Relative contribution of antipsychotics, negative symptoms and executive functions to social functioning in stable schizophrenia

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Abstract

The purpose of this study was to examine the relative contributions of antipsychotic medication, negative symptoms and executive functions to impairment in social functioning in a sample of outpatients with stable schizophrenia.

One-hundred and sixty-eight consecutive outpatients with stable schizophrenia were enrolled in a cross-sectional study. We performed a path analysis using multiple regression technique in order to assess the specific effect of antipsychotic type (first-generation antipsychotics versus second-generation antipsychotics) on social functioning and the possible mediating role of executive functions and negative symptoms.

Our findings suggested that (i) second generation antipsychotics (SGAs) use predicted better social functioning (Beta = .24, p = .003) and better executive functions (Beta = .25, p = .003); conversely SGAs use was not associated with lesser negative symptoms (Beta = .00, p = .981); (ii) impaired executive functions and severity of negative symptoms were associated with worse social functioning (Beta = .19, p = .016; Beta = .28, p = .001); (iii) when we inserted in the model Positive and Negative Syndrome Scale — Negative Symptom subscale (PANSS-N) and Wisconsin Card Sorting Test — number of achieved sorting categories (WCST-cat), the former failed to show a mediation effect, while the latter seemed to mediate partially the effect of SGAs on social functioning.

Taken together, the present results suggest that it is critical to examine individually executive functions and negative symptoms because they seem to relate to social functioning in different and independent ways and thus might represent separable treatment targets. Furthermore, social functioning appears a complex outcome multiply determined with no single predictor variable explaining a sufficient amount of variance.

Introduction

Schizophrenia can lead to a significant impairment of psychosocial functioning, including poor social interaction, particularly difficulty maintaining relationships with family and friends or function in the workplace. It has been hypothesized that one of the primary reasons for the historically lack of improvement in functional outcome is a general lack of success in treating the aspects of schizophrenia that have the strongest associations with functional outcome (Burns and Patrick, 2007, Harvey et al., 2004, Green, 1996, Green et al., 2000).

Functional outcome in schizophrenia can be affected by a number of factors like age, gender, education, illness duration, cognitive dysfunctions, symptoms, and pharmacological and psychosocial treatments (Hofer et al., 2005, Wittorf et al., 2008). The factors identified are not always consistent across studies but cognitive dysfunctions and negative symptoms emerged as the most reliable (Bromet et al., 2005, Grant and Beck, 2008, Green, 1996, Milev et al., 2005).

Cognitive deficits are supposed to be more closely associated with social functioning in schizophrenia than any other symptom domain (Evans et al., 2004, Green, 1996, Green et al., 2000, Green et al., 2004a, Green et al., 2004b, Green and Nuechterlein, 1999, Milev et al., 2005) even if recently published results have been somewhat conflicting (Bowie et al., 2006, Harvey et al., 2006a, Heslegrave et al., 1997, Kurtz et al., 2005, Mohamed et al., 2008, Wegener et al., 2005). The amount of variance in functioning accounted for by cognitive impairment is variable; between 20% and 60% of the variance of functional outcome can be explained by cognitive functioning in general (Green et al., 2000, Green et al., 2004a, Green et al., 2004b), with some abilities sharing as little as 10% of variance (Green, 1996). The measures most consistently related to community functioning were secondary verbal memory and executive functions (Green and Nuechterlein, 1999).

Whereas some studies showed a strong independent association between cognition and social functioning, the role of negative symptoms on social functioning is contentious (Green, 1996, McGurk and Meltzer, 2000, McGurk et al., 2000, Velligan et al., 2000). Furthermore, negative symptoms have been assumed to contribute only indirectly through their link with cognition or other mediators with social outcome (Grant and Beck, 2008, Greenwood et al., 2005). Indeed, several studies have shown an association between negative symptoms and many different cognitive domains (i.e. verbal and visual memory, working memory, verbal fluency, visual–motor sequencing, cognitive impairments in QI, processing speed, and executive functions) (George et al., 1996, Heslegrave et al., 1997). Also, Norman et al. (1999) outlined that symptoms level in later stages of illness and after an optimized treatment might be better predictors of functioning than those in acute phases.

The development of second generation antipsychotics (SGAs) with improved tolerability and a broader spectrum of efficacy across the symptomatic domains of schizophrenia has raised expectations among patients and physicians concerning this issue. Overall, SGAs have been found to be more efficacious than first-generation antipsychotics (FGAs) in the treatment of negative symptoms (Beasley et al., 1996, Leucht et al., 2002) and cognitive dysfunction, albeit to a small extent (Harvey et al., 2004, Kasper and Resinger, 2003, Meltzer, 2004). Conversely, a number of studies failed to find a significant efficacy relative to either negative symptoms or cognitive impairment (Bender et al., 2006, Green et al., 1992). Regarding social functioning, there is no body of knowledge of any differences with SGAs and FGAs (Priebe, 2007, Saleem et al., 2002). Moreover, it is not clear how antipsychotics could affect social functioning. Two possible mechanisms have been suggested. First, antipsychotics could improve psychopathological symptoms. A lower symptom level could enable patients with schizophrenia to function and perform better in their social context and subsequently achieve more favourable social outcomes. Second, antipsychotics could have an impact on cognitive symptoms that are illness-related, therefore patients might be more likely to establish and maintain useful relationships and improve social outcomes (Priebe, 2007). Due to the indirect nature of the potential treatment effect on social functioning, its impact on social outcome has been termed “distal”, as opposed to the more “proximal” outcome criterion of psychopathological symptoms (Watts and Priebe, 2002).

The purpose of the present study was to assess the relative contribution of antipsychotic medication, negative symptoms and executive function to social functioning in a sample of outpatients with stable schizophrenia. Executive function was targeted because of its close link both to negative symptoms and to poor functioning in the community. Executive functioning is a broad concept including multiple abilities, such as conceptual flexibility, abstract reasoning, maintenance and shifting of cognitive sets, hypotheses testing, and self-monitoring of goal-directed behaviour (Goldman et al., 1996); thus it logically follows that they would be important for guiding behaviour during dynamic interpersonal interactions (Bowie et al., 2008). In the current study, executive function was measured with the Wisconsin Card Sorting Test (WCST) (Berg, 1948, Grant and Berg, 1948). The WCST is a widely used neuropsychological measurement of “executive function” or “higher-order cognitive functions” such as working memory, abstract thinking, maintenance of set, and response to feedback. It doesn't tap the full extent of executive functions deficits. It investigates some facets of these deficits, including conceptual flexibility and abstraction (Heaton et al., 1993). WCST performance is considered to reflect aspects of executive functioning rather than be representative of the entire construct. Moreover, for the purpose of our study, we chose to use the Global Assessment of Functioning (GAF) to quantify the global functioning of patients in the spheres of psychological, social and occupational or educational functioning. This scale was chosen because it is internationally recognized and of practical use in standard clinical trials. It is also considered a reliable and fast measure of disturbance in functioning, which can be readily used by multidisciplinary raters, without the need for extensive training (Jones et al., 1995).

Aims and hypotheses of the current study, guided by previously reported literature, were as follows:

  • 1)

    To investigate the ability of antipsychotic type (SGAs versus FGAs) to predict social functioning. Given the mixed results of previous studies, we intended this as an exploratory analysis and expected that SGAs would significantly predict a better social functioning.

  • 2)

    To investigate the ability of executive functions and negative symptoms to predict social functioning. As the same of the first hypothesis, we expected that both of them would significantly predict social functioning.

  • 3)

    To investigate whether antipsychotic medication continued to predict social functioning when both executive functions and negative symptoms were also considered. It was expected that antipsychotic medication, executive functions and negative symptoms interact in influencing social functioning, WCST and negative symptoms being partial mediators of the relationship between antipsychotic medication and social functioning.

Section snippets

Patient population

Patients were referred to the Psychiatric Section, Department of Neuroscience, University of Turin, and the Mental Health Department 1 South of Turin in the period between January 2003 and December 2004. Patients were initially evaluated by a clinician–psychiatrist, and if they met DSM-IV-TR (APA, 2000) criteria for schizophrenia, they were seen subsequently by our research team (C.M., M.G.). Of these, a sample of consecutive subjects fulfilling the following criteria were included in the study:

Results

Patients in our sample had a DSM IV-TR diagnosis of schizophrenia paranoid subtype (n = 106, 63%), disorganised subtype (n = 9, 5%), undifferentiated subtype (n = 41, 25%) and residual subtype (n = 12, 7%). The mean age (± S.D.) was 38.4 (± 9.94) years. The mean average duration of illness (± S.D.) was 13.3 (± 9.87) years. They were 69 females (41%) and 99 males (59%). One-hundred and one (60%) were treated with SGAs and 67 (40%) with FGAs. Mean ratings of GAF was 57.8 (S.D. = 14.2).

Subjects showed a

Discussion

The purpose of the present study was to examine the complex relationships of antipsychotic type (SGAs versus FGAs), negative symptoms, and executive functions in predicting social functioning within a demographically representative sample of outpatients with stable schizophrenia, characterized by a reasonably chronic course, a high level of disability, and moderately severe positive and negative symptoms. For the purpose of our analysis, we aimed to test three hypotheses.

First, as hypothesized,

Conclusions

Our results would support the hypothesis that social functioning as measured by GAF is partially influenced by SGAs, executive functions and negative symptoms. However, even if there was evidence of better executive functions and better social functioning during SGAs use, the effect of SGAs on GAF seemed partially mediated by their effect on executive functions. Taken together, the present results would suggest that it is critical to examine individually executive functions and negative

Acknowledgements

This study was supported by grant # 2003-1421 funded by Compagnia di San Paolo, Torino, Italy and by “Bando Regionale per il finanziamento di Progetti di Ricerca Sanitaria Finalizzata, 2004” from REGIONE PIEMONTE.

References (97)

  • HoferA. et al.

    Patient outcomes in schizophrenia II: the impact of cognition

    Eur Psychiatry

    (2005)
  • HongK.S. et al.

    Effects of risperidone on information processing and attention in first-episode schizophrenia

    Schizophr Res

    (2002)
  • KasperS. et al.

    Cognitive effects and antipsychotic treatment

    Psychoneuroendocrinology

    (2003)
  • KawaiN. et al.

    High-dose of multiple antipsychotics and cognitive function in schizophrenia: the effect of dose reduction

    Progr Neuro-Psychopharm Biol Psy

    (2006)
  • KeefeR.S. et al.

    One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia

    Schizophr Res

    (2006)
  • LeeS.M. et al.

    Effects of antipsychotics on cognitive performance in drug-naive schizophrenic patients

    Prog Neuro-Psychopharmacol Biol Psychiatry

    (2007)
  • McGurkS.R. et al.

    The role of cognition in vocational functioning in schizophrenia

    Schizophr Res

    (2000)
  • MullerU. et al.

    Prefrontal cognitive deficits in patients with schizophrenia treated with atypical or conventional antipsychotics

    Eur Psychiatr

    (2005)
  • MurphyB.P. et al.

    Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review

    Schizophr Res

    (2006)
  • RenX.S. et al.

    Patient characteristics and the likelihood of initiation on olanzapine or risperidone among patients with schizophrenia

    Schizophr Res

    (2005)
  • SankaranarayananJ. et al.

    Antipsychotic use at adult ambulatory care visits by patients with mental health disorders in the United States, 1996–2003: national estimates and associated factors

    Clin Ther

    (2007)
  • Tabarès-SeisdedosR.T. et al.

    Neurocognitive and clinical predictors of functional outcome in patients with schizophrenia and bipolar I disorder at one-year follow-up

    J Affect Disord

    (2008)
  • Villalta-GilV. et al.

    Neurocognitive performance and negative symptoms: are they equal in explaining disability in schizophrenia outpatients?

    Schizophr Res

    (2006)
  • WillhiteR. et al.

    Gender difference in symptoms, functioning and social support in patients at ultra-high risk for developing a psychotic disorder

    Schizophr Res

    (2008)
  • AltshulerL.L. et al.

    Subsyndromal depression is associated with functional impairment in patients with bipolar disorder

    J Clin Psychiatry

    (2002)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders

    (2000)
  • AparasuR.R. et al.

    Patterns and determinants of antipsychotic prescribing in children and adolescents, 2003–2004

    Curr Med Res Opin

    (2007)
  • BaronR.M. et al.

    The moderator–mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations

    J Personal Soc Psychology

    (1986)
  • BellM.D. et al.

    Neurocognitive enhancement therapy and work therapy in schizophrenia: work outcomes at 6 months and 12 month follow-up

    Biol Psychiatry

    (2004)
  • BenderS. et al.

    Influence of atypical neuroleptics on executive functioning in patients with schizophrenia: a randomized, double-blind comparison of oalnzapine vs. clozapine

    Int J Neuropsychopharmacol

    (2006)
  • BergE.A.

    A simple objective treatment for measuring flexibility in thinking

    J Gen Psychol

    (1948)
  • BowieC.R. et al.

    Determinants of real-world functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and symptoms

    Am J Psychiatry

    (2006)
  • BrometE.J. et al.

    Long-term diagnostic stability and outcome in recent first-episode cohort studies of schizophrenia

    Schizophr Bull

    (2005)
  • BuchananR.W. et al.

    Olanzapine treatment of residual positive and negative symptoms

    Am J Psychiatry

    (2005)
  • BuchleyP.F. et al.

    Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or Cul-de-sac?

    Acta Psychiatr Scand

    (2007)
  • BurnsT. et al.

    Social functioning as a n outcome measure in schizophrenia studies

    Acta Psychiatr Scand

    (2007)
  • ChanR.C.K. et al.

    Assessment of executive function for schizophrenia in Hong Kong

    Hong Kong J Psychiatry

    (2005)
  • CohenJ. et al.

    Applied multiple regression/correlation analysis for the behavioural sciences

    (2003)
  • DiattaT. et al.

    Patterns and frequency of atypical antipsychotic prescribing in psychiatric medical centers: a cross-sectional national survey

    Fundam Clin Pharamacol

    (2007)
  • FirstM.B. et al.

    Structured Clinical Interview for DSM-IV Disorders (SCID)

    (1997)
  • GeorgeR.M. et al.

    Cognitive deficits in relation to quality of life in chronic schizophrenics

    NIMHANS J

    (1996)
  • GoldmanR.S. et al.

    Neuropsychological aspects of schizophrenia

  • GrantD.A. et al.

    A behavioural analysis of the degree of reinforcement and ease of shifting to new responses in a Wigl-type card sorting problem

    J Exp Psychol

    (1948)
  • GrantP. et al.

    Defeatist beliefs as a mediator of cognitive impairment, negative symptoms, and functioning in schizophrenia

    Schizophr Bull

    (2008)
  • GreenM.F.

    What are the functional consequences of neurocognitive deficits in schizophrenia?

    Am J Psychiatry

    (1996)
  • GreenM.F.

    Cognition, drug treatment, and functional outcome in schizophrenia: a tale of two transitions

    Am J Psychiatry

    (2007)
  • GreenM.F. et al.

    Should schizophrenia be treated as a neurocognitive disorder?

    Schizophr Bull

    (1999)
  • GreenM.F. et al.

    Wisconsin Card Sorting Test performance in schizophrenia: remediation of a stubborn deficit

    Am J Psychiatry

    (1992)
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