Research report
Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study

https://doi.org/10.1016/j.jad.2007.05.009Get rights and content

Abstract

Background

To evaluate the 12-week outcomes (effectiveness, tolerability, and patterns of medication use) of olanzapine (either in antimanic monotherapy or in combination with other antipsychotics, anticonvulsants, and/or lithium) in patients with bipolar mania or mixed mania.

Method

EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a 24-month prospective observational study of in- and outpatients with acute mania/mixed mania conducted in 14 European countries. Primary outcome measures included Clinical Global Impressions–Bipolar Disorder scale (overall, mania, and depression); 5-item Hamilton Depression Rating Scale; and Young Mania Rating Scale. Tolerability measures included a questionnaire to assess patients’ symptomatic complaints.

Results

Overall, 2004 patients received olanzapine (olanzapine monotherapy, n = 673; olanzapine combination, n = 1331). Concomitant therapy with antidepressants and/or anxiolytics was possible in both groups. The countries significantly differed in the use of olanzapine monotherapy versus olanzapine combination (p < .0001). Baseline-to-endpoint changes on the CGI-BP subscales, YMRS, and HAMD-5 were significant within both treatment groups (p < .0001). Olanzapine monotherapy was generally better tolerated than olanzapine combination, particularly with regard to sedation (12% vs 17%; p < .001), tremor (2% vs 5%; p < .001), and akathisia (3% vs 6%; p < .001).

Discussion

The acute-phase EMBLEM results suggest that in naturalistic settings, olanzapine (both as monotherapy and combination) may be effective in treating patients with bipolar mania. The use of olanzapine monotherapy or combination varies significantly across countries, but combination is generally the rule, rather than the exception.

Introduction

Over the last 5 years, our knowledge on the treatment of mania has outstandingly increased due to the data from randomized clinical trials: Atypical antipsychotics such as olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole have been compared with placebo and with active compounds (haloperidol, lithium, and divalproex), and the evidence base for the use of all these compounds has been considerably enriched (Vieta and Goikolea, 2005). The knowledge of the actual use of antimanic agents in routine clinical conditions is quite limited, however, and large observational studies are rare (Vieta et al., 2001). Observational studies are more likely to be challenged for their internal validity than randomized clinical trials, but provide relevant data about the actual use of therapies either as monotherapy or combination therapy in “real world” patients (that is, without excluding comorbidities or suicide risk, including flexible and broader dose ranges, and across all ranges of illness severity).

Olanzapine has been tested in randomized designs in mania and compared with placebo (Tohen et al., 1999, Tohen et al., 2000), haloperidol (Tohen et al., 2002b, Tohen et al., 2003), divalproex (Zajecka et al., 2002, Tohen et al., 2002a), and risperidone (Perlis et al., 2006). Olanzapine cotherapy with lithium or divalproex was also compared with lithium and divalproex alone in one trial (Tohen et al., 2002b, 2004). Olanzapine proved to be effective for the acute treatment of mania and beyond (Vieta, 2004). Hence, a good number of studies provide an excellent evidence base for the use of olanzapine (both in mono- and combination therapy) as an antimanic agent, but less is known about the factors that drive the choice of olanzapine as monotherapy or combination, its dosages in routine clinical practice, and the patterns of use across different countries.

To close this gap, we conducted the EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication), one of the largest observational studies ever conducted in patients suffering form bipolar mania. The objectives of the EMBLEM were to learn about the clinical and functional outcomes and patterns of use of antimanic therapy including olanzapine (both in monotherapy and in combination therapy) across several European countries.

Section snippets

Study objective

EMBLEM is a large, prospective, multicentre, observational study on the outcomes of patients after an episode of mania. From December 2002 to June 2004, 530 investigators enrolled patients from 14 European countries (Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, The Netherlands, Norway, Portugal, Spain, Switzerland, and the UK). Observations were completed with 5 further data collections as part of the acute phase, which lasted for 12 weeks, until October 2004. Further

Baseline patient characteristics

Of 3681 manic patients enrolled in the study, 2004 (54.4%) received olanzapine for the treatment of their manic or mixed symptoms. Of the 2004 patients, 673 (33.6%) were treated with olanzapine as antimanic monotherapy, and 1331 (66.4%) received olanzapine in combination with other antipsychotics, anticonvulsants, and/or lithium.

The demographic characteristics of the sample are shown in Table 1. Of the sample studied, 35% of patients were inpatients, and alcohol and cannabis abuse were present

Discussion

The acute-phase results of this large, multicentre, observational study that investigated the use of olanzapine (as either monotherapy or combination therapy) in European patients with mania showed significant within-group improvements from baseline to endpoint in all of the following scales: CGI-BP overall, mania, and depression; YMRS; and HAMD-5. Moreover, the rates of work impairment significantly decreased in both treatment groups at endpoint.

Although results of observational studies should

Acknowledgements

The authors of this report would like to thank the EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) Advisory Board for their participation in the design and conduct of the study: Prof Bernard Sabbe (Belgium); Dr Jens Knud Larsen (Denmark); Prof Hannu Koponen (Finland); Dr Isabelle Gasquet and Prof Jean Michel Azorin (France); Dr Heinz Grunze (Germany); Prof Giovanni Battista Cassano (Italy); Prof Willem Nolen and Prof Jim van Os (Netherlands); Dr Trond Aarre (Norway);

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Role of funding source: The EMBLEM study is funded by Eli Lilly and Company Limited, Windlesham, Surrey, UK. Contributors: All the authors have been sufficiently involved in the study submitted. Conflict of interest: Eduard Vieta, has acted as a consultant, received grants, or been hired as a speaker by the following companies: Almirall, AstraZeneca, Bial, Bristol-Myers-Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Merck Sharp & Dohme, Novartis, Organon, Otsuka, Pfizer, Sanofi Aventis, Servier, UCB. He has acted as consultant and has received grants from the Spanish Ministry of Health, Instituto de Salud Carlos III, RETICS RD06/0011 (REM-TAP) and from the Stanley Medical Research Institute. Iris Goetz, Catherine Reed, and Mauricio Tohen are Eli Lilly and Company employees. Francesco Panicali and Merce Comes have no conflict of interest.

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