Brain Volume Changes After Withdrawal of Atypical Antipsychotics in Patients With First-Episode Schizophrenia

Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.
Journal of clinical psychopharmacology (Impact Factor: 3.24). 02/2011; 31(2):146-53. DOI: 10.1097/JCP.0b013e31820e3f58
Source: PubMed

ABSTRACT The influence of antipsychotic medication on brain morphology in schizophrenia may confound interpretation of brain changes over time. We aimed to assess the effect of discontinuation of atypical antipsychotic medication on change in brain volume in patients. Sixteen remitted, stable patients with first-episode schizophrenia, schizoaffective or schizophreniform disorder and 20 healthy controls were included. Two magnetic resonance imaging brain scans were obtained from all subjects with a 1-year interval. The patients either discontinued (n = 8) their atypical antipsychotic medication (olanzapine, risperidone, or quetiapine) or did not (n = 8) discontinue during the follow-up period. Intracranial volume and volumes of total brain, cerebral gray and white matter, cerebellum, third and lateral ventricle, nucleus caudatus, nucleus accumbens, and putamen were obtained. Multiple linear regression analyses were used to assess main effects for group (patient-control) and discontinuation (yes-no) for brain volume (change) while correcting for age, sex, and intracranial volume. Decrease in cerebral gray matter and caudate nucleus volume over time was significantly more pronounced in patients relative to controls. Our data suggest decreases in the nucleus accumbens and putamen volumes during the interval in patients who discontinued antipsychotic medication, whereas increases were found in patients who continued their antipsychotics. We confirmed earlier findings of excessive gray matter volume decrements in patients with schizophrenia compared with normal controls. We found evidence suggestive of decreasing volumes of the putamen and nucleus accumbens over time after discontinuation of medication. This might suggest that discontinuation reverses effects of atypical medication.

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Available from: Wiepke Cahn, Sep 28, 2015
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    • "Speculatively, these changes in the morphology of Iba1 + microglia may therefore be linked to potential loss of neuropil in the ACC and S2 cortices, leading to a volume decrease. This hypothesis is consistent with recent evidence that microglia are critical mediators of activity-dependent synaptic remodelling and plasticity in the healthy brain (Boonstra et al., 2011; Cazorla et al., 2014; Kettenmann et al., 2013; Wake et al., 2009; Zatorre et al., 2012). In contrast, increases in "
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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
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    • "We also indicate which of the findings pass the more conservative Bonferroni multiple comparison-corrected threshold of p o0.00625 (two-tailed). Based on evidence for the effects of antipsychotic medication on basal ganglia volumes (Gur et al., 1998; Hulshoff Pol and Kahn, 2008; Boonstra et al., 2011; Li et al., 2011), we examined the effect of current antipsychotic medication type (typical/atypical) and dose (chlorpromazine-equivalent dose) on basal ganglia volumes, using mixed model regression and correlation analysis, respectively. Cohen's d weighted mean effect sizes based on each of the seven single site samples and also based on the full sample were computed. "
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    ABSTRACT: Schizophrenia patients show significant subcortical brain abnormalities. We examined these abnormalities using automated image analysis software and provide effect size estimates for prospective multi-scanner schizophrenia studies. Subcortical and intracranial volumes were obtained using FreeSurfer 5.0.0 from high-resolution structural imaging scans from 186 schizophrenia patients (mean age±SD=38.9±11.6, 78% males) and 176 demographically similar controls (mean age±SD=37.5±11.2, 72% males). Scans were acquired from seven 3-Tesla scanners. Univariate mixed model regression analyses compared between-group volume differences. Weighted mean effect sizes (and number of subjects needed for 80% power at α=0.05) were computed based on the individual single site studies as well as on the overall multi-site study. Schizophrenia patients have significantly smaller intracranial, amygdala, and hippocampus volumes and larger lateral ventricle, putamen and pallidum volumes compared with healthy volunteers. Weighted mean effect sizes based on single site studies were generally larger than effect sizes computed based on analysis of the overall multi-site sample. Prospectively collected structural imaging data can be combined across sites to increase statistical power for meaningful group comparisons. Even when using similar scan protocols at each scanner, some between-site variance remains. The multi-scanner effect sizes provided by this study should help in the design of future multi-scanner schizophrenia imaging studies.
    Psychiatry Research: Neuroimaging 04/2014; 222(1-2). DOI:10.1016/j.pscychresns.2014.02.011 · 2.42 Impact Factor
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