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Region Hovedstaden - en del af Københavns Universitetshospital

Structural Brain Changes in Antipsychotic-Naïve First-Episode Schizophrenia Patients Before and After Six Months of Antipsychotic Monotherapy

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Magnetic resonance imaging (MRI) studies have widely demonstrated the presence of structural brain abnormalities in multiple brain regions in schizophrenia patients compared to healthy control subjects. Accumulating evidence from longitudinal studies in schizophrenia patients suggest that structural brain abnormalities are not static, but progress over the course of illness. Because the patients included in longitudinal studies have often been treated with several different antipsychotic compounds before and during the investigation period it is difficult to disentangle effects related to the disease from medication effects on brain structure.
This project encompasses structural MRI studies in antipsychotic-naïve schizophrenia patients before and after six months of antipsychotic monotherapy with quetiapine. Structural MRI and functional fMRI data were
acquired. For fMRI we have used a verbal working memory (N-Back) task. The fMRI data at baseline have been analyzed and are submitted (by Ayna Nejad, please, see later). Data on white matter integrity as been
obtained by diffusion tensor imaging (DTI) and analyses of these data are currently running.
In the following the analyses of structural data (GM and CSF) are described. In the baseline study, we used voxel-based morphometry (VBM) to investigate whether ventricular enlargement, and hippocampal and
caudate volume reductions are morphological traits in 38 antipsychotic-naïve first episode schizophrenia patients compared with 43 matched healthy control subjects. This hypothesis was based on two recent
meta-analyses on first-episode schizophrenia patients and on previous findings in antipsychotic-naïve schizophrenia patients, including findings in cohort A. We also examined associations with clinical variables.
Finally, we examined the possible effect of any lifetime substance abuse diagnosis. As hypothesized, we found that hippocampal and caudate nucleus volumes were decreased in patients. Ventricular enlargement
was absent. No differences in global volumes were found and no significant associations between tissue volumes and duration of untreated illness and psychopathology, respectively, were observed. The hippocampal reductions appeared to be influenced by a history of abuse. Exploratory analyses indicated
reduced nucleus accumbens volumes in the patients.
We concluded that hippocampal and caudate volume reductions may constitute a morphological trait in antipsychotic-naïve first episode schizophrenia patients. From a cross-sectional perspective the clinical implications of these findings are unclear. The data indicated that past substance abuse may accentuate
hippocampal volume reductions. MRI studies explicitly addressing the potential effects of substance abuse in antipsychotic-naïve first episode schizophrenia patients are warranted.
After the baseline investigations the patients were treated with the second generation antipsychotic compound quetiapine for 6 months in flexible doses according to their clinical need.
In the follow-up study, we used tensor-based morphometry (TBM) to investigate volumetric effects of quetiapine in 22 patients matched with 28 healthy control subjects. Whereas first-generation antipsychotics have been widely associated with striatal volume increases, the effects of second-generation antipsychotics
(SGA’s) on striatal volumes are unclear. Neuroprotective effects of SGA’s have been suggested on hippocampal volumes, whereas ventricular enlargement may be associated with clinical outcome. Dosedependent volumetric effects of individual SGA’s have been scarcely investigated. Finally, we wanted to explore possible associations between psychopathology and progressive brain changes.
We found that after six months of quetiapine treatment patients had significant volume loss in striatum and hippocampus. The striatal volume loss was most pronounced at low quetiapine doses and less apparent at high doses. Conversely, hippocampal volume loss appeared more pronounced at high quetiapine doses than at low doses. Clinically, higher baseline positive symptoms were associated with more striatal and hippocampal volume loss over time. Although patients’ ventricles did not change significantly, ventricular
increases correlated with less improvement on negative symptoms.
We concluded that progressive regional volume loss in quetiapine-treated first-episode schizophrenia patients may be dose-dependent and clinically relevant. The mechanisms underlying progressive brain changes, specific antipsychotic compounds and clinical symptoms warrant further clarification.

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