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Bohlken M.M.,University Utrecht | Brouwer R.M.,University Utrecht | Mandl R.C.W.,University Utrecht | Van Den Heuvel M.P.,University Utrecht | And 5 more authors.
JAMA Psychiatry | Year: 2016

IMPORTANCE Schizophrenia is accompanied by a loss of integrity of white matter connections that compose the structural brain network, which is believed to diminish the efficiency of information transfer among brain regions. However, it is unclear to what extent these abnormalities are influenced by the genetic liability for developing the disease. OBJECTIVE To determine whether white matter integrity is associated with the genetic liability for developing schizophrenia. DESIGN, SETTING, AND PARTICIPANTS In 70 individual twins discordant for schizophrenia and 130 matched individual healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on brain connectivity and disease liability. The data for this study were collected from October 1, 2008, to September 30, 2013. The data analysis was performed between November 1, 2013, and March 30, 2015. MAIN OUTCOME MEASURES Structural connectivity and network efficiencywere assessed through diffusion-weighted imaging, measuring fractional anisotropy (FA) and streamlines. RESULTS The sample included 30 monozygotic twins matched to 72 control participants and 40 dizygotic twins matched to 58 control participants. Lower global FA was significantly correlated with increased schizophrenia liability (phenotypic correlation, 0.25; 95%CI, 0.38 to 0.10; P = .001), with 83.4%explained by common genes. In total, 8.1% of genetic variation in global FA was shared with genetic variance in schizophrenia liability. Local reductions in network connectivity (as defined by FA-weighted local efficiency) of frontal, striatal, and thalamic regions encompassed 85.7%of genetically affected areas. Multivariate genetic modeling revealed that global FA contributed independently of other genetic markers, such as white matter volume and cortical thickness, to schizophrenia liability. CONCLUSIONS AND RELEVANCE Global reductions in white matter integrity in schizophrenia are largely explained by the genetic risk of developing the disease. Network analysis revealed that genetic liability for schizophrenia is primarily associated with reductions in connectivity of frontal and subcortical regions, indicating a loss of integrity along the white matter fibers in these regions. The reported reductions in white matter integrity likely represent a separate and novel genetic vulnerability marker for schizophrenia. Copyright © 2016 American Medical Association. All rights reserved. Source


De Hert M.,Zorg Ku Leuven University Psychiatric Center | Sermon J.,Janssen Cilag SAS | Geerts P.,Janssen Cilag SAS | Vansteelandt K.,Zorg Ku Leuven University Psychiatric Center | And 2 more authors.
CNS Drugs | Year: 2015

Background: Although continuous treatment with antipsychotics is still recommended as the gold standard treatment paradigm for all patients with schizophrenia, some clinicians question whether continuous antipsychotic treatment is necessary, or even justified, for every patient with schizophrenia who has been stabilized on antipsychotics. Objective: The primary objectives of this systematic review and meta-analysis were (i) to compare relapse/hospitalization risks of stabilized patients with schizophrenia under active versus intermittent or placebo treatment conditions; (ii) to examine the role of several study characteristics, possibly intervening in the relationship between relapse risk and treatment condition; and (iii) to examine whether time to relapse is associated with antipsychotic treatment duration. Methods: A systematic literature search, using the MEDLINE database (1950 until November 2014), was conducted for English-language published randomized controlled trials, covering a follow-up time period of at least 6 months, and investigating relapse/rehospitalization and/or time-to-relapse rates with placebo or intermittent treatment strategies versus continuous treatment with oral and long-acting injectable first- or second-generation antipsychotics (FGAs/SGAs) in stabilized patients with schizophrenia. Additional studies were identified through searches of reference lists of other identified systematic reviews and Cochrane reports. Two meta-analyses (placebo versus continuous and intermittent versus continuous treatment) were performed to obtain an optimal estimation of the relapse/hospitalization risks of stabilized patients with schizophrenia under these treatment conditions and to assess the role of study characteristics. For time-to-relapse data, a descriptive analysis was performed. Results: Forty-eight reports were selected as potentially eligible for our meta-analysis. Of these, 21 met the inclusion criteria. Twenty-five records, identified through Cochrane and other systematic reviews and fulfilling the inclusion criteria, were added, resulting in a total of 46 records. Stabilized patients with schizophrenia who have been exposed for at least 6 months to intermittent or placebo strategies, respectively, have a 3 (odds ratio [OR] 3.36; 95 % CI 2.36-5.45; p < 0.0001) to 6 (OR 5.64; 95 % CI 4.47-7.11; p < 0.0001) times increased risk of relapse, compared with patients on continuous treatment. The availability of rescue medication (p = 0.0102) was the only study characteristic explaining systematic differences in the OR for relapse between placebo versus continuous treatment across studies. Studies reporting time-to-relapse data show that the time to (impending) relapse is always significantly delayed with continuous treatment, compared with placebo or intermittent treatment strategies. Although the interval between treatment discontinuation and symptom recurrence can be highly variable, mean time-to-relapse data seem to indicate a failure of clinical stability before 7-14 months with intermittent and before 5 months with placebo treatment strategies. For all reports included in this systematic review, median time-to-relapse rates in the continuous treatment group were not estimable as <50 % of the patients in this treatment condition relapsed before the end of the study. Conclusions: With continuous treatment, patients have a lower risk of relapse and remain relapse free for a longer period of time compared with placebo and intermittent treatment strategies. Moreover, 'success rates' in the intermittent treatment conditions are expected to be an overestimate of actual outcome rates. Therefore, continuous treatment remains the 'gold standard' for good clinical practice, particularly as, until now, only a few and rather general valid predictors for relapse in schizophrenia are known and subsequent relapses may contribute to functional deterioration as well as treatment resistance in patients with schizophrenia. © 2015 Springer International Publishing Switzerland. Source

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