Why doesn’t lithium work for 70% of bipolar disorder patients?

bipolar disorder patients, LEF1
©Cao Yan

Salk Institute scientists believe they have solved this mystery for bipolar disorder patients – the answer involves a specific gene, and proposes changes to the future of treatment

Bipolar disorder (BD) impacts roughly 45 million people worldwide. If 70% are resistant to what is considered the best available treatment, that means 31.5 million of those patients are struggling to manage BD.

Bipolar disorder

Kanye West, an American rapper, is one of the most famous examples of a bipolar disorder patient, who has shone light on the mental health condition by simply existing in the open. He was admitted to hospital in 2016, during a period of particularly erratic behaviour. His campaign to run for President and liaison with President Donald Trump were subtly attributed to the mania stage of BD by his wife, Kim Kardashian.

The life-threatening mood swings that take a BD patient from manic to depressive episodes are separated by normal moods. This can quickly devolve into elevation, euphoria and inflated self-esteem – or cycle into irritability and fury, directed often at the Self.

Medicines for BD are thought of as mood stabilisers, which are part of the long-term treatment available to patients – including psychosocial support, like therapy and a good network of loved ones. Lack of successful treatment can lead to episodes of depression that last six to twelve months, with episodes of mania that can also last between three to six months.

Bipolar disorder can then be devastating to a person’s quality of life – the friendships and relationships they build, their personal finances, their reputation, their physical health and their livelihoods. Patients could spend all their money, insult their closest friends, engage in dangerous sexual encounters and become homeless as a result of a particularly bad mania stage. Any of these moments can lead to suicidal ideation and self-harm, a sense of innate ‘wrongness’ or being further exploited by those who sense a vulnerability.

Without an educated support system, a person can feel deeply lonely with BD.

What can the Salk study explain about lithium?

In this new research led by Salk Professor and President Rusty Gage, the decreased activation of a gene called LEF1 is creating new information about how the bipolar brain works in response to certain medications. Because LEF1 is decreased in activation, ordinary neuronal function is disrupted and this then pushes the brain cells to become hyper-excitable. This hyper-excitability is a key component of bipolar disorder.

This revelation could change how drugs target bipolar disorder, and what biomarkers are used to assess how well treatments are working.

“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.”

Working with the LEF1 gene

They looked at many genes across the board, but LEF1 stood out as one of the most different in unresponsive BD patients. Normally, LEF1 plays a decisive role in neuronal function by pairing with another protein called beta-catenin. The pairing typically activates other genes that regulate the level of activity in the neuron. In control or responding neurons, lithium enables beta-catenin to pair with LEF1.

But in unresponsive BD patients, lithium is ineffective because LEF1 levels are too low for the pairing to occur, so there’s no regulation of cell activity.

“When we silenced the LEF1 gene, the neurons became hyperexcitable,” says Shani Stern, co-first author on the study and a Salk visiting scientist.

“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.”

How can this revelation change BD treatment?

LEF1 could cut out the treatment “will it work, won’t it work?” stage from 1 year – down to however long it takes to check biomarkers in the body. This is most certainly less time than one year, possibly around a month, depending on how quickly doctors are able to test an individual and return results. By decreasing this wait time, the mental health of a BD patient can be further preserved – instead of using a drug that may not work and losing mental energy as the episodes keep coming, the patient could be onto a responsive therapy in less than half of that time.

The research team is doing a number of things – including now looking to find drugs that can activate LEF1, which can then regulate the hyperexcitability of the braincells.

“LEF1 works in various ways in different parts of the body, so you can’t just turn it on everywhere,” says Carol Marchetto, co-corresponding author and Salk research collaborator.

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

Read the study here.


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