The authors have declared that no competing interests exist.
Conceived and designed the experiments: YY YX. Performed the experiments: YY LT. Analyzed the data: LK YY. Contributed reagents/materials/analysis tools: YY HS LT YX. Wrote the paper: LK YY JW CL YX.
Both schizophrenia and antipsychotic treatment are known to modulate brain morphology. However, it is difficult to establish whether observed structural brain abnormalities are due to disease or the effects of treatment. The aim of this study was to investigate the effects of illness and antipsychotic treatment on brain structures in antipsychotic-naïve first-episode schizophrenia based on a longitudinal short-term design. Twenty antipsychotic-naïve subjects with first-episode schizophrenia and twenty-four age- and sex-matched healthy controls underwent 3T MRI scans. Voxel-based morphometry (VBM) was used to examine the brain structural abnormality in patients compared to healthy controls. Nine patients were included in the follow-up examination after 8 weeks of treatment. Tensor-based morphometry (TBM) was used to identify longitudinal brain structural changes. We observed significantly reduced grey matter volume in the right superior temporal gyrus in antipsychotic-naïve patients with schizophrenia compared with healthy controls. After 8 weeks of treatment, patients showed significantly increased grey matter volume primarily in the bilateral prefrontal cortex, insula, right thalamus, left superior occipital cortex and the bilateral cerebellum. In addition, a greater enlargement of the prefrontal cortex is associated with the improvement in negative symptoms, and a more enlarged thalamus is associated with greater improvement in positive symptoms. Our results suggest the following: (1) the abnormality in the right superior temporal gyrus is present in the early stages of schizophrenia, possibly representing the core region related to schizophrenia; and (2) atypical antipsychotics could modulate brain morphology involving the thalamus, cortical grey matter and cerebellum. In addition, examination of the prefrontal cortex and thalamus might facilitate an efficient response to atypical antipsychotics in terms of symptom improvement.
Schizophrenia is a complex psychotic disorder characterized by significant brain abnormalities. Numerous imaging studies have revealed reduced grey matter volume in patients with schizophrenia involving multiple brain regions, such as the frontal cortex, temporal lobe, and insula [
Accumulating evidence has indicated that antipsychotic medication might modulate brain morphology. For example, in a cross-sectional study comparing drug-free schizophrenia patients to schizophrenia patients treated with antipsychotics, Dazzan et al. (2005) demonstrated that increased thalamus volume was associated with atypical antipsychotics by comparing drug-free patients and patients with the use of antipsychotics [
In the present study, we first investigated whole brain structural changes by comparing antipsychotic-naïve patients with first-episode schizophrenia to healthy controls to identify the core regions related to schizophrenia. We further examined the effects of antipsychotics on brain structures after 8 weeks of atypical antipsychotic treatment. Few investigations to our knowledge have performed such a comprehensive study using antipsychotic-naïve patients to investigate disease-related changes in brain structure and then further performed a longitudinal study to examine the effects of atypical antipsychotics. This longitudinal study will be helpful in identifying small structural changes in the brain due to antipsychotic treatment in the early stage of disease.
Twenty-five subjects diagnosed with first-episode schizophrenia were recruited for the present study. Two subjects did not complete scanning, and 3 subjects were excluded because of poor image quality. Therefore, 20 patients (10 males and 10 females) were ultimately included in the patient group, with a mean age of 24.45 years (SD = 5.51) and an average of 11.95 years of education (SD = 2.61). Patients received atypical antipsychotics at an average daily dose of 285 mg/day (SD = 108.94) of chlorpromazine equivalents (CPZ; [
All subjects were scanned on a GE Sigma 3.0 T MR (GE Medical Systems, Milwaukee, Wisconsin) with T1-Weighted 3D magnetization with the following parameters: time to repetition (TR) = 7.8 ms; time to echo (TE) = 3.0 ms; flip angle = 7°; matrix = 256×256; voxel size = 1×1×1 mm3. Each scan was supervised by a trained technologist.
All of the T1-weighed MRI images were processed using the voxel-based morphometry (VBM) toolbox in SPM8 (The Wellcome Department of Imaging Neuroscience, London;
To investigate the volume changes in regional tissue after 8 weeks of treatment, MRI images were processed using tensor-based morphometry (TBM) [
Student’s t-test and chi-square tests using SPSS 17 (SPSS Inc., Chicago, IIIinois) were utilized to examine group differences in basic demographic characteristics and clinical data. Between-group differences in grey matter volume based on VBM analysis were analyzed using a t-test in SPM8, with age as a covariate. The results were obtained on a voxel-level height of threshold p<0.001, uncorrected, and a cluster-level extent threshold of 50 continuous voxels. The associations of grey matter volume in the distinct regions with PANSS and its subscores as well as untreated duration of illness were further performed using SPSS. The effect of untreated duration of illness on grey matter volume in the whole brain was also tested in the patients group by general linear models (GLM) in SPM.
The demographic characteristics of the follow-up and non follow-up groups were performed using Student’s t-test and chi-square tests using SPSS. The normality of the grey matter volume of the sample was conducted with descriptive statistics in SPSS. A paired t-test in SPM was used to identify regional grey matter changes after 8 weeks of treatment. Multi-regression analysis was used to examine the associations between the changes in regional grey matter volume and PANSS scores. The results were observed with a voxel-level height of threshold p<0.05, family-wise error (FWE) corrected, and cluster size of 100. The change in PANSS from baseline to follow-up was examined using a t-test in SPSS 17. The effect of dosage of medication on grey matter volume was tested in the patients group by GLM in SPM.
There were no significant differences between patients and healthy subjects in age, sex or education. The detailed information was described in
(a) | Controls (n = 24) Mean (SD) | Patients (n = 20) Mean (SD) | ||
Age (years) | 24.79 (6.11) | 24.45 (5.51) | 0.19 | 0.848 |
Education (years) | 13.17 (2.16) | 11.95 (2.61) | 1.69 | 0.098 |
Sex (M/F) | 13/11 | 10/10 | 0.783 |
|
PANSS | n/a. | 88.95 (14.86) | ||
Positive score | n/a. | 21.25 (5.42) | ||
Negative score | n/a. | 19.10 (6.26) | ||
General psychopathology | n/a. | 48.60 (8.19) | ||
Duration of illness (years) | n/a. | 1.91 (1.94) | ||
Medication (mg) | n/a. | 285 (108.94) | ||
(b) | follow-up group (n = 9) Mean (SD) | non follow-up (n = 11) Mean (SD) | ||
Age (years) | 23.00 (4.80) | 25.64 (5.99) | -1.07 | 0.299 |
Education (years) | 11.22 (2.64) | 12.55 (2.54) | -1.14 | 0.270 |
Sex (M/F) | 4/5 | 6/5 | 0.653 |
|
Duration of illness (years) | 1.68 (1.84) | 2.10 (2.09) | -0.47 | 0.642 |
Medication (mg) | 300 (150.00) | 272 (64.67) | 0.55 | 0.591 |
Data expressed as the means (SD); SD: standard deviation; df: degrees of freedom; PANSS: positive and negative syndrome scale; n/a.: not applicable;
*: χ2-test
Anatomical structure | Cluster size (voxel) | Peak Talairach coordinates x, y, z | |
---|---|---|---|
(a) | |||
Right superior temporal gyrus | 50 | 3.89 | 56, -6, -11 |
(b) | |||
Left superior frontal cortex, extending to right superior frontal cortex and left/right supplementary motor area | 965 | 48.20 | -2, 22, 40 |
Right middle frontal cortex | 226 | 34.62 | 42, 10, 40 |
Left middle frontal cortex | 348 | 28.78 | -22, 22, 46 |
Left insula | 451 | 27.41 | -38, -14, 18 |
Left superior occipital cortex | 147 | 25.47 | -16, -78, 30 |
Right insula | 518 | 25.11 | 38, -10, 16 |
Right cerebellum, extending to left cerebellum | 304 | 23.91 | 2, -54, -50 |
Right thalamus | 364 | 23.54 | 12, -24, 10 |
(a) Height threshold p<0.001, uncorrected, cluster size = 50;
(b) Height threshold p<0.05, corrected for family-wise error rate, cluster size = 100.
There were no significant difference between the follow-up group and non follow-up group in age, sex and education. The detailed information of the two sub-groups was described in the
After 8 weeks of treatment, pronounced grey matter increases were noted mainly in the prefrontal cortex (bilateral superior and middle frontal cortex), bilateral insula, left superior occipital cortex, left/right cerebellum and right thalamus (
Baseline Mean (SD) | Follow-up Mean (SD) | |||
---|---|---|---|---|
PANSS | 94.33 (17.33) | 59.11 (17.20) | 8.48 | 0.000 |
Positive score | 21.56 (6.63) | 10.78 (2.91) | 4.72 | 0.002 |
Negative score | 21.00 (5.5) | 14.89 (5.57) | 4.06 | 0.004 |
General psychopathology | 51.78 (10.22) | 33.44 (11.66) | 7.72 | 0.000 |
In this study, we first used VBM to investigate regional grey matter abnormalities in antipsychotic-naïve schizophrenia patients compared to healthy controls. We then examined the effect of antipsychotics on brain structures after 8 weeks of treatment in patients with schizophrenia. Our principal findings were that (1) decreased grey matter volume in the right superior temporal gyrus was observed in the early stage of the disease; and (2) after 8 weeks of antipsychotic treatment, patients showed significantly increased grey matter volume mainly in the bilateral prefrontal cortex, insula, right thalamus, left superior occipital cortex and the bilateral cerebellum. In addition, the grey matter volume in the prefrontal cortex and thalamus was associated with negative and positive symptoms, respectively.
Decreased grey matter volume in the right superior temporal gyrus was observed in the antipsychotic-naïve patients with schizophrenia relative to the healthy controls, which suggests an alteration in this region due to the disease. Our present results are consistent with those from a previous study investigating brain structural abnormality in antipsychotic-naïve patients with deficits in the superior temporal cortex [
Research has documented the ability of antipsychotic medication to produce brain volumetric changes even over a short period of time [
Increased prefrontal volume was also found after treatment, which is consistent with the previous findings of increased cortical thickness in the prefrontal cortex over 8 weeks of atypical antipsychotic treatment in first-episode schizophrenia [
The insula plays an important role in the regulating of emotion and cognition [
The cerebellum is known to be involved with motor coordination as well as with aspects of cognitive functioning such as attention, working memory, and sensory discrimination [
Finally, we also observed an increase in grey matter volume of the superior occipital cortex associated with atypical antipsychotics. Prior research has also shown volume enlargement of the superior occipital cortex to be associated with antipsychotics [
The present study also has some limitations. The modest sample size is the main limitation, although the study design was longitudinal. Additionally, this was a naturalistic study, meaning that the choice of medicine is clinician-led. In addition, the untreated duration of illness in the present study is a little long (mean duration of illness were 1.91 years). Although whether untreated duration of illness was associated with brain morphology in patients with schizophrenia was still equivalent [
Therefore, based on our findings, we suggest that (1) the right superior temporal gyrus may represent the core region of pathological change in schizophrenia; and (2) the effects of atypical antipsychotics could involve multiple regions, and examination of increased grey matter volume in the prefrontal cortex and thalamus may be particularly effective in evaluating the efficiency of response to exposure to atypical antipsychotics in the improvement of schizophrenia symptoms.
The authors thank our patients for participating this study.