Almost 50 years after lithium was first approved to treat patients in the US, scientists think they've finally identified the molecular mechanism behind its effectiveness in treating the symptoms of bipolar disorder.
This is a huge deal. One of the biggest hold-ups in pursuit of safer and more effective bipolar medications has been not understanding the treatments we already have.
"The only way that you can make a therapy better is to understand how it was working to begin with," says lead researcher Evan Snyder from the Sanford Burnham Prebys Medical Discovery Institute.
Bipolar disorder affects approximately 5.7 million adults in the US alone, and is the sixth leading cause of disability in the world. The incapacitating condition causes extreme mood swings between emotional highs (mania) and devastating lows (depression), which can prevent them from living their regular lives.
And to make matters worse, the available treatments are relatively primitive and unreliable.
Lithium only works in approximately one-third of patients. But even if the drug does work, it comes with a raft of side effects, including nausea, muscle tremors, emotional numbing, weight gain, and birth defects.
The good news is that, if this research is verified and we do finally know lithium's molecular target, researchers will be able to start screening for gentler and more effective drugs that do the same thing.
It also opens up new possibilities for better ways to test for the condition and predict who will respond to the drug.
As Snyder explains:
"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."
To figure out how lithium was affecting the brain, the researchers mapped it response pathway using human induced pluripotent stem cells (hiPS) - regular cells taken from bipolar patients that either did or didn't respond to lithium, and were then reprogrammed to behave like stem cells.
They found that a protein called CRMP2 was inactive in the bipolar patients' cells - a protein that's associated with nerve cell communication.
But when lithium was added to hiPS cells generated from lithium-responsive patients, it rectified, and CRMP2 activity was returned to normal.
This suggests that the mechanism behind bipolar disorder isn't necessarily always genetic, as many researchers had previously assumed, but instead is an issue with how the CRMP2 protein is regulated in the cell.
That's good news, because it indicates that it could be possible to fix the problem with the right medication.
"We realised that studying the lithium response could be used as a 'molecular can-opener' to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the post-translational regulation (phosphorylation) of the product of a gene - in this case, CRMP2, an intracellular protein that regulates neural networks," says 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 team verified their findings using brain specimens from deceased patients with bipolar disorder, showing that they also had neurons with less active than usual CRMP2. They also showed the same mechanism worked in animal models and in cultured live neurons. They also mapped the upstream and downstream effects of the target, creating a map of what they call the "lithium response pathway".
For now, this is only one study, and the molecular pathway needs to be verified by independent teams before we rewrite the textbooks. It's also probable that there are many underlying causes of the complex condition, so it's unlikely that this one mechanism will be the answer to every case of bipolar.
But any knowledge that can help us take better care of the millions of people around the world living with mental health issues is a big step in the right direction.
The next move for the team is to start screening existing drugs to see if they can find any molecules that target this same pathway, but with fewer side effects or more success than lithium.
The research has been published in the Proceedings of the National Academy of Sciences.