The Standard Treatment For Bipolar Disorder Doesn’t Work For Everyone......Forbes Healthcare - by Jackie Rocheleau

Lithium is the first-line treatment for bipolar disorder, but only works for about a third of patients.

The Standard Treatment For Bipolar Disorder Doesn’t Work For Everyone, And Now Scientists Might Know Why

Lithium is often the first treatment option for bipolar disorder. But it’s only effective for about a third of people with the disorder. Scientists may have a clue as to why and discovered a drug target for new treatments.

Bipolar disorder, characterized by episodes of depression and mania, affects about 2.8% of adults in the U.S. and 2.9% of adolescents each year. Medication is one part of the treatment plan and helps balance mood. "Lithium is a classic treatment for bipolar disorder," said Rodrigo Mansur, a psychiatrist and clinician-scientist at the University Health Network in Toronto, and a professor of psychiatry at the University of Toronto. "It has been used for 70 years all over the world."

But lithium has some drawbacks and long-term use may lead to kidney problems. "And sometimes the side effects are really difficult to handle, so it's frequent that patients will stop the treatment," said Renata Santos, a staff researcher at the Institute of Psychiatry and Neuroscience of Paris at the University of Paris.

While decades of studies have produced results showing how effective lithium can be in treating bipolar disorder, a large proportion of individuals don't find relief, and psychiatrists can't reliably predict who will and won't respond well.

"The only reliable way we have is to actually try the medication, and trying medication can be costly, can be time consuming or can be labor intensive," said Mansur. A patient's dose also needs to be carefully managed, and healthcare practitioners need to conduct regular blood tests during treatment to make sure the current dose isn't toxic.

"If we could know beforehand who is going to respond to lithium and who is not, that would save us a lot of work, that would be safer overall and that would probably improve overall outcomes in treating the disease," said Mansur.

An international team of scientists tried to figure out why lithium doesn't work for everyone in this new study. By studying neurons, the researchers saw how lithium might work in the brain. Their results could be used to develop new treatments.

To look at neurons from live people with bipolar disorder without extracting these cells from the brain, the researchers took a blood sample and genetically reprogrammed the patients' lymphocytes, immune cells in the blood, to revert them to an embryonic-like stage. These cells are called induced pluripotent stem cells.

The scientists could then grow and differentiate these cells into the desired cell type. For this study, the scientists wanted the kind of cells heavily affected in bipolar disorder: neurons from a structure in the brain important for learning, memory and emotion, called the hippocampus.

Before this latest research, some of the investigators had previously shown that neurons derived from stem cells of people with bipolar disorder were hyper-excitable, and lithium reduced that excitability. In other words, with lithium treatment, neurons didn't fire or signal to each other as easily as they did before, without lithium treatment. The research group, from the Salk Institute in La Jolla, found that this occurred only in cells of bipolar disorder patients who were responsive to lithium treatment.

When Santos, co-first author of the new study, arrived as a visiting research collaborator at the Salk Institute in California, she wanted to see if she could reproduce those results with cells from a different set of patients.

She not only replicated the earlier findings, but she also saw that the lithium-responsive and the non-responsive neurons looked very different from each other. "So I decided that this cohort would give us the possibility to really look into what gave resistance to lithium in neurons," which led to the present study.

Santos and her collaborators worked with cells from three patients with bipolar disorder who responded to Lithium, three patients who didn’t and four individuals without bipolar disorder, to serve as a control group. All participants were white men, ranging in age from 25 to 62.

They looked at what genes were expressed in neurons of each group of patients to see where lithium-resistant neurons differed from the rest. In the neurons from patients resistant to lithium treatment, the scientists saw that the expression of a particular gene, LEF1, was low compared to the other neurons. This made sense, as the scientists also knew that lithium targets a signaling pathway that involves LEF1.

The scientists then treated the nonresponsive cells with a different medication for bipolar disorder, valproic acid. This drug, often prescribed to people who don’t respond to lithium, worked where the lithium didn’t. It increased the expression of the LEF1 gene, and reduced the excitability of the neurons. 

The findings, published in Molecular Psychiatry earlier this month, point to the LEF1 gene and a certain cell-signaling pathway that could be promising drug targets. "It makes sense considering findings from previous studies," said Mansur.

But the scientists could only look at a small subset of neurons in just six patients with bipolar disorder, all of them white males, which limits the generalizability of these findings. "It's hard to extrapolate findings from small samples," said Mansur. "We don't know, for example, if this applies to women, which make up half of the population affected by bipolar disorder."

This work still provides a foundation for future studies on bipolar disorder and lithium treatment, Santos points out, as well as potential drug targets.

“All of the drugs that are used to treat bipolar patients have been used for decades. Lithium has been used for 70 years, and the atypical antipsychotics have been used for 20 years. And then you have molecules like valproic acid, antiepileptics," said Santos. "They will prevent crisis of either depression or mania, but only in a very low amount of patients."

This means that patients need alternatives. But going from lab studies of neurons to drug development takes a long time.

"But that [study] laid down the foundation in terms of subsequent investigations," said Mansur. "Eventually that can be translated into some kind of test, a diagnostic or predictive test, that can be used before we start or don't start a specific medication."

Similar issues, like intolerable side effects and the inability to predict who will respond best to which medication, complicate the treatment of other psychiatric disorders too, in part because scientists can't peer into the brains of living patients to see exactly what's happening inside their neurons.

"There has been progress in terms of understanding better the bases of these conditions," said Mansur, "which hopefully, eventually, will be translated into treatments."