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Slaying the stress monster

Illuminating the genetic and biological underpinnings of anxiety may lead to new therapies and clinical treatments, and vastly improve quality of life.

Stress representation.
Stress

Though stress and its surrogates—anxiety, trauma, and despair—are ubiquitous, their root causes have long been subjected to debate. They’re often categorized as ailments over which a disciplined individual has some conscious control; however, more recent research has challenged this assumption. By examining the genetic and biological underpinnings of stress, investigators at the Yale Stress Center and the VA Connecticut Healthcare System have provided insight into its causes and illuminated potential avenues for treatment.

“People used to think stress was an affliction of the mind, and suggested that just talking to someone—telling them to pull themselves up—would fix it,” said Rajita Sinha, PhD ’92, Foundations Fund Professor of Psychiatry; professor in the Child Study Center and of neuroscience; and director of the Yale Stress Center. “We’re very cognitive individuals, so we like to believe we can control things with our thoughts. But this only addresses one component of the stress response.”

Hardwired for stress

In reality, humans are hardwired for stress, and its psychological and physiological components can be difficult to disentangle. In small doses, anxiety is a critical survival mechanism: when we’re threatened, stress helps our bodies adapt. Yet stress can also be pernicious—particularly when its cause is unpredictable, uncontrollable, or chronic. Over time, these environmental conditions can elicit bodily sensations like stomachaches, irritable bowel syndrome, or high blood pressure. These responses accompany—and exacerbate—such familiar symptoms as inattentiveness, helplessness, or despair. And because these are embodied responses to stressors, Sinha pointed out, they don’t respond particularly well to cognitive solutions like logic or planning. In fact, they can even inhibit these mental tools.

“High levels of uncontrollable stress have an impact on our everyday brain function, especially our higher-order functioning,” Sinha said. “This includes things we often take for granted, like executive function, memory, planning, and problem solving.”

Sinha and her colleagues have mapped these responses—over time and on multiple levels—and identified regions of the brain that show increasingly blunted reactions when subjected to high levels of stress. They’ve also found that the circuits activated when coping with stress, which constitute our capacity for resilience, can degrade when faced with prolonged exposure to a stressor.

Joel Gelernter, MD, Foundations Fund Professor of Psychiatry and professor of genetics and of neuroscience; and Daniel Levey, PhD, a postdoctoral associate, also shed light on the underlying biology of stress and despair. Through a partnership with the Million Veteran Program (MVP), a large biobank committed to studying traits and disorders relevant to the veteran population, they’ve identified specific genes associated with post-traumatic stress disorder (PTSD) and anxiety.

“I remember a time long ago when people argued about whether PTSD was a physiological disorder or a construct that didn’t correspond to a distinctive biological entity,” Gelernter said. “There’s been a lot of progress showing that it’s a true disorder with tangible biological evidence. Our studies have added to that, because now we can identify genes that are significantly associated with PTSD.”

While PTSD is characterized by three major symptom domains—re-experiencing, avoidance, and hyper-arousal—Gelernter and Levey chose to home in on re-experiencing because it has the least diagnostic similarity to other psychiatric conditions. Their gene map depicted an overlap (both across the entire genome and at individual gene loci) between genes associated with re-experiencing and schizophrenia. The association encouraged them to compare hallucinations, a common component of schizophrenia, to the symptoms they see in veterans with PTSD.

“Someone with PTSD recognizes re-experiencing as an intrusive event based on prior experience, whereas someone with schizophrenia probably doesn’t recognize the internal origin of a hallucination,” Gelernter said, “but otherwise there’s a lot of phenomenological overlap. This made us consider whether people with PTSD who have these risk alleles might be good candidates for drugs that have been successfully used to treat schizophrenia.”

In another study, Gelernter and Levey identified significant links between anxiety and several other genes, such as those encoding Estrogen Receptor-alpha, a global regulator of genes; and the Opiate-Related Nociceptin Receptor 1, OPRL1. “We’ve identified some novel connections that will warrant future investigation under more stringent conditions,” said Levey. The research, which is the largest genome-wide association study of anxiety traits to date, offers promising findings for understanding predisposition to anxiety and its connection to other psychiatric diseases.

Therapeutic outlook

Understanding the biological underpinnings of stress and anxiety has salient implications for highly individualized pharmacological and behavioral therapeutics. “When stress pathways are compromised, we need to get these circuits back online,” said Sinha. “We’ve tested medications that can rescue these parts of the brain that are associated with stress and resilience. We’ve also looked at practices like mindfulness, which can help decrease stress and improve high-level cognitive function.”

Likewise, Gelernter and Levey are optimistic that their research will help doctors identify promising PTSD medications based on patients’ genetic profiles. They also hope informing individuals about their genetic susceptibility to anxiety might empower them to seek out coping strategies. “The genetics of these conditions can be stigmatizing, but I hope that our research can make the biology helpful rather than stressful,” Levey said.

Sinha emphasizes the need to avoid a one-size-fits-all approach to understanding treatments for stress and anxiety, as adaptations and disruptions can manifest differently across the population. “Something you need is different from something I need,” she said. “Maybe mindfulness will work for both, but we also have to go to the molecular level and find other therapies that target it there. It’s exciting to have an interdisciplinary stress center where we can rapidly translate science into treatment.”