A Gene That Could Help Explain Why Lithium Stabilizes Mood

It's always been a mystery why the drug works to treat bipolar disorder, but a new study sheds light on a possible mechanism.

The salt flats of Uyuni, Bolivia hold the world’s largest lithium reserves.  (Stringer / AP)

Like Viagra and penicillin, the modern-day use of lithium—a common treatment for bipolar disorder—came about by accident. The story goes that in 1949, John Cade, the Australian psychiatrist credited with popularizing the drug, was trying to find a way to safely inject guinea pigs with his manic patients’ urine as part of an experiment to better understand their illness. Why urine? He thought mania might be caused by a chemical in the body, and that chemical might be detectable in urine (his wife was weirded out by it too). In order to do that, he mixed it with a lithium compound, which made it easier to inject. Cade realized that the guinea pigs who were given the lithium cocktail became calm, but he had no clue why. And no one’s been able to give a full explanation since.

While the description of bipolar disorder in the various editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM)—the American Psychiatric Association's sometimes maligned guide to psychiatric diagnosis—has changed over the years, lithium has remained a standby treatment. “It’s still arguably one of the best medications,” even if it’s not completely understood, says Ben Cheyette, a professor of psychiatry at the University of California, San Francisco. Now, a new study published on Tuesday by Cheyette’s group in Molecular Psychiatry sheds some light on lithium’s effects on the brain.

The researchers bred mice to lack a key gene in a pathway in the brain that seems to determine how neurons grow and form connections with one another, according to Cheyette. The mice without this gene were found to develop normally, but showed “behavioral abnormalities” compared to their siblings who were not missing the gene. They took longer to eat when introduced to a new environment, gave up faster during an escape task, and were less social than their peers. When the more troubled mice were given lithium, their behavior returned to normal.

Cheyette’s group also examined the difference between the brains of the “wild-type” mice and the mice who were missing the gene. The brains of the experimental mice had fewer dendritic spines—tree-like parts of a neuron that branch out and form connections with other neurons. On its own that might suggest this gene shapes the development of these connections, and that the lack of those connections likely explains the mice’s abnormal behavior. Cheyette’s group also treated some of the experimental mice with lithium, and found that they developed more connections, leaving them with about as many as the normal mice. And while Cheyette wouldn’t say this is “the absolute 100 percent answer” to the question of why lithium works, it “adds a lot of weight” to the argument that it targets this pathway.

The study also looked at thousands of cases worth of human genetic data from Cheyette’s collaborators to see if defects in the same gene in humans were associated with bipolar disorder, schizophrenia, or ASD (autism spectrum disorder). It’s important to note here that very few people have these mutations to begin with, according to Cheyette. And while mutations in this gene were quite rare, among the small number who had them, there were nearly twice as many cases of people with those disorders (.9% of the total cases) than those without the disorders (.5% of the total cases).

This research does have its limits: As Cheyette said, “mice are not humans.” Some things are bound to be lost in translation when using animal models for human psychiatric symptoms. He also emphasized that “by itself, this gene is only going to account for a small increase in risk in small numbers of patients.” It by no means explains every occurrence of bipolar disorder, schizophrenia, and ASD. Instead, he believes it may be one of many overlapping, interacting genes that contribute to risk. “But it’s an still important clue in [figuring out] the kinds of defects in patients that may exist at the biological level,” Cheyette said. And, according to Cheyette, that deeper understanding may answer questions that have plagued the field for decades.

With little working understanding of the brain, psychiatrists have always done the best they could to categorize diseases based off what they could observe in their patients. And, working with what they had, they built diagnostic categories around these behaviors with the hope that, eventually, “those disorders would correspond to very different underlying biology when we finally understood it,” Cheyette said. For years, luck and careful observation were quite helpful—several other psychiatric drugs that formed the basis for current treatments were discovered by accident. But that approach has only come so far, and pharmacological treatments for psychiatric disorders have “hit a wall” in the past decade, Cheyette says.

Moving forward, Cheyette believes that precision medicine—the thorough analysis of large amounts of clinical data to better characterize individual patients’ conditions—could help uncover the underlying biology of psychiatric disorders, and could provide better diagnostic categories to describe them. Given that genes like the one this paper focuses on seem to have some effect on multiple diagnoses according to psychiatry’s current system (in this case bipolar disorder, schizophrenia, and ASD)—there might be reason to think those categories need revisiting, according to Cheyette.

He draws the analogy to cancer: “It became clear in the last few decades … that breast cancer wasn’t just one disease. Pancreatic cancer is not just one disease. Every cancer is actually many many diseases in different people, and the molecular defects that underlie each kind of cancer are different in different patients, and those differences really matter.” Cheyette believes, as do many other researchers, that the same might hold for psychiatric disorders. “The underlying biology could be very different between Patient A, Patient B, and Patient C. We need to know what’s wrong in each patient to tailor treatment for each patient,” he said.

And though sequencing—and likely any personalized drugs developed from it (none exist as of yet)—is still expensive, according to Cheyette, it’s becoming cheaper and more feasible.

“If we can do this, the promise is that we’re really going to get treatments that work really well with a minimum of side effects in patients,” Cheyette said, “The good news is we’re getting there, the bad news is it’s complicated.”

While coincidence did lead to one of psychiatry’s most effective drugs—this line of research might allow scientists to take the opposite approach, and develop therapies based off a stronger understanding of the disease rather than depending on chance.