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Microglia and Brain Plasticity in Acute Psychosis and Schizophrenia Illness Course: A Meta-Review.

ABSTRACT: Objective:Schizophrenia poses a tremendous health, social, and economic burden upon patients and society, indicating current treatment options remain inadequate. Recent findings from several lines of evidence have pointed to the importance of immune system involvement in not only premorbid neurodevelopmental but also subsequent symptom generation and aging processes of brain change in schizophrenia. In this meta-review, we use the summarized evidence from recent quantitative systematic reviews (SRs) and meta-analyses of several subspecialties to critically evaluate the hypothesis that immune-related processes shape the symptomatic presentation and illness course of schizophrenia, both directly and indirectly through altered neuroplasticity. Methods:We performed a data search in PubMed for English language SRs and meta-analyses from 2010 to 2017. The methodological quality of the SRs was assessed with the AMSTAR instrument. In addition, we review in this paper 11 original publications on translocator protein (TSPO) positron emission tomography (PET) imaging in schizophrenia. Results:We reviewed 26 SRs and meta-analyses. Evidence from clinical observational studies of inflammatory or immunological markers and randomized controlled drug trials of immunomodulatory compounds as add-on in the treatment of schizophrenia suggests psychotic exacerbations are accompanied by immunological changes different from those seen in non-acute states, and that the symptoms of schizophrenia can be modified by compounds such as non-steroidal anti-inflammatory drug and minocycline. Information derived from post-mortem brain tissue analysis and PET neuroimaging studies to evaluate microglial activation have added new perspectives to the available evidence, yet these results are very heterogeneous. Each research domain comes with unique opportunities as well as inherent limitations. A better understanding of the (patho-)physiology of microglial cells and their role in neuroplasticity is key to interpreting the immune-related findings in the context of schizophrenia illness exacerbations and progression. Conclusion:Evidence from clinical studies analyzing patients' blood and cerebrospinal fluid samples, neuroimaging and post-mortem brain tissue suggests that aberrant immune responses may define schizophrenia illness' course through altered neuroplasticity representing abnormal aging processes. Most findings are however prone to bias and confounding, and often non-specific to schizophrenia, and a multidisciplinary translational approach is needed to consolidate these findings and link them to other schizophrenia hypotheses.

SUBMITTER: De Picker LJ

PROVIDER: S-EPMC5696326 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Microglia and Brain Plasticity in Acute Psychosis and Schizophrenia Illness Course: A Meta-Review.

De Picker Livia J LJ Morrens Manuel M Chance Steven A SA Boche Delphine D

Frontiers in psychiatry 20171116

<h4>Objective</h4>Schizophrenia poses a tremendous health, social, and economic burden upon patients and society, indicating current treatment options remain inadequate. Recent findings from several lines of evidence have pointed to the importance of immune system involvement in not only premorbid neurodevelopmental but also subsequent symptom generation and aging processes of brain change in schizophrenia. In this meta-review, we use the summarized evidence from recent quantitative systematic r ...[more]

PMID: 29201010

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Project description:ImportanceQuestions of whether and how cortical thickness (CTh) alterations differ over the course of schizophrenia (SCZ) have yet to be resolved.ObjectiveTo characterize CTh alterations across illness stages in SCZ.Data sourcesPubMed, Embase, Web of Science, and Science Direct were screened for CTh studies published before June 15, 2021.Study selectionOriginal studies comparing whole-brain CTh alterations from healthy controls in individuals at clinical high-risk (CHR), first episode of psychosis (FEP), and long-term illness stages of SCZ were included.Data extraction and synthesisThis preregistered systematic review and meta-analysis followed PRISMA reporting guidelines. Separate and pooled meta-analyses were performed using seed-based d mapping. Meta-regression analyses were conducted.Main outcomes and measuresCortical thickness differences from healthy control individuals across illness stages.ResultsTen studies comprising 859 individuals with CHR (mean [SD] age, 21.02 [2.66] years; male, 573 [66.7%]), 12 studies including 671 individuals with FEP (mean [SD] age, 22.87 [3.99] years; male, 439 [65.4%]), and 10 studies comprising 579 individuals with long-term SCZ (mean [SD] age, 41.58 [6.95] years; male, 396 [68.4%]) were included. Compared with healthy control individuals, individuals with CHR showed cortical thinning in bilateral medial prefrontal cortex (z = -1.01; P < .001). Individuals with FEP showed cortical thinning in right lateral superior temporal cortex (z = -1.34; P < .001), right anterior cingulate cortex (z = -1.44; P < .001), and right insula (z = -1.14; P = .002). Individuals with long-term SCZ demonstrated CTh reductions in right insula (z = -3.25; P < .001), right inferior frontal cortex (z = -2.19; P < .001), and left (z = -2.37; P < .001) and right (z = -1.94; P = .002) temporal pole. There were no significant CTh differences between CHR and FEP. Individuals with long-term SCZ showed greater cortical thinning in right insula (z = -2.58; P < .001), right inferior frontal cortex (z = -2.32; P < .001), left lateral temporal cortex (z = -1.91; P = .002), and right temporal pole (z = -1.82; P = .002) than individuals with FEP. Combining all studies on SCZ, accelerated age-related CTh reductions were found in bilateral lateral middle temporal cortex and right pars orbitalis in inferior frontal cortex.Conclusions and relevanceThe absence of significant differences between FEP and CHR noted in this systematic review and meta-analysis suggests that the onset of psychosis was not associated with robust CTh reduction. The greater cortical thinning in long-term SCZ compared with FEP with accelerated age-related reduction in CTh suggests progressive neuroanatomic alterations following illness onset. Caution in interpretation is needed because heterogeneity in samples and antipsychotic treatment may confound these results.

Project description:Schizophrenia is the eighth leading cause of disability worldwide in people aged 15-44 years. Before antidopaminergic antipsychotics were introduced in the 1950s, no effective medications existed for the treatment of schizophrenia. This review summarizes key meta-analytic findings regarding antipsychotic efficacy in the acute treatment of schizophrenia, including clozapine in treatment-resistant patients. In the most comprehensive meta-analysis of randomized controlled trials conducted in multi-episode schizophrenia, antipsychotics outperformed placebo regarding total symptoms, positive symptoms, negative symptoms, depressive symptoms, quality of life and social functioning. Amongst these outcomes, the standardized mean difference for overall symptoms was largest, that is, 0.47 (95% credible interval = 0.42-0.51), approaching a medium effect size, being reduced to 0.38 when publication bias and small-trial effects were accounted for. A comparison of two meta-analyses indicated that first-episode patients, compared with multi-episode patients, were more likely to have at least minimal treatment response [?20% Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) score reduction: 81% versus 51%] and good response (?50% PANSS/BPRS score reduction: 52% versus 23%). In multi-episode schizophrenia, no response or worsening after 2 weeks of a therapeutic antipsychotic dose was highly predictive of not achieving a good response at endpoint (median treatment = 6 weeks: specificity = 86%; positive predictive value = 90%), suggesting a change in treatment should be considered in such cases. In first-episode psychosis, adequately dosed antipsychotic treatment trials for more than 2 weeks are recommended before using no response or worsening as a decision point for aborting a given antipsychotic. In clearly defined treatment-resistant schizophrenia, clozapine generally outperformed other antipsychotics, especially when dosed appropriately (target = 3-6 months' duration; trough clozapine level ?350-400 ?g/L) with a response rate (?20% PANSS/BPRS) of 33% by 3 months of treatment. High antipsychotic doses and psychotropic combinations are unlikely to be superior to standard doses of antipsychotic monotherapy. Acute antipsychotic efficacy in schizophrenia depends on the targeted symptom domain (greater efficacy: total and positive symptoms, lesser efficacy: negative symptoms, depressive symptoms, social functioning and quality of life). Greater antipsychotic efficacy is associated with higher total baseline symptom severity, treatment-naïveté/first-episode status, shorter illness duration, and trials that are nonindustry sponsored and that have a lower placebo effect. The heterogeneity of antipsychotic response across individuals and key symptom domains, the considerable degree of nonresponse/treatment resistance in multi-episode patients, and the adverse effect potential of antipsychotics are major limitations, underscoring the need to develop new medications for the treatment of schizophrenia. Drug development should include matching patient subgroups, which are identified by means of clinical and biomarker variables, to mechanisms of action of novel medications, targeting specific symptom domains, and investigating mechanisms of action other than dopaminergic blockade.

Dataset Information

Microglia and Brain Plasticity in Acute Psychosis and Schizophrenia Illness Course: A Meta-Review.

Publications

Microglia and Brain Plasticity in Acute Psychosis and Schizophrenia Illness Course: A Meta-Review.

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