A 40-week double-blind aripiprazole versus lithium follow-up of a 12-week acute phase study (total 52 weeks) in bipolar I disorder

doi:10.1016/j.jad.2011.11.043

Journal of Affective Disorders

Volume 136, Issue 3, February 2012, Pages 258-266

https://doi.org/10.1016/j.jad.2011.11.043 Get rights and content

Abstract

Background

This study followed manic or mixed bipolar I subjects for an additional 40 weeks after initial randomization to 12 weeks of lithium versus aripiprazole monotherapy. This is the only long-term, double-blind study comparing lithium and aripiprazole.

Methods

Patients continued receiving either aripiprazole 15 or 30 mg/day, or lithium 900, 1200 or 1500 mg/day in a double-blind fashion for 40 weeks after completing a 12-week double-blind study (52 weeks total treatment). Efficacy endpoints included adjusted mean change from baseline to Week 52 in Young Mania Rating Scale (YMRS) total score and Montgomery–Åsberg Depression Rating Scale (MADRS) total scores (observed cases). Remission was defined as YMRS total score ≤ 12. Safety and tolerability were also assessed.

Results

Of the 66 patients who entered the extension phase, only 20 patients (30.3%) completed the entire phase (aripiprazole n = 7; lithium n = 13). The significant improvement that occurred over the first 12 weeks was maintained over the 40 weeks of blinded continuation (from Week 12 through Week 52). The most common treatment-emergent adverse events in the extension phase for aripiprazole were akathisia, headache, somnolence, anxiety and nasopharyngitis (all 8%), and for lithium were insomnia (15.8%), headache (13.2%), diarrhea (13.2%) and vomiting (10.5%). Mean weight change was + 2.71 kg for lithium and + 5.66 kg for aripiprazole (p = 0.46).

Limitations

This trial was not powered to statistically compare active treatments, and long-term completion rates were low in both groups.

Conclusions

Aripiprazole monotherapy appears to be equivalently useful to lithium for the extended treatment of mixed or manic bipolar disorder patients.

Introduction

Bipolar disorder is a lifelong episodic illness requiring long-term treatment. However, despite some recent long-term controlled studies (Bowden et al., 2003, Calabrese et al., 2003, Denicoff et al., 1997, Greil et al., 1997, Tohen et al., 2005), there remains a dearth of comparative long-term data. In the absence of data, experts believe that effective acute-phase treatments are reasonable options for ongoing maintenance therapy (APA, 2002, Suppes et al., 2005). Lithium and valproate remain first-line maintenance therapy choices (APA, 2002, Suppes et al., 2005), supported by previous placebo-controlled studies (Bowden et al., 2003, Calabrese et al., 2003, Denicoff et al., 1997, Greil et al., 1997, Kane et al., 1982, Prien et al., 1973, Tohen et al., 2005). More recently, there is a growing body of knowledge supporting the use of second-generation antipsychotics (Surja et al., 2006).

Aripiprazole is an atypical antipsychotic with a distinct pharmacologic profile of partial agonist activity at dopamine D₂, D₃ (Burris et al., 2002, Shapiro et al., 2003) and 5-HT_1A receptors (Jordan et al., 2002, Stark et al., 2007), and antagonist activity at 5-HT_2A (Jordan et al., 2004, Stark et al., 2007). Aripiprazole has demonstrated its acute and prolonged efficacy in bipolar illness (Keck et al., 2003, Keck et al., 2006, Keck et al., 2007, Keck et al., 2009, Sachs et al., 2006b, Young et al., 2009). In one study, aripiprazole was investigated in acutely manic subjects who were then followed for 12 weeks (Keck et al., 2009). In this placebo- and lithium-controlled trial, aripiprazole and lithium were both significantly more efficacious than placebo for the early improvement of manic symptoms in bipolar disorder, as measured by mean YMRS total score from baseline to Week 3 (aripiprazole − 12.6 vs. placebo − 9.0; p < 0.001; lithium − 12.0 vs. placebo − 9.0; p = 0.005). Improvements in YMRS total scores were maintained to Week 12 for aripiprazole (− 14.5) and lithium (− 12.7). Although this trial demonstrates that the magnitudes of improvement with aripiprazole and lithium are similar over 12 weeks, the longer-term efficacy of aripiprazole relative to the gold standard, lithium, has not been examined. The present study is the first randomized, controlled trial to evaluate the long-term efficacy and safety of aripiprazole monotherapy relative to lithium monotherapy for the treatment of patients with bipolar I disorder.

Section snippets

Study design and patients

Patients who completed a 12-week, randomized, double-blind, placebo-controlled study had the option to enter a 40-week extension phase. Full details of the initial randomized, double-blind, placebo-controlled study have been published previously (Keck et al., 2009). In brief, patients with acute bipolar I mania or mixed mania (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [DSM-IV-TR]) (APA, 2000) requiring hospitalization, were randomized to aripiprazole,

Patient disposition and demographics

Patient disposition is shown in Fig. 1. Sixty-six patients originally randomized to aripiprazole or lithium entered the double-blind extension treatment phase, of which 20 patients (30.3%) completed; 7 patients receiving aripiprazole and 13 patients on lithium (Fig. 1). The most common reasons for discontinuation during the extension phase were AEs in the lithium group (6.3%) and withdrawal of consent in the aripiprazole group (4.5%) (Fig. 1). Time to discontinuation for any reason during the

Discussion

The magnitude of initial improvement in manic symptoms seen with aripiprazole was similar to that seen with lithium. In the small fraction of patients that remained in the study, both lithium and aripiprazole were associated with maintenance of the improvement seen in the initial 12 weeks. Furthermore, remission was maintained during the 40 weeks of extension treatment for patients in both treatment groups who achieved remission following the initial 12-week treatment period and rates of

Role of funding source

This study was supported by Bristol-Myers Squibb (Princeton, NJ) and Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). Bristol-Myers Squibb had a role in the study design, analysis interpretation of the data, writing of report and decision to submit the paper for publication. Editorial support for the preparation of this manuscript was provided by Ogilvy Healthworld Medical Education; funding was provided by Bristol-Myers Squibb.

Conflict of interest

Rif El Mallakh has received research support funding in the past 3 years from Forest Laboratories, and Shire Pharmaceuticals, and is on the speakers' bureau of AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Eli Lilly, Merck, and Pfizer. The author is not getting any reimbursement for his efforts on this manuscript.

Christine Baudelet and Ronald N Marcus are employees of Bristol-Myers Squibb and Randall Owen is a former employee of Bristol-Myers Squibb.

William H Carson and Robert D McQuade

Acknowledgments

The authors would like to thank Jim Eudicone, MS, MBA, for providing extra statistical analyses for this manuscript.

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After screening the titles/abstracts, 43 full-text articles were assessed for eligibility, of which 22 were excluded (Fig. 1 and Supplementary Table 2). Therefore, 20 articles were eligible for the current meta-analysis (Carlson et al., 2012; El-Mallakh et al., 2012, 2010; Findling et al., 2013, 2009, 2012; Jeong et al., 2012; Kanba et al., 2014; Keck et al., 2007, 2003, 2009; Muzina et al., 2008; Quante et al., 2010; Sachs et al., 2006; Thase et al., 2008; Tramontina et al., 2009; Vieta et al., 2005, 2008; Woo et al., 2011; Young et al., 2009) (Table 1). Among the 20 eligible articles, two investigated the efficacy of aripiprazole monotherapy in comparison with haloperidol (Vieta et al., 2005; Young et al., 2009) (aripiprazole participants = 340; haloperidol participants = 337).
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Un panel de expertos formado por 7 miembros discutió una serie de casos clínicos. Cuando se llegó a un consenso, sacaron sus conclusiones. Además, se revisaron e incluyeron los datos y la evidencia clínica de los ensayos clínicos de aripiprazol más relevantes de los últimos 10 años.
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Research reportA 40-week double-blind aripiprazole versus lithium follow-up of a 12-week acute phase study (total 52 weeks) in bipolar I disorder

Abstract

Background

Methods

Results

Limitations

Conclusions

Introduction

Section snippets

Study design and patients

Patient disposition and demographics

Discussion

Role of funding source

Conflict of interest

Acknowledgments

Biological Psychiatry

Journal of Affective Disorders

European Journal of Pharmacology

European Journal of Pharmacology

Journal of Affective Disorders

Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition

Practice guideline for the treatment of patients with bipolar disorder (revision)

The American Journal of Psychiatry

A rating scale for drug-induced akathisia

The British Journal of Psychiatry

Pharmacological interventions for the prevention of relapse in bipolar disorder: a systematic review of controlled trials

Journal of Psychopharmacology

A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder

Archives of General Psychiatry

Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors

The Journal of Pharmacology and Experimental Therapeutics

A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder

The Journal of Clinical Psychiatry

Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-week, open-label comparison with olanzapine

Psychopharmacology

Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder

The Journal of Clinical Psychiatry

Abnormal Involuntary Movement Scale (AIMS)

Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison

Archives of General Psychiatry

Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia

The International Journal of Neuropsychopharmacology

Bipolar disorder, obesity, and pharmacotherapy-associated weight gain

The Journal of Clinical Psychiatry

Research report
A 40-week double-blind aripiprazole versus lithium follow-up of a 12-week acute phase study (total 52 weeks) in bipolar I disorder