Lithium Pharmacogenetics: Where Do We Stand?

Abstract

Preclinical Research Bipolar disorder (BPD) is a chronic and disabling psychiatric disorder with a prevalence of 0.8-1.2% in the general population. Although lithium is considered the first-line treatment, a large percentage of patients do not respond sufficiently. Moreover, lithium can induce severe side effects and has poor tolerance and a narrow therapeutic index. The genetics of lithium response has been largely investigated, but findings have so far failed to identify reliable biomarkers to predict clinical response. This has been largely determined by the highly complex phenotipic and genetic architecture of lithium response. To this regard, collaborative initiatives hold the promise to provide robust and standardized methods to disantenagle this complexity, as well as the capacity to collect large samples of patietnts, a crucial requirement to study the genetics of complex phenotypes. The International Consortium on Lithium Genetics (ConLiGen) has recently published the largest study so far on lithium response reporting significant associations for two long noncoding RNAs (lncRNAs). This result provides relevant insights into the pharmacogenetics of lithium supporting the involvement of the noncoding portion of the genome in modulating clinical response. Although a vast body of research is engaged in dissecting the genetic bases of response to lithium, the several drawbacks of lithium therapy have also stimulated multiple efforts to identify new safer treatments. A drug repurposing approach identified ebselen as a potential lithium mimetic, as it shares with lithium the ability to inhibit inositol monophosphatase. Ebselen, an antioxidant glutathione peroxidase mimetic, represents a valid and promising example of new potential therapeutic interventions for BD, but the paucity of data warrant further investigation to elucidate its potential efficacy and safety in the management of BPD. Nevertheless, findings provided by the growing field of pharmacogenomic research will ultimately lead to the identification of new molecular targets and safer treatments for BPD. Drug Dev Res 77 : 368-373, 2016. © 2016 Wiley Periodicals, Inc.

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

“…An alternative explanation may be that the effects of lithium are highly dependent on the ‘diseased’ genotype/phenotype. This goes along with the increasing body of evidence suggesting a key role of pharmacogenetics in the response to lithium (Pisanu et al, 2016a). Accordingly, different, more homogeneous phenotypes have been identified within patients regarding their likelihood of showing an adequate response to lithium treatment (responders vs. nonresponders) (Geoffroy et al, 2017; Oedegaard et al, 2016; Scott et al, 2017; Sportiche et al, 2016), and the genetic basis of lithium responsiveness has been consistently shown by several studies (Alda, 2015; Alda et al, 2005; Grof et al, 2009; Grof et al, 2002; Hou et al, 2016).…”

Genomics of Lithium Action and Response

“…These have been reviewed extensively elsewhere [21, 22]; only 2 will be briefly summarized here. First is lithium’s known inhibition of the protein GSK3β [23–25].…”

Autism-associated Shank3 is essential for homeostatic plasticity and neuronal circuit stability

“…Li has wide efficacy to treat many neurological disorders, but the mechanism of action is debated (Pisanu et al, 2016). Several recent case studies suggest that Li has therapeutic potential for treating human Shankopathies (Darville et al, 2016;Egger et al, 2017;Serret et al, 2015), leading us to wonder whether Li might rescue the synaptic scaling defect induced by Shank3 loss.…”