A new study finds that decreased activation of the LEF1 gene in patients with bipolar disorder (BD) could be a useful biomarker for lithium nonresponsiveness, streamlining treatment. Nearly 70% of BD patients do not respond to lithium, the first-line long-term treatment for mood stabilization, leaving them at risk for debilitating mood swings.
Researchers from the Salk Institute published the findings online in Molecular Psychiatry.
Participants in the study included lithium responders, nonresponders, and people without BD (controls). Using stem-cell methods, researchers grew neurons from their blood cells of participants. They then compared the genetic disposition and behavior of those neurons for the 3 groups.
"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," researcher Renata Santos, PhD, said.
LEF1 paired with the protein beta-catenin typically activates other genes that regulate the level of neuron activity. Lithium enables beta-catenin to pair with LEF1, but due to low levels of LEF1 in nonresponders, it is ineffective and results in no regulation of cell activity, the study found.
Valproic acid, a treatment often used for lithium nonresponders, was administered to participants. "When we silenced the LEF1 gene, the neurons became hyperexcitable," researcher Shani Stern, PhD, said. "And when we used valproic acid, expression of LEF1 increased, and we lowered the hyperexcitability. That shows there is a causative relationship, and that's why we think LEF1 may be a possible target for drug therapy."
Currently, it could take about a year for clinicians to determine whether a patient is responsive to lithium by administering a complete course of treatment. Moving forward, utilizing LEF1 activity as an indicator may be a more efficient way to determine treatment options.
Researchers plan to study other cell types, identify other genes that could be beneficial for nonresponders, and potentially find other drugs that can activate LEF1—in the hopes of better understanding the bipolar neural network as a whole to streamline treatment.
Santos R, Linker SB, Stern S, et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Molecular Psychiatry: 2021 January 4;[Epub ahead of print.].