Although modern pharmacology has developed formulas to aid people with mental illness, the method by which the drugs actually work is often obscure.
The University of Michigan Medical School study of brain tissue helps reveal what might actually be happening. And further research using stem cells programmed to act like brain cells is already underway.
Using genetic analysis, the new study suggests that certain medications may help “normalize” the activity of a number of genes involved in communication between brain cells.
The study is published in the journal Bipolar Disorders.
Researchers studied brain tissue from deceased people with and without bipolar disorder. Investigators then analyzed the tissue to see how often certain genes were activated, or expressed.
“We found there are hundreds of genes whose activity is adjusted in individuals taking medication – consistent with the fact that there are a number of genes that are potentially amiss in people with bipolar,” said senior author Melvin McInnis, M.D.
“Taking the medications, specifically ones in a class called antipsychotics, seemed to normalize the gene expression pattern in these individuals so that it approached that of a person without bipolar.”
The mechanism for bipolar disorder is influenced by genetic differences in the brain — though scientists are still searching for the specific gene combinations involved.
McInnis and his colleagues have now embarked on research developing several a lines of induced pluripotent stem cells derived (iPSC) from volunteers with and without bipolar disorder, which will allow even more in-depth study of the development and genetics of bipolar disorder.
The new study looked at the expression, or activity levels, of 2,191 different genes in the brains of 14 people with bipolar disorder, and 12 with no mental health conditions.
The brains were all part of a privately funded nonprofit brain bank that collected and stored donated brains, and recorded what medications the individuals were taking at the time of death.
Seven of the brains were from people with bipolar disorder who had been taking one or more antipsychotics when they died.
These drugs include clozapine, risperidone, and haloperidol, and are often used to treat bipolar disorder. Most of the 14 brain donors with bipolar disorder were also taking other medications, such as antidepressants, at the time of death.
When the researchers compared the gene activity patterns among the brains of bipolar disorder patients who had been exposed to antipsychotics with patterns among those who weren’t, they saw striking differences.
Then, when they compared the activity patterns of patients who had been taking antipsychotics with those of people without bipolar disorder, they found similar patterns.
Researchers say the similarities were strongest in the expression of genes involved in the transmission of signals across synapses – the gaps between brain cells that allow cells to ‘talk’ to one another.
Furthermore, there were also similarities in the organization of nodes of Ranvier — locations along nerve cells where signals can travel faster.
Using “gene chip” analysis to measure the presence of messenger RNA molecules that indicate gene activity, and sophisticated data analysis, investigators were able to map the expression patterns from the brains and break the results down by bipolar status and medication use.
The bipolar and control (non-bipolar) brains were matched by age, gender and other factors.
“In bipolar disorder, it’s not just one gene that’s involved — it’s a whole symphony of them,” said McInnis, who has helped lead U-M’s bipolar genetics research for nearly a decade.
“Medications appear to nudge them in a direction that aligns more with the normal expression pattern.”
Among those that were “nudged” were genes that have already been shown to be linked to bipolar disorder, including glycogen synthase kinase 3 beta (GSK3β), FK506 binding protein 5 (FKBP5), and Ankyrin 3 (ANK3).
McInnis believes future studies of cell culture studies will provide more information on how medications for bipolar disorder work, and will allow analysis of new molecules that could serve as potential new medications.
Source: University of Michigan