bipolar I disorder, but are likely to be underdiagnosed because of their clinical complexity and lack of a universal definition (Akiskal et al., 1998, Dilsaver and Benazzi, 2008, Ghaemi, 2008, González-Pinto et al., 2007, Hantouche et al., 2006, Henry et al., 2007, McElroy, 2008, Swann et al., 2009, Vieta and Morralla, 2010). Data from the French national multisite collaborative study (EPIMAN) on the clinical epidemiology of mania revealed prevalence estimates for mixed symptoms of 6.7% and 37% among patients with bipolar I disorder characterized according to narrow or broader diagnostic criteria, respectively (Akiskal et al., 1998). More recent observations from the same study showed a 30% prevalence of mixed mania (defined by at least two symptoms of depression) in patients hospitalized for acute mania (Hantouche et al., 2006). Irrespective of diagnostic challenges, existing epidemiological evidence suggests a significant presence of mixed states within bipolar disorder.

Mixed states are believed to represent a more severe form of bipolar disorder (González-Pinto et al., 2007). Despite treatment, mixed states are associated with worse clinical and functional outcomes than pure symptom states among patients with bipolar I disorder (Azorin et al., 2009, Baldessarini et al., 2010, Dodd et al., 2010, Goldberg et al., 1998, Rosa et al., 2009). Moreover, the presence of a mixed state is a significant predictor of a shorter time to recurrence of a mood event in patients with bipolar I disorder (Kora et al., 2008). Undoubtedly, a significant unmet clinical need remains for pharmacologic treatments to effectively resolve the mixed-state symptoms among patients with bipolar disorder (Vieta, 2005).

The efficacy and safety of quetiapine in combination with lithium or divalproex for the prevention of mood events in patients with bipolar I disorder has been demonstrated in two independent, albeit identically designed, long-term phase III studies (Suppes et al., 2009, Vieta et al., 2008). In both studies, quetiapine combination treatment was significantly more effective than placebo plus lithium or divalproex in delaying the time to recurrence of any mood event up to 104 weeks (p<0.001), equivalent to risk reductions of 72% (Study 126) (Vieta et al., 2008) and 68% (Study 127) (Suppes et al., 2009). However, the efficacy of quetiapine in patients with bipolar I disorder with mixed symptoms was not determined separately in these studies.

We present here a pooled post hoc analysis of these data, which investigated the effectiveness of quetiapine combination therapy in a subgroup of patients with bipolar I disorder who had mixed symptoms. The efficacy of quetiapine combination treatment for the prevention of mixed events was also evaluated in the total pooled patient population. Given the paucity of published reports on the treatment of mixed symptoms, these analyses have been conducted with the objective of elucidating effective treatment strategies for this difficult-to-treat patient population.

Section snippets

Study design

This was a post hoc analysis of the long-term efficacy and safety of quetiapine plus lithium or divalproex versus placebo plus lithium or divalproex in patients with bipolar I disorder with a mixed index episode. Pooled data were derived from two identically designed, multicenter, double-blind, placebo-controlled, randomized trials of quetiapine in combination with lithium or divalproex for the maintenance treatment of patients with bipolar I disorder up to 104 weeks (D1447C00126, N=706;

Study population

A combined total of 3414 patients with bipolar I disorder were enrolled in the prerandomization phases of studies 126 and 127. Overall, 1326 of the 1334 patients who were randomized to treatment with quetiapine (n=646) or placebo (n=680) in combination with lithium or divalproex received at least one dose of study treatment and were included in the ITT population (Fig. 1). Of the ITT population, 445 patients had a recent mixed episode at study entry and received combination treatment with

Discussion

The efficacy of quetiapine in combination with lithium or divalproex therapy versus placebo and lithium or divalproex for the prevention of mood events in patients with bipolar I disorder among patients who had achieved 12 weeks’ clinical stability while receiving quetiapine in combination with lithium or divalproex was previously demonstrated in the long-term Studies 126 and 127 (Suppes et al., 2009, Vieta et al., 2008). These analyses utilized combined data from Studies 126 and 127 to focus

Conclusions

This combined subgroup analysis of Studies 126 and 127 represents one of the few controlled studies focusing on difficult-to-treat mixed states. Among patients with bipolar I disorder presenting with mixed symptoms and who had achieved 12 weeks’ clinical stability while receiving quetiapine in combination with lithium or divalproex, quetiapine in combination with lithium or divalproex was significantly more efficacious for the prevention of any mood event in patients than placebo combination

Role of funding source

Funding for this study was provided by AstraZeneca Pharmaceuticals LP.

Conflict of interest

Eduard Vieta has received grants and served as consultant, advisor or speaker for the following entities: Almirall, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen-Cilag, Jazz, Johnson and Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Sanofi-Aventis, Servier, Schering-Plough, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), the Stanley Medical

Acknowledgments

We thank Dr Anusha Bolonna from PAREXEL, who provided medical writing support funded by AstraZeneca.

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