Lithium is considered the gold standard for treating bipolar disorder (BD), but nearly 70 percent of people with BD don’t respond to it. This leaves them at risk for debilitating, potentially life-threatening mood swings. Researchers at the Salk Institute have found that the culprit may lie in gene activity—or lack of it.
A new study led by Salk Professor and President Rusty Gage, which published in the journal Molecular Psychiatry on January 4, 2021, shows that decreased activation of a gene called LEF1 disrupts ordinary neuronal function and promotes hyperexcitability in brain cells—a hallmark of BD. The work could result in a new drug target for BD as well as a biomarker for lithium nonresponsiveness.
“Only one-third of patients respond to lithium with disappearance of the symptoms,” says Renata Santos, co-first author on the study and a Salk research collaborator. “We were interested in the molecular mechanisms behind lithium resistance, what was blocking lithium treatment in nonresponders. We found that LEF1 was deficient in neurons derived from nonresponders. We were excited to see that it was possible to increase LEF1 and its dependent genes, making it a new target for therapeutic intervention in BD.”