Predicting Psychosis: Field Moves From Assessment of Clinical Risk to Search for Biomarkers
Though it has had its limitations, the effort to use Clinical High Risk criteria to identify individuals at risk for psychosis was a dramatic shift toward primary prevention of serious mental illness. It has evolved today into a 21st century search for biomarkers led by the National Institute of Mental Health.
Nearly 50 years ago, psychiatrist Thomas McGlashan, M.D., went to work at Chestnut Lodge, the residential treatment facility in Rockville, Md., renowned for its psychoanalytic approach to treating patients with schizophrenia. The lodge’s mission was a heroic effort by dedicated therapists to see the “person behind the disease,” but in terms of altering the trajectory of schizophrenia, it was minimally successful. In 1986, McGlashan published a landmark follow-up study of 163 patients that arrived at a dispiriting conclusion—roughly two-thirds of the patients were functioning marginally or worse at follow-up.
NIMH Project to Ask Novel Questions About Clinical High Risk Trajectory
Forty-two sites specializing in identifying and treating people who meet Clinical High Risk criteria for psychosis are set to begin enrolling patients to participate in the Accelerating Medicines Partnership-Schizophrenia (AMP-SCZ). The sites are in the United States, Canada, Australia, Europe, and Asia. Advocacy organizations—including the APA Foundation—are supporting AMP-SCZ.
Many of the participating sites—such as those that were begun under the National Institute of Mental Health’s North American Prodrome Longitudinal Study and sites in Australia founded by Patrick McGorry, M.D.—have a very long track record of recruiting and following people at risk. Subjects’ participation in the project and in data collection efforts as part of AMP-SCZ is voluntary.
Linda Brady, Ph.D., co-chair of the AMP-SCZ Steering Committee, described a 21st century endeavor that will use neuroimaging, electrophysiology, digital technologies, cognitive measures, genomic studies, and collection of blood for inflammatory and other markers to search for true biological indicators of psychosis risk.
One especially novel approach the project will employ to learn more about the trajectory of people at risk is “ecological momentary assessment”—using smartphones and wearable devices to map how an individual’s activity and environment encourage resilience or may contribute to psychosis. “There is evidence that living in an area with green space enhances resilience, well-being, and health,” Brady said. “Conversely, some features of urban environments can diminish a person’s mental health. We hope to use that kind of information about exposures and activity to better understand how people at risk do over time.”
As another example of the breadth of data that will be accumulated, subjects’ voices will be recorded, with their consent, during clinical assessments. “We know that speech is a very sensitive indicator of psychiatric and neurological changes over time,” Brady said.
Data collection will be harmonized across the 42 sites so that they will use the same methods and standards, and data will be collected on a website for sharing across sites. Brady said it will likely be fall before the first data are publicly available and a year or more before “we have biomarkers that tell us something about CHR individuals and their trajectories of illness.”
Brady said the project also incorporates the expertise of people with lived experience of being at risk for psychosis. “We are going to have really important input from people who understand all of the issues people face in this very early stage of illness,” she said.
“There is an enormous amount of promise in this study and what it can tell us about the trajectory of people who are at clinical high risk for psychosis.”
Yet within the voluminous case histories of patients who passed through the institution was something McGlashan recognized as illuminating. “For all of the patients who were admitted to Chestnut Lodge, there was this fantastically rich developmental dataset that raised the question, ‘When did the disorder start?’ These records went way back [in each patient’s history] and were very detailed,” McGlashan told Psychiatric News in 2014. “You could tell that in almost every case, something started going wrong three or four years or more before the first psychotic break” ("Recalling Chestnut Lodge: Seeking the Human Behind the Psychosis"). In the 1980s, the seeds of a new movement aimed at early intervention and prevention of acute psychosis began to take root in Australia with the work of Patrick McGorry, M.D., and Allison Yung, M.D., who advocated staged treatment of at-risk individuals in the preclinical phase of the illness.
It captured the attention of McGlashan, and when he left Chestnut Lodge in 1990, he resolved that the “prodrome”—the distinctive risk period prior to acute psychosis—would become the focus of his work. In 1996 he founded the PRIME Research Clinic at Yale to study the course of symptoms and how to prevent the development of frank psychosis and schizophrenia.
In time, collaboration between researchers and clinicians led to a consensus around a set of Clinical High Risk (CHR) or Ultra High Risk (UHR) criteria aimed at identifying people at risk for psychosis and treating them before their first episode. In 2004, the National Institute of Mental Health (NIMH) funded the North American Prodrome Longitudinal Study (NAPLS), a consortium of nine programs in the United States and Canada that recruited individuals in the community who met criteria for CHR and followed them over time.
Nearly two decades later, what has become of the effort to “predict” and prevent schizophrenia? Research has shown some 30% of individuals who meet CHR criteria do go on to have a psychotic episode—but others experience a range of other outcomes, and a small subset even appear to recover. Critics say that the CHR criteria are too general, encompassing many people who will never develop psychosis, and that labeling young people as being at high risk is potentially stigmatizing.
Dutch psychiatrist and epidemiologist Jim van Os, M.D., Ph.D., wrote in a 2017 World Psychiatry article, “A review of the literature indicates that UHR/CHR samples are highly heterogeneous and represent individuals diagnosed with common mental disorders (anxiety/depression/substance use disorder) and a degree of psychotic experience.”
CHR Pivots to a Broader Framework
Robert Heinssen, Ph.D., says that the Accelerating Medicines Partnership-Schizophrenia project is a natural evolution of the effort to predict and prevent schizophrenia involving many of the clinics that have been enrolling people who meet the Clinical High Risk criteria.
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Nevertheless, the effort at early identification of people at risk for psychosis was a dramatic and important shift in psychiatry toward primary prevention of serious mental illness.
“I think the biggest success of the CHR approach was to promote the idea that prevention was something we should strive for in psychiatry, especially when it comes to more severe illnesses, like psychotic illnesses,” said Ian Kelleher, M.D., Ph.D., an associate professor of psychiatry at University College Dublin. “That has inspired a generation of psychiatrists, including me, to think about the bold idea of psychosis prevention.”
William Carpenter, M.D., who chaired the DSM-5 Psychotic Disorders Work Group, said it is true that the criteria capture many people who will never develop psychosis—but he said almost all of them are in need of some level of intervention. “The CHR field has moved away from the original goal of prevention of schizophrenia to a broader framework in which CHR identifies people with a variety of symptoms that merit clinical attention but who may or may not develop psychosis.”
Robert Heinssen, Ph.D., director of the Division of Services and Intervention Research at NIMH who was the scientific program officer at NIMH for the NAPLS project, agreed. “These are individuals who have depressive or anxiety disorders with significant impairment in functioning.”
Systems-Based Approach Designed to Identify Individuals at Risk of Psychosis
“The Clinical High Risk (CHR) approach to identification of individuals at risk for psychosis has been incredibly important for psychosis research and for the idea of preventive psychiatry generally,” said psychiatrist and researcher Ian Kelleher, M.D., Ph.D., an associate professor of psychiatry at University College Dublin. “At the same time, the CHR approach identifies just a small proportion of individuals at risk. It may prove to be very helpful for those it identifies, but we need to find additional ways to identify people at risk of serious mental illness.”
While the CHR approach relies on identifying “symptomatic risk,” Kelleher and colleagues have looked at what he calls “systems risk.”
“The idea behind this approach is to leverage the unobservable risk for psychosis that arises from nonrandom sampling associated with making contact with a particular system,” he explained. “One doesn’t need to assess the individual for symptoms—psychotic or otherwise—and there are no assumptions about causality in this approach. It just involves identifying high-risk individuals based solely on knowledge about their contact with a given system.”
In an October 2021 study published in Schizophrenia Bulletin, Kelleher and colleagues used a Finnish birth registry with nearly 60,000 enrollees to follow the outcome of individuals who went to hospital emergency departments for self-harm up to age 28. Of 481 individuals who were in this category, 12.9% were later diagnosed with psychosis and 9.4% with bipolar disorder before they reached age 28.
Among those who presented before age 18, 29.1% developed psychosis or bipolar disorder by age 28—a proportion roughly similar to that for people who meet CHR criteria during clinical assessment.
“We’re talking about using readily available, routinely collected hospital administrative data” as one new approach to identify high-risk individuals, he said.
Kelleher emphasized that this finding does not suggest that self-harm by itself is a risk for psychosis; rather, it is something about presenting to the emergency department for self-harm (many individuals who self-harm do not present at theemergency department). “This approach leverages whatever it is about people who do present to the emergency department with self-harm because this system ‘captures’ that risk in a way that a general population survey about self-harm would not,” Kelleher said.
In the Schizophrenia Bulletin article, Kelleher and colleagues wrote: “[T]he same neurodevelopmental vulnerabilities and environmental exposures (trauma and violence exposure) that predispose to risk of psychosis or mania may also increase risk for self-harm. … [I]t may also be the case that the combination of self-harm and neurodevelopmental features makes hospital presentation more likely than when self-harm occurs outside of the context of neurodevelopmental risk.”
He told Psychiatric News, “Our goal with this ‘systems risk’ approach is to increase our clinical capacity to identify individuals at risk of serious mental illness—to expand the number of people who are able to access early or preventive intervention.”
Still others, he said, have psychotic-like symptoms that do not meet the diagnostic threshold for a psychotic disorder—what has been termed “attenuated psychosis syndrome” (APS). APS appears in Section III as a “Condition for Further Study” in DSM-5-TR, which states: “Compared with full psychotic disorders, the symptoms are less severe and more transient. Moreover, the individual maintains reasonable insight into the psychotic-like experiences and generally appreciates that perceptions are altered, and magical ideation is not compelling. Attenuated psychosis does not have the fixed nature that is necessary for the diagnosis of a full-blown psychotic disorder.”
“In this sense,” Heinssen said, “the CHR criteria have been very useful for identifying a pool of individuals who experience significant clinical distress and are good candidates for early intervention—so it hasn’t been a failure.”
AMP-Schizophrenia Is a Natural Evolution
Kelleher told Psychiatric News that CHR research has been based on a large series of clinical studies but without an epidemiological foundation. “So it’s difficult to generalize the findings from specific studies to the rest of the population because we don’t know a lot about the basic characteristics or representativeness of CHR study participants,” he said. “That’s not the fault of CHR researchers. That’s the fault of the rest of us in the research community who haven’t come up with additional approaches to complement or build upon the CHR approach” (see box titled: "Systems-Based Approach Designed to Identify Individuals at Risk of Psychosis").
Enter the Accelerating Medicines Partnership-Schizophrenia (AMP-SCZ). AMP-SCZ is a five-year joint venture of NIMH, the National Alliance on Mental Illness, the pharmaceutical industry, and other nonprofit and private organizations—including the APA Foundation—to identify early biomarkers of risk for schizophrenia and other outcomes (see box titled: "NIMH Project to Ask Novel Questions About Clinical High Risk Trajectory"). AMP was initiated by the National Institutes of Health in 2014 with three original disease targets; schizophrenia is the fifth disease target in the project ("Foundation Joins NIH-Directed Search for Schizophrenia Biomarkers").
Heinssen said AMP-SCZ is a natural evolution of the effort to identify individuals at high risk for schizophrenia and prevent the disorder, an international endeavor involving many of the NAPLS clinics that have been enrolling people who meet CHR criteria. “Our goal is to identify biomarkers that can predict the various trajectories of people who meet CHR criteria,” he said. “This effort will result in a richer mechanistic understanding of how risk plays out over time, which then opens up an opportunity for targeted therapies.”
Linda Brady, Ph.D., director of the Division of Neuroscience and Basic Behavioral Science at NIMH, told Psychiatric News that as evidence is gathered about the existence of various markers—genetic, biological, behavioral—pharmaceutical companies will be able to determine “which compounds might plausibly work to affect” the course of the disorder. She is co-chair of the AMP-SCZ Steering Committee.
What began 30 years ago as an effort to identify at-risk individuals using clinical criteria describing subjective mental states has evolved into a 21st century effort to identify genetic and biological markers of schizophrenia.
Said Kelleher, “I believe it is absolutely reasonable to expect that risk for psychosis can be identified earlier in life and that we can develop interventions to prevent psychosis onset and the major morbidity associated with psychosis.” ■
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Published online: 25 April 2022
Published in print: May 1, 2022 – May 31, 2022
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