A racing heartbeat, tightness in the chest, quickened breathing, sweaty palms. People suffering a panic attack for the first time usually end up in the emergency room, thinking they are about to have a heart attack and die. Because of the severe physical symptoms, the path to therapeutic help often involves a long and complex medical journey.
While there a currently no exact statistics, it is estimated that 16% of the population in Austria suffers from an anxiety disorder that would require treatment. Women are affected significantly more often than men. The diagnosis is usually made by a general practitioner. Antidepressants are often prescribed – too often and too quickly, says Nicolas Singewald. “For mild forms of anxiety and depression, studies have shown that antidepressants do not necessarily work any better than placebos,” says the head of the Neuropharmacology Group at the University of Innsbruck, warning that it is still not known exactly how psychotropic drugs affect the brain in the long term. For this reason, he advocates the use of these important drugs only in severe cases, and only as a brief intervention rather than for years.
Overall, higher levels of anxiety and stress can also be observed today as a social phenomenon. Threats such as the war in Ukraine, inflation, and the climate crisis are permanently present through media coverage and discussions on social networks, causing fears to build up. The problem is, constant worry permanently activates the brain’s fear network.
Fear is actually an important achievement in evolution, because it helps us to recognize danger and mobilize forces to either flee or fight. Anxiety originates in developmentally early core areas of the brain, the limbic system. There, signals from the sensory organs alert a part of the brain called the amygdala, which stimulates other brain areas to flood the body with stress hormones. This triggers the archaic flight-or-fight reflex: The pulse rises, the muscles get an energy boost, sweating makes the skin slippery and difficult to grasp. Thinking is largely switched off. If you want to survive, you have to react as fast as lightning. This is what the program was originally intended to do.
But when does this system go off the rails? “If a fear response to an actual threat situation is too severe or goes on for too long, or if it occurs without an identifiable threat, then we call it an anxiety disorder,” Singewald says. The pharmacologist has been researching the causes of pathological anxiety for decades with the goal of developing new, individualized therapies. Exactly how anxiety disorders develop is a very complex process, a mix of heredity, unconscious learning, and external stimuli.
According to Singewald, neurobiologists assume that there is a gene-environment interaction. There is no single “fear gene,” but rather so-called candidate genes that when affected simultaneously, result in an increased risk of developing an anxiety disorder. Whether this disorder eventually manifests depends on an interaction of genetic makeup with previous – often early childhood – experiences and lifestyle.
“Stress plays an important role, both as a predisposing and as a trigger factor,” says Singewald. These factors do not directly influence the genes, but control their activity via epigenetic markers, i.e. how much of the respective gene product (protein) is formed. If these mechanisms interact, the fear network in the brain can become distorted. The initially useful sensation of fear becomes pathological and arises even without a real threat.
Another problem is that patients often develop a fear of anxiety itself and try to avoid certain situations, which puts a strain on their daily lives and impairs their quality of life. If left untreated, secondary illnesses such as depression or alcohol addiction can develop.
Psychology distinguishes between 500 forms of fear. There are specific fears, such as a fear of certain animals or of heights, and non-specific fears, such as panic disorder or generalized anxiety disorder (GAS), in which sufferers live constantly with heightened levels of anxiety and worry about everything all the time. Anxiety disorders are often accompanied by other mental illnesses such as depression.
The most commonly prescribed therapy includes psychotherapy, especially cognitive behavioral therapy and confrontation therapy, medication, and exercise. “Especially for anxiety patients, any form of exercise works very well,” says the researcher, “because it stimulates neuroplasticity in the brain.” Neuroplasticity is the brain's ability to continuously change, adapt to different stimuli, and even grow in some regions.
This process consists of a variety of biochemical and metabolic reactions, which allow us to respond to new stimuli and information and to establish new neural connections. Increasingly, science is applying modern imaging technology to study the effects of meditation techniques on the brain’s function and structure.
It has been shown that meditation and yoga can, among other effects, reduce the release of stress hormones. In a longitudinal study in cooperation with neuroradiologist Elke Gizewski from the Medical University of Innsbruck and the sports scientist and meditation expert Michaela Waibel, healthy subjects were examined over several weeks. The researchers were able to prove that breath-focused meditation changes the brain structure. After just seven weeks of regular meditation, changes in the brain and a reduction in anxiety levels were evident. Gray matter increased in the activated areas, like muscles do when bodybuilding. This was particularly evident in the areas of body awareness, the ability to concentrate, and attention. Singewald now wants to investigate these effects in anxiety patients.
In the future, this knowledge could be used in a structured form to treat mild forms of anxiety disorders or depression without the side effects of antidepressants, which do not necessarily work any better than placebos in these cases.“There is a lot of research being done in this area around the world,” Singewald says. For example, studies have also shown that inflammation, which also plays a role in stress-associated diseases, can be reduced through meditation.
One factor that the pharmacologist is also investigating is the effect of positive emotions on brain neuroplasticity. A study that looked at 30,000 Americans with equivalent stress levels showed that how an individual evaluates their stress affects their likelihood of getting sick, and ultimately their life expectancy. Those who experienced the same stress more negatively died younger. “Positive thoughts calm the primal fear center in the brain. These findings will be very important in the future,” says the researcher.
A novel development in the field of pharmacology is the use of scents or pheromone-like neurosteroids, which are currently being studied for anxiety-relieving effects. Smelling also involves very old areas of the brain that are very closely linked to the limbic, or emotional, system. Scents can therefore have a direct influence on an individual’s feelings or emotions. “Even primitive societies were aware of the importance of proper breathing and the sense of smell. Knowledge that has been handed down can sometimes later be explained scientifically and used therapeutically,” Singewald explains.
A great deal of research is currently being done in the area of psychedelics, as they can apparently trigger neuroplasticity quickly and effectively. It’s important, however, that this neuroplasticity be guided in the right direction by combining it with psychotherapeutic approaches. In post-traumatic stress disorders, for example, the use of MDMA (ecstasy) has shown positive results in Phase III clinical trials. Singewald assumes this will be the first psychedelic substance to be used clinically. “The expectation is that if the patient takes the substance a few times before attending what we call integration sessions, it can have the same effect as taking antidepressants for weeks,” he explains.
The initial assumption that all patients will react the same is one of the biggest problems the pharmacologist sees, both in studies and in drug development. The idea of lumping everyone together and curing all the different patients with one and the same drug is completely naïve, in his opinion. “Twenty years from now, people will say: You just gave everyone the same dose of the same drug, regardless of whether they were male or female? Unbelievable!” he says, shaking his head. Anxiety disorders in particular are multifactorial and individual. One key prerequisite in personalized medicine, however, is knowing the right biomarkers. Singewald and his colleague Simone Sartori are working worldwide to identify them.
Singewald became fascinated by research as a pharmacy student when he took a summer job in a Hoffmann-La Roche laboratory in Basel. He came to his own field of study through a research fellowship at the University of Oxford, a move he describes as the cornerstone of his career. The stay was funded with an Erwin Schrödinger grant from the FWF. “Young people have to get out there in the world!” he says, emphasizing the importance of leaving your comfort zone and finding your own field of research. In Oxford, he examined the effects on the brain of different substances that trigger fear in both animals and humans. The impetus for his subsequent career after returning to the University of Innsbruck was the first of a total of ten FWF-funded research projects in 2001, in which he investigated stress-associated diseases such as anxiety disorders and depression. What motivates him, even when faced with the defeats of a researcher's life? “You have to be on fire for the topic”, he says.
Nicolas Singewald studies the neurobiological mechanisms that lead to disorders such as anxiety, trauma-related disorders, and depression, as well as emerging therapeutic approaches at the University of Innsbruck. A research fellowship abroad at the University of Oxford, Great Britain, financed by the FWF, sparked his interest for this field of research.
