Personalized medicine in bipolar disorder: how can we overcome the barriers to clinical translation?

Abstract

Bipolar disorder (BD) is a complex mood disorder characterized by recurrent episodes of mania and depression, affecting 1–4% of the general population [1]. The phenotypic representation of BD is highly heterogeneous, a characteristic that is reflected in the variability in response to mood-stabilizing drugs observed in bipolar patients. Mood stabilizers are a class of drugs that includes anticonvulsants, second-generation antipsychotics and lithium, with the latter being the mainstay in BD treatment. In 1949, John Cade described, for the first time, lithium’s antimanic effect [2]. In the following years, many trials demonstrated lithium’s efficacy in shortterm and prophylactic treatment of BD [3]. The choice of lithium as the first treatment in BD patients has also been influenced by its welldescribed antisuicidal effect – suicide being one of the leading causes of death in BD patients [4]. For these reasons, the vast majority of studies on response to drugs used in BD have thus far been focused on lithium more than any other mood stabilizer. While a significant proportion of patients chronically treated with lithium show full remission with stabilization of mood alterations, approximately 70% of subjects present partial or complete nonresponse [5]. This significant rate of insufficient response, together with the potentially serious adverse effects of lithium treatment, has stimulated a growing body of research aimed at the identification of predicting factors and new drug targets. The first step for the design of targeted therapies should consist of the identification of predictive markers of response. Nevertheless, with the exception of clinical factors, findings have so far provided weak evidence for specific predictors of lithium response. The main barriers