Long a first-line treatment for bipolar disorder, lithium is nonetheless effective for only about one-third of patients with the illness, and it can sometimes take up to a year to know whether or not it will be effective.
In a new study, scientists at Salk Institute say they have found a way to predict, with 92 percent accuracy, which individuals with bipolar will respond to lithium. The findings verify the lab’s discovery of a cellular basis for the disorder and could help patients who will respond to lithium as well as the vast majority of patients who will not, sparing them the painful process of taking an ineffective treatment.
“What’s remarkable about this system is that you don’t need to use 500 or 600 cells from multiple patients,” said senior author Dr. Rusty Gage, a professor in Salk’s Laboratory of Genetics. “Five cells from one patient is enough to define whether someone is responsive or nonresponsive to lithium.”
More than five million Americans suffer from bipolar disorder, a progressive psychiatric condition that, left untreated, puts sufferers at high risk for suicide. Lithium is the preferred drug to treat the disorder, but it isn’t clear why it works for some people and not others.
The research team’s previous work offered a clue, showing that the neurons of people with bipolar disorder are more easily stimulated, firing electrical impulses more rapidly than the neurons of people without the disorder. The findings showed that maintaining some people’s neurons in a lithium-infused medium calmed this hyperexcitability.
“In 2015 we discovered that the brain cells of people with bipolar disorder are more sensitive to stimuli than those of other people,” said Gage. “Since then, we have been able to characterize that sensitivity in greater detail and discern clear patterns in the neurons of bipolar patients that allow us to predict who will respond to lithium and who will not.”
For the new study, the researchers set out to gain a better understanding of why, despite seemingly equivalent hyperactivity, some bipolar patients’ neurons respond to lithium while others’ do not.
This time, instead of using skin cells, the researchers reprogrammed lymphocytes (immune cells) from six entirely new bipolar patients, some of whom are known lithium responders. The team found the same hyperexcitability in the lymphocyte-derived neurons, confirming their previous results.
“But then we started to see something more,” said Dr. Shani Stern, a Salk research associate and co-first author of the new paper. “Although responders and nonresponders both produce more electrical impulses and spontaneous activity, when we look at the electrophysiological properties, the two groups are very different from each other.”
The researchers characterized the electrical firing patterns of all six patients’ neuronal lines, measuring spike height, spike width, the threshold for evoking a reaction, and other qualities. The overall patterns were noticeably different in responders versus nonresponders.
“This work was exciting because we replicated the previous finding of neuron hyperexcitability in neurons derived from a new cohort of patients diagnosed by a different psychiatrist, confirming the robustness of this characteristic and its potential use for drug development,” said Dr. Renata Santos, co-first author and a Salk research collaborator.
Wondering whether the differences could be predictive of lithium responsiveness, the researchers trained a computer program to recognize the variations between the profiles of responders and nonresponders using the firing patterns of 450 total neurons over six independent training rounds.
In each round, they started anew using the neurons of five of the patients to train the system. They then tested the system with the neurons of the sixth patient, whose lithium responsivity was known to the team but not to the program. They repeated the process five more times, which allowed them to build essentially six independent models.
Each model was trained on the data from five out of the six patients, leaving a different patient out of the training data each time, and then letting the model identify the last patient as a responder or nonresponder. Using the firing patterns of just five of any patient’s neurons, the system identified the person as a responder or nonresponder with 92 percent accuracy.
The researchers say their method could be applied to lymphocytes taken from bipolar patients’ blood samples to help determine whether specific individuals would be responsive to lithium.
“Replication of scientific results is not very sexy, but it’s crucial,” said Gage. “When different scientists are able to get the same results in different cells from different patients, we can have more confidence that we are really on to something that will be beneficial for patients.”
The new findings are published in the journal Molecular Psychiatry.
Source: Salk Institute