Focal Gray Matter Changes in Schizophrenia across the Course of the Illness: A 5-Year Follow-Up Study

Abstract

Recent volumetric magnetic resonance imaging (MRI) studies have suggested brain volume changes in schizophrenia to be progressive in nature. Whether this is a global process or some brain areas are more affected than others is not known. In a 5-year longitudinal study, MRI whole brain scans were obtained from 96 patients with schizophrenia and 113 matched healthy comparison subjects. Changes over time in focal gray and white matter were measured with voxel-based morphometry throughout the brain. Over the 5-year interval, excessive decreases in gray matter density were found in patients in the left superior frontal area (Brodmann areas 9/10), left superior temporal gyrus (Brodmann area 42), right caudate nucleus, and right thalamus as compared to healthy individuals. Excessive gray matter density decrease in the superior frontal gray matter was related to increased number of hospitalizations, whereas a higher cumulative dose of clozapine and olanzapine during the scan interval was related to lesser decreases in this area. In conclusion, gray matter density loss occurs across the course of the illness in schizophrenia, predominantly in left frontal and temporal cortices. Moreover, the progression in left frontal density loss appears to be related to an increased number of psychotic episodes, with atypical antipsychotic medication attenuating these changes.

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

“…29,30 MRI studies using diffusion tensor imaging in vivo have indicated abnormalities in white matter in prefrontal cortex and other brain areas of patients with schizophrenia, indicating the possibility of disturbed maintenance of myelination through oligodendrocytes [31][32][33][34] although not all studies agree. 35,36 Recently, postmortem gene expression profiling has boosted the field by showing that many myelinrelated genes are downregulated in several brain regions of patients with schizophrenia compared with controls [37][38][39][40][41] Furthermore, it is interesting to note that while most of the myelination occurs shortly postnatally, 42 the peak of myelination in the cortical areas and especially in the prefrontal cortex occurs during the adolescence and early adulthood, 43,44 thus coinciding with a critical period for the onset of schizophrenia. 45,46 Myelin is composed of 70% cholesterol, and impaired cholesterol biosynthesis by disruption of the squalene synthase (an SREBP-controlled gene), has been shown to severely disrupt myelination.…”

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

“…Furthermore, several studies have found these structural brain abnormalities to be progressive over time (van Haren et al, 2007;Kempton et al, 2010;Fusar-Poli et al, 2013), with greater rates of progression potentially associated with a poorer clinical outcome (Cahn et al, 2006;van Haren et al, 2008). In addition, widespread cortical thinning of the cerebral cortex involving not just frontotemporal regions but also parietal and occipital regions has been demonstrated in individuals with schizophrenia compared with healthy controls (Nesvåg et al, 2008;Sprooten et al, 2013).…”

“…For example, typical antipsychotic agents have consistently but not universally been associated with increased volume of the basal ganglia including the caudate (Scherk and Falkai, 2006;Ebdrup et al, 2013). However, clozapine monotherapy has consistently been associated with a reduction in caudate volume (Scheepers et al, 2001;van Haren et al, 2007), with this reduction in volume associated with clinical improvement (Scheepers et al, 2001). Similarly, in contrast to typical antipsychotic agents (Lieberman et al, 2005;van Haren et al, 2007), clozapine treatment has been associated in longitudinal studies with either an increase (Molina et al, 2005) or an attenuated loss of volume of the frontal lobe compared with typical antipsychotic agents (van Haren et al, 2007).…”

Association between a longer duration of illness, age and lower frontal lobe grey matter volume in schizophrenia

“…GM volume decrease in frontal and temporal regions over a five-year period has been observed, with a progressive GM loss in the left frontal lobe as the number of psychotic episodes increased [23]. One study [24] of 20 schizophrenia patients (mean age = 37 years, median duration of illness = 15 years [2-41 years]) did not observe any association between duration of illness and GM volume across the brain.…”