Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative
Authors: Scott Jan , Hidalgo-Mazzei Diego , Strawbridge Rebecca , Young Allan , Resche-Rigon Matthieu , Etain Bruno , Andreassen Ole A. , Bauer Michael , Bennabi Djamila , Blamire Andrew M. , Boumezbeur Fawzi , Brambilla Paolo , Cattane Nadia , Cattaneo Annamaria , Chupin Marie , Coello Klara , Cointepas Yann , Colom Francesc , Cousins David A. , Dubertret Caroline , Duchesnay Edouard , Ferro Adele , Garcia-Estela Aitana , Goikolea Jose , Grigis Antoine , Haffen Emmanuel , Høegh Margrethe C. , Jakobsen Petter , Kalman Janos L. , Kessing Lars V. , Klohn-Saghatolislam Farah , Lagerberg Trine V. , Landén Mikael , Lewitzka Ute , Lutticke Ashley , Mazer Nicolas , Mazzelli Monica , Mora Cristina , Muller Thorsten , Mur-Mila Estanislao , Oedegaard Ketil Joachim , Oltedal Leif , Pålsson Erik , Papadopoulos Orfanos Dimitri , Papiol Sergi , Perez-Sola Victor , Reif Andreas , Ritter Philipp , Rossi Roberto , Schulze Thomas , Senner Fanny , Smith Fiona E. , Squarcina Letizia , Steen Nils Eiel , Thelwall Pete E. , Varo Cristina , Vieta Eduard , Vinberg Maj , Wessa Michele , Westlye Lars T. , Bellivier Frank 
Published: September 2019

Abstract

Background
Lithium is 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.

Structure
The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. 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, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. 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; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; 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. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence.

Conclusions
The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.