Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia

Abstract

Background: Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia.

Methods: We obtained high-resolution 3-dimensional T1-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse.

Results: We found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia.

Limitations: This study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small.

Conclusion: Reductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.

Trial registration: ClinicalTrials.gov NCT00207064.

Fig. 1

Voxel-wise hippocampal grey matter volume reductions in first-episode schizophrenia patients for the right (right, mirrored) and left hemispheres (left). Voxel-wise nonparametric statistic results showing areas were all schizophrenia patients had smaller hippocampal grey matter volumes than healthy controls (yellow), areas where patients with any lifetime substance abuse had smaller volumes than healthy controls (red), and the overlap of the 2 contrasts (orange). Displayed voxels survived a false discovery rate–corrected (p < 0.05) small volume correction restricted to the hippocampus. Results are projected on sagittal slices of the average of all DARTEL-warped magnetization-prepared rapid-gradient echo images. From top to bottom, the images are 18, 23 and 28 mm, respectively, from the midsagittal plane.

Fig. 2

Boxplot of hippocampal volumes in schizophrenia patients with any lifetime substance abuse (Pt_ab), patients with no lifetime substance abuse (Pt_non-ab) and matched healthy controls. Volumes are corrected for age, sex and intracranial volume. In the box-and-whisker plot, the central box represents the values from the lower to upper quartile. The transverse line in the box represents the median corrected volume. The vertical line extends from the minimum to the maximum value, excluding outside values. Outside values are defined as values smaller or larger than the lower quartile minus 1.5 times the interquartile range and are displayed as separate points (?). No outliers were identified.

Fig. 3

Voxel-wise caudate grey matter volume reductions in patients with first-episode schizophrenia in the right (right, mirrored) and left (left) hemispheres. Voxel-wise nonparametric statistic results showing areas were all patients had smaller caudate nucleus grey matter volumes than healthy controls (yellow), areas where patients with no lifetime substance abuse diagnosis had smaller volumes than healthy controls (purple) and the overlap of the 2 contrasts (orange). Displayed voxels survived a false discovery rate–corrected (p < 0.05) small volume correction restricted to the caudate nucleus. Results are projected on sagittal slices of the average of all DARTEL warped magnetization-prepared rapid-gradient echo images. From top to bottom, the images are 13, 18 and 23 mm, respectively, from the midsagittal plane.

Fig. 4

Boxplot of caudate nucleus volumes in schizophrenia patients with any lifetime substance abuse (Pt_ab), patients with no life-time substance abuse (Pt_non-ab) and matched healthy controls. Volumes are corrected for age, sex and intracranial volume. See Figure 2 for information about interpretation of the boxplot.