First stem cell study of bipolar disorder offers hope for better treatments

When it comes to understanding bipolar disorder, many questions remain unanswered – such as what truly causes the condition and why finding proper treatments is so difficult.

But now, researchers have taken a huge step towards solving some of the disorder’s complex mysteries.

Through groundbreaking stem cell research, scientists from the University of Michigan Medical School and the Heinz C. Prechter Bipolar Researcher Fund transformed skin cells from people with bipolar disorder into neurons that mimicked those found in their brains.  They were then able to compare these nerve stem cells with cells derived from people without bipolar disorder – and study how the neurons responded to medications for the condition.

Detailed in the journal Translational Psychiatry, this study marks the first time researchers have derived a stem cell line specific to bipolar disorder.

“Once we have derived nerve cells, we’re able to study those cells and determine how they behave compared to other cells and how they behave in response to medications,” principal investigator Dr. Melvin McInnis, of the Prechter Bipolar Research Fund, told “So if we can understand the basic biological problems with these cells, we can potentially identify interventions that further how we understand the illness and how we treat it.”

Also known as manic-depressive illness, bipolar disorder is a brain condition characterized by intense shifts in mood – alternating between periods of high energy and mania to periods of severe anxiety and depression.  While the condition is known to run in families, scientists still aren’t fully certain what causes its development, believing it to be a combination of genetics and other factors.

Additionally, the most common form of treatment for the disorder, lithium, is also somewhat of a mystery.

“We really do not know and understand what drives these fluctuations in moods; we don’t understand how the medications truly work that help individuals with variability in their moods,” McInnis said.  “We don’t know why an individual will become ill at a particular time.  All we know is really at an observational level.”

In order to better understand what is happening in the bipolar mind, McInnis and his team took small samples of skin from individuals who had been diagnosed with bipolar disorder.  These samples were then exposed to specific growth factors, which coaxed the cells into becoming induced pluripotent stem cells (iPSCs) – meaning they had the ability to turn into any type of cell. Subsequently, the cells were exposed to an additional set of growth factors, which coaxed them into becoming neurons.

This process has also been used to better understand other complex brain disorders, such as schizophrenia and conditions that cause seizures.  According to McInnis, the technique allows researchers to examine how cells behave as they develop into a whole new type of cell, as well as how they function when they finally become neurons.

“It becomes a nerve cell and takes on all the properties of nerve cells and they start to interact with each other in the way nerve cells are want to do – such as sending nerve impulses,” McInnis said. “And it’s that behavior we’re able to monitor and measure.”

The researchers first examined gene expression in the stem cells, noticing very specific differences in the bipolar cells as they developed into neurons. Specifically, the bipolar stem cells expressed more genes for membrane receptors and ion channels compared to the non-bipolar stem cells. This suggests that genetic differences expressed during early brain development may contribute to the onset of bipolar symptoms.

Additionally, the nerve stem cells from bipolar patients had significantly different signaling patterns than the stem cells derived from people without the condition.

“The experiment involved the cells sending message between each other – sending a nerve signal or a transmission signal.  It’s like an electrical current firing; the cells ‘fire.’….And we noticed an intrinsically different pattern of nerve conduction, or cellular firing patterns, [in the bipolar nerve cells]. There appears to be different mechanisms that these cells are reacting to between each other.”

Meanwhile, the bipolar neurons also reacted differently than the non-bipolar neurons when exposed to lithium.  Though the stem cells didn’t completely normalize, McInnis said the drug had a calming effect on the way the cells fire.

Given the wealth of their findings, McInnis said this stem cell technique could fundamentally alter how bipolar disorder is understood and handled.  Rather than using a “one-size-fits-all” approach to researching and treating the condition, doctors could potentially personalize the disorder for each patient, allowing them to find the best treatment techniques for each individual.

“This research changes our approach to the problem, because we now have the technology to study the individual as an individual,” McInnis said.  “We have the ability to look at specific biochemical pathways, particular mechanisms, and different cell types and see how they interact and how they behave.  So the ideal would be if someone develops bipolar disorder, we could determine at the level of the cell the most appropriate treatment – using this technique to help us refine the treatment strategy.”