Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Mirko Manchia, Mazda Adli, Nirmala Akula, Raffaella Ardau, Jean Michel Aubry, Lena Backlund, Claudio E.M. Banzato, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Joanna M. Biernacka, Clara Brichant-Petitjean, Elise Bui, Cynthia V. Calkin, Andrew Tai Ann Cheng, Caterina Chillotti, Sven Cichon, Scott Clark, Piotr M. Czerski, Clarissa DantasMaria Del Zompo, J. Raymond DePaulo, Sevilla D. Detera-Wadleigh, Bruno Etain, Peter Falkai, Louise Frisén, Mark A. Frye, Jan Fullerton, Sébastien Gard, Julie Garnham, Fernando S. Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Rebecca Hoban, Liping Hou, Stéphane Jamain, Jean Pierre Kahn, Layla Kassem, Tadafumi Kato, John R. Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Po Hsiu Kuo, Ichiro Kusumi, Gonzalo Laje, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Carlos A. López Jaramillo, Mario Maj, Alain Malafosse, Lina Martinsson, Takuya Masui, Philip B. Mitchell, Frank Mondimore, Palmiero Monteleone, Audrey Nallet, Maria Neuner, Tomás Novák, Claire O'Donovan, Urban Ösby, Norio Ozaki, Roy H. Perlis, Andrea Pfennig, James B. Potash, Daniela Reich-Erkelenz, Andreas Reif, Eva Reininghaus, Sara Richardson, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Oliver K. Schubert, Barbara Schweizer, Florian Seemüller, Maria Grigoroiu-Serbanescu, Giovanni Severino, Lisa R. Seymour, Claire Slaney, Jordan W. Smoller, Alessio Squassina, Thomas Stamm, Jo Steele, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Naomi R. Wray, Adam Wright, Peter P. Zandi, David Zilles, Michael Bauer, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze, Martin Alda

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93 Scopus citations


Objective:The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.Materials and Methods:Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.Results:Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).Conclusions:We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Original languageEnglish (US)
Article numbere65636
JournalPloS one
Issue number6
StatePublished - Jun 19 2013

ASJC Scopus subject areas

  • General


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