Progressive Brain Atrophy and Cortical Thinning in Schizophrenia after Commencing Clozapine Treatment

Abstract

Despite evidence that clozapine may be neuroprotective, there are few longitudinal magnetic resonance imaging (MRI) studies that have specifically explored an association between commencement of clozapine treatment for schizophrenia and changes in regional brain volume or cortical thickness. A total of 33 patients with treatment-resistant schizophrenia and 31 healthy controls matched for age and gender underwent structural MRI brain scans at baseline and 6-9 months after commencing clozapine. MRI images were analyzed using SIENA (Structural Image Evaluation, using Normalization, of Atrophy) and FreeSurfer to investigate changes over time in brain volume and cortical thickness respectively. Significantly greater reductions in volume were detected in the right and left medial prefrontal cortex and in the periventricular area in the patient group regardless of treatment response. Widespread further cortical thinning was observed in patients compared with healthy controls. The majority of patients improved symptomatically and functionally over the study period, and patients who improved were more likely to have less cortical thinning of the left medial frontal cortex and the right middle temporal cortex. These findings demonstrate on-going reductions in brain volume and progressive cortical thinning in patients with schizophrenia who are switched to clozapine treatment. It is possible that this gray matter loss reflects a progressive disease process irrespective of medication use or that it is contributed to by switching to clozapine treatment. The clinical improvement of most patients indicates that antipsychotic-related gray matter volume loss may not necessarily be harmful or reflect neurotoxicity.

Figure 1

(a) Masks applied to highly significnt clusters of RPFC, LPFC, and PVA identified with volume loss at follow-up in the patient group (n=33) compared with the control group (n=31). (b, c) Significant differences at follow-up in SIENA analysis between patients and controls in regional brain tissue edge movements (as a measure of regional brain volume change) in RPFC (MWW=141, p<0.001), LPFC (MWW=149, p<0.001), and PVA (MWW=61, p<0.001). No difference noted between responders (n=20) and nonresponders (n=13) to clozapine. LPFC, left prefrontal cortex; MWW, Mann–Whitney U-test; PVA, periventricular area; RPFC, right prefrontal cortex.

Figure 2

Differential changes in cortical thickness in patients (n=33) and controls (n=31) demonstrating regions of comparatively greater cerebral cortex thinning in patients. The significance in this display is a −log (10) p-value. Orange/yellow indicates greater thinning in patients than controls, whereas blue represents greater thinning in controls than patients.

Figure 3

Greater cortical thinning of LMFC and RMTC in NR patients (n=13) compared with RS (n=20). LMFC, left medial frontal cortex; NR, nonresponders; RMTC, right middle temporal cortex; RS, responders to clozapine.