Periodic Reporting for period 3 - R-LiNK (Optimizing response to Li treatment through personalized evaluation of individuals with bipolar I disorder: the R-LiNK initiative) Reporting period: 2021-01-01 to 2022-06-30 Summary of the context and overall objectives of the project 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 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. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Authorisation from the relevant National Competent authorities and Ethical Committees in all countries involved were obtained and the clinical study started. The study is being undertaken in accordance with the Revised Declaration of Geneva (Parsa-Parsi, 2017). At the end of December 2020, 25 patients have been included. The eCRF is operational and a central database was implemented. The database organization follows international standards (such as BIDS for neuroimaging) and uses the best possible de-identification procedure.The clinical assessment protocol and documentation was finalised, ready for lithium response measurement, health economics and optional modules (adherence and actigraphy packages). The clinical centres were trained for rating scales and the harmonization between centres was tested. The site-specific configurations and development of patient handout, as well as legal documents related to the package to be used by patients to self-report daily mood, symptoms, behaviour and medication adherence are in progress. Good progress has been made as well with development of the pre-industrial Li level monitoring device: detection of Li has been validated in laboratory environments, and the parameters for performing tests are currently being optimised. Images acquired with different MRI machines show subtle differences, particularly due to the acquisition parameters used by each scanner. For this reason, the project made a huge effort for harmonising acquisitions in all centers. Not only R-LiNK MRI centers use MRI scanners from different manufacturers, but also different models by the same manufacturers are employed. The project accomplished a delicate coordinating process which obtained a harmonized protocol to be used in the different centers. One of the tasks of R-LiNK is also the acquisition of novel 7Li-MRI and 1H-MRSI data at 6 selected centres. Working from standardised operating guidelines, all centres have acquired 7Li-MRI and 1H-MRSI data from human volunteers. Data analysis techniques have been developed in a pilot study. Harmonised standard operating procedures for blood sample collection, processing and shipment to the biobanks were established. The sample collection was tested in the real trial phase. Finally, preliminary results on an already recruited sample have been obtained and will guide the analyses to be performed on the biological samples collected during R-LiNK.With regards to communication activities, the R-LiNK project has been presented in several international meetings. Several papers were published i.e. in Lancet Psychiatry, the International Journal of Bipolar Disorders or Biological Psychiatry. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) 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.