Why Some Bipolar Disorder Patients Are Lithium Non-Responders

Deficient LEF1 expression is linked to lithium resistance in BD patients.

Posted Jan 08, 2021

 Ben Mills (Benjah-bmm27)/Public domain
Space-filling model of lithium carbonate crystal structure.
Source: Ben Mills (Benjah-bmm27)/Public domain

Lithium alleviates mania and depression symptoms in some bipolar disorder (BD) patients; those who respond to this medication are referred to as "lithium responders." However, for reasons that haven't been well understood until recently, not everyone responds to lithium. For example, a systematic review and meta-analysis (Geddes et al., 2004) concluded that roughly two-thirds of people with BD are so-called "lithium non-responders."

Unfortunately, it can take up to 12 months after someone with bipolar disorder starts taking lithium to know if that person will ultimately be classified as a "responder" or "non-responder." For those who are treatment-resistant to lithium, taking this medication for a year to see whether or not it's going to be efficacious can be futile and potentially harmful due to adverse reactions. (See the FDA's black box warnings.)

On the bright side, a few years ago, researchers at the Salk Institute led by Fred "Rusty" Gage and first author Shani Stern developed a stem cell-based method of predicting someone's responsiveness to lithium with 92 percent accuracy. These findings (Stern et al., 2017) were published in Molecular Psychiatry.

Rusty Gage is President of the Salk Institute for Biological Studies, a professor in the Laboratory of Genetics, and Principal Investigator of the Gage Lab. "In 2015, we discovered that the brain cells of people with bipolar disorder are more sensitive to stimuli than those of other people," he said in a March 20, 2017 news release. "Since then, we have been able to characterize that sensitivity in greater detail and discern clear patterns in the neurons of bipolar patients that allow us to predict who will respond to lithium and who will not."

Now, a recently published follow-up study (Santos et al., 2021) by Gage and his Salk Institute colleagues advances our understanding of why nearly 70 percent of BD patients don't respond to lithium. According to the researchers, their latest lithium resistance study shows that "decreased activation of a gene called LEF1 disrupts ordinary neuronal function and promotes hyperexcitability in brain cells—a hallmark of bipolar disorder." These findings were published on January 4 in Molecular Psychiatry.

"Only one-third of patients respond to lithium with disappearance of the symptoms. We were interested in the molecular mechanisms behind lithium resistance, what was blocking lithium treatment in non-responders," co-first author Renata Santos said in a recent news release. "We found that LEF1 was deficient in neurons derived from non-responders. 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."

The researchers speculate that LEF1 has the potential to be used as a biomarker when screening for lithium responsiveness. "Currently, clinicians can only determine whether a patient is responsive to lithium by administering a complete course of treatment, which could take a year," the authors explain. "Now, subdued activity of LEF1 may be an indicator that a patient won't respond to lithium, enabling a faster and more efficient way to approach therapy."

The next step for the Salk researchers is to pinpoint targeted ways to activate this gene. "LEF1 works in various ways in different parts of the body, so you can't just turn it on everywhere," coauthor Carol Marchetto noted. "You want to be more specific, either activating LEF1 on a targeted basis or activating downstream genes that are relevant for lithium non-responsiveness."

Although more research is needed, the latest discovery of an association between LEF1 and lithium resistance shows promise. "Our results suggest that LEF1 may be a useful target for the discovery of new drugs for bipolar disorder treatment," the authors conclude.


Renata Santos, Sara B. Linker, Shani Stern, Ana P. D. Mendes, Maxim N. Shokhirev, Galina Erikson, Lynne Randolph-Moore, Vipula Racha, Yeni Kim, John R. Kelsoe, Anne G. Bang, M. Alda, Maria C. Marchetto, Fred H. Gage. "Deficient LEF1 Expression Is Associated With Lithium Resistance and Hyperexcitability in Neurons Derived From Bipolar Disorder Patients." Molecular Psychiatry (First published: January 04, 2020) DOI: 10.1038/s41380-020-00981-3

Shani Stern, Renata Santos, Maria C. Marchetto, Anna P. D. Mendes, Guy A. Rouleau, S. Biesmans, Q-W Wang, Jun Yao, Patrick Charnay, Anne G. Bang, Martin Alda, Fred H. Gage. "Neurons Derived From Patients With Bipolar Disorder Divide Into Intrinsically Different Sub-Populations of Neurons, Predicting the Patients' Responsiveness to Lithium." Molecular Psychiatry (First published: February 28, 2017) DOI: 10.1038/mp.2016.260