Lieberman, J. et al. Longitudinal study of brain morphology in first episode schizophrenia. Biol. Psychiatry 49, 487-499

Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Biological Psychiatry (Impact Factor: 10.26). 04/2001; 49(6):487-99. DOI: 10.1016/S0006-3223(01)01067-8
Source: PubMed


Beginning with Kraepelin, schizophrenia has been viewed as a progressive disorder. Although numerous studies of the longitudinal course of schizophrenia have demonstrated the clinical deterioration that occurs predominantly in the early stages of the illness, the pathophysiology of this clinical phenomenon has not been established. This aspect of the illness may be of critical importance to understanding the pathogenesis of schizophrenia and determining preventive therapeutic strategies. Abnormalities in brain morphology have been consistently described in schizophrenia, but it is not known when in the natural history of the illness they arise and whether they are progressive. Previous studies of brain morphology have been inconclusive, in part because of the variability of methods for image acquisition and analysis, assessment of patients already at chronic stages of their illness with extensive prior treatment exposure, and inadequate periods of follow-up.
To address these questions we examined 107 patients in their first episode of schizophrenia or schizoaffective disorder and 20 healthy volunteers using high resolution magnetic resonance imaging (MRI) and clinical assessments of psychopathology and treatment outcome for periods of up to 6 years. Fifty-one patients and 13 control subjects had MRIs after at least 12 months of follow-up.
Results confirm the findings of ventricular enlargement and anterior hippocampal volume reductions in first episode schizophrenia patients that have been previously reported. In addition, we found changes in selected structures over time in relation to treatment outcome, including increases in ventricular volume that were associated with poor outcome patients. Contrary to our hypothesis, there were no significant reductions in cortical and hippocampal volumes over time.
The finding of progressive ventricular enlargement in patients with poor outcome schizophrenia is consistent with the hypothesis that persistent positive and negative symptoms result in progressive brain changes in the form of ventricular enlargement, possibly due to neurodegeneration rather than the confounding effects of treatment. Future studies of first episodes of schizophrenia should utilize higher resolution imaging techniques that compare clinically well characterized patients with and without poor outcome and recurrent symptoms to control subjects who are well matched to patients for age and gender. There is also a need to control for treatment effects of typical antipsychotic medication on brain structure.

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    • "This process is characterized by a switch in microglia phenotype from the quiescent or " resting " state to an activated, amoeboid state, including migration to the site of injury and the release of cytokines (Kettenmann et al., 2013). Microglial activation has been suggested to be involved in grey matter loss in a number of disorders, including SCZ (Kahn and Sommer, 2014; Lieberman et al., 2001; Wright et al., 2000). Cognitive symptoms in SCZ patients have also been linked to increases in markers of inflammation (Dickerson et al., 2007; Dickerson et al., 2012; Pedersen et al., 2008). "
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    ABSTRACT: Neuroinflammation is increasingly implicated in the pathogenesis of Schizophrenia (SCZ). In addition, there is increasing evidence for a relationship between the dose and duration of antipsychotic drug (APD) treatment and reductions in grey matter volume. The potential contribution of microglia to these phenomena is however not yet defined. Adult rats were treated with a common vehicle, haloperidol (HAL, 2mg/kg/day) or olanzapine (OLZ, 10mg/kg/day) for 8 weeks via an osmotic mini-pump implanted subcutaneously. Microglial cells, identified by their Iba-1 immunoreactivity, were quantified in four regions of interest chosen based on previous neuroimaging data: the hippocampus, anterior cingulate cortex, corpus striatum, and secondary somatosensory cortex. Those cells were also analysed according to their morphology, providing an index of their activation state. Chronic APD treatment resulted in increased density of total microglia in the hippocampus, striatum, and somatosensory cortex, but not in the ACC. Importantly, in all brain regions studied, both APD tested led to a dramatic shift towards an amoeboid, reactive, microglial morphology after chronic treatment compared to vehicle-treated controls. These data provide the first in vivo evidence that chronic APD treatment at clinically relevant doses leads to microglial proliferation and morphological changes indicative of activated microglia in the naïve rat brain. Although caution needs to be exerted when extrapolating results from animals to patients, these data suggest a potential contribution of antipsychotic medication to markers of brain inflammation. Further investigation of the links between antipsychotic treatment and the immune system are warranted. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European Neuropsychopharmacology 08/2015; DOI:10.1016/j.euroneuro.2015.08.004 · 4.37 Impact Factor
    • "continuous medication and frequent hospitalization ) on brain structure in the respective major depression and schizophrenia subgroups. Illness duration was the time between MRI scanning and disease onset defined retrospectively by the onset of symptoms paralleled by a general decline in social and role functioning (Lieberman et al., 2001). Following these definitions, the mean (SD) illness duration in the major depression/schizophrenia (MD FE /SZ FE ) samples was 0.34 (0.24)/0.37 (0.68) years, while the respective values for the MD RE /SZ RE were 9. "
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    ABSTRACT: Magnetic resonance imaging-based markers of schizophrenia have been repeatedly shown to separate patients from healthy controls at the single-subject level, but it remains unclear whether these markers reliably distinguish schizophrenia from mood disorders across the life span and generalize to new patients as well as to early stages of these illnesses. The current study used structural MRI-based multivariate pattern classification to (i) identify and cross-validate a differential diagnostic signature separating patients with first-episode and recurrent stages of schizophrenia (n = 158) from patients with major depression (n = 104); and (ii) quantify the impact of major clinical variables, including disease stage, age of disease onset and accelerated brain ageing on the signature's classification performance. This diagnostic magnetic resonance imaging signature was then evaluated in an independent patient cohort from two different centres to test its generalizability to individuals with bipolar disorder (n = 35), first-episode psychosis (n = 23) and clinically defined at-risk mental states for psychosis (n = 89). Neuroanatomical diagnosis was correct in 80% and 72% of patients with major depression and schizophrenia, respectively, and involved a pattern of prefronto-temporo-limbic volume reductions and premotor, somatosensory and subcortical increments in schizophrenia versus major depression. Diagnostic performance was not influenced by the presence of depressive symptoms in schizophrenia or psychotic symptoms in major depression, but earlier disease onset and accelerated brain ageing promoted misclassification in major depression due to an increased neuroanatomical schizophrenia likeness of these patients. Furthermore, disease stage significantly moderated neuroanatomical diagnosis as recurrently-ill patients had higher misclassification rates (major depression: 23%; schizophrenia: 29%) than first-episode patients (major depression: 15%; schizophrenia: 12%). Finally, the trained biomarker assigned 74% of the bipolar patients to the major depression group, while 83% of the first-episode psychosis patients and 77% and 61% of the individuals with an ultra-high risk and low-risk state, respectively, were labelled with schizophrenia. Our findings suggest that neuroanatomical information may provide generalizable diagnostic tools distinguishing schizophrenia from mood disorders early in the course of psychosis. Disease course-related variables such as age of disease onset and disease stage as well alterations of structural brain maturation may strongly impact on the neuroanatomical separability of major depression and schizophrenia. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 05/2015; DOI:10.1093/brain/awv111 · 9.20 Impact Factor
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    • "Most direct health care costs related to this mental illness are attributable to hospitalization for initial episodes and subsequent relapses.20 In addition to increasing inpatient care costs, repeated relapses may cause patients, family, and caregivers to become increasingly discouraged and pessimistic about the course of illness,9 which may produce secondary consequences of nonadherence: neurological deterioration,32 comorbid illness progression,33 substance use,34 criminal behavior,35 suicide attempts,36 re-hospitalization,23,37 or homelessness.38 "
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    ABSTRACT: There is strong evidence supporting the link between nonadherence to antipsychotic medication and relapse of schizophrenia. However, less obvious are the economic consequences of nonadherence. The systematic review reported here evaluated the economic aspects of nonadherence to antipsychotic medication. A systematic review of scientific papers in the PubMed MEDLINE, Embase, PsychINFO, BIOSIS, and Evidence-Based Medicine Reviews databases was undertaken. Studies that measured adherence to antipsychotic medication and that provided comparative information on health care costs were included. Eight studies met the inclusion criteria. All were observational. Despite the differences between the studies in terms of design, adherence measures, and cost components analyzed, the results of this systematic review indicate that nonadherence to antipsychotic medication is associated with increased hospitalization rates and resource utilization, resulting in increased direct health care costs. Nonadherence to antipsychotic medication results in poor health and economic outcomes; therefore, the authors suggest endorsing interventions aimed at improving adherence because they can improve patient health without substantially increasing costs.
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