Correlates of cognitive deficits in first episode schizophrenia

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Abstract

Objective: The presence of cognitive dysfunction in schizophrenia has been well documented, but questions remain about whether there are relationships between this dysfunction and clinical symptomatology. If present, such relationships should be most clearly observable in patients with first episode schizophrenia; that is, before the effects of chronic illness, institutionalization, or treatment might confound them. Method: 307 schizophrenia subjects in their first episode of illness were recruited to participate in a clinical trial comparing the long-term efficacy of haloperidol and risperidone. The psychopathology, cognitive functioning, early treatment history, and duration of untreated psychosis of these subjects were assessed prior to their assignment to randomized, double-blind treatment. Approximately two-thirds of the subjects were receiving antipsychotic treatment at the time of assessment; however, the duration of treatment was limited to 12 weeks or less. Results: The severity of negative symptoms at the time of assessment was associated with deficits in memory, verbal fluency, psychomotor speed and executive function. Positive symptoms were not associated with cognitive deficits. Also, the duration of untreated illness (DUI) prior to assessment was not significantly associated with cognitive impairment. Conclusions: The results of this study of first episode schizophrenia patients suggest that a relationship exists between negative symptoms and cognitive dysfunction. However, that relationship accounts for only a minor portion of the variance (i.e., 10–15%) in the severity of cognitive dysfunction after controlling for a number of potentially confounding factors. This finding provides support for the theory that the neurobiological processes that give rise to symptomatology and cognitive dysfunction in schizophrenia are partially overlapping.

Introduction

The heterogeneity of schizophrenia has been examined in a number of different ways, including symptom profiles, cognition, and course of illness. The study of cognitive deficits has particular relevance to advancing our understanding of the underlying biological factors in schizophrenia because such symptoms predict social and occupational functioning and may occupy an intermediate position between clinical symptoms and underlying neuroanatomical substrates Davidson and McGlashan, 1997, Green, 1996, Klapow et al., 1997. The nature of cognitive dysfunction in schizophrenia has been described as generalized or diffuse by a number of researchers Bilder et al., 1992, Goldberg et al., 1990, Heaton et al., 1978, Kolb and Whishaw, 1983, Seidman, 1983, but in many studies, the majority of subjects have been chronically ill, so that what appears to be a generalized deficit may actually be the result of long-term medication or institutionalization. This issue can be addressed to some degree by the investigation of cognition in patients who are in their first episode of illness and have thus had limited exposure to antipsychotic drugs and other treatments. In some studies with first episode subjects, generalized deficits were reported Censits et al., 1997, DeLisi et al., 1995, Hoff et al., 1992, Mohamed et al., 1999, Nuechterlein et al., 1986, Heinrichs and Zazkanis, 1998, though other studies have identified more specific dimensions of cognitive dysfunction, such as relatively impaired verbal learning and memory, speed of processing, and attention/vigilance Riley et al., 2000, Saykin et al., 1994. In addition, cluster analytic models have provided evidence of discrete subgroups of patients with distinct patterns of cognitive impairment (Goldstein et al., 1998). However, the validity of some of these studies can be criticized due to small sample sizes, choice of cognitive measures, and questionable clinical stability among the subjects.

Researchers have also attempted to determine whether there is a relationship between cognitive deficits and particular dimensions of psychopathology in patients with schizophrenia. The majority of such studies found no relationship between positive symptoms (including a “disorganized” factor) and cognitive functioning Brazo et al., 2002, Malla et al., 2002, Mass et al., 2000, Penades et al., 2001, though some researchers have reported a correlation between positive symptoms and impairments in auditory processing (Rubin et al., 1995), verbal memory (Strauss et al., 1993), and auditory distractibility (Green and Walker, 1985). In general, there has been more support for correlations between negative symptoms and cognitive functioning, though the amount of explained variance is limited (Green and Walker, 1985).

A related question is whether cognitive deficits in patients with first episode schizophrenia may be associated with the severity or duration of prior symptomatology. Correlations have been reported between the duration of untreated illness (DUI) and a poor prognosis Crow et al., 1986, Haas et al., 1998, Edwards et al., 1998, Johnstone et al., 1986, Barnes et al., 2000, Loebel et al., 1992, Robinson et al., 1999, Carbone et al., 1999, Drake et al., 2000, Larsen et al., 2000, McGorry et al., 1996, Szymanski et al., 1995, Wiersma et al., 1998, greater relapse rates (Crow et al., 1986), slow rate of recovery from psychosis (Robinson et al., 1999), and decreased psychosocial functioning Barnes et al., 2000, Drake et al., 2000, Larsen et al., 2000. In chronic patients, an association between repeated psychotic episodes and general intellectual decline has been reported Bilder et al., 1992, Frith et al., 1991, Wyatt, 1995, and has led to the suggestion that the rate of cognitive decline rather the severity of cognitive dysfunction at a single time point should be the focus of attention in this area of research (Amminger et al., 2002). These findings and others have prompted several investigators to suggest that untreated illness may be associated with a neurotoxic process Fenton and McGlashahan, 1991, Inoue et al., 1986, Lo and Lo, 1977, Scully et al., 1997, Waddington et al., 1995, Waddington et al., 1998, Wyatt, 1991. However, in a number of more recent studies, no relationship between the duration of untreated illness and cognitive dysfunction has been found in patients with schizophrenia Ho et al., 2000, Ho et al., 2003, Craig et al., 2000, Hoff et al., 2000, Norman et al., 2001, Verdoux et al., 2001.

Research on the effects of untreated illness in patients with schizophrenia has also been subject to criticism on methodological grounds. In a number of the referenced studies, data were gathered before the advent of antipsychotic drugs Scully et al., 1997, Waddington et al., 1998, often from subjects who had been institutionalized for more than 10 years. Also, the majority of such studies have been retrospective, with poorly characterized samples and no control of factors likely to alter the outcome of schizophrenia. More recent findings from prospective studies Loebel et al., 1992, McGorry et al., 1996 have been criticized because of small sample sizes and controversial definitions of illness onset, diagnosis, and outcome (Verdoux et al., 2001).

In the present study, we sought to replicate and extend the results of prior studies examining the association between cognitive dysfunction and both present and past psychopathology in a sample of 307 schizophrenia subjects in their first episode of illness. The psychopathology, cognitive function, and early treatment history of these subjects were carefully assessed prior to their entry into a randomized, double-blind clinical trial designed to compare the long-term efficacy of risperidone and haloperidol. We hypothesized that the overall severity of cognitive deficits would be correlated with the severity of present psychopathology, as well as the duration of illness. In addition, we hypothesized that there would be a particularly strong correlation between the severity of cognitive deficits and the severity of negative symptoms. In order to avoid possible moderating variables, we included age, gender, education, and prior drug treatment as covariates in our analyses.

Section snippets

Subject selection and clinical assessment

The subjects were recruited from the United States and Canada as part of a long-term, double-blind trial comparing the efficacy of risperidone and haloperidol. The sample included 307 individuals (74 females, 233 males) with a DSM-IV (American Psychiatric Association, 1994) diagnosis of schizophreniform disorder (n=114), schizophrenia (n=164; disorganized type=15; catatonic type=3; paranoid type=99, undifferentiated type=47) or schizoaffective disorder (n=29). All subjects were between the ages

Results

Table 1 summarizes the characteristics of the total sample.

Table 2 presents the means and standard deviations of cognitive scores for the total sample. In reference to age and education norms, the schizophrenic subjects indicated mild-to-moderate impairment on all measures (Lezak, 1995).

Standardized coefficients for Pearson correlations between cognitive performance scores and PANSS symptom scores for subjects with DUI<1000 days are shown in Table 3. More severe negative symptoms at the time of

Discussion

We hypothesized that the overall severity of cognitive deficits would be correlated with the severity of present psychopathology as well as the duration of illness prior to treatment. In addition, we hypothesized that there would be a particularly strong correlation between the severity of cognitive deficits and the severity of negative symptoms. Our data suggest that the severity of negative symptoms is associated with several neuropsychological deficits, specifically deficits in memory,

Acknowledgments

The authors wish to thank Janssen Research Foundation, Piscataway, NJ, USA. The sponsor provided all data, but the sponsor was not involved in data analysis or in the preparation of the manuscript.

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