Bipolar disorder type I (BDI) is a prevalent mental disorder and a leading cause of burden, cost and suicide. Indeed, the high relapse rates of BD episode represent a major individual burden and a large global and economic cost to society. Lithium (Li) is the key treatment...
Bipolar disorder type I (BDI) is a prevalent mental disorder and a leading cause of burden, cost and suicide. Indeed, the high relapse rates of BD episode represent a major individual burden and a large global and economic cost to society. Lithium (Li) is the key treatment for prevention of BD relapse and has a proven suicide prevention effect. Li is also recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. Overall, identifying biomarkers for predicting Li response would enable personalization of treatment, define criteria for stratification of BD cases and further refine the clinical response phenotype.
In this context, R-LiNK aims to (i) improve outcomes of individuals with BD-I by optimizing the stabilization of their mental state through the application of stratified approaches; (ii) improve the early prediction of Li response using a set of multi-modal biomarkers (“blood omicsâ€, Magnetic Resonance Imaging (MRI) and Li7-MRI derived-markers); (iii) develop a multidisciplinary multinational network of experts to undertake this and future projects on personalized diagnostics and therapeutics in BD; and (iv) implement new, powerful technologies to characterize brain Li distribution and the blood molecular signature of Li in responders and non-responders. This cutting edge approach will identify the eligibility criteria for treatment with Li in BD in terms of response, safety and tolerability.
To reach its objectives, R-LiNK brought together 21 partners from 8 EU Members. The R-LiNK project benefit from several expertise of the members of the consortium: (i) clinical phenotyping based on validated instruments, (ii) neuroimaging techniques including lithium imaging (7Li-MRI), a novel technique that directly measures brain lithium distribution, (iii) blood biological signature of lithium effect (referred as “OMIC†approaches and (iv) novel approaches to combine all biomarkers to generate composite predictors of response.
The first 18 months of the project focused on the preparation of the clinical trial. Such a large-scale collaborative venture requires considerable preparatory work.
Regulatory processes: The study is being undertaken in accordance with the Revised Declaration of Geneva (Parsa-Parsi, 2017). Ethical approvals were obtained in all countries.
Preparation of the assessment procedures: Developing and translating clinical assessments, protocol and documentation is a critical component for this multinational study. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants’ response to lithium according to predefined criteria that consider evidence of relapse, remission, changes in illness activity or treatment failure and adherence to lithium.
Harmonization between centres: To guaranty that the data can be pooled at the end of the collection, standard operating procedures (SOPs) and inter-rater reliability have to be established before the start of the study. SOPs are now completed and validated for all modalities: clinical assessment and follow-up procedures, patient labelling and anonymization, MRI acquisition, Li imaging, blood processing and shipping, secured data transfer to the centralized database. Two training sessions have been organized with the data collectors to establish inter-rater reliability.
A shared secured web-based tool to collect clinical data: We defined the database organization for the neuroimaging data based on the international BIDS format. An electronic case report form (e-CRF) has been elaborated and tested. The production of the final version of the e-CRF is ongoing and the database server is now up and running.
Good progress has been made with development of the pre-industrial lithium level monitoring device. Detection of lithium has been validated in laboratory environments, and work on saliva composition and volume sampling is in progress.
With regard to communication activities, the R-LiNK project has been presented in several international meetings. A protocol paper is in press in the International Journal of Bipolar Disorders.
Early prediction of long-term response is a potential benefit both for responders (continuation and adaptation of Li treatment) and non-responders (early treatment modification) as this approach will prevent the patient from unnecessary, unsuccessful treatment trials for people unlikely to benefit. The development of a home-based Li salivary monitoring device will also improve the monitoring of Lithium exposure as well as patients’ engagement and autonomy. All these are likely to improve clinical and social functioning leading to better quality of life.
The current state of our knowledge indicates that the search for phenotypes or ‘responder/nonresponder’ subgroups requires a combination of systematic exploration of clinical characteristics, prospective longitudinal monitoring of illness activity during treatment, alongside the search for biomarkers derived from several dimensions (e.g. « omics », neuroimaging, actigraphy, etc.). In BD-I, research efforts directed towards the identification of biosignatures for Li response or tolerability are preferable as it is unlikely that a single unidimensional biomarker with robust predictive validity will be found. Integrative approaches to clinical and multimodal response markers may allow a composite ‘prediction algorithm’ to be developed and tested in new populations.
Altogether, expected impacts include enhanced clinical practice with improved clinician’s decision-making and clinical guidelines on the selection of BDI cases for lithium treatment. For the society, it will led to a longer-term reduction in cost and global burden of BD-I.
As for the industry, the impact will be reflected through exploitation of the results: medical devices, biological and neuroimaging diagnostic kits to guide clinicians based on the blood molecular signature and the neuroimaging signature of response/non response. Expected results will also strengthen our understanding of the brain regions and the molecular pathways involved in lithium response in BDI. In particular, 7Li-MRI will allow to investigating the link between the cerebral distribution of lithium and the level of response. Finally, little is known about the mechanism of action of Li or the reasons for the variability of the response. Biological and neuroimaging signatures of prophylactic responders and non-responders will provide the field with targets to be used in the development of novel mood stabilisers.
More info: https://rlink.eu.com/.