Science Explains Why Anxiety Can Be So Hard to Treat

Anxiety, and more broadly, stress, is a common part of everyone’s lives, and for good reason: It actually has its roots in a survival mechanism that allows the body to recognize threats and respond accordingly.

But that system can get stuck in overdrive, leading to a constant state of anxiety that can be debilitating and unhealthy. Nearly 20% of the U.S. population has an anxiety disorder. Scientists know what triggers stress and anxiety — psychological and physical events that lead hormones, especially cortisol, to be released — but drugs that tamp down these substances don’t always translate into relief of anxiety symptoms.

Thanks to new research, that may soon change. In an animal study published in the journal Molecular Psychiatry, a team led by Dr. Joseph Majzoub, chief of endocrinology at Boston Children’s Hospital, found that a set of neurons in the brain’s stress control center, the hypothalamus, play a critical role in masterminding the anxiety response.

These neurons control the release cortisol, but they also have connections to other parts of the brain that are involved in behavioral responses to stress, such as an increased heart rate and breath. The scientists genetically engineered mice to be missing a gene that controls the release of cortisol in these neurons and found that not only did the animals have lower levels of stress, but they also showed fewer signs of anxiety in their behavior. These mice, for example, were more adventurous in exploring an elevated gangplank-like maze, and in seeking out exposed areas in their environment, compared to control mice who behaved fearfully, sticking to the periphery of the maze.

“To our surprise, those few neurons in the hypothalamus not only projected to the region expected to control the [hormonal] response to anxiety”—like those cortisol spikes—”but those same neurons also projected to several areas of the brain known to regulate behavioral responses,” says Majzoub.

Existing anti-anxiety medications that target cortisol levels, he says, may not be as effective as doctors hoped because they are too broad; they may lower cortisol levels in some parts of the brain while elevating it in others, so the two effects may cancel each other out.

These results provide an important advance in understanding anxiety, highlighting the fact that anti-anxiety strategies may need to be more specific to certain neurons in the brain. That could lead to more effective medications that can better address symptoms. Majzoub says the next step is to figure out to which other areas of the brain those neurons affect—and better understand how stress hormones like cortisol contribute to symptoms like elevated blood pressure and shallow breathing.

After that, scientists will look for a way to translate the findings into a new drug. “That’s not going to be easy, frankly,” he says. “But we are working on it. The goal would be that if in humans the same thing occurs, we would be able to reduce anxiety particularly in people with chronic anxiety. This is a good start.”