European Network of Bipolar Research Expert Centre (ENBREC): a network to foster research and promote innovative care

Background

Bipolar disorders (BD) are characterised by recurrent manic and depressive episodes that usually commence in early adulthood and affect 1% to 4% of the general population (Merikangas et al. 2007). According to the World Health Organization study on global burden of disease, BD are ranked sixth amongst the most disabling illnesses in working age adults worldwide (above schizophrenia which is ranked eighth) (Lopez and Murray 1998) - findings that are reinforced by the recent European study on the burden of mental health (Olesen et al. 2012).

Despite its high prevalence, BD is often unrecognised or misdiagnosed leading to inappropriate or delayed treatments, with significant and devastating health and social consequences (Baca-Garcia et al. 2007; Hirschfeld et al. 2003; Scott and Leboyer 2012). Even when the diagnosis is established, it is clear that the management of BD is a major challenge, and surveys confirm that suboptimal treatment is a common concern across Europe (Scott et al. 2006). The significant disease burden attributable to BD is amplified by additional, often multiple psychiatric and physical comorbidities, and premature mortality (Leboyer and Kupfer 2010). The reduced life expectancy in BD due to medical comorbidity and adverse lifestyles is about 10 years for men and 11 for women (Chang et al. 2011). Furthermore, rates of completed suicide have generally been estimated to be between 10% and 20% (Müller-Oerlinghausen et al. 2002). Even if recent studies are more optimistic, rates in BD exceed unipolar depression and schizophrenia (Bostwick and Pankratz 2000; Dutta et al. 2007).

Whilst adherence to clinical practice guideline recommendations can improve outcome for patients (Goodwin et al. 2009; Nivoli et al. 2011a, b), many of the algorithms for BD patients are derived from efficacy data from randomised controlled clinical trials (RCTs). Such RCTs usually recruit homogeneous samples of patients who will represent only about 20% of the BD population treated in day-to-day clinical practice (Vieta and Cruz 2012). Also, guidelines are not consistent in their recommendations, differing in their advice on when to use adjunctive psychological therapies or which type of therapy to offer to different patient subpopulations (Henry et al. 2011). As a consequence, clinicians often find it difficult to systematically apply recommendations to individual cases. For example, many guidelines suggest monotherapy as maintenance treatment (based on findings from RCTs); the clinical reality is that many patients receive polypharmacy for mood stabilisation (Frye et al. 2000; Wolfsperger et al. 2007). Other strategies, extending beyond the use of guidelines, therefore need to be examined, especially because the evidence suggests that efforts made to spread good clinical practice invariably result in gains for patients. For example, Bauer et al. (2009) have shown that promoting systematic assessments and offering local support to clinicians working with BD improve patient outcomes. Similar national initiatives are being undertaken, e.g. the French BD network developed by Fondation FondaMental (Henry et al. 2011) and the CIBERSAM in Spain (Vieta 2011). However, to date, there have been few attempts to facilitate an international programme on the translation of research knowledge into evidence-based clinical practice. This is especially likely to be beneficial in multifaceted disorders such as BD, where a ‘personalised medicine’ approach represents the best way to take into account the diversity of clinical presentation, including the frequent presence of comorbidities, and the range and optimal combinations of pharmacological and psychosocial treatments (Scott 2011).

The nature and complexity of BD mean that successful translational research requires the integration of advances in clinical and basic science to develop targeted treatments that are more specific for BD. However, improving research in the field of severe and complex disorders increasingly requires the development of a critical mass of expertise through broadly based collaborative networks. Multicentre projects maximise the likelihood of recruitment of large clinical cohorts that reflect the heterogeneity of the disorder and facilitate cross-national epidemiological studies, as well as providing subgroups with adequate statistical power to explore pathophysiological and gene-environment interactions and to conduct clinical trials. This type of research is only usually achievable through the development and implementation of shared research protocols across a large number of centres (Vieta et al. 2011).

In order to disseminate systematic clinical assessment and high quality treatment protocols and to foster research to improve the management of BD and to develop a better understanding of the mechanisms underlying this complex condition, we have developed a network of bipolar expert centre at a European level: European Network of Bipolar Research Expert Centre (ENBREC, http://www.enbrec.eu). This network was set up via FP7 funding but is maintained through the support from the European College of Neuropsychopharmacology (ECNP) network initiative (ECNP-NI). In this paper, we describe the development of the ENBREC network and the common, cross-national clinical and research tools we are introducing.

Resources and goals

Following a successful application to the ‘Support Action’ call of the European FP7 programme in 2009, we set about developing the infrastructure for ENBREC, a disease-oriented EU-wide network designed to foster multinational collaboration among centres with expertise in the clinical management of and/or research in BD. The programme has now evolved into one of the networks supported by the ECNP. For Europe, the added value of ENBREC is that expertise in different research fields including epidemiology, genetics and clinical trial design is shared across centres and that leading researchers in the field of BD gain early access to large patient cohorts, improving the clinical representativeness of research samples and enhancing the external validity and statistical power of proposed studies. A core goal of ENBREC is to establish connections between leading centres in the field and to foster the development of or support existing national networks, with some of the national centres being incorporated into the Europe-wide network.

From a clinical perspective, the goal of ENBREC is to develop assessment tools and procedures to improve the diagnosis and management of BD. In addition, the cross-centre links enhance clinical investigations and observational studies, which benefit from the pooling of relevant resources including access to patients. To achieve this, there was first a need for centres to work together to develop a common assessment protocol and to develop mechanisms for efficient sharing of clinical data and biomaterial.

A separate but linked goal for the network is to disseminate clinical and basic research ideas to others working in BD in Europe and elsewhere and to produce consensus papers that highlight how to translate research findings into improved health care and clinical practice. The network also offers an unrivalled opportunity to undertake joint training of the next generation of researchers and clinicians wishing to develop expertise in BD, and joint applications for postgraduate training have been produced.

Participants and organisation

A standardised assessment package

All centres are in the process of adopting the same evaluation package, with many having already achieved full implementation (Henry et al. 2011). The package comprises a wide-ranging psychobiosocial assessment that systematically explores all aspects of BD including clinical presentation, personal history and factors that potentially influence the course and outcome of BD. The measures provide a high quality, structured evaluation that can inform clinical decision making, but the tools selected are also relevant and applicable to research projects. Valid, reliable and established observer- and self-rating scales were chosen in preference to idiosyncratic or untested measures. Where appropriate, assessment tools were translated into different languages, and validation studies have been undertaken as required.

Data collection: electronic records and shared database

It is important for multisite collaborations that involve simultaneous collation of assessments to have efficient procedures for data capture that do not overburden clinicians or researchers but that maximise the likelihood of complete and accurate data entry. To help in this process, a specific case report form was produced, incorporating all the items in the standardised assessment package which was then translated into the languages of participating countries for local use.

A web-based application, e-ENBREC©, has also been developed to collate assessment data for clinical monitoring and research purposes. Access to the system is carefully regulated, and approval has to be obtained from the committee in charge of the safety of computerised databases in each country. To optimise data entry and retrieval, free text input has been minimised, and drop-down lists and other approaches leading to standardised inputs have been chosen whenever possible. The XML format is used to transfer data from e-ENBREC©(European network of bipolar research) expert centre into an anonymised common database for research purpose.

Specific research projects

Brain imaging techniques have revolutionised the understanding of the human brain, with potential to identify brain pathology underlying psychiatric disorders, including bipolar disorders (Rimol et al. 2010). In addition, it has the potential to become a tool for early identification, subgrouping, disease monitoring and treatment stratification. The overall aim of the ENBREC project is to develop a common MRI protocol which allows pooling of data acquired with standard clinical MRI scanners that can be used in multisite studies of bipolar disorders.

Structural MRI studies usually provide global estimates of gray or white matter volume changes, or a small number of regions of interest. Recent advances in structural imaging now allow for a more comprehensive evaluation of brain changes by providing continuous maps of cortical thickness and surface area, subcortical volumes and measures of white matter microstructure throughout the brain (Fischl and Dale 2000). White matter can now be quantified using diffusion tensor imaging. It will be important to cross this information with cognitive data in large cohorts of patients in order to address any structural features underlying the pathology (Forcada et al. 2011). In the future and if funding permits, it is hoped to extend the imaging protocols of functional MRI.

Promoting innovative care and treatment protocols

A significant number of patients with BD, who achieve neither clinical remission nor functional recovery despite high levels of medication adherence (Rosa et al. 2011) and recurrence rates following a manic episode, are about 40% to 60% even when receiving maintenance drug therapy (Gitlin et al. 1995). Such data highlight the need to address nonpharmacological factors in order to improve outcome and to encourage patients to take an active role in the management of their illness and collaborate in the care process. Surveys of patient preferences reveal that there is a strong wish by patients with BD to undertake self-help and participate in psychological interventions (Pontin et al. 2009).

Despite promising research findings, dissemination remains an unresolved issue. Within the ENBREC network, a working group has been mandated to recommend how best to extend psycho-education techniques that have been shown to be effective into every level of everyday psychiatric care.

Sustainability of the network: links maintained beyond initial phase of ENBREC

By the time the FP7 funding ended (June 2011), ENBREC members had engaged in and continue to be involved in several joint research projects at a Europe-wide level. The ongoing support of ECNP-NI is also vital to the continuation of the collaborative group. The sustainability of the network is secured because the centres involved in the collaboration are all clinically active, offering expert care and treatment of BD. Resources are provided within each country to ensure continuity of clinical care. The common clinical and cognitive assessment and the follow-up protocol chosen for ENBREC represent a basic, but systematic and comprehensive assessment of cases which allows the expert centres to provide high-quality advice on diagnosis and treatment to the referrers and patients in each participating country. At the same time, a major potential barrier to cross-national research has been overcome, allowing easier implementation of new basic science and clinical research studies in the future. The closely identified research group will also be in a strong position to apply for multicentre research grants and potentially represents an attractive option to international industrial partners who, for example, wish to plan and execute pilot studies or pivotal randomised controlled clinical trials. Industry-funded unrestricted educational grants are also being explored to help support the training initiatives that have grown out of the research programme.