Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative

Jan Scott (1, 2, 3) , Diego Hidalgo-Mazzei (4) , Rebecca Strawbridge (3) , Allan H. Young (3) , Matthieu Resche-Rigon (5, 6) , Bruno Etain (7, 8) , Ole J Andreassen , Michael Bauer , Djamila Bennabi (9, 10) , Andrew M Blamire (1) , Fawzi Boumezbeur (11) , Paolo Brambilla , Nadia Cattane , Annamaria Cattaneo , Marie Chupin (12, 13) , Klara Coello , Yann Cointepas (11, 12) , Francesc Colom , David Cousins , Caroline Dubertret (14, 15) , Edouard Duchesnay (16) , Adele Ferro , Aitana Garcia-Estela , Jose Goikolea , Antoine Grigis (17) , Emmanuel Haffen (9, 10) , Margrethe Høegh , Petter Jakobsen , Janos Kalman , Lars Kessing , Farah Klohn-Saghatolislam , Trine Lagerberg , Mikael Landén , Ute Lewitzka , Ashley Lutticke , Nicolas Mazer (14, 15) , Monica Mazzelli , Cristina Mora , Thorsten Muller , Estanislao Mur-Mila , Ketil Joachim Oedegaard , Leif Oltedal , Erik Pålsson , Dimitri Papadopoulos-Orfanos (11) , Sergi Papiol (18) , Victor Perez-Sola , Andreas Reif , Philipp Ritter , Roberto Rossi , Thomas G. Schulze , Fanny Senner , Fiona Smith , Letizia Squarcina , Nils Eiel Steen , Pete Thelwall , Cristina Varo , Eduard Vieta (19) , Maj Vinberg , Michèle Wessa , Lars Westlye , Frank Bellivier (7, 8)

1 Newcastle University [Newcastle]
2 UPD7 - Université Paris Diderot - Paris 7
3 King‘s College London
4 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
5 CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
6 SBIM - Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA)
7 VariaPsy - U1144 - Variabilité de réponse aux Psychotropes
8 AP-HP - Hopital Saint-Louis [AP-HP]
9 Inserm CIC 1431 - Centre d'Investigation Clinique de Besançon
10 UBFC - Université Bourgogne Franche-Comté [COMUE]
11 NEUROSPIN - Service NEUROSPIN
12 CATI - CATI Multicenter Neuroimaging Platform
13 ICM - Institut du Cerveau = Paris Brain Institute
14 Hôpital Louis Mourier - AP-HP [Colombes]
15 U894 / UMS 1266 - Institut de psychiatrie et neurosciences
16 LNAO - Laboratoire de Neuroimagerie Assistée par Ordinateur
17 UNATI - Unité Analyse et Traitement de l'Information
18 Max-Planck-Institut
19 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)

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; ) 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.

Keywords: Bipolar; Precision; Personalization; Lithium; Response; Phenotype; Digital; Actigraphy; Omics; Neuroimaging

Domains: Life Sciences [q-bio]

Jan Scott, Diego Hidalgo-Mazzei, Rebecca Strawbridge, Allan H. Young, Matthieu Resche-Rigon, et al.. Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative. International Journal of Bipolar Disorders, 2019, 7 (1), pp.20. ⟨10.1186/s40345-019-0156-x⟩. ⟨cea-02316734⟩