Meta-analysis of the P300 and P50 waveforms in schizophrenia
Introduction
Event related potentials (ERPs) are changes in the electrophysiological activity of the brain, which occur in response to stimuli. The P300 waveform has been conceptualised as the physiological correlate of a working memory update of changes in the environment (Donchin and Coles, 1988) or as an index of allocation of attentional resources (Posner, 1975). The P50 suppression (a decrease in the P50 amplitude in response to the second of two paired auditory stimuli) is thought to reflect a sensory gating mechanism, aimed at protecting against information overload Freedman et al., 1987, Braff and Geyer, 1990, Freedman et al., 1996. In the last 10 years alone, over 100 journal articles on the P300 in schizophrenia and over 75 on the P50 have been published. Although the majority of studies coincide in finding P300 amplitude reductions in schizophrenia, results are less consistent for the P300 latency and the P50 measures. There are a number of methodological reasons for the discrepancies reported. Many of the results have not been corrected for age, gender and drug treatment, and differences in technical aspects could also account for some of the differences found. Importantly, most studies report their results with an emphasis on significance tests rather than confidence intervals, and this may give the misleading impression of a large number of inconsistent positive or negative findings.
Much of this work has been fuelled by the hope that abnormalities in the P300 or P50 might represent endophenotypes of schizophrenia that could ultimately contribute to our understanding of the genetic basis of the illness (Wickham and Murray, 1997). According to Gottesman and Gould (2003), amongst other criteria, a putative endophenotype should be associated with the illness and should therefore distribute differently between healthy and affected individuals. We set out to address the question of whether P300 and P50 phenotypes fulfil this fundamental requirement, and to quantify the magnitude of any differences in the waveforms between patients and healthy volunteers.
Section snippets
Method
We carried out computer searches of the databases MEDLINE and SCIENCE CITATION INDEX. We searched the databases for papers published between January 1994 and August 2003 using the following Medical Subject Heading (MeSH) categories: P300 AND [Psychosis OR Schizophrenia], P50 AND [Psychosis OR Schizophrenia] for the P300 and the P50 components, respectively. We also conducted a manual search of papers published between January and August 2003 in the following journals: American Journal of
Results
We identified 46 studies on the P300 wave that were suitable for analysis. These included a total of 1443 patients with schizophrenia and 1251 controls. For the P50 we identified 20 studies suitable for analysis, which included 421 patients and 401 healthy volunteers. The articles included are described in Table 1, Table 2 and the main results of the meta-analysis are summarised in Table 3. Full details of the data are available upon request from the authors.
How severe are P50/P300 deviances in schizophrenia?
We conclude that patients with schizophrenia have severe deficits in their P50 gating and their P300 amplitude. The mean P50 ratio for patients was 1.56 standard deviations larger than the mean for controls. The P300 amplitude shows a robust decrease in schizophrenia with a standardised effect size of 0.85. This result is in full agreement with findings by Jeon and Polich (2001), who conducted a meta-analysis of the early literature on P300 amplitude topography in schizophrenia. These effect
Conclusion
Our study confirms that patients with schizophrenia have clear P50/P300 abnormalities compared to healthy volunteers. The magnitude of these differences is comparable with the most robust findings reported for brain morphometric and neuropsychological abnormalities in schizophrenia. Longitudinal studies to explore the effect of psychopathology and duration of illness upon neurophysiological markers are now needed.
Acknowledgements
This research was supported by The Wellcome Trust and the Schizophrenia Research Fund. Dr. E. Bramon is a Wellcome Research Training Fellow.
We would like to thank Claude Alain, Douglas Blackwood, Nashaat Boutros, Anke Brockhaus-Dumke, Gerard Bruder, Judith Ford, Robert Freedman, Holger Hill, Yi Jin, Jürgen Kayser, Manuel Martı́n-Loeches, Robert Mccarley, Dorien Nieman, Ann Olincy, Dean Salisbury, Eric Vuurman, Merilyne Waldo, Georg Winterer and Cindy Yee-Bradbury whose helpful correspondence
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