Pharmacogenetics of Lithium Long-Term Treatment: Focus on Initiation and Adaptation Mechanisms

Abstract

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.

Genetic Influences on Response to Mood Stabilizers in Bipolar Disorder

“…The pharmacogenetic response to lithium was the topic of four excellent review papers published in the past 3 years [28–31]. These reviews mostly focused on candidate gene studies where candidate genes were selected, either on the basis of the mechanisms of action of lithium and/or the neurobiology of bipolar disorder.…”

Lithium decreases VEGF mRNA expression in leukocytes of healthy subjects and patients with bipolar disorder

“…However, VEGF mRNA levels in this study were decreased 2 weeks after discontinuation. Interestingly, recent evidences suggest that lithium induces long‐lasting changes (more than 2 weeks after discontinuation) in the expression profile of genes in neurons (Serretti and Drago, ). Thus, it is possible that lithium might induce long‐lasting downregulation of VEGF mRNA levels in the leukocytes.…”

“…Lithium is known to exert the effects on neurons such as growth cone enlargement and enhanced adult neurogenesis. The effect may be mediated by depletion of inositol, upregulation of BCL‐2, inhibition of glycogen synthase kinase 3b, altered glutamate receptor trafficking, inhibition of glucocorticoid receptor function, and upregulation of brain‐derived neurotrophic factor; however, the exact molecular mechanism is still unknown (reviewed in Serretti and Drago, ).…”

Behavior Genetics of Psychopathology

“…Most of these studies have focused on polymorphisms in genes involved in the serotonin or dopamine metabolism pathways, as these are the site of action of many antipsychotics and antidepressants. Comprehensive reviews of the candidate gene literature have been undertaken for lithium response (Serretti & Drago, 2010 ;Smith, Evans, & Craddock, 2010 ), antipsychotic response and side effects (Zhang & Malhotra, 2011 ) and antidepressant response (Kato & Serretti, 2010 ). The most studied variants are the serotonin receptor short/long polymorphism (5HTTLPR) and a 48 bp tandem repeat in the DRD4 gene.…”