Deadly Highs and Lows – Tackling Bipolar Disorder

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In recent times, there has been prominent discourse surrounding mental disorders; familiarising us with issues surrounding depression, anxiety, and even psychopathy and schizophrenia. Pop culture has been party to acquainting us with the latter two, but with seemingly more awareness, we within the Science community, or outside, have developed a reasonable understanding of these disorders, beyond that of what TV shows tell us about them, of course.

This post, on that note, will address a slightly less well-known disorder: Bipolar Disorder (BD). BD is incredibly debilitating, even deadly, affecting over 2% of the world’s population.

In 2011, the World Health Organization (WHO) determined BD as the second most disabling disorder (physical or mental) using days in a year in which an individual was unable to work, as a measure. BD followed neurological disorders and was noted to be 3 times more disabling than cancer.

Bipolar Disorder is a major psychiatric disorder characterised by extreme mood swings going from a depressive to a manic (high-energy) state. It is strongly associated with suicidal ideations, the rate of suicide among BD patients being approximately 10-30 times higher than the corresponding rate in the general population — tragically, up to 20% of BD individuals end their life by suicide, and 20–60% of them attempt suicide at least once in their lifetime.

For years, lithium (pills) has been the main treatment for BD. However, only 30% of patients respond to this!

In a new study by Salk and colleagues, the researchers sought to understand the molecular mechanism behind lithium resistance in nonrespondent BD patients. This research was founded on previous literature suggesting that neurons of lithium non-responders fire differently and also have increased potassium flow than the responding patients.

On further investigation, they also found a specific deficiency of LEF1 protein in non-responders’ neurons. This finding was especially important as there is potential to increase LEF1 and its dependent genes to tackle this issue.

LEF1 protein. Wikipedia (2020).
LEF1 protein. Wikipedia (2020)

For this study, they used stem cells to grow neurons using the blood of lithium responders, non-responders, as well as non-BD patients. Following which, they compared the genetic disposition and behaviour of the neurons. From a general observation of the three different groups’ genes, they found that LEF1 was scarce in non-responders compared to the other patients.

LEF1’s function is to pair with another protein, beta-catenin, to further activate other genes responsible for neuron’s level of activity. In comparison to responders and controls, non-responders were unable to achieve this pairing due to the low amount of LEF1. As a consequence of this shortage, there was no regulation of cell activity.

The researchers considered a treatment for non-responders, where valproic acid was used to increase LEF1 levels and, consequently, activation of other genes. Shani Stern, one of the researchers remarked, “When we silenced the LEF1 gene, the neurons became hyperexcitable, per contra, when we used valproic acid, expression of LEF1 increased, and we lowered the hyperexcitability.”

This established a causal relationship, from which they determined LEF1 gene a target for drug therapy.

Researchers pondered over the use of this new finding for screening responsiveness to lithium which, at this time, is believed to take over a year to test. However, recognising a lesser activity level of LEF1 can be considered indicative of a likely unresponsive patient, this could result in a reduced amount of time needed to find an effective therapy for BD patients.

As the understanding of this protein is still limited, the findings about the activity of LEF1 cannot be construed as a final step towards finding effective treatment mechanisms for BD. Researchers are building on this discovery by looking into other avenues; particularly, cell types to understand the bipolar neural network, other genes that might contribute to the responsiveness to lithium and other drugs to activate LEF1.

By broadening our understanding of how the bipolar neural network works, we could inch closer to developing effective therapies for this deadly disorder.

Want to find out more about BD? Check out this video: https://www.youtube.com/watch?v=XQ2PbPr2AH4&feature=emb_title

Original Source-
Santos, R., Linker, S. B., Stern, S., Mendes, A. P. D., Shokhirev, M. N., Erikson, G., … Gage, F. H. (2021). Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Molecular Psychiatry. http://doi.org/10.1038/s41380-020-00981-3

Link to Study-
https://www.nature.com/articles/s41380-020-00981-3

Featured photo-
Karolina Grabowska by Pexels

Edited by Malavika Ramanand

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