Summary: Schizophrenia and psychosis do not follow a single predictable course. A landmark 10-year study of 357 patients has mapped the complex interplay between brain maturation, antipsychotic treatment, and cognitive symptoms, revealing patterns of early cortical loss and subsequent partial recovery linked to clinical stabilization and medication.
Using a percentile-based, normative modelling approach—similar to the growth charts clinicians use for height and weight—the researchers identified atypical cortical volumes in people after a first psychotic episode. The results show pronounced cortical reductions at illness onset, particularly in brain regions rich in serotonin and dopamine receptors, and indicate that clinical treatment is associated with a slowed rate of further structural decline in many patients.
Key Facts
- Early Cortical Reduction: At the first psychotic episode, patients commonly show significant reductions in cortical volume, most notably in areas with high densities of serotonin and dopamine receptors—regions implicated in psychosis and targeted by antipsychotic drugs.
- Percentile-Based Detection: The study applied centile or percentile analysis to brain measures for the first time in this context, enabling individualized assessment of whether specific cortical regions are atypical relative to a healthy population.
- Treatment Interaction: Structural differences tend to lessen during clinical follow-up, suggesting that treatment and clinical stabilization are associated with convergence toward typical maturation trajectories. That said, people who require higher cumulative antipsychotic doses tend to show more persistent volume differences—likely reflecting greater baseline severity rather than a direct causal effect of medication.
- Cognitive Course: Cognitive deficits in attention, memory, and processing speed are evident early but can partially improve with symptom stabilization. Improvement is generally smaller in those needing higher-dose treatments.
- Role of Non-Neuronal Cells: Analyses suggest that non-neuronal cells involved in immune and inflammatory processes may contribute to the atypical cortical patterns observed in psychosis.
Source: University of Seville
Researchers at the University of Seville examined cortical alterations in people with psychosis.
Their longitudinal findings indicate that psychosis follows diverse trajectories determined by the interaction of brain maturation, clinical symptoms, cognition, and treatment history. The authors stress the need for more personalized clinical approaches that account for individual differences in brain structure and functional outcomes.
Psychosis—characterized by symptoms such as hallucinations and delusions that reflect a loss of contact with reality—can begin with a first episode that unfolds very differently across individuals. This heterogeneity complicates efforts to predict long-term outcomes in schizophrenia spectrum disorders.
The study reports that, at illness onset, patients show reduced cortical volumes in regions with dense serotonin and dopamine receptor expression. These neurotransmitter systems are central both to the biology of psychosis and to how most antipsychotic medications act. The data also implicate inflammatory and immune-related brain cells in the disease process, suggesting a multimodal biological substrate.
Importantly, structural deviations tend to decrease during treatment follow-up, indicating that clinical intervention can attenuate the pace of cortical deterioration. Persistent differences are more common among individuals who require higher antipsychotic doses over time, a pattern that likely reflects more severe or treatment-resistant illness rather than a simple medication effect.
Cognitive impairment is present from early stages of first-episode psychosis. Over the decade of follow-up, many patients showed improvements in symptoms and cognitive measures—especially attention, memory, and processing speed—consistent with partial recovery accompanying clinical stabilization. However, cognitive gains were smaller in patients needing higher-dose regimens.
The longitudinal study, led by Claudio Alemán Morillo and Rafael Romero García at the Neuroimaging and Brain Networks Laboratory of the University of Seville and published in the British Journal of Psychiatry, acquired magnetic resonance images to measure cortical volumes in 357 individuals with schizophrenia-spectrum first-episode psychosis (FEP) and 195 healthy controls. Participants underwent assessments at baseline and at 1, 3, 5, and 10 years, providing 1,209 MRI scans and cognitive and symptom evaluations in total.
A key innovation was the use of normative centile modelling: each participant’s cortical volume measurements were converted into subject-specific centile scores to identify regional deviations from normative brain maturation. The centile association maps were further examined against cytoarchitectural and molecular atlases, revealing relationships with regional serotonin and dopamine receptor densities and other neurobiological features.
Key Questions Answered:
A: The study indicates that early cortical loss occurs but is not always irreversible. Clinical intervention and stabilization can slow further deterioration, and many patients experience partial recovery in cognitive functions such as memory and attention.
A: The relationship is complex. Higher cumulative medication exposure was associated with more persistent volume differences, but this is likely confounded by greater illness severity in those patients. Overall, the data suggest that consistent treatment is associated with reduced progression of structural abnormalities compared with untreated illness.
A: Similar to pediatric growth percentiles, centile-based normative modelling compares an individual’s regional brain volumes to a healthy reference distribution. This reveals whether specific regions are unusually small or large for that person’s age and sex, enabling a more personalized assessment of brain health.
Editorial Notes:
- Edited by an editor at Neuroscience News.
- The full journal article was reviewed for accuracy.
- Additional contextual information was provided by editorial staff.
About this schizophrenia and psychosis research news
Author: María García Gordillo
Source: University of Seville
Contact: María García Gordillo – University of Seville
Image: Image credit: Neuroscience News
Original Research: Open access.
“Medication and atypical brain maturation in psychosis associated with long-term cognitive decline and symptom progression” by Claudio Alemán-Morillo, Natalia García-San-Martín, Richard A. I. Bethlehem, Lena Dorfschmidt, María Alemany-Navarro, Patricia Segura, Alessia Pasquini, Manuel Muñoz-Caracuel, Manuel Canal-Rivero, Jakob Seidlitz, Rosa Ayesa-Arriola, Javier Vázquez-Bourgon, John Suckling, Miguel Ruiz-Veguilla, Benedicto Crespo-Facorro, and Rafael Romero-García. British Journal of Psychiatry.
DOI: 10.1192/bjp.2025.10482
Abstract
Medication and atypical brain maturation in psychosis associated with long-term cognitive decline and symptom progression
Background
Progression in psychotic disorders has been linked to grey matter abnormalities that reflect atypical cortical development. The heterogeneous nature of these maturational trajectories and their interaction with psychopathology has made it difficult to identify neuroanatomical markers that reliably predict symptomatic decline.
Aims
This study aimed to track longitudinal deviations in cortical volume in first-episode psychosis (FEP) using normative centile modelling and to relate those deviations to long-term cognitive and clinical outcomes and their underlying cytoarchitectural and molecular features.
Method
Magnetic resonance imaging (MRI), cognitive assessments, and symptom ratings were collected from 195 healthy controls and 357 minimally medicated or drug-naïve FEP individuals, with follow-ups at 1, 3, 5, and 10 years (1,209 MRI scans and assessments total). Normative modelling produced subject-specific centile scores for cortical volume to detect atypical regional deviations and to link these to long-term cognitive and symptomatic trajectories. Resulting centile association maps were characterized using normative cytoarchitectural and neurobiological atlases.
Results
At baseline, FEP patients showed widespread reductions in cortical centiles. Over the course of treatment, centile scores increased overall, indicating a partial convergence toward normative maturation trajectories, though this improvement was attenuated in highly medicated individuals. Early cognitive impairments tended to worsen under long-term medication exposure in some patients. Positive symptom severity correlated negatively with regional centiles, and individuals with higher centile scores derived the greatest benefit from treatment. Cytoarchitectural and molecular analyses linked affected regions to specific features such as serotonin and dopamine receptor density.
Conclusions
These findings highlight percentile-based normative modelling as a promising tool to better understand how atypical cortical development contributes to long-term clinical progression in neurodevelopmental disorders such as schizophrenia and to support more individualized therapeutic strategies.