To beat sleepiness of anxiety drugs, team looks to body’s clock

Drugs that treat anxiety can be real downers. While they may help you feel less anxious, drugs such as Valium and Xanax can leave you drowsy and unfocused. Long-term use of these compounds, a class of drugs called the benzodiazepines, can lead to dependence and tolerance. And patients often need higher and higher doses to calm their anxiety. Getting off the drugs requires careful weaning to avoid insomnia, tremors and other nasty withdrawal effects.

But Subhashis Banerjee and colleagues at the Scripps Research Institute in Jupiter, Fla., have identified a potential new target for anti-anxiety drugs that avoids the drowsiness and other side effects that come with the standard treatments. The target is an integral part of the body’s internal clock, and in tests in mice, compounds aimed at it reduced measures of anxiety while keeping the mice awake. The possibilities show how basic science questions, such as how the body produces sleep and internal rhythms, could have clinical applications. But it’s important to remember that it’s a long way between mice and people.

The proteins REV-ERB alpha and REV-ERB beta are found in cell nuclei throughout the body. These proteins are receptors that sense levels of heme, subsections of chemicals in the body containing iron atoms. Levels of heme rise and fall based on a cell’s activity. REV-ERB responds to these heme level changes by controlling the activation of genes within the cell’s nucleus that govern the cell’s 24-hour internal clock. This circadian rhythm plays an important role in controlling our sleep.

Banerjee and colleagues were interested in the connection between sleep and anxiety-related behaviors, so they began to develop compounds that stimulated the REV-ERB receptors in mice. “There is some human data to suggest that people with anxiety disorders have altered circadian rhythm function,” says study coauthor Thomas Burris, a pharmacologist at the St. Louis School of Medicine. “When we were examining the metabolic effects of these compounds, we noticed the animals were less anxious when they were handled.” 

The scientists gave the new compounds to mice at different times of day. If it was during their active period, the mice showed no response. But if the mice were given the compounds when they were supposed to be asleep, the animals stayed awake for several extra hours, making up the sleep the next day.

In numerous tests for anxiety in the mice, the REV-ERB compounds chilled the mice out without making them sleepy, a drastic difference from the sedative effects of many current anxiety drugs on the market, Banerjee, Burris and their colleagues report December 23 in Nature Communications.

“Certainly we’d like to see some of these drugs provide a clinical benefit,” Burris says. The scientists have continued to develop drugs that target REV-ERB, some that show more promise than the ones tested in the study. But Burris remains cautious about their potential. After all, new side effects could emerge, the drugs’ effectiveness could be less than expected. Who knows? They may not even work in humans at all.

The anti-anxiety effects are an “important first step,” but testing the drugs in other animals, especially those active during the day, is crucial, says Colleen McClung, a neuroscientist at the University of Pittsburgh. Mice are nocturnal. Humans are not, and the drug might have different effects when faced with such a radically different body clock.

It’s also important to find out what doses have effects on sleep and anxiety, and how long the drug needs to be given. In the new study, a single dose of the drug had an effect on sleep, but it took three days or more for the drugs to have an effect on anxiety. This longer dosing might have very different effects on the body’s clock than a single dose.

Burris and Banerjee are also hopeful that drugs targeting the REV-ERB receptors might treat anxiety without the dependence seen with many current drugs. They ran mice through a test called conditioned place preference. A mouse is placed in an apparatus with two chambers. Over several days, scientists dose the mouse with a drug and put it in one chamber, or dose it with saline and put it in the other. On the final day, the mouse gets to choose which chamber it prefers. If it has been dosed with an addictive drug such as saline, the mouse will spend more time in the saline-paired chamber. That’s a clue that the drug might induce dependence.

But the REV-ERB drug did not make mice prefer the paired chamber. The drug also reduced the preference for a chamber associated with cocaine. But McClung notes that more doses will need to be tested.

And how exactly these new compounds work to relieve anxiety in the mice is still an open question. Current anxiety medications often target GABA, one of the major inhibitory chemical messengers in the brain. The REV-ERB-targeting compounds may also affect GABA or other messengers indirectly, or they may work through a different mechanism entirely. Understanding precisely how they relieve anxiety could reveal the drugs’ potential side effects or benefits.

But whether or not these drugs end up in the clinic, the results show how research into basic functions, such as sleep, can yield clues to treating human conditions. “We have this fascination with general biology, how you generate sleep,” says Russell Foster, a circadian neurobiologist at Oxford University in England. “And this shows all these fundamental questions are related to something much bigger, to health and welfare. It’s an example of how the fundamental biology is translating to areas of clinical impact.”

Editor’s note: This post was updated at 4:50 p.m. on Jan. 14, 2015, to remove Ambien from the first paragraph. While it can be taken for anxiety, it is not a benzodiazepine.