Ann Arbor Times

Researchers at the University of Michigan have developed a mathematical model to study how circadian rhythms influence the way bodies respond to medications. The findings, published in PLOS Computational Biology, suggest that synchronizing drug dosing with patients’ natural biological clocks could improve the effectiveness of certain treatments.

The research focused on dopamine reuptake inhibitors (DRIs), which are used for conditions like narcolepsy and depression. According to Tianyong Yao, an undergraduate researcher in the U-M Department of Mathematics and lead author of the study, “These findings provide a mechanistic basis for chronotherapeutics—optimizing drug efficacy by considering circadian timing. This could improve treatment for conditions such as ADHD, depression and fatigue.”

Senior author Ruby Kim, a postdoctoral research fellow with Michigan Medicine, explained that their model was built using data from modafinil, a DRI prescribed for narcolepsy. Kim stated, “Our mathematical model suggests that taking DRIs a few hours before your body’s natural rise in dopamine can help prolong the treatment’s effects.” She added that while their model does not replace experiments or clinical trials, it can help guide future studies: “Dopamine can vary a lot throughout the day, but there haven’t been many experimental studies looking at time-of-day effects. Our study shows that it’s important to take these effects into account.”

Yao noted that doctors could use this model to predict how dose and timing impact similar drugs: “We can examine some more generalized cases and consider a lot of different combinations of dose timing and concentration. The model could thus help doctors zero in on the most promising regimens for their patients.”

The researchers found that dosing modafinil out of sync with natural dopamine cycles can cause abrupt changes in dopamine levels, while proper timing helps maintain stable levels longer. Yao said, “Taking modafinil at the wrong time of day can trigger sharp spikes and crashes in dopamine levels, while dosing at the right circadian window sustains dopamine levels much longer.”

Additionally, the team explored how DRIs interact with another biological rhythm known as an ultradian rhythm—a cycle repeating several times daily—which also affects dopamine levels. Their work may provide new insights into this less-understood process. As Yao explained, “People didn’t really understand the circadian rhythm 100 years ago, but they gathered evidence and came up with a hypothesis. That’s sort of where we are with this ultradian rhythm.”

The project received support from the federal Multidisciplinary University Research Initiatives program.