New study identifies functional declines that predict psychosis risk

A new analysis of data from a large international consortium indicates that social and academic difficulties often arise years before the onset of recognizable clinical symptoms in young people at risk for psychosis. The findings suggest that these functional declines, particularly in social settings, may serve as early warning signs that precede the hallucinations or delusions typically associated with the condition. This research was published in Schizophrenia Bulletin.

The primary method for identifying individuals at Clinical High Risk (CHR) for psychosis currently relies on the presence of attenuated psychotic symptoms. These include experiences such as perceptual abnormalities, hearing indistinct whispers, or harboring heightened suspiciousness. While these symptoms are diagnostic markers, they often emerge after a young person has already begun to struggle with daily life.

Previous smaller studies, largely conducted in North America, indicated that problems with peer relationships and school performance frequently predate the clinical diagnosis. The scientific community needed to determine if these patterns held true across diverse cultures and if they were specifically linked to negative symptoms or cognitive deficits.

Negative symptoms refer to a reduction in normal functions, such as a lack of motivation, diminished emotional expression, or social withdrawal. These are distinct from positive symptoms, which involve an excess of experience like hallucinations.

The research team sought to replicate prior findings using updated assessment tools that better distinguish negative symptoms from other issues like depression. They also aimed to clarify whether these functional problems are merely a byproduct of anxiety or mood disorders.

The study was led by Henry R. Cowan of Michigan State University. The team included a vast network of collaborators from the Accelerating Medicines Partnership®—Schizophrenia (AMP® SCZ). This public-private partnership involves researchers from 43 sites across 13 countries, spanning five continents.

To conduct this investigation, the researchers recruited 1,056 adolescents and young adults. The participants ranged in age from 12 to 30 years old. All individuals met the criteria for being at Clinical High Risk for psychosis. The sample was notably diverse, including participants from North America, Australia, Europe, Asia, and South America.

The study utilized a comprehensive set of clinician-administered interviews and self-report questionnaires. To assess functioning before the onset of symptoms, the researchers used the Premorbid Adjustment Scale.

This tool evaluates sociability, peer relationships, and academic performance during childhood, early adolescence, and late adolescence. The clinicians scored these developmental periods retrospectively, looking at the time up to six months before the participants’ first psychotic-like symptoms appeared.

The team assessed negative symptoms using the Negative Symptom Inventory-Psychosis Risk. This specific measure evaluates five domains: anhedonia, asociality, amotivation, blunted affect, and poverty of speech. It is designed to evaluate both observed behavior and the participant’s internal experience. The researchers also measured cognitive ability using the Penn Computerized Neurocognitive Battery, specifically focusing on verbal learning and estimated IQ.

To ensure the results were specific to psychosis risk, the researchers also assessed depression and anxiety. Depression was measured using the Calgary Depression Scale for Schizophrenia. Anxiety was tracked using the Overall Anxiety Severity and Impairment Scale. The researchers controlled for these variables in their statistical models to rule them out as the primary cause of functional decline.

The results provided evidence of a consistent pattern across the international sample. Participants who displayed more severe negative symptoms at the start of the study tended to have a history of poorer social adjustment. This link was particularly strong for symptoms related to motivation and pleasure, such as lack of interest in socializing or activities.

Academic struggles showed a slightly different pattern. Poor premorbid academic adjustment was associated with negative symptoms, but it was also strongly linked to cognitive impairment. Participants who had performed poorly in school tended to have lower scores on tests of verbal learning and IQ at the time of the study.

The researchers categorized participants into two groups based on when their symptoms started. The “early-symptom” group experienced their first attenuated psychotic symptoms in childhood or early adolescence. The “late-symptom” group developed these symptoms in late adolescence or adulthood.

For the late-symptom group, the researchers used growth curve modeling to track changes in functioning over time. The analysis showed that social adjustment tended to deteriorate as these individuals moved from childhood through late adolescence. This decline occurred before the onset of their clinical high-risk symptoms. This suggests that a drop in social functioning is a dynamic process that precedes the more obvious signs of illness.

In contrast to negative symptoms and cognition, the severity of attenuated psychotic symptoms themselves—such as suspiciousness—was largely unrelated to the history of social or academic functioning. This lack of association implies that the “positive” symptoms of psychosis may develop along a different pathway than the functional deficits. It suggests that social withdrawal and school failure are not simply consequences of being suspicious or hearing things.

The study also found that depression and anxiety were common in the sample. High levels of depression and anxiety correlated with worse premorbid adjustment. However, even when the researchers statistically adjusted for these mood issues, the relationships between negative symptoms, cognition, and premorbid functioning remained significant. This indicates that the functional declines are uniquely tied to the psychosis-risk state and are not solely explained by comorbid mood disorders.

The findings were largely consistent when the researchers analyzed the subgroup of participants residing outside of North America. This replication supports the idea that the developmental trajectory of psychosis risk shares common features globally. There were minor regional variations, but the core associations remained robust.

There are limitations to consider regarding this study. The assessment of premorbid adjustment relied on retrospective reporting. This means participants and their families had to recall functioning from childhood, which can be subject to memory errors. Additionally, the Premorbid Adjustment Scale assumes that children attend school full-time, which may not be the norm in all cultural contexts included in the study.

Future research aims to collect longitudinal data to see how these participants fare over time. The current study looked backward, but tracking these individuals forward will determine who eventually transitions to a full psychotic disorder. Researchers also suggest investigating how cultural norms regarding adolescent independence might influence these functional trajectories.

The study, “Premorbid adjustment problems, negative symptoms, and cognitive impairment in a large international sample at clinical high risk for psychosis: Findings from the Accelerating Medicines Partnership—Schizophrenia,” was authored by Henry R Cowan, Danielle Pratt, Jai L Shah, Scott W Woods, Luis Alameda, Martin Lepage, Stewart A Shankman, Jean Addington, Celso Arango, Carrie E Bearden, Sylvain Bouix, Nicholas J K Breitborde, Matthew R Broome, Kristin S Cadenhead, Monica E Calkins, Rolando I Castillo-Passi, Eric Yu Hai Chen, Jimmy Choi, Philippe Conus, Cheryl M Corcoran, Barbara A Cornblatt, Covadonga M Diaz-Caneja, Lauren M Ellman, Paolo Fusar-Poli, Pablo A Gaspar, Carla Gerber, Louise Birkedal Glenthøj, Cláudia Gonçalves, Leslie E Horton, Christy Lai Ming Hui, Joseph Kambeitz, Lana Kambeitz-Ilankovic, Rene S Kahn, John M Kane, Matcheri S Keshavan, Minah Kim, Sung-Wan Kim, Nikolaos Koutsouleris, Jun Soo Kwon, Kerstin Langbein, Daniel Mamah, Daniel H Mathalon, Patrick D McGorry, Barnaby Nelson, Merete Nordentoft, Ofer Pasternak, Godfrey D Pearlson, Jesus Perez, Diana O Perkins, Albert R Powers, Jack Rogers, Fred W Sabb, Jason Schiffman, Martha E Shenton, Steven M Silverstein, Stefan Smesny, William S Stone, Gregory P Strauss, Judy L Thompson, Rachel Upthegrove, Swapna Verma, Jijun Wang, Daniel H Wolf, Alison Yung, Tianhong Zhang, Courtney Crawford, Walid Yassin, Sinead Kelly, Michael Coleman, Grace Jacobs, Kathryn E Lewandowski, Nora Penzel, Justin Baker, Guillermo Cecci, Kelly Allott, Kate Buccilli, Sophie Tod, Lauren Addamo, Lihua Xu, and Vijay A Mittal.