Auditory P300 in high-risk, recent-onset and chronic schizophrenia
Introduction
Interest in the pre-onset or “prodromal” stage of schizophrenia has greatly increased over the past decade (Cornblatt et al., 2003, Lieberman et al., 2001, Miller et al., 1999, Miller et al., 2002, Yung and McGorry, 1996). The prodromal stage refers to the period between the premorbid healthy (asymptomatic) state and the onset of the first florid psychotic episode. This stage is currently characterized by functional decline and the presence of nonspecific and attenuated psychotic symptoms presumed to herald the onset of the full-blown clinical disorder (e.g., McGlashan et al., 2003, Pantelis et al., 2003, Yung et al., 2003). The prodromal stage could be a critical period in the pathophysiological processes leading to schizophrenia. Moreover, if the associated subthreshold syndrome could be accurately recognized prospectively, this stage could be the optimal point to start early, pre-onset detection and therapeutic intervention strategies in an effort to delay, ameliorate or even prevent the onset of schizophrenia.
Researchers focusing on the prodromal stage currently utilize a combination of trait and state risk factors in an effort to identify people who are at ultra high risk of developing psychosis (e.g., McGlashan et al., 2003, Pantelis et al., 2003). In contrast to traditional family-based high-risk studies, which have been limited by long follow-up periods, high rates of attrition and low levels of transition to psychosis, the advantage of this identification strategy is in finding a relatively high rate of transition to psychosis within a short follow-up period (Pantelis et al., 2003, Yung et al., 2003). To date, however, the clinical signs and symptoms that characterize the prodromal state are subtle, equivocal and have only limited predictive power in relation to subsequent psychosis. A current challenge lies in the identification of neurobiological markers that are directly linked to the underlying illness pathophysiology and that help to improve the diagnostic accuracy and predictive power of prodromal symptoms for schizophrenia. In the present study, we hypothesized that the P300 component of the human event-related brain potential (ERP) may provide such a marker of schizophrenia risk.
The P300 is a late cognitive-related ERP component associated with attention and memory processes (Donchin and Coles, 1988, Polich and Herbst, 2000). We focused on the auditory P300 because it has been well documented that the generation of this brain response is typically impaired in subjects in the recent-onset and chronic stages of schizophrenia (Ford, 1999, Pritchard, 1986, Roth and Cannon, 1972, Salisbury et al., 1998), irrespective of clinical symptom severity and antipsychotic medication status (Blackwood et al., 1987, Duncan, 1988, Jeon and Polich, 2003). Furthermore, first-episode and chronic schizophrenia patients often show auditory P300 amplitude decrements specifically over the left temporal scalp (Faux et al., 1993, Jeon and Polich, 2001, McCarley et al., 1991, Salisbury et al., 1998, Salisbury et al., 1999, Turetsky et al., 1998, van der Stelt et al., 2004, Winterer et al., 2001), which correlate with magnetic resonance imaging (MRI) evidence of cortical gray matter volume reductions within the underlying left temporal lobe (McCarley et al., 1993, McCarley et al., 2002). Auditory P300 amplitude abnormalities similar, albeit less severe, to those seen in schizophrenia patients have also been observed in subjects with schizotypal personality disorder (Salisbury et al., 1996, Trestman et al., 1996), who are assumed to have some genetic vulnerability for schizophrenia, although only a small portion of them actually go on to develop schizophrenia or other psychotic disorders (DSM-IV; American Psychiatric Association, 1994, p. 643).
It has been demonstrated that auditory P300 amplitude abnormalities are present in patients in the early and advanced stages of schizophrenia, but it is unknown when in the course of the patient's lifetime or illness these abnormalities emerge. Family-based high-risk studies of unaffected biological relatives of schizophrenia patients have, so far, yielded mixed results as to whether P300 abnormalities are already present in the premorbid stage of illness (for review, see Bharath et al., 2000). Similarly, it is unknown whether P300 abnormalities characterize the initial prodromal stage of schizophrenia. Thus, it is uncertain whether auditory P300 abnormalities in schizophrenia represent a pre-existing vulnerability that precedes illness onset or emerge only in association with the first florid psychotic episode.
The present study was aimed at examining whether auditory P300 abnormalities associated with impaired attention and brain function are present in patients clinically considered at risk of being prodromally symptomatic for schizophrenia. Additionally, we intended to compare the P300 recorded from these high-risk subjects to the P300 recorded from patients in the recent-onset and chronic stages of schizophrenia. We hypothesized that, if the auditory P300 indeed represents a trait or vulnerability marker of schizophrenia, P300 abnormalities similar to those observed in patients in the recent-onset and chronic stages of schizophrenia would be evident in patients at high imminent risk for developing a first florid psychotic episode.
Section snippets
Participants
Subjects consisted of 10 patients at risk of being prodromally symptomatic for schizophrenia, 10 patients with recent-onset schizophrenia, 14 patients with chronic schizophrenia, 14 young healthy comparison subjects, who were age-matched to the high-risk and recent-onset schizophrenia groups, and 14 older healthy comparison subjects, who were age-matched to the chronic schizophrenia group. Table 1 summarizes group demographic and clinical characteristics. The experimental protocol had approval
Performance data
No significant differences in task performance were observed between the recent-onset and chronic schizophrenia groups, but both groups displayed a significantly lower hit rate and tended to have a longer reaction time as compared to the young and older comparison groups, who did not differ from each other (Table 2). High-risk subjects performed at a level intermediate to the levels of performance observed in comparison subjects and schizophrenia subjects, but they did not differ significantly
Discussion
The results of this study indicate that patients at high imminent risk for developing a first florid psychotic episode show auditory P300 amplitude abnormalities that are similar, but not identical, to those evident in patients in the recent-onset and chronic stages of schizophrenia. These findings add to the evidence that impaired auditory P300 generation in schizophrenia reflects an enduring and core feature of the illness (Duncan, 1988, Ford, 1999, McCarley et al., 1991, McCarley et al., 1993
Acknowledgements
This study was supported by grant MH58251 from the National Institute of Mental Health, Bethesda, MD, grant MH64065 from the University of North Carolina Schizophrenia Research Center—National Institute of Mental Health Silvio O. Conte Center for the Neuroscience of Mental Disorders, Chapel Hill, NC, and the Foundation of Hope of Raleigh, NC. Preliminary data of this study were presented at the 11th Annual Meeting of the Cognitive Neuroscience Society, San Francisco, CA, USA, April 18–20, 2004.
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