Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response

Bridget King; Dara M Cannon; Nicolas A Crossley; Alfonso Gonzalez-Valderrama; Brian Hallahan; Wi Hoon Jung; Matthew J Kempton; Seoyoung Kim; Andrew J Lawrence; James H MacCabe; Colm McDonald; Cristián Mena; Shinichiro Nakajima; Andrew Papale; Samira Raminfard; Deepak K Sarpal; Hyejin Sim; Giulia Tronchin; Lauri Tuominen; Euitae Kim; Alice Egerton

doi:10.64898/2026.06.06.26354980

Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response

Bridget King
, Dara M Cannon
, Nicolas A Crossley
, Alfonso Gonzalez-Valderrama
, Brian Hallahan
, Wi Hoon Jung
, Matthew J Kempton
, Seoyoung Kim
, Andrew J Lawrence
, James H MacCabe
, Colm McDonald
, Cristián Mena
, Shinichiro Nakajima
, Andrew Papale
, Samira Raminfard
, Deepak K Sarpal
, Hyejin Sim
, Giulia Tronchin
, Lauri Tuominen
, Euitae Kim

Alice Egerton^*

^*Corresponding author for this work

King's College London
Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway.
Department of Psychiatry, Pontificia, Universidad Catolica de Chile, Santiago, Chile.
Centro de Interés Nacional para Investigación e Innovación en Niñez, Adolescencia, Resiliencia y Adversidad (IINARA), Santiago, Chile.
Finis Terrae University
Dr José Horwitz Barack Psychiatric Institute
Gachon University
Seoul National University
Keio University
University of Pittsburgh School of Medicine
University of Ottawa

Research output: Working paper/Preprint › Preprint

Abstract

In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapine's pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT 1A, 5-HT 2A and 5-HT 4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapine's activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.

Original language	English
Publisher	MedRxiv
DOIs	https://doi.org/10.64898/2026.06.06.26354980
Publication status	Published - 10 Jun 2026

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Name	MedRxiv
Publisher	Cold Spring Harbor Laboratory Press

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King, B., Cannon, D. M., Crossley, N. A., Gonzalez-Valderrama, A., Hallahan, B., Jung, W. H., Kempton, M. J., Kim, S., Lawrence, A. J., MacCabe, J. H., McDonald, C., Mena, C., Nakajima, S., Papale, A., Raminfard, S., Sarpal, D. K., Sim, H., Tronchin, G., Tuominen, L., ... Egerton, A. (2026). Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response. (MedRxiv). MedRxiv. https://doi.org/10.64898/2026.06.06.26354980

@techreport{08027456e4a3490fa5835c890eda220c,

title = "Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response",

abstract = "In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapine's pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT 1A, 5-HT 2A and 5-HT 4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapine's activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis. ",

author = "Bridget King and Cannon, \{Dara M\} and Crossley, \{Nicolas A\} and Alfonso Gonzalez-Valderrama and Brian Hallahan and Jung, \{Wi Hoon\} and Kempton, \{Matthew J\} and Seoyoung Kim and Lawrence, \{Andrew J\} and MacCabe, \{James H\} and Colm McDonald and Cristi{\'a}n Mena and Shinichiro Nakajima and Andrew Papale and Samira Raminfard and Sarpal, \{Deepak K\} and Hyejin Sim and Giulia Tronchin and Lauri Tuominen and Euitae Kim and Alice Egerton",

year = "2026",

month = jun,

day = "10",

doi = "10.64898/2026.06.06.26354980",

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King, B, Cannon, DM, Crossley, NA, Gonzalez-Valderrama, A, Hallahan, B, Jung, WH, Kempton, MJ, Kim, S, Lawrence, AJ , MacCabe, JH, McDonald, C, Mena, C, Nakajima, S, Papale, A, Raminfard, S, Sarpal, DK, Sim, H, Tronchin, G, Tuominen, L, Kim, E & Egerton, A 2026 'Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response' MedRxiv, MedRxiv. https://doi.org/10.64898/2026.06.06.26354980

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AU - King, Bridget

AU - Cannon, Dara M

AU - Crossley, Nicolas A

AU - Gonzalez-Valderrama, Alfonso

AU - Hallahan, Brian

AU - Jung, Wi Hoon

AU - Kempton, Matthew J

AU - Kim, Seoyoung

AU - Lawrence, Andrew J

AU - MacCabe, James H

AU - McDonald, Colm

AU - Mena, Cristián

AU - Nakajima, Shinichiro

AU - Papale, Andrew

AU - Raminfard, Samira

AU - Sarpal, Deepak K

AU - Sim, Hyejin

AU - Tronchin, Giulia

AU - Tuominen, Lauri

AU - Kim, Euitae

AU - Egerton, Alice

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N2 - In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapine's pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT 1A, 5-HT 2A and 5-HT 4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapine's activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.

AB - In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapine's pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT 1A, 5-HT 2A and 5-HT 4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapine's activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.

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DO - 10.64898/2026.06.06.26354980

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T3 - MedRxiv

BT - Longitudinal brain structural changes during clozapine treatment

PB - MedRxiv

ER -

Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response

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