Bipolar disorder: Montreal researchers may have found the ‘Holy Grail’

A team of Montreal researchers has made a crucial breakthrough in the understanding of bipolar disorder, which could eventually lead to new therapies for those who suffer from it.

“In our field, what we call the ‘mood switch’ is really considered the holy grail of bipolar disorder research,” said the team’s leader, Professor Kai-Florian Storch of McGill University’s Department of Psychiatry.

“What activates this switch? What triggers the transition from one state to another?”

Professor Storch and his colleagues found that a brain rhythm associated with the body’s natural sleep-wake cycle could explain the alternation between manic and depressive periods experienced by people with bipolar disorder, leading to a new understanding of what causes the alternation between the two states.

This alternation seems to be linked to two “clocks”: the better known circadian rhythm, which imposes a 24-hour cycle, and a clock regulated by dopaminergic neurons, responsible for vigilance. A lack of synchronization between these two clocks would explain the manifestation of manic and depressive states.

The second clock may even be completely dormant in non-bipolar people.

“The rhythm that these dopamine neurons produce can be 48 hours, it can be 72 hours, it can be just a little bit longer than 24 hours,” Storch explained. “It’s a highly tunable oscillator. So, it can have different periodicities (…) and that’s our key finding, or the key model that we’re proposing, is that these two clocks can align and misalign. And when they align, we hypothesize that a manic state occurs.”

This might explain, he continues, why some patients with bipolar disorder alternate between the two states with the regularity of Japanese public transport: manic one day, depressive the next, and so on for weeks and months and years, to the point where they are able to plan their daily lives accordingly.

“This could mean that the clocks are synchronized every two days,” Storch summarized. “But our model can in principle explain all types of cyclicity in bipolar disorder.”

In their study, the scientists activated this second clock in mice to create behavioral rhythms similar to the mood swings characteristic of bipolar disorder.

When they then disrupted the activity of dopamine-producing neurons in the reward center of the mice’s brains, these rhythms disappeared ― evidence, they say, of dopamine’s key role in mood swings in people with bipolar disorder.

Current treatments for bipolar disorder attempt to stabilize patients’ moods, but almost never target the causes of the problem.

Current medications, Storch said, are able to influence this oscillator and moderate its fluctuations. But in light of this new study, we see that we could possibly succeed in putting the second clock to sleep, which could have a huge impact on the quality of life and care of patients.

“What is interesting is that patients feel that these periods are going to end, they can anticipate a few days in advance when they will enter the depressive phase,” said Professor Storch. 

This may be why there is a higher suicide rate among patients with bipolar disorder, he added, since it must be “terrible” for these patients to feel like they are leaving their euphoric state and plunging into a “black hole.”

The researchers will now try to better understand the exact molecular functioning of the dopamine-regulated clock, and the genetic and environmental factors that can activate it in humans. The team will therefore focus on these triggers and on the molecular gears.

The findings of this study were published in the journal Science Advances.

–This report by La Presse Canadienne was translated by CityNews