| Summary: | Clinical practice guidelines identify lithium as a first line treatment for mood stabilization and reduction of suicidality in bipolar disorders (BD); however, most individuals show sub-optimal response. Identifying biomarkers for lithium response could enable personalization of treatment and refine criteria for stratification of BD cases into treatment-relevant subgroups. Existing systematic reviews identify potential biomarkers of lithium response, but none directly address the conceptual issues that need to be addressed to enhance translation of research into precision prescribing of lithium. For example, although clinical syndrome subtyping of BD has not led to customized individual treatments, we emphasize the importance of assessing clinical response phenotypes in biomarker research. Also, we highlight the need to give greater consideration to the quality of prospective longitudinal monitoring of illness activity and the differentiation of non-response from partial or non-adherence with medication. It is unlikely that there is a single biomarker for lithium response or tolerability, so this review argues that more research should be directed toward the exploration of biosignatures. Importantly, we emphasize that an integrative science approach may improve the likelihood of discovering the optimal combination of clinical factors and multimodal biomarkers (e.g., blood omics, neuroimaging, and actigraphy derived-markers). This strategy could uncover a valid lithium response phenotype and facilitate development of a composite prediction algorithm. Lastly, this narrative review discusses how these strategies could improve eligibility criteria for lithium treatment in BD, and highlights barriers to translation to clinical practice including the often-overlooked issue of the cost-effectiveness of introducing biomarker tests in psychiatry.
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