Periodic Reporting for period 5 - R-LiNK (Optimizing response to Li treatment through personalized evaluation of individuals with bipolar I disorder: the R-LiNK initiative)
Reporting period: 2023-07-01 to 2024-06-30
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 mental state stabilization through the application of stratified approaches; (ii) improve the early prediction of Li response using a set of multi-modal biomarkers (“blood omics”, 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 22 partners from 8 countries. 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.
In this context, R-LiNK aims to (i) improve outcomes of individuals with BD-I by optimizing the mental state stabilization through the application of stratified approaches; (ii) improve the early prediction of Li response using a set of multi-modal biomarkers (“blood omics”, 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 22 partners from 8 countries. 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 recruitment phase ended on June 30, 2022, with the last patients completing follow-up by June 2024. Since July 2024, significant progress has been made in monitoring clinical data across centers, with final queries related to quality control now underway. The central database adheres to international standards like BIDS for neuroimaging and uses robust de-identification procedures.
The development of the pre-industrial lithium monitoring device has advanced, with lithium detection validated in lab environments and a semi-integrated demonstrator available. Variations in MRI images from different machines prompted extensive efforts to harmonize acquisition protocols across centers, despite using various scanner manufacturers and models.
R-LiNK also involves acquiring novel 7Li-MRI and 1H-MRSI data at six centers. All centers followed standardized guidelines to collect these data from human volunteers, and data analysis techniques were developed in a pilot study. Harmonised standard operating procedures for blood sample collection, processing, and shipping to biobanks have been established and tested, with preliminary results guiding further analyses of biological samples.
For OMICs analyses, biological samples were shipped to centralized biobanks in Brescia and Munich, followed by quality control and pre-processing. All OMIC modalities (mirnomic, transcriptomic, methylomic, proteomic) and genome-wide genotyping were completed by May 2024. Except for proteomic data, which required additional quality checks, all raw data were transferred to the central database.
With quality control completed in May 2024, WP4 (MRI), WP5 (Li imaging), and WP6 (OMICs) conducted the first round of biomarker analyses, including descriptive and pre-post lithium initiation comparisons. These analyses will guide the strategy for the primary and secondary outcome analyses.
The classification of patients' lithium response status after 24 months of follow-up began in July 2024. Each patient is rated by two independent assessors, with a third in case of discrepancies. The process involved identifying and training 19 experts, testing the algorithm on 5 patient files, creating a secure web platform for ratings, and randomly assigning files to experts. This started in May 2024, with file assignment completed by July. Experts are to submit ratings by September, and a consortium meeting to finalize the data analysis strategy is scheduled for September 2024.
The R-LiNK project has been presented at international meetings and published in journals such as Lancet Psychiatry and Biological Psychiatry (https://rlink.eu.com/publications/(opens in new window))
The development of the pre-industrial lithium monitoring device has advanced, with lithium detection validated in lab environments and a semi-integrated demonstrator available. Variations in MRI images from different machines prompted extensive efforts to harmonize acquisition protocols across centers, despite using various scanner manufacturers and models.
R-LiNK also involves acquiring novel 7Li-MRI and 1H-MRSI data at six centers. All centers followed standardized guidelines to collect these data from human volunteers, and data analysis techniques were developed in a pilot study. Harmonised standard operating procedures for blood sample collection, processing, and shipping to biobanks have been established and tested, with preliminary results guiding further analyses of biological samples.
For OMICs analyses, biological samples were shipped to centralized biobanks in Brescia and Munich, followed by quality control and pre-processing. All OMIC modalities (mirnomic, transcriptomic, methylomic, proteomic) and genome-wide genotyping were completed by May 2024. Except for proteomic data, which required additional quality checks, all raw data were transferred to the central database.
With quality control completed in May 2024, WP4 (MRI), WP5 (Li imaging), and WP6 (OMICs) conducted the first round of biomarker analyses, including descriptive and pre-post lithium initiation comparisons. These analyses will guide the strategy for the primary and secondary outcome analyses.
The classification of patients' lithium response status after 24 months of follow-up began in July 2024. Each patient is rated by two independent assessors, with a third in case of discrepancies. The process involved identifying and training 19 experts, testing the algorithm on 5 patient files, creating a secure web platform for ratings, and randomly assigning files to experts. This started in May 2024, with file assignment completed by July. Experts are to submit ratings by September, and a consortium meeting to finalize the data analysis strategy is scheduled for September 2024.
The R-LiNK project has been presented at international meetings and published in journals such as Lancet Psychiatry and Biological Psychiatry (https://rlink.eu.com/publications/(opens in new window))
Early prediction of long-term response would be a major advance both for people who respond (continuation and adaptation of Li treatment) and for those who do not respond (early modification of treatment), as this approach will avoid unnecessary and unsuccessful therapeutic trials for people who are 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/non responder’ 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 (development of companion tests). 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.
The current state of our knowledge indicates that the search for phenotypes or ‘responder/non responder’ 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 (development of companion tests). 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.