Pharmacogenomics of Lithium Response in Bipolar Disorder

Abstract

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium’s therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium’s exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

Cognitive dysfunction in schizophrenia patients caused by down-regulation of γ-aminobutyric acid receptor subunits

“…Cl - are pumped out through the Na + /K + /Cl - pump transporter, which reduces the intracellular Cl - concentration and causes the hyperpolarization of neurons. Failure to maintain the glutamate-GABA balance may be related to schizophrenia, epilepsy, and anxiety[ 29 ]. Glutamate-GABA regulates the neuronal excitation-inhibition balance, which can cause neurodegenerative diseases and cognitive impairment[ 30 ].…”

A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes

“…Despite these limitations, the potential strength of this study is that it highlights that the three established and most widely used approaches to operationalizing the Li response do not produce consistent signals. This is important as nearly all genetic studies of the Li response have reported their findings based on the Alda Cats approach alongside one of the two continuous measures [10]. The disparities in findings across these three traditional response phenotypes are a cause for concern and, whilst imperfect, the revised algorithms do show greater consistency.…”

“…The ideal research assessment of the Li response would involve the systematic prospective follow-up of Li-naive cases that are prescribed this medication for the first time [9]. However, this gold-standard approach is complex, so most genetic studies [10][11][12] identify clinical phenotypes of the Li response from ratings of the Retrospective Assessment of Response to Lithium Scale (usually referred to as the Alda scale) [13]. The Alda scale comprises two subscales: The A scale (which measures overall response) and the B scale (which assesses five potential confounders of response).…”

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

“…The gold standard for assessing drug response is the prospective clinical trial, but sample sizes for such studies are orders of magnitude smaller (500 vs 50 000) than those currently successful for genome-wide association studies (GWASs). Furthermore, there are few GWASs focusing on lithium response, most suffering from lack of power or failure in replication [ 7 ]. Though more data is being accumulated [ 8 – 14 ], GWAS has so far not had the power to consistently detect reproducible genes.…”