Executive function in schizophrenia: Influence of substance use disorder history

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Abstract

Cognitive function in schizophrenia has been associated with different sociodemographic and clinical variables. Substance use disorder (SUD) history has also been associated with cognition in schizophrenia; however, contradictory results have been found regarding its influence on cognitive function. Our aim was to study the relationship between executive function and a) age, b) duration of illness, c) number of psychotic episodes, d) positive symptoms, and e) negative symptoms, in a sample of schizophrenic patients, and secondly to study whether these relationships persisted after stratification of the sample according to the presence or absence of SUD history. A final sample of 203 schizophrenic patients were evaluated for psychotic symptoms using the PANSS, and assessed using a neuropsychological battery to calculate a composite executive function score. Linear regression analyses were performed, with this executive score as the dependent variable, and age, duration of illness, number of psychotic episodes, positive PANSS score and negative PANSS score as independent variables. For the total sample, the regression model showed three variables to be significant predictors of the executive score: age (p = 0.004), number of episodes (p = 0.027), and PANSS negative score (p = 0.003). However, once the sample was stratified, the regression model showed age (p = 0.011) and number of episodes (p = 0.011) to be predictor variables for the executive score in the group of schizophrenic patients with SUD history, while age (p = 0.028) and PANSS negative score (p = 0.006) were predictors in the group of schizophrenic patients without such history. These findings highlight the importance of considering SUD history in studies of cognitive function in schizophrenia.

Introduction

From the first conceptualizations of the disorder, cognitive dysfunction has been considered a fundamental characteristic of schizophrenia (Kraepelin, 1919, Bleuler, 1950). This cognitive deficit has not only been described in schizophrenic patients with a long duration of illness, but also in those with a first psychotic episode, as well as in antipsychotic-naïve patients (Addington et al., 2003, Albus et al., 1996, Mohamed et al., 1999, Saykin et al., 1994, Torrey, 2002). The cognitive performance of schizophrenic patients has been found to be 1–2 standard deviations below performance in control subjects (Bilder et al., 2000, Keefe and Fenton, 2007). A meta-analysis including 204 studies of cognitive function in schizophrenia (Heinrichs and Zakzanis, 1998) found effect sizes of 0.53–1.41. Although several cognitive areas appear to be affected, attention, memory and executive functions seem to be the most impaired domains (Bowie and Harvey, 2005, Heinrichs, 2005). Of these, executive function has been one of the most studied, given its strong relationship with the prefrontal cortex and dopaminergic function, both of which have been clearly implicated in the pathophysiology of schizophrenia (Toda and Abi-Dargham, 2007).

Between 40 and 50% of schizophrenic patients will have a comorbid substance use disorder (SUD) during their lifetime (Regier et al., 1990, Kavanagh et al., 2002). Since substance use has been associated with cognitive deficits in the general population (Yücel et al., 2007, Scheurich, 2005, Spiga et al., 2008, Lundqvist, 2005, Rogers and Robbins, 2001, Verdejo-García et al., 2005), it could be hypothesized that schizophrenic patients with SUD history will exhibit a greater cognitive deficit than schizophrenic patients without this history. However, studies of cognitive function comparing schizophrenic patients with and without SUD history have yielded contradictory results. Thus, different studies have found a worse (Serper et al., 2000a, Serper et al., 2000b, Sevy et al., 1990), similar (Thoma et al., 2007, Addington and Addington, 1997, Cleghorn et al., 1991, Nixon et al., 1996, Pencer and Addington, 2003), or even better (Carey et al., 2003, Joyal et al., 2003, Herman, 2004, Potvin et al., 2005, Stirling et al., 2005, McCleery et al., 2006) cognitive performance in schizophrenic patients with a SUD. These conflicting results may be partly due to methodological issues, such as not taking into account other variables like age, duration of illness, number of psychotic episodes, positive symptoms, or negative symptoms, which could also be associated with cognitive deficits in schizophrenia.

Regarding the course of these cognitive deficits, only longitudinal studies can clarify whether cognitive function in schizophrenia follows a stable course or not, and whether this course is associated with that of other symptoms of the disorder (Heaton et al., 2001, Hill et al., 2004, Hoff et al., 1999, Rund, 1998). Although a progressive deterioration of cognitive function has been described in institutionalized patients aged over 65 (Harvey et al., 1999a, Harvey et al., 1999b, Friedman et al., 2001, Friedman et al., 2002), longitudinal studies with younger schizophrenic patients find stability of cognitive performance in up to 10 years of follow-up (Censits et al., 1997, Lieh-Mak and Lee, 1997, Hoff et al., 1999, Hoff et al., 2005, Gold et al., 1999, Heaton et al., 2001). Thus, the increased impairment found as years go by could be attributed to the older age of patients, rather than to the duration of illness itself. The two main review studies addressing this issue seem to confirm this (Rund, 1998, Kurtz, 2005).

In the aforementioned studies, the duration of illness and the age of patients have been considered as variables. It has been hypothesized that each psychotic episode may have an impact on the brain that would increase the deterioration (Wyatt, 1991), so that the total duration of illness would not be as important as the total time during which the subject has been actively psychotic (Ho et al., 2000). Most studies in this respect have focused on the relationship between the duration of initial untreated psychosis and the functional and cognitive prognosis, and their contradictory findings have questioned the proposed “toxicity” of psychosis (Ho et al., 2003, Rund et al., 2004, Hoff et al., 2000, Craig et al., 2000, Melle et al., 2008). However, few studies of cognitive function in schizophrenia have considered its relationship with the number of psychotic episodes.

Regarding the relationship between psychotic symptoms and cognition in schizophrenia, most studies have ruled out an association between positive psychotic symptoms and cognitive function. However, a relationship between negative symptoms and cognitive performance has been described by several authors (Addington et al., 1991, Rosse et al., 1993, Perry and Braff, 1998, Breier et al., 1991, Buchanan et al., 1994, Capleton, 1996, Berman et al., 1997), although not by others (Cuesta et al., 1995, Himelhoch et al., 1996, Ragland et al., 1996, Liddle and Morris, 1991, Chen et al., 1996). A meta-analysis by Nieuwenstein et al. (2001) found a significant relationship between negative symptoms and a poorer performance in the Wisconsin Card Sorting Test (WCST), although the associations were weak. In this respect, our group has recently reported that the association between negative symptoms and cognitive function is found in schizophrenic patients without SUD history, but not in patients with this history (Rodriguez-Jimenez et al., 2008). This highlights the importance of considering comorbid SUD history in studies of cognition in schizophrenia, and makes stratification according to the presence or absence of SUD history advisable.

In summary, different variables have been associated with cognitive function in schizophrenia. However, the influence on these associations of SUD history, which is present in an important subgroup of schizophrenic patients and could help explain some of the contradictory findings of previous studies, has hardly been taken into account in the existing literature.

The objective of the present study was to analyze the relationship between executive function and a) age, b) duration of illness, c) number of psychotic episodes, d) positive symptoms and e) negative symptoms in a sample of schizophrenic patients, and to determine whether these relationships held after stratification of the sample according to SUD history.

Section snippets

Sample

The present cross-sectional study was carried out with 240 clinically stable outpatients (164 male, 76 female) aged 18 to 60 years old, consecutively referred by their treating psychiatrists, who had been diagnosed with DSM-IV schizophrenia (APA, 1994) using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) (First et al., 1995). All patients were on antipsychotic treatment and had been clinically stable (no hospital admissions, no changes in treatment, and no significant

Results

Table 1 shows the sociodemographic and clinical variables and the neuropsychological assessment results for the total sample, the Sch-SUD+ group and the Sch-SUD− group, as well as the results of the comparison between these two subgroups. As can be seen, Sch-SUD+ patients had a significantly lower mean age (36.2; SD: 10.3) than Sch-SUD− patients (39.5; SD: 8.9) (p = 0.016). The Sch-SUD+ group has a greater proportion of males (89.0% vs. 57.9%; p < 0.001), and more previous psychotic episodes (4.1;

Discussion

When comparing the two subgroups of schizophrenic patients, the present study found that those with SUD history were younger and more often male, had suffered more psychotic episodes and exhibited more severe positive symptoms than Sch-SUD− patients. These sociodemographic and clinical findings are in line with previous studies of dually diagnosed patients which described a younger age, a predominance of males (Talamo et al., 2006, Mueser et al., 2000, Maynard and Cox, 1998), more psychotic

Role of funding source

Funding for this study was provided by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) of the Instituto de Salud Carlos III; CIBERSAM had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Contributors

RRJ and TP designed the study and wrote the protocol. AB, IMG and MAJA managed the literature searches and analyses. EMSM, MA and JLS selected the sample and evaluated patients. RRJ, GP and GR undertook the statistical analysis. RRJ, AB and TP wrote the first draft of the manuscript. The Psychosis and Addictions Research Group (PARG) is a Spanish research group of psychiatrists and psychologists who have contributed to the design of the study and selection of the sample, as well as in the

Conflict of interest

The authors declare that they have no conflicts of interest.

Acknowledgements

We thank the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) of the Instituto de Salud Carlos III.

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