Structural brain changes associated with antipsychotic treatment in schizophrenia as revealed by voxel-based morphometric MRI: an activation likelihood estimation meta-analysis

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Abstract

Background

The results of multiple studies on the association between antipsychotic use and structural brain changes in schizophrenia have been assessed only in qualitative literature reviews to date. We aimed to perform a meta-analysis of voxel-based morphometry (VBM) studies on this association to quantitatively synthesize the findings of these studies.

Methods

A systematic computerized literature search was carried out through MEDLINE/PubMed, EMBASE, ISI Web of Science, SCOPUS and PsycINFO databases aiming to identify all VBM studies addressing this question and meeting predetermined inclusion criteria. All studies reporting coordinates representing foci of structural brain changes associated with antipsychotic use were meta-analyzed by using the activation likelihood estimation technique, currently the most sophisticated and best-validated tool for voxel-wise meta-analysis of neuroimaging studies.

Results

Ten studies (five cross-sectional and five longitudinal) met the inclusion criteria and comprised a total of 548 individuals (298 patients on antipsychotic drugs and 250 controls). Depending on the methodologies of the selected studies, the control groups included healthy subjects, drug-free patients, or the same patients evaluated repeatedly in longitudinal comparisons (i.e., serving as their own controls). A total of 102 foci associated with structural alterations were retrieved. The meta-analysis revealed seven clusters of areas with consistent structural brain changes in patients on antipsychotics compared to controls. The seven clusters included four areas of relative volumetric decrease in the left lateral temporal cortex [Brodmann area (BA) 20], left inferior frontal gyrus (BA 44), superior frontal gyrus extending to the left middle frontal gyrus (BA 6), and right rectal gyrus (BA 11), and three areas of relative volumetric increase in the left dorsal anterior cingulate cortex (BA 24), left ventral anterior cingulate cortex (BA 24) and right putamen.

Conclusions

Our results identify the specific brain regions where possible associations between antipsychotic drug usage and structural brain changes in schizophrenia patients are more consistently reported. Additional longitudinal VBM studies including larger and more homogeneous samples of schizophrenia patients may be needed to further disentangle such alterations from those possibly linked to the intrinsic pathological progressive process in schizophrenia.

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Most cited references 90

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Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space.

D L Collins, P Neelin, T Peters … (1994)

In both diagnostic and research applications, the interpretation of MR images of the human brain is facilitated when different data sets can be compared by visual inspection of equivalent anatomical planes. Quantitative analysis with predefined atlas templates often requires the initial alignment of atlas and image planes. Unfortunately, the axial planes acquired during separate scanning sessions are often different in their relative position and orientation, and these slices are not coplanar with those in the atlas. We have developed a completely automatic method to register a given volumetric data set with Talairach stereotaxic coordinate system. The registration method is based on multi-scale, three-dimensional (3D) cross-correlation with an average (n > 300) MR brain image volume aligned with the Talariach stereotaxic space. Once the data set is re-sampled by the transformation recovered by the algorithm, atlas slices can be directly superimposed on the corresponding slices of the re-sampled volume. the use of such a standardized space also allows the direct comparison, voxel to voxel, of two or more data sets brought into stereotaxic space. With use of a two-tailed Student t test for paired samples, there was no significant difference in the transformation parameters recovered by the automatic algorithm when compared with two manual landmark-based methods (p > 0.1 for all parameters except y-scale, where p > 0.05). Using root-mean-square difference between normalized voxel intensities as an unbiased measure of registration, we show that when estimated and averaged over 60 volumetric MR images in standard space, this measure was 30% lower for the automatic technique than the manual method, indicating better registrations. Likewise, the automatic method showed a 57% reduction in standard deviation, implying a more stable technique. The algorithm is able to recover the transformation even when data are missing from the top or bottom of the volume. We present a fully automatic registration method to map volumetric data into stereotaxic space that yields results comparable with those of manually based techniques. The method requires no manual identification of points or contours and therefore does not suffer the drawbacks involved in user intervention such as reproducibility and interobserver variability.

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Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia.

Beng-Choon Ho, Nancy C. Andreasen, Steven Ziebell … (2011)

Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement. Because antipsychotics are prescribed for long periods for schizophrenia patients and have increasingly widespread use in other psychiatric disorders, it is imperative to determine their long-term effects on the human brain. To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change. Predictors of brain volume changes were assessed prospectively based on multiple informants. Data from the Iowa Longitudinal Study. Two hundred eleven patients with schizophrenia who underwent repeated neuroimaging beginning soon after illness onset, yielding a total of 674 high-resolution magnetic resonance scans. On average, each patient had 3 scans (≥2 and as many as 5) over 7.2 years (up to 14 years). Brain volumes. During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted. Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.

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Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia.

Bryan Roth, Douglas Sheffler, Wesley K. Kroeze (2004)

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Author and article information

Journal

Journal ID (nlm-ta): BMC Psychiatry

Journal ID (iso-abbrev): BMC Psychiatry

Title: BMC Psychiatry

Publisher: BioMed Central

ISSN (Electronic): 1471-244X

Publication date Collection: 2013

Publication date (Electronic): 20 December 2013

Volume: 13

Page: 342

Affiliations

[1 ]Post-Graduate Program in Radiology, Institute of Radiology (INRAD), University of Sao Paulo Medical School, Sao Paulo, Brazil

[2 ]Laboratory of Neuroimaging in Psychiatry (LIM-21), Institute of Psychiatry, University of Sao Paulo Medical School, Centro de Medicina Nuclear, 3º andar, Rua Dr. Ovídio Pires Campos, s/n, Sao Paulo, Sao Paulo, 05403-010, Brazil

[3 ]Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Sao Paulo, Brazil

[4 ]Department of Radiology, Hospital de Base, São José do Rio Preto Medical School, Sao Paulo, Brazil

[5 ]Department of Psychiatry, University of Basel, Basel, Switzerland

[6 ]Department of Psychosis Studies, Institute of Psychiatry, King’s College, London, UK

Article

Publisher ID: 1471-244X-13-342

DOI: 10.1186/1471-244X-13-342

PMC ID: 3878502

PubMed ID: 24359128

SO-VID: ba7a9ecd-dbc2-4da1-9f65-f0c988215a6b

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural brain changes associated with antipsychotic treatment in schizophrenia as revealed by voxel-based morphometric MRI: an activation likelihood estimation meta-analysis

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Abstract

Background

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Most cited references 90

Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space.

Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia.

Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia.

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