Research Points to New Therapies to Lessen the Severity of Delusions for Patients with Schizophrenia

New research has found that improvements to the severity of delusions in patients with schizophrenia-spectrum disorder recovering from an acute psychotic episode were significantly associated with reductions in volatility priors—someone’s expectations about the unpredictability of their environment. The findings from the new study, appearing in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier, suggest that volatility priors are modifiable, pointing to a potential novel treatment target.

As the most common psychotic symptom, delusions are strongly held beliefs that persist despite contradictory evidence and can cause significant distress and disability for millions of people around the world. Defined by the DSM-5 as “beliefs based on false inference,” there is limited knowledge about how these false inferences arise. Previous research suggests that delusional thinking may be related to how people experience volatility priors in their environment.

In schizophrenia-spectrum disorders, the brain’s volatility prior is often set abnormally high, so patients expect the world to be unpredictable, chaotic, and unstable even when it is not. To make sense of this, the brain generates delusions, which can be devastating to patients and families and contribute to social isolation, suicidality, incarceration, and functional disability. Current clinical approaches offer variable and often poor treatment options.

“Patients deserve more effective treatments,” explains lead investigator Julia M. Sheffield, PhD, Vanderbilt University Medical Center, Department of Psychiatry and Behavioral Sciences. “We sought to extend previous cross-sectional research and ask whether these volatility priors change alongside delusion severity, suggesting a state-marker (temporary condition) that could be modified with treatment, or whether they are stably elevated in patients prone to delusions, suggesting a trait-marker (permanent vulnerability) that could be a target for prevention.

Seventy-five adults with schizophrenia-spectrum disorders recovering from an acute psychotic episode that included delusional thought content were recruited from an inpatient psychiatric hospital. Researchers assessed volatility priors and delusional thinking at six timepoints over six months. Data were compared with a non-clinical control group of 71 individuals. To estimate volatility priors, participants performed a probabilistic reversal learning task, which was analyzed using computational modeling.

At the beginning of the study participants with schizophrenia-spectrum disorders had significantly elevated volatility priors compared to the control group. The severity of delusional thinking, paranoia, and volatility priors remained elevated at the end of six-month study period in schizophrenia-spectrum disorder, never fully normalizing. Critically, volatility priors were longitudinally associated with delusional thinking and paranoia, but not with depression or worry. Results remained unchanged after controlling for antipsychotic medication and baseline cognitive ability. There is also some evidence of stronger associations with delusions of a paranoid/persecutory theme, consistent with previous work.

Longitudinal assessment of a cognitive process using a behavioral paradigm can be challenging due to practice effects. People can learn the task and improve in their behavior as a result of task exposure, rather than a fundamental change in their cognitive state. Although investigators worked to mitigate it, their findings are confounded by this effect. However, despite that, patients continued to show elevated volatility priors at six months, at their sixth exposure to the task. This provided some validation that the task was not simply being over-learned, but that the task and modeling scheme were sensitive to volatility priors above and beyond practice effects.

“Leveraging the unique opportunity to recruit schizophrenia-spectrum disorder participants with delusions during an acute psychiatric episode and follow them over time, we demonstrate that a computational marker of belief updating – volatility priors – are significantly elevated at baseline, reduce over time, and longitudinally relate to the severity of specific, well-characterized clinical delusions,” notes Dr. Sheffield. “These data suggest that volatility priors are a state-sensitive cognitive marker of delusional thinking that can change with recovery, making it a potential candidate for treatment development to improve clinical delusions.”

Historically, delusions have been treated broadly with antipsychotic medications that dampen dopamine systems. By identifying that volatility priors are elevated at baseline and reduce over time in relation to reductions in delusion severity, this study provides foundational evidence that adjusting someone’s expectations about the volatility or unpredictability of their environment is a potential new treatment target.

Dr. Sheffield concludes, “These findings are an exciting step in understanding the mechanisms of delusions and lay the groundwork for bridging computational psychiatry and clinical treatment. Psychological interventions, such as cognitive behavioral therapy for psychosis, can incorporate this knowledge to develop novel treatments, promoting recovery from a disabling and distressing symptom of serious mental illness. The ultimate task is to improve the lives of patients and families.”

Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine School of Medicine, adds, “This research represents the first time that volatility priors have been assessed longitudinally in psychotic disorders during recovery. By tracking these changes over six months, the investigators provide the most comprehensive picture yet of how this underlying brain mechanism drives the severity of delusions.”

The article is “Longitudinal Associations Between Volatility Priors and Delusions in Individuals Recovering from an Acute Psychotic Episode,” by Julia M. Sheffield, Lauren M. Hall, Jinyuan Liu, Essence Leslie, Ali F. Sloan, Kendall Beals, Annalise Halverson, Sarah G. Vassall, Praveen Suthaharan, Neil D. Woodward, Stephan Heckers, and Philip R. Corlett (https://doi.org/10.1016/j.bpsc.2026.06.013). It appears online in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

The article is openly available at https://www.biologicalpsychiatrycnni.org/article/S2451-9022(26)00188-6/fulltext.

This work was supported by the National Institute of Mental Health grant (K23-MH126313).

The authors’ affiliations and disclosures of financial relationships and conflicts of interest are available in the article.

Cameron S. Carter, MD, is Chair of the Department of Psychiatry & Human Behavior at the University of California Irvine School of Medicine. His disclosures of financial relationships and conflicts of interest are available here.

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is an official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal focuses on studies using the tools and constructs of cognitive neuroscience, including the full range of non-invasive neuroimaging and human extra- and intracranial physiological recording methodologies. It publishes both basic and clinical studies, including those that incorporate genetic data, pharmacological challenges, and computational modeling approaches. The 2025 Journal Impact Factor ^TM score, from Clarivate, for Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is 4.9. www.sobp.org/bpcnni

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