Pharmacogenetics of lithium long-term treatment: focus on initiation and adaptation mechanisms

Bipolar disorder is a common disease with a high impact in terms of personal suffering and socioeconomic burden. The disentanglement of the molecular deregulations that cause this disorder is pivotal to the understanding of its etiology. This will hopefully cast the engineering of new and more favorable treatments. New insights in the molecular aspects of bipolar disorder may be brought by the understanding of the pharmacodynamics of lithium, the first-line treatment for this disease. The mechanisms by which lithium exerts its activity in the central nervous system are not fully clarified: it is hypothesized that lithium may drive acute molecular events whose activation over time triggers long-lasting modifications in critical neuronal nets. These events are associated with long-lasting changes in the expression profile of genes in neurons that are embedded in these crucial nets. The molecular events that are acutely and chronically triggered by lithium will be reviewed here and matched with the evidence that arises from the pharmacogenetics investigations. Moreover, the pharmacogenetics reports that are not strictly associated with the mechanisms that are thought to be acutely and chronically elicited by lithium will be included in the final part of the paper.