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This study examined brain structural changes in 143 individuals with treatment-resistant schizophrenia during the first five months of clozapine treatment using combined MRI data from five longitudinal datasets. Clozapine was associated with volume reductions in multiple subcortical regions, ventricular enlargement, and widespread cortical thinning, with the greatest thinning occurring in areas with high densities of serotonergic receptors. However, these structural changes did not correlate with clinical improvement in symptom severity, and baseline brain structure did not predict treatment response.
Why it matters
These findings suggest that clozapine-induced brain structural changes may reflect neurobiological effects related to its serotonergic activity rather than mechanisms underlying its therapeutic efficacy. This challenges assumptions about the relationship between brain structure changes and clinical outcomes in antipsychotic treatment, potentially informing how we interpret neuroimaging findings in psychiatric medication research.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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 clozapines 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-HT1A, 5-HT2A and 5-HT4 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 clozapines 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.