Under the Hood

Bipolar Disorder Treatment: Brain Cells May Reveal Why Lithium Doesn't Work For Everyone

Medication
Lithium works well for some bipolar patients, but not all. dean812 (CC BY 2.0)

In one of the first studies to show how bipolar disorder affects the brain at a cellular level, researchers have discovered that the brains of people with the disorder are more sensitive to stimuli than those in people without it.

The findings, published in the journal Nature, also suggested the reason why some bipolar patients respond to treatment with lithium while others do not. “Researchers hadn’t all agreed that there was a cellular cause to bipolar disorder,” said Rusty Gage, a professor in Salk’s Laboratory of Genetics and senior author of the study, in a press release. “So our study is important validation that the cells of these patients really are different.”

Bipolar disorder, which affects over five million Americans, is characterized by severe mood swings between depression and elation. The disorder can be challenging to treat because when lithium doesn’t improve the mood swings, mental health professionals must piece together a unique treatment plan with antipsychotic drugs, antidepressants, and mood stabilizers. Oftentimes, though, these treatments only affect one of the mood extremes, not both.

For the study, Gage and his team recruited six bipolar patients and collected skin cell samples. They reprogrammed the cell samples into stem cells, then coaxed the stem cells into becoming neurons. These induced bipolar neurons were then compared to the normal neurons of healthy people.

“Neurons are normally activated by a stimuli and respond,” said Jerome Mertens, a postdoctoral research fellow and first author of the new paper. “The cells we have from all six patients are much more sensitive in that you don’t need to activate them very strongly to see a response.”

Mertens also noted that the mitochondria — the energy producing powerhouse of the cell — were more active in the bipolar neurons.

Three of the bipolar patients’ cells responded to lithium treatment, while the three others’ did not. The scientists tested how the cells reacted to growing in a liquid with lithium, and then remeasured how sensitive they were. Though all of the bipolar patients’ neurons had been more sensitive than healthy ones in the first test, this test showed they behaved differently after lithium exposure.

Cells from the patients who responded to lithium showed weakened excitability after growing in the lithium bath, while cells from patients who hadn’t been helped by the drug remained hyperexcitable. The findings didn’t explain why exactly lithium works in certain patients but not others, but it provided a great starting point for probing at what those differences are.

“Now that we have neurons that show differences in excitability, we can use them to screen for better drugs,” Mertens said.

For example, a new drug that reverses the hyperexcitability at a cellular level would likely be able to treat bipolar disorder in patients. The team plans to study the affected cells for longer periods to determine whether the hyperexcitability it measured is simply an initial manic phase or more long-lasting.

“After a few months, it’s possible that this hyperexcitability becomes too much for the cell to handle and it crashes into a less excitable state,” Gage said. “That could signal the shift between the depression and mania that patients experience.”

Source: Gage R, Mertens J, Yongsung K, Yu D, Pham S, Diffenderfer K, et al. Bipolar patients’ brain cells predict response to lithium. Nature. 2015. 

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