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

There it is in a nutshell, folks: “Neurons are normally activated by a stimuli and respond. The cells we have from all six (bipolar) patients are much more sensitive in that you don’t need to activate them very strongly to see a response.”

Researchers took skin cells from 6 people with bipolar d/o. They made them turn into stem cells, which then differentiated into neurons. When they activated these neurons, they saw that neurons from people with bipolar d/o didn’t need a very strong stimulus to become activated. So our neurons can be activated by very weak stimuli. In other words we react much more strongly to things than people who don’t have bipolar d/o! Hunh! I think I already knew that! I do it all the time. I have extreme reactions to small stimuli! And now here is the reason, in black and white, our neurons fire at stimuli that wouldn’t make the neurons of people without bipolar d/o.

“Mitochondria — the energy producing powerhouse of the cell — were more active in the bipolar neurons.” This means that bipolar neurons also produce more, therefore have more energy.

“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.”

So cells from people who respond to lithium show weakened excitability in response to lithium, whereas cells of people who don’t respond to lithium keep being hyperexcitable. Again a difference at the cellular level.

This is so amazing, because now for lithium resistant patients, they can test other medications to see which will decrease the hyperexcitability.

http://www.medicaldaily.com/bipolar-disorder-treatment-brain-cells-may-reveal-why-lithium-doesnt-work-everyone-359316

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.

6 thoughts on “Bipolar Disorder Treatment: Brain Cells May Reveal Why Lithium Doesn’t Work For Everyone

    • Yes!!! Of I drink coffee when I am not on adequate doses of lithium, I am horribly excitable, not so when I am on the right dose. I think our moods mirror the sensitivity of our neurons. They must be very insensitive indeed in depression because nothing can excite them or us!

      Liked by 1 person

  1. Excellent sleuthing! I’m impressed and grateful that you dedicate your time to researching these important aspects of our illness. This one can help people who are treated with lithium but not responding. There’s a chance their doctor has not read this yet, so it would be s good thing to print and take to the next appointment. Then the question is going to be: If lithium doesn’t help, then what will? There is DNA sequencing that will answer that question, but I don’t know whether insurance covers it…

    Liked by 2 people

    • In reference to Laura’s comment about the DNA sequencing, I found that in their Abstract for this paper in Nature that they reference up regulations of PKA and PKC from post mortem brains of BD patients. They found that even though the levels of expression and activity are much higher, they found through RT-PCR of the protein kinases that there weren’t any differences in mRNA levels between them and the controls. So they are assuming it’s some sort of posttranscriptional mechanism rather than actual gene regulation or mRNA stability. Maybe there is some sort of contranslational interference or something wrong with the RNA binding protein because it sounds like it’s not at the nucleotide level. I’d love to actually read the papers to see if they did any transcriptomics on that but unfortunately I don’t have access (aka money to buy) to Nature’s articles. Here is the link to the study they reference on NCBI:
      http://www.ncbi.nlm.nih.gov/pubmed/12941458?dopt=Abstract&holding=npg

      ….and yes. Talk nerdy to me! 😉

      Liked by 2 people

    • Yes! Also they can take people’s skin cells and get stem cells from them, which can then be coaxed into becoming neurons. Then they can possibly do drug development by exposing these neurons and seeing which drugs make them less sensitive. Very cool ways for treating BPD!

      Liked by 1 person

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s