OBJECTIVE: To undertake a large-scale clinical study of predictors of lithium (Li) response in bipolar I disorder (BD-I) and apply contemporary multivariate approaches to account for inter-relationships between putative predictors. METHODS: We used network analysis to estimate the number and strength of connections between potential predictors of good Li response (measured by a new scoring algorithm for the Retrospective Assessment of Response to Lithium Scale) in 900 individuals with BD-I recruited to the Consortium of Lithium Genetics. RESULTS: After accounting for co-associations between potential predictors, the most important factors associated with the good Li response phenotype were panic disorder, manic predominant polarity, manic first episode, age at onset between 15-32 years and family history of BD. Factors most strongly linked to poor outcome were comorbid obsessive-compulsive disorder, alcohol and/or substance misuse, and/or psychosis (symptoms or syndromes). CONCLUSIONS: Network analysis can offer important additional insights to prospective studies of predictors of Li treatment outcomes. It appears to especially help in further clarifying the role of family history of BD (i.e. its direct and indirect associations) and highlighting the positive and negative associations of different subtypes of anxiety disorders with Li response, particularly the little-known negative association between Li response and obsessive-compulsive disorder.

Département de Psychiatrie et de Médecine Addictologique AP HP GH Saint Louis Lariboisière F Widal Paris France

Department of Pharmacology Dalhousie University Halifax NS Canada

Department of Psychiatry Dalhousie University Halifax NS Canada

Institute of Neuroscience Newcastle University Newcastle UK

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Munich Germany

National Institute of Mental Health Klecany Czech Republic

Section of Psychiatry Department of Medical Sciences and Public Health University of Cagliari Cagliari Italy

Université Paris Diderot and INSERM UMRS1144 Paris France

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