Abstract
Background
The association of antipsychotic medication with abnormal brain morphometry in schizophrenia remains uncertain. Early studies investigating a switch from first generation antipsychotic to clozapine have steadily shown a decrease of caudate volume over time; however nowadays most patients are already on second generation antipsychotic medications prior to clozapine commencement and it remains unclear whether switching to clozapine in such circumstances would have any such effect on the basal ganglia. In this study we aimed to comprehensively investigate whether after 6 months of switching to clozapine, subcortical structures demonstrate any progressively neuroanatomical changes in patients with treatment-resistant schizophrenia compared to healthy controls, and whether any such changes are related to clinical variables including treatment response and amount of clozapine taken.
Methods
MRI images were acquired for all participants at baseline and after 6 months at University Hospital Galway in a 1.5 T scanner. The longitudinal pipeline of Freesurfer v.5.3.0, based on an unbiased within-subject anatomical template, was employed to segment eight subcortical regions-of-interest: lateral ventricle, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala and nucleus accumbens. Subcortical volumes were bilaterally extracted following quality check of raw data and segmentation. Clinical assessments included the Positive and Negative Syndrome Scale (PANSS), The Scale for the Assessment of Positive Symptoms (SAPS), The Scale for the Assessment of Negative Symptoms (SANS) and Global Assessment Functioning Score (GAF). Two-way repeated ANCOVA was used to assess group differences in subcortical volumes over time and partial correlations to determine association with clinical variables. Change in volume was expressed using the following formula: (Follow Up -Baseline)/Baseline x 100.
Results
33 patients with treatment-resistant schizophrenia (TRS) and 31 healthy volunteers (HC) matched for sex and age were successfully recruited at both baseline prior to clozapine treatment and after 6 months. There was a significant effect of time on subcortical brain volumes between TRS and controls (F(7,143)= 52.54, p<0.001). Corrected post-hoc analyses demonstrated that patients had significant enlargement of lateral ventricles (F(1,59)= 48.89; p<0.001) and reduction of thalamus (F(1,59)= 34.85; p<0.001), caudate (F(1,59)= 59.35; p<0.001), putamen (F(1,59)= 87.20; p<0.001) and hippocampus (F(1,59)= 14.49; p<0.001) volumes. Thalamus and putamen volume reduction was associated with improvement in PANSS (r=0.42; p=0.021, r=0.39; p=0.033), SANS (r=0.36; p=0.049, r=0.40; p=0.027) and GAF (r=-0.39; p=0.038, r=-0.42; p=0.024). Reduced thalamic volume over time was associated with increased serum level at follow-up (r=-0.44; p=0.010). There was no significant overall effect of time on subcortical brain structures between patients responding to clozapine compared to patients non-responding to clozapine (F(7,20)=0.50; p=0.834).
Discussion
This study demonstrates that, despite the clinical and functional improvement of most patients with schizophrenia who are switched to clozapine, there is a counterintuitive progressive volume reduction in several subcortical structures over time. Furthermore, patients who have the greatest symptomatic improvement display the largest thalamo-putaminal reductions, indicating that volume reduction reflects an adaptive response associated with symptom improvement rather than a harmful or neurotoxic process in these patients.
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