Background Deficits in automatic sensory discrimination, as indexed by a reduction in the mismatch negativity (MMN) and P3a event-related potential amplitudes, are well documented in chronic schizophrenia. However, MMN and P3a have not been sufficiently studied early in the course of psychotic illness. The present study aimed to investigate MMN, P3a, and reorienting negativity (RON) across the course of schizophrenia, from prodrome to the chronic phase of illness. Methods MMN, P3a, and RON were assessed in 118 subjects across 4 groups 1) prodromal patients putatively at risk for psychosis (N=26), 2) recent-onset patients (N=31), 3) chronic patients (N=33), and 4) normal controls (N=28) during a duration-deviant auditory oddball paradigm. Results Frontocentral deficits in MMN and P3a were present in all patient groups. The at-risk group's MMN and P3a amplitudes were intermediate between those of the control and recent-onset groups. The recent-onset and chronic groups, but not the at-risk group, showed significant RON amplitude reductions, relative to the control group. Associations between MMN, P3a, RON and psychosocial functioning were present in the chronic group only. Impaired P3a and RON correlated with more severe negative symptoms in the at-risk group. Conclusions Abnormalities in the automatic processes of sensory discrimination, orienting and reorienting of attention are evident in the early phases of schizophrenia and raise the possibility of progressive worsening across stages of the illness. The finding that MMN and P3a, but not RON, were reduced before psychosis onset supports the continued examination of these components as potential early biomarkers of schizophrenia.

Understanding the trajectory of cognitive changes in the development of schizophrenia may shed light on the neurodevelopmental processes in the beginning stage of illness. Subjects at risk for psychosis (AR, n=48), patients in their first episode of schizophrenia (FE, n=20) and normal comparison subjects (NC, n=29) were assessed on a neurocognitive battery at baseline and at a 6-month follow-up. There were significant group differences across all cognitive domains as well as a significant group by time interaction in the verbal learning domain. After statistically controlling for practice effects and regression to the mean, a high proportion of FE subjects showed an improvement in verbal learning, while a significant number of AR subjects improved in general intelligence. Moreover, a higher than expected percentage of FE subjects, as well as AR subjects who later converted to psychosis, showed a deterioration in working memory and processing speed. These inconsistent trajectories suggest that some domains may improve with stabilization in the early stages of psychosis, while others may decline with progression of the illness, indicating possible targets for cognitive remediation strategies and candidate vulnerability markers for future psychosis. Keywords NEUROPSYCHOLOGICAL; LONGITUDINAL; SCHIZOPHRENIA; AT RISK; PRODROMALThe schizophrenia prodrome is a period of rapid developmental change that precedes illness onset and is characterized by a substantial functional decline together with the emergence of subthreshold psychotic symptoms (Yung & McGorry, 1996). Longitudinal studies have shown that the population who meets the "prodromal" definition, based on carefully defined criteria combining subsyndromal psychotic symptoms, family history and functional decline (Miller et al., 2003), has a 20 to 30% chance of converting to psychosis within one year of ascertainment (e.g., Cannon et al., 2008;Olsen and Rosenbaum, 2006;Yung et al., 2004).Correspondence concerning this article should be addressed to Kristin Cadenhead, Department of Psychiatry, 0810, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0810. Phone: (619) 260-8437. kcadenhead@ucsd.edu. Publisher's Disclaimer: The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omissions of this manuscript version, any version derived from this manuscript by NIH, or other third parties. The published version is available at www.apa.org/journals/nue. NIH Public Access Author ManuscriptNeuropsychology. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Neuropsychology. 2010 January ; 24(1): 109-120. doi:10.1037/a0016791. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTh...

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Objectives Bipolar disorder and schizophrenia share common pathophysiological processes and may have similar perceptual abnormalities. Mismatch negativity (MMN) and P3a—event-related potentials associated with auditory preattentional processing—have been extensively studied in schizophrenia, but rarely in bipolar disorder. Furthermore, MMN and P3a have not been examined between diagnostic subgroups of patients with bipolar disorder. We evaluated MMN and P3a in patients with bipolar disorder compared to patients with schizophrenia and healthy controls. Methods MMN and P3a were assessed in 52 bipolar disorder patients, 30 schizophrenia patients, and 27 healthy control subjects during a duration-deviant auditory oddball paradigm. Results Significant MMN and P3a amplitude reductions were present in patients with bipolar disorder and schizophrenia relative to controls. The MMN reduction was more prominent in patients with schizophrenia than bipolar disorder, at a trend level. P3a did not differ significantly between patient groups. There were no MMN or P3a differences between patients with bipolar I (n = 34) and bipolar II (n = 18) disorder. Patients with bipolar I disorder failed to show lateralized MMN, in contrast to the other groups. No MMN or P3a differences were found between patients with bipolar disorder taking (n = 12) and not taking (n = 40) lithium, as well as between those taking (n = 30) and not taking (n = 22) antipsychotic medications. Conclusions Patients with bipolar disorder showed deficits in preattentive auditory processing, including MMN deficits that are less severe and P3a deficits that are slightly more pronounced, than those seen in schizophrenia.