Scientists think they know how lithium helps treat bipolar disorder

Scientists think they have finally found the molecular mechanism that makes lithium work to treat the symptoms of bipolar disorder, almost 50 years after it was first approved for use in the US.

This is very important. One of the biggest problems in finding safer and more effective treatments for bipolar disorder has been that we don’t fully understand the treatments we already have.

“The only way to make a therapy better is to figure out how it worked in the first place,” says Sanford Burnham Prebys Medical Discovery Institute lead researcher Evan Snyder.

About 5.7 million adults in the US alone have bipolar disorder. It is the sixth leading cause of disability in the world. Extreme mood swings, like mania and depression, make it hard for them to live their normal lives.

Even worse, the treatments that are available are mostly old and not very reliable.

Lithium only helps about one-third of people who take it. But even if the drug works, it has a lot of bad side effects, such as nausea, muscle twitches, numbing of emotions, weight gain, and birth defects.

After a long process of trial and error, the two-thirds of patients who don’t respond are left to look for other options, such as antipsychotics, antidepressants, or even electric shock therapy.

The good news is that if this research is true and we finally know lithium’s molecular target, researchers will be able to start looking for drugs that do the same thing but are safer and work better.

It also gives researchers a chance to think of better ways to test for the disease and figure out who will respond to the drug.

As Snyder explains:

Lithium has been used to treat bipolar disorder for many years, but until now, we didn’t know why it worked or didn’t work for a certain patient. This led to unnecessary dosing and made it take longer to find a treatment that worked. Also, many patients can’t stand the side effects, which makes it hard to use and makes it urgent to find more targeted drugs with fewer risks.

Importantly, our results show a clear way to find new drugs that are safe and work well. Just as important, it helped us figure out what kinds of things cause these kinds of mental health problems.

Researchers used human induced pluripotent stem cells (hiPS), which were regular cells taken from bipolar patients that either responded to lithium or didn’t, and then reprogrammed to act like stem cells. This helped them figure out how lithium affected the brain.

They found that the cells of bipolar patients didn’t have enough of a protein called CRMP2 that helps nerve cells talk to each other.

But when lithium was added to hiPS cells made from patients who responded to lithium, the problem was fixed and CRMP2 activity went back to normal.

This shows that the cause of bipolar disorder might not always be genetic, as many researchers had thought before. Instead, it might be a problem with how the CRMP2 protein is controlled in the cell.

That’s good news because it means that the problem might be able to be fixed with the right medicine.

“We realized that studying the lithium response could be used as a “molecular can-opener” to figure out the molecular pathway of this complex disorder, which turns out not to be caused by a defect in a gene but by the post-translational regulation (phosphorylation) of the product of a gene, which in this case is CRMP2, an intracellular protein that controls neural networks,” says Snyder.

“This “molecular can-opener” approach, in which we used a drug we knew worked well but didn’t know exactly why, let us look at and figure out how bipolar disorder started.

The team used brain samples from people who had died with bipolar disorder to prove their findings. This showed that their neurons also had less active CRMP2 than usual. They also showed that the same process worked in animal models and in live neurons that had been grown in a lab. They also made a map of the target’s effects before and after it. This is what they call the “lithium response pathway.”

At the moment, this is just one study, and the molecular pathway needs to be confirmed by other teams before the textbooks need to be changed. It’s also likely that the complex condition has many underlying causes, so it’s unlikely that this one mechanism will solve all cases of bipolar.

But any new information that helps us take better care of the millions of people with mental health problems around the world is a big step in the right direction.

The next step for the team is to start looking at existing drugs to see if there are any molecules that target the same pathway as lithium but have fewer side effects or work better.

Snyder says in the video above that they could start clinical trials on a candidate drug that is already being used if they can find one.