Bipolar disorder treatment: New evidence may explain limits of lithium

Scientists have identified a gene that may explain why some people with bipolar disorder respond to lithium treatment, while others do not.

  • One of the main treatments for bipolar disorder is lithium, a mood stabilizer.
  • A significant number of patients, however, do not respond to lithium treatment.
  • New research suggests that insufficient levels of the LEF1 protein may be responsible for the lithium’s lack of effectiveness in such cases.

In a new study, scientists have discovered a possible explanation of why some people with bipolar disorder respond to lithium — the cornerstone of treatment options — while others do not.

The research, published in the journal Molecular Psychiatry, identifies the gene LEF1 as a crucial mediator for the effectiveness of lithium treatment.

The study paves the way for future investigations, which are needed to confirm the findings and determine potential clinical interventions involving the gene.

Bipolar disorder

Bipolar disorder is a mental disorder characterized by unexpected changes in levels of energy, mood, concentration, and the ability to carry out day-to-day tasks.

Doctors recognize three types: Bipolar I involves having one or more manic episodes that have lasted at least 7 days. Or, it involves symptoms of mania that require immediate hospital care.

Bipolar II is defined by a pattern of less severely manic, or hypomanic, episodes followed by depressive episodes.

Cyclothymic disorder, the third type, involves having hypomanic and depressive symptoms over a period of at least 2 years. The symptoms do not meet the full criteria of a hypomanic or depressive episode.

The causes of bipolar disorder are still unclear, and scientists believe that a number of factors may be involved. They have shown particular interest in the relationship between a person’s genetics and their environment.

Treatment for bipolar disorder usually entails a combination of medication and talk therapy. Researchers have shown that the two types of intervention together are more effective than medications alone.

Lithium, a mood stabilizer, has been the standard drug treatment for bipolar disorder for more than 70 years. It can be highly effective, but a significant number of people do not respond to it.

Lithium and genes

Dr. Renata Santos, co-first author of the new investigation and a research collaborator at the Salk Institute for Biological Studies, in San Diego, CA, observes:

“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 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 bipolar disorder.”

The scientists had previously found that people with bipolar disorder that is resistant to lithium typically have larger neurons that are more easily stimulated and also have increased potassium flow.

In the present study, the team worked with three groups of participants: people with bipolar disorder that did not respond to lithium, people with bipolar disorder that did respond to the drug, and people without bipolar disorder.

The scientists used blood samples from the participants to grow neurons using stem cell technology. They were then able to see how the neurons from the participant groups compared when treated with lithium.

The LEF1 gene stood out in the nonresponder group. This gene has an important role in neuronal functioning by pairing with the protein beta-catenin.

In the group of lithium responders and the control group, the drug enabled LEF1 and the beta-catenin proteins to pair. However, in the participants who did not respond to lithium, LEF1 levels were too low for the drug to be effective.

To further confirm the role of LEF1 in enabling lithium treatment, the scientists administered valproic acid to neurons derived from the nonresponders. Doctors often use this acid to treat bipolar disorder that does not respond to lithium treatment.

The scientists found that the nonresponders’ LEF1 levels then increased, and their neurons started functioning more like those of the other groups.

According to Dr. Shani Stern, co-first author of the study and a senior lecturer at the University of Haifa, in Israel: “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.”

“That shows there is a causative relationship, and that’s why we think LEF1 may be a possible target for drug therapy.”

Future clinical role?

As well as opening the door to possible future therapies, LEF1 may also help clinicians screen for responsiveness to lithium treatment. Currently, a doctor can only tell whether a person responds to lithium after they have undergone the treatment for up to 1 year.

The scientists intend to further their research by identifying other cell types and genes that may affect responsiveness to lithium treatment. This is important because though LEF1 appears to be a significant piece of the puzzle, it is only one piece.

Dr. Carol Marchetto, co-corresponding study author and senior staff scientist at Salk, explains: “LEF1 works in various ways in different parts of the body, so you can’t just turn it on everywhere. You want to be more specific, either activating LEF1 on a targeted basis or activating downstream genes that are relevant for lithium nonresponsiveness.”

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