While lithium has long been recognised for its effectiveness in treating bipolar disorder, it has been resisted by many due to the side effects and myths, or it does not work on some patients.

In a recent US study, however, scientists have discovered the molecular mechanism behind lithium’s effectiveness in treating bipolar disorder. If the research is verified, the researchers hope to be able to find gentler and more effective drugs other than lithium.

"The only way that you can make a therapy better is to understand how it was working to begin with," said lead researcher Evan Snyder from the Sanford Burnham Prebys Medical Discovery Institute in San Diego, California.

A huge deal for people with bipolar disorder

As the researchers explained, one of the biggest obstacles in pursuing safer and more effective bipolar medications is not understanding the treatments that are already present.

In the US, bipolar disorder affects approximately 5.7 million adults, and is also the sixth leading cause of disability in the world. The symptoms of this illness include extreme mood swings between emotional highs (mania) and devastating lows (depression), which may disturb the patients from leading their everyday life.

Currently, the available treatments are said to be rather primitive and unreliable, reasons being lithium only works in about one third of patients. Even when it does, it comes with a range of side effects, including nausea, muscle tremors, emotional numbing, weight gain and birth defects.

The case of Linda Logan, a mother of three kids, reflected the difficulties of the treatment of bipolar disorder. She was a PhD candidate in geography and a mother juggling between studies and family when she was affected by bipolar disorder at the age of 27. Over the years of treatment and medications, she was regularly hospitalised and seeking for her self and identity even though the psychiatrists usually dismissed it.

The author in 1980, pregnant with her first child. Photo credit: New York Times.
The author in 1980, pregnant with her first child. Photo credit: New York Times.

After 20-odd years of battle with bipolar disorder, Logan is now feeling healthier and having a nimble mind at the age of 60. She also became a creative writer after gradually picking up the old self she lost long ago. Thus, discovering the new possibilities to treat bipolar disorder more effectively means a huge deal to the patients.

How molecular mechanism works with lithium

Snyder explained, "Lithium has been used to treat bipolar disorder for generations, but up until now, our lack of knowledge about why the therapy does or does not work for a particular patient led to unnecessary dosing and delayed finding an effective treatment. Further, its side effects are intolerable for many patients, limiting its use and creating an urgent need for more targeted drugs with minimal risks.”

“Importantly, our findings open a clear path to finding safe and effective new drugs. Equally as important, it helped give us insight into what type of mechanisms cause psychiatric problems such as these," he added.

In order to find out how lithium attacks the brain, the researchers mapped its response pathway using human induced pluripotent stem cells (hiPS), regular cells obtained from bipolar patients who either did or did not respond to lithium that were reprogrammed to behave like stem cells.

As a result, the researchers found that a protein called CRMP2, which is associated with nerve cell communication, was inactive in bipolar patients cells. Nevertheless, it rectified when lithium was added to hiPs cells generated from lithium-responsive patients, and CRMP2 activity became normal again.

A positive indicator to the effective treatment of bipolar disorder

The results suggested that the mechanism behind bipolar disorder might not always be genetic as many researchers previously assumed. Instead, it is concerned with how the CRMP2 protein is regulated in the cell. The researchers also found the same mechanism reflected in animal models and cultured live neurons.

"We realised that studying the lithium response could be used as a 'molecular can-opener' to unravel the molecular pathway of this complex disorder," said Snyder. "This 'molecular can-opener' approach - using a drug known to have a useful action without exactly knowing why - allowed us to examine and understand an underlying pathogenesis of bipolar disorder."

The positive results from the study motivated the team to start screening existing drugs in light of finding molecules that target the same pathway, yet with fewer side effects or more success than lithium. Snyder remarked that the team hopes to conduct their clinical trials within one or two years once a candidate drug is identified. MIMS

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