What if you could identify youth at risk for psychosis and intervene early to stem the sequelae of broken lives these serious mental disorders often cause? That’s the overarching goal of Jacqueline Clauss, MD, PhD, an instructor in psychiatry at Mass General Brigham (MGB) and a 2021 trainee in Harvard Catalyst’s two-year Clinical/Translational (C/T) Research Academy. In an ambitious effort to unravel the neurobiological roots of psychosis and change the trajectory of clinical outcomes, Clauss is mining the database of a large public repository of adolescent brain scans and conducting scans on a local clinical population at high risk for psychosis.

What clinical gap does this research seek to fill?

We’re interested in how serious psychiatric illnesses like schizophrenia and other psychotic disorders develop. We have identified a subgroup of individuals that we call clinical high risk for psychosis. I see these young people as the medical director of the MGH RE-SET program (Resilience Evaluation Social Emotional Training), our clinical high risk for psychosis program.

These are young people, typically adolescents or young adults, who might hear something that other people don’t hear, like whispers or sounds, or see things other people don’t see, like a shadowy figure or some distortion in their vision. They may have some changes in how they’re thinking or functioning.

These kinds of experiences are relatively common in adolescence, affecting about 7% of late adolescents at least once. If they persist, a person might meet the criteria for clinical high risk for psychosis. About 20% of those who meet these criteria develop a serious illness such as schizophrenia or schizoaffective disorder. Many of those who don’t continue to have unusual experiences and may go on to develop other serious psychiatric illnesses such as major depression, bipolar disorder, or obsessive compulsive disorder.

One of the things that struck me in psychiatry training is that within any given diagnosis, people have a wide range of outcomes. Even with schizophrenia, some people go on to very competitive colleges, hold jobs, and achieve goals traditionally viewed as “success.” Other people really struggle.

My research is focused on understanding the different pathways in the brain that might predict which trajectory an individual is going down. By understanding what’s going on in the brain, we might have more information about how to bend those trajectories. Are there ways we can intervene that could help improve people’s functioning and allow them to have a rich and meaningful path forward?

“Are there ways we can intervene that could help improve people’s functioning and allow them to have a rich and meaningful path forward?”

You’re zeroing in on the neurocircuitry of a tiny structure in the middle of the brain, the bed nucleus of the stria terminalis. Why that?

The bed nucleus of the stria terminalis (BNST) has not been commonly studied in humans because it’s so small, but it’s been really well studied in rodent models. A number of researchers–most prominently  Emory University neuroscientist Michael Davis–have shown in rodents that the bed nucleus responds to uncertainty or unpredictable potential threats in the environment. Davis’ work differentiated the bed nucleus response to a potential threat from the amygdala response to discrete fear events, like the prototypical example of a snake in the woods.

I became interested in BNST as a graduate student at Vanderbilt working with Jennifer Blackford, where we published the first connectivity study of this area of the brain in humans. As I became more interested in early psychosis, it seemed a natural region to look at because in both anxiety and psychosis, there’s an aberrant response to potential threat.

In anxiety, you might be afraid of what could happen. If you have social anxiety, you might be fearful of how you could be evaluated in a social situation. If you have generalized anxiety, you might have a fear that a random earthquake or another potential catastrophe could occur.

In psychosis, there’s also this kind of misperception of threat, or attribution of potential threat to things that are benign. A person might see certain numbers on a license plate and perceive that somebody wants to harm them, or see trees moving outside their bed at night and perceive that to be threatening in some way.

To me, the BNST circuitry really matches onto the overlap between these categories of symptoms.

How did you get interested in this area of clinical research?

My background is in anxiety risk, and my PhD focused on behavioral inhibition, which can be experienced by children as well as adults as a tendency to be shy or avoidant in novel situations. Behavioral inhibition was originally characterized by Jerome Kagan, a psychologist at Harvard University, and many of the early studies were done at Massachusetts General Hospital. That was my entree into risk in psychiatric disorders.

“Understanding why people behave the way they do and what it is about their brains that is different are what motivated me to become a psychiatrist.”

We know that behavioral inhibition increases the risk for anxiety disorders, but not in everyone. Is there something different occurring in the brains of people who have anxiety that makes them more prone to psychotic-like experiences or developing the high-risk syndrome?

Understanding why people behave the way they do and what it is about their brains that is different are what motivated me to become a psychiatrist. I became a child psychiatrist because adolescence and young adulthood are really important periods for intervening to help people to stay on course for getting through high school or college, for finding meaningful work, and maintaining relationships. Once you get off course, it becomes so much harder to rebuild your life.

You’re at the tail end of a two-year training with the Clinical/Translational Research Academy. What value has the program brought you as a young investigator?

The number one thing is being in a cohort of other physician scientists across the Harvard affiliates. It is incredibly helpful to have a group of peers at a similar stage of career development that you can talk with about these issues, and to learn from one another. At various points we’ve done group projects together, and we often watch each other present and offer feedback on presentations.

The university and affiliate healthcare centers make up such a large system that it’s easy to be in your own lab and not necessarily interact with the wide breadth of investigators out there. There are people from different fields in our group; two of us are psychiatrists, but a range of training specialties are represented. That can be really interesting and useful to learn from.

It is a career development program, so we’ve received feedback on our grant sections. We have worked on didactic exercises around how to run a clinical trial. We’ve studied biostatistics, which is one of those things that I think as a scientist, you can never have enough of. We’ve had presentations on how to interact with industry. Last week we attended a talk on ways to reduce physician burnout and improve physician wellness.

Any perspectives you garnered that you’d like to share on managing work/life balance as a young investigator?

The research shared in this talk was really helpful, especially this idea that burnout is separate from wellness, that you can feel burned out in parts of your job but at the same time, do things to promote wellness. Sometimes parts of your job are frustrating and not changeable, but maybe you can engage more on the positive side of things. I thought that was a useful perspective.

For myself, it’s accepting that you only have 24 hours in the day and you’re probably sleeping for seven of them, so how do you prioritize the other hours? The idea that I can somehow cram extra hours into my day has failed me for many years now. So I’m taking a thoughtful approach to prioritizing my time and what is most important for me to get done.