Summary: Schizophrenia and psychosis do not follow a single, predictable path. A landmark 10-year study has mapped the complex interaction between brain maturation, medication, and cognitive symptoms in 357 patients.
The research used a “percentile-based analysis”—similar to how pediatricians track a child’s height and weight—to identify atypical brain volumes. The findings show that while a first psychotic episode is marked by significant cortical volume loss, particularly in serotonin and dopamine-rich regions, clinical stabilization and treatment can actually attenuate the rate of brain deterioration over time.
Key Facts
- Cortical Reduction: At the first psychotic episode, patients show a marked reduction in cortical volume, specifically in areas dense with serotonin and dopamine receptors.
- The Percentile Method: For the first time, researchers applied percentile-based analysis to detect brain deviations, providing a more personalized “growth chart” for psychiatric health.
- Medication Interaction: Structural differences tend to diminish with treatment, suggesting that medication helps slow down brain deterioration. However, those with more severe symptoms requiring higher doses show more persistent volume loss.
- Cognitive Recovery: While cognitive impairments appear early, clinical stabilization is often accompanied by a partial recovery of attention, memory, and processing speed.
- Inflammatory Component: The study suggests that non-neuronal brain cells involved in immune and inflammatory processes play a significant role in the pathophysiology of psychosis.
Source: University of Seville
Researchers at the University of Seville have analysed alterations in the cerebral cortex in people suffering from psychosis.
Their findings show that psychosis does not follow a single trajectory, but rather its evolution depends on a complex interaction between brain development, symptoms, cognition and treatment.
The authors therefore emphasise the need to adopt more personalised approaches that take individual differences into account in order to better understand the disease and optimise long-term therapeutic strategies.
Psychosis is a set of symptoms—such as hallucinations and delusions—that are common in schizophrenia and involve a loss of contact with reality. From their first manifestation, known as the first psychotic episode, these symptoms can appear and evolve in very different ways between individuals, thus making schizophrenia a particularly complex disorder.
The results of the study show that, at the time of the first episode, people with psychosis present a reduction in cortical volume, which is particularly marked in regions with a high density of serotonin and dopamine receptors, key neurotransmitters in both the pathophysiology of psychosis and the mechanism of action of antipsychotics.
The data also suggest that both neurons and other brain cells involved in inflammatory and immunological processes may play an important role in the disease.
These structural differences tend to diminish during treatment, thereby suggesting that the rate of brain deterioration is attenuated by clinical intervention. However, more marked differences persist in people who receive higher doses of antipsychotic medication over time. This does not necessarily imply that the medication causes volume loss, but rather that those patients with more severe symptoms often require higher doses.
The study also confirms that these patients show cognitive impairments from very early stages. Throughout follow-up, many individuals experienced improvement in both symptoms and cognition, thus suggesting that clinical stabilisation may be accompanied by partial recovery of these functions. However, this improvement is less pronounced in those who require higher-dose treatments.
In the 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, magnetic resonance images were acquired to calculate the volume of different regions of the cerebral cortex in 357 patients with schizophrenia and 195 controls.
One of the most relevant aspects of the study is that the participants were evaluated over a period of ten years, thereby allowing an analysis of how the brain changes in the long term and how these changes are related to clinical symptoms and cognitive performance, including possible difficulties in attention, memory, or processing speed.
In addition, the study applies a percentile-based analysis for the first time. Just as percentiles are used in paediatrics to identify deviations in weight or height, they can now be used to detect whether certain brain regions have atypical volumes.
Key Questions Answered:
A: The study shows that while there is an initial loss of cortical volume, it isn’t necessarily a one-way street. Clinical intervention and stabilization can slow down this deterioration, and some patients even see a partial recovery of cognitive functions like memory and attention.
A: It’s a complex relationship. The study found that while people on higher doses had more brain volume loss, this is likely because they had more severe symptoms to begin with. In fact, the data suggests that consistent treatment helps the brain “catch up” and reduces the rate of deterioration compared to being untreated.
A: Just like a doctor checks if a baby is in the 50th percentile for height, this method checks if your brain regions are “atypical” compared to a healthy population. This allows for a much more personalized approach to treatment, rather than treating everyone with the same diagnosis as if they have the same brain.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this schizophrenia and psychosis research news
Author: María García Gordillo
Source: University of Seville
Contact: María García Gordillo – University of Seville
Image: The image is credited to 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
Clinical progression during psychosis has been closely associated with grey matter abnormalities resulting from atypical brain development. However, the complex interplay between psychopathology and heterogeneous maturational trajectories challenges the identification of neuroanatomical features that anticipate symptomatic decline.
Aims
To investigate cortical volume longitudinal deviations in first-episode psychosis (FEP) using normative modelling, exploring their relationship with long-term cognitive and symptomatic outcomes, as well as their cytoarchitectural and neurobiological underpinnings.
Method
We collected magnetic resonance imaging (MRI), cognitive and symptomatic data from 195 healthy controls and 357 drug-naïve or minimally medicated FEP individuals that were followed up 1, 3, 5 and 10 years following the first episode (1209 MRI scans and assessments in total).
Using normative modelling, we derived subject-specific centile scores for cortical volume to investigate atypical deviations in FEP and their relationship to long-term cognitive and symptomatic deterioration. The resulting centile association maps were further characterised by examining their cytoarchitectural and neurobiological attributes using normative atlases.
Results
FEP centiles demonstrated a widespread reduction at treatment initiation, with longitudinal analysis showing an increase during treatment time, indicating convergence towards normal maturation trajectories. Interestingly, this effect was reduced in highly medicated individuals. Additionally, we found that cognitive impairments experienced during early FEP stages worsened under long-term medication.
Positive symptomatology was negatively associated with regional centiles, and individuals with higher centiles benefited most from treatment. Cytoarchitectural and neurobiological analyses revealed that regional centiles related to FEP, as well as to symptomatology, were associated with specific molecular features, such as regional serotonin and dopamine receptor densities.
Conclusions
Collectively, these findings underscore the potential use of centile-based normative modelling for a better understanding of how atypical cortical development contributes to the long-term clinical progression of neurodevelopmental conditions.
