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      Brain Structural Effects of Antipsychotic Treatment in Schizophrenia: A Systematic Review

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          Abstract

          The findings about the progressive brain changes in schizophrenia are controversial, and the potential confounding effect of antipsychotics on brain structure is still under debate. The goal of the current article was to review the existing longitudinal neuroimaging studies addressing the impact of antipsychotic drug treatment on brain changes in schizophrenia. A comprehensive search of PubMed was performed using combinations of key terms distributed into four blocks: “MRI”, “longitudinal”, “schizophrenia” and “antipsychotic”. Studies were considered to be eligible for the review if they were original articles. Studies that examined only changes in brain density were excluded. A total of 41 MRI studies were identified and reviewed. Longitudinal MRI studies did not provide a consistent notion of the effects of antipsychotic treatment on the pattern of brain changes over time in schizophrenia. Overall, most of the included articles did not find a linear relationship between the degree of exposure and progressive brain changes. Further short- and longterm studies are warranted to a better understanding of the influence of antipsychotics in brain structural changes in schizophrenia and also to verify whether first and second generation antipsychotics may differentially affect brain morphometry.

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          Most cited references66

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

          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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            Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress.

            The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.
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              Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies.

              Studies of people with schizophrenia assessed using magnetic resonance imaging (MRI) usually include patients with first-episode and chronic disease, yet brain abnormalities may be limited to those with chronic schizophrenia. To determine whether patients with a first episode of schizophrenia have characteristic brain abnormalities. Systematic review and meta-analysis of 66 papers comparing brain volume in patients with a first psychotic episode with volume in healthy controls. A total of 52 cross-sectional studies included 1424 patients with a first psychotic episode; 16 longitudinal studies included 465 such patients. Meta-analysis suggests that whole brain and hippocampal volume are reduced (both P<0.0001) and that ventricular volume is increased (P<0.0001) in these patients relative to healthy controls. Average volumetric changes are close to the limit of detection by MRI methods. It remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.
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                Author and article information

                Journal
                Curr Neuropharmacol
                Curr Neuropharmacol
                CN
                Current Neuropharmacology
                Bentham Science Publishers
                1570-159X
                1875-6190
                July 2015
                July 2015
                : 13
                : 4
                : 422-434
                Affiliations
                Department of Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, Santander, Spain, CIBERSAM (Centro Investigación Biomédica en Red Salud Mental), Spain
                Author notes
                [* ]Address correspondence to this author at the Unidad Investigación Psiquiatría, Hospital Universitario Marqués de Valdecilla, CIBERSAM, Avda. Valdecilla s/n, 39008, Santander, Spain; Tel: +34-942-203826; E-mail: rroiz@ 123456humv.es
                [†]

                These authors contributed equally to this work.

                Article
                CN-13-422
                10.2174/1570159X13666150429002536
                4790397
                26412062
                e588f6e2-80e0-480e-9b6b-131ed73f6529
                © 2015 Bentham Science Publishers

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 January 2015
                : 7 March 2015
                : 5 April 2015
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                antipsychotic,longitudinal studies,schizophrenia,structural magnetic resonance imaging.

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