Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness.

BACKGROUND: Structural brain abnormalities in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, but it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression of brain abnormalities in schizophrenia, information from cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls may also be useful to further clarify this issue. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, age of onset, illness duration and overall illness severity. METHODS: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes. RESULTS: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses (p < 0.05, FWE-corrected), including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). GM volumes in several of those brain regions were directly correlated with age of disease onset on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. There were also widespread foci of significant negative correlation between duration of illness and relative GM volumes, but such findings remained significant only for the right dorsolateral prefrontal cortex after accounting for the influence of age of disease onset. Finally, significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. CONCLUSION: The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe) cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions.

Psychotic symptoms in older people without dementia from a Brazilian community-based sample.

BACKGROUND: The international prevalence of psychotic symptoms in older subjects without dementia varies from 0.9% to 8.0%. However, an analysis of these symptoms in developing countries has not been undertaken. AIMS: To determine the prevalence and to correlate these symptoms with socioeconomic and clinical characteristics. METHOD: A community-based sample aged 60 years and older was evaluated. Those who screened positive for dementia, cognitive and functional impairment or significant depressive symptoms were excluded, resulting in 1125 individuals. RESULTS: The prevalence of psychotic symptoms was 9.1% (visual/tactile hallucinations, 7.8%; auditive hallucinations, 7.5%; persecutory delusions, 2.9%). Subjects with psychotic symptoms had lower Mini Mental State Examination and The Bayer Activities of Daily Living Scale scores, fewer years of schooling, belonged to lower socioeconomic classes compared with non-psychotic subjects, and 80% had clinical comorbidities. CONCLUSIONS: The prevalence was in the upper range of international data. Significant relationships were found between psychotic symptoms and lower Mini Mental State Examination score, fewer years of schooling and lower socioeconomic class. Clinical comorbidity was also very frequent.

Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature.

BACKGROUND: Cognitive deficits have been described in patients with schizophrenia from the first descriptions of dementia praecox to current concepts of cognitive dysmetria. Nevertheless, little is known about how to deal with them. In Alzheimer disease, cholinergic deficit is found and cholinesterase inhibitors have been used to delay the progression of memory and cognitive dysfunction. Several lines of evidence suggest that the cholinergic system may be disrupted in schizophrenia. OBJECTIVE: To evaluate cognitive and clinical effects of adjunctive cholinesterase inhibitors in patients with schizophrenia and schizoaffective disorder. METHOD: We conducted a literature search on PubMed and EMBASE (up to December 2008) for articles that investigated adjunctive cholinesterase inhibitors in patients with schizophrenia. The terms 'schizophrenia', 'acetylcholinesterase inhibitors', 'rivastigmine', 'donepezil', 'galantamine' and 'cognitive deficit' were searched with restriction for English language and without a year limit. All articles that presented original data from randomized, double-blind, placebo-controlled trials with donepezil, rivastigmine or galantamine in patients with schizophrenia or schizoaffective disorder were included in the meta-analysis. Studies were excluded for the following reasons: (i) case study/letter/correspondence/review; (ii) animal study; (iii) molecular/genetic investigation; and (iv) inclusion of patients with schizophrenia and co-morbid dementia. Few appropriate data for meta-analysis were found because of the large heterogeneity of the assessment instruments used. Nevertheless, effects of cholinesterase inhibitors in some cognitive domains (executive function, memory and language), psychopathology (using the Positive and Negative Syndrome Scale) and extrapyramidal symptoms could be analysed. RESULTS: Six open-label and 24 double-blind studies were found. In five open-label studies there was an improvement in memory, attention and executive functions. Thirteen double-blind studies (four with rivastigmine, six with donepezil and three with galantamine) contributed to the meta-analysis. Significant improvement was found in this analysis for memory and the Trail Making test part A. CONCLUSIONS: The reviewed studies suggest that specific cognitive deficits (memory, and the motor speed and attention part of executive function) of patients with schizophrenia and schizoaffective disorder are responsive to rivastigmine, donepezil and galantamine as adjunctive therapy. Confirmatory studies are needed to determine the clinical utility of this treatment strategy.