Lithium Resistance in Bipolar Tied to Deficient Gene Expression

Deborah Brauser

January 13, 2021

A decrease in activation of a specific gene may explain why many patients with bipolar disorder (BD) do not respond to lithium, new research suggests.

Although lithium is considered to be the "gold standard" for treating the disorder, almost 70% of patients with BD do not respond to the medication, researchers report.

In the small study, deficiencies in the LEF1 gene were found in treatment nonresponders. Decreased activation of LEF1 not only disrupted normal neuronal function, it also promoted cell hyperexcitability.

Eventually, this research "could result in a new drug target for BD as well as a biomarker for lithium nonresponsiveness," the investigators note in a press release.

Dr Renata Santos

For now, however, this should be considered a "foundational" study for future research to build upon, lead author Renata Santos, PhD, research collaborator at the Salk Institute for Biological Studies, La Jolla, California, told Medscape Medical News.

"We are starting to understand what is going on with these patients who do not respond to lithium, [and] that could help us find treatment for them," said Santos, who is also at the Institute of Psychiatry and Neuroscience of Paris in France.

The findings were published online January 4 in Molecular Psychiatry.

Molecular Mechanisms

In an article published last summer in Biological Psychiatry, the Salk investigative team found that neurons in patients with BD who did not respond to lithium were larger, were more easily stimulated, and had an increased flow of potassium.

In the current study, the researchers wanted to build upon the previous research and "were interested in the molecular mechanisms behind lithium resistance, what was blocking lithium treatment in nonresponders," Santos said in the release.

In other words, "we searched for specific targets" related to lithium resistance, the investigators add.

The study included three participants with BD type 1 who were classified as "responders" to treatment based on a validated scale measurement, three who had BD type 1 and were classified as "nonresponders," and four who did not have BD and acted as the healthy control group.

The mean age for the three groups was 41.7 years, 49.7 years, and 47.8 years, respectively. All participants were men and White.

Neurons from the participants' blood cells were grown using stem cell methods. Disposition and behavior of these neurons were then compared across the groups.

Causative Relationship?

Although several genes were examined, results showed that LEF1 was the gene that most stood out in the nonresponder group.

"Here, we…observed that the Wnt/ß-catenin signaling pathway is profoundly affected, with a significant decrease in expression of LEF1," the researchers write.

LEF1 commonly pairs with beta-catenin, which typically leads to the activation of other genes for regulating neuronal activity levels.

In neurons from the control group and responders, lithium allowed beta-catenin to pair with LEF1. However, lithium was ineffective in the nonresponder neurons because the LEF1 levels there "were too low for the pairing to occur, so there's no regulation of cell activity," the press release noted.

Interestingly, when valproic acid was administered, the neurons showed increased gene activation, including increased levels of LEF1.

In further analyses, "when we silenced the LEF1 gene, the neurons became hyperexcitable; and when we used valproic acid, expression of LEF1 increased and we lowered the hyperexcitability," co-investigator Shani Stern, PhD, Salk visiting scientist, reported.

"That shows there is a causative relationship, and why we think LEF1 may be a possible target for drug therapy," Stern added.

The investigators note that, although "excitability and Wnt signaling phenotypes" have now been shown in two different cohorts (in the current and previous studies), it will be important to also assess a third cohort — this time comprising female patients.

Future plans also include identifying other genes that may play a beneficial role for nonresponders and identifying whether any other drugs can activate LEF1.

"LEF1 works in various ways in different parts of the body, so you can't just turn it on everywhere," co-corresponding author Maria C. "Carol" Marchetto, PhD, senior staff scientist at the Salk Institute, noted.

"You want to be more specific, either activating LEF1 on a targeted basis or activating downstream genes that are relevant for lithium nonresponsiveness," Marchetto said.

The study was funded by the National Institutes of Health, the Chapman Foundation and Helmsley Charitable Trust, the National Cancer Institute, the National Cooperative Reprogrammed Cell Research Groups, the JPB Foundation, the Robert and Mary Jane Engman Foundation, and the Zuckerman STEM leadership program. The study authors have reported no relevant financial relationships.

Mol Psychiatry. Published online January 4, 2021. Abstract

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