Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers
Introduction
A growing body of research indicates that cognition in schizophrenia is critically important for functional outcome. For example, the severity of cognitive deficits is more predictive of social and vocational outcome in schizophrenia than either positive or negative symptoms (Green, 1996, Harvey et al., 1998, Green et al., 2000, Gold et al., 2002). As has been highlighted by Keefe and Davidson, social and occupational impairments experienced by individuals with schizophrenia lead the largest indirect costs of this illness, both for the individual and for society (Sevy and Davidson, 1995). As such, if we could improve cognition in schizophrenia, and if improved cognition leads to reduced social and occupational dysfunction, such interventions could have a beneficial effect for both individuals with schizophrenia and for society (Davidson and Keefe, 1995).
The growing recognition of the central role of cognition in determining outcome in schizophrenia has lead to a dramatic increase in interest in evaluating whether existing therapies improve cognition, as well on developing new treatments for improving cognition in schizophrenia (Davidson and Keefe, 1995). While there is little evidence that typical antipsychotics improve cognition in schizophrenia (Goldberg and Weinberger, 1996), there is somewhat more evidence that the newer generation of atypical antipsychotics do a better job of improving cognitive function in schizophrenia than the typical antipsychotics (Keefe et al., 1999, Harvey and Keefe, 2001). These are modest effects whose functional significance remains unknown and the interpretation of these effects as specifically related to improved cognitive functioning, rather than an absence of negative side effects in comparison typical agents has also been challenged (Carpenter and Gold, 2002).
Another approach is to examine the use of adjunctive treatments, administered in addition to either typical or atypical antipsychotics, which may specifically target one or more cognitive functions in schizophrenia. For example, one cognitive function that is impaired in schizophrenia is working memory, typically defined as the ability to temporarily maintain and manipulate information (Baddeley, 1986). In part because of the working memory deficits shown by individuals with schizophrenia, there has been interest in agents that influence dopamine function as a potential type of adjunctive treatment for individuals with schizophrenia. This focus on dopamine is driven in large by findings in studies of non-human primates suggesting that optimal dopamine function is critical for working memory performance (Goldman-Rakic et al., 2000). For example, working memory function is impaired in non-human primates following 6-hydroxy-dopamine lesions in PFC (Brozoski et al., 1979), or administration of dopamine antagonists (Sawaguchi and Goldman-Rakic, 1994). In addition, administration of low dose DA agonists can improve working memory in monkeys (Williams and Goldman-Rakic, 1995), especially those with impaired performance (Arnsten et al., 1994, Cai and Arnsten, 1997, Castner et al., 2000).
There is also growing evidence that the administration of dopamine agonists can improve cognition in humans, including working memory. Methylphenidate (Clark et al., 1986, Elliott et al., 1997, Mehta et al., 2000), amphetamine (Mattay et al., 1996, Mattay et al., 2000), bromocriptine (Luciana et al., 1992, Kimberg et al., 1997, Luciana and Collins, 1997, Luciana et al., 1998), and pergolide (Muller et al., 1998, Kimberg and D'Esposito, 2003) have all been shown to improve working memory in healthy human participants. Interestingly, there is also research to suggest that dopamine agonists may be particularly effective for those individuals with the worst performance in the absence of drug (Kimberg et al., 1997, Mattay et al., 2000, Mattay et al., 2003, Mehta et al., 2001, Kimberg and D'Esposito, 2003). For example, individuals with the high activity form of the COMT gene (leading to more catabolism of dopamine) have worse working memory performance than individuals with the low activity form of the COMT gene (Egan et al., 2001, Malhotra et al., 2002), and also show the greatest positive benefit of amphetamine (Mattay et al., 2003). Although several of these agents are not selective for dopamine, and it is likely that all of these drugs influence neurotransmitter systems other than the dopamine system, such results are generally consistent with the hypothesis that administration of dopamine agonists can improve working memory. Further, there is evidence that levodopa can improve working memory and related cognitive functions in individuals with impaired dopamine function, such as those with Parkinson's Disease (Cooper et al., 1992, Lange et al., 1995, Kulisevsky et al., 1996, Kulisevsky et al., 2000, Cools et al., 2002, Costa et al., 2003).
Interestingly, there is also some evidence that individuals with schizophrenia taking haloperidol show improved performance on the Wisconsin Card Sort Task with the administration of amphetamine, despite minimal or no exacerbation of positive symptoms (Daniel et al., 1991, Goldberg et al., 1991). Further, individuals with schizotypal personality disorder also show improved performance on the Wisconsin Card Sorting Task and a spatial working memory task with the administration of amphetamine (Siegel et al., 1996, Kirrane et al., 2000). It has been suggested that cognition is improved with schizophrenia with the co-administration of haloperidol and amphetamine because treatment with a typical antipsychotic blocks D2 receptors in subcortical regions, preventing a negative impact of a dopamine agonists of positive symptoms, leaving D1 receptors in regions such as prefrontal cortex free to benefit for enhanced cholinergic transmission (Goldberg et al., 1991).
The goal of the current study was to further examine the hypothesis that adjunctive treatment with a dopamine agonist could improve at least some cognitive functions in medicated individuals with schizophrenia. To do so, we conducted a double-blind placebo controlled study of the acute effects of d-amphetamine (d-AMPH) on cognitive function in medicated individuals with schizophrenia and healthy controls. In the individuals with schizophrenia, we examined whether d-AMPH could improve their cognitive function on measures of working memory, language production, and selective attention. We choose measures of language production and selective attention in addition to a working memory measure because of the evidence that both are supported by working memory function in healthy individuals (Levelt, 1989, Cohen et al., 1999), and because language production and selective attention deficits are correlated with working memory deficits in schizophrenia (Docherty et al., 1996, Barch and Carter, 1998, Barch, 1999, Cohen et al., 1999, Kerns and Berenbaum, 2002, Melinder and Barch, 2003). However, we did not expect as strong an influence of d-AMPH in controls on such tasks, as controls typically perform close to ceiling on these measures at baseline. Therefore, we administered versions of each of the tasks to controls that were designed to reduce the their performance via a mechanism conceptually similar to that occurring in schizophrenia, an approach we have used successfully in past research (Barch and Berenbaum, 1994). Specifically, we administered version of the tasks that were designed to reduce the level of working memory capacity available to perform the primary task by asking subjects to simultaneously perform secondary tasks that also engaged working memory resources (e.g., “dual-task” manipulations).
Section snippets
Participants
Participants were: 10 DSM-IV schizophrenic or schizoaffective patients and 22 normal controls (1 control was missing data on the spatial working memory tasks). The schizophrenic/schizoaffective patients were all outpatients at the Schizophrenia Treatment and Research Center at Western Psychiatric Institute and Clinic. All patients were deliberately selected to be on stable typical antipsychotics (haldol or prolixin) at constant dosages for at least 2 weeks. Patient diagnoses were based on the
Spatial working memory
The error and RT data from the spatial working memory task were analyzed using 3-Factor ANOVAs, with group as a between subject factor, and both session (placebo, d-AMPH) and delay (0 s, 8 s) as within-subject factors. For errors, the ANOVA revealed a main effect of delay, F(1,29)=61.5, p<0.001, with both groups performing worse at the long delay. There was also a group by session interaction, F(1,29)=4,1, p=0.05. As shown in Table 2, the patients were impaired compared to controls on placebo (p
Discussion
The goal of the current study was to further examine the hypothesis that agents that augment the function of the dopamine system would be effective at improving cognition in individuals with schizophrenia who were being treated with typical antipsychotics. Consistent with this hypothesis, we found that the acute administration of d-AMPH improved: 1) spatial working memory in individuals with schizophrenia, reflected in both accuracy and speed; 2) language production, both the amount of speech
Acknowledgements
Dr. Barch is supported by the National Institute of Mental Health, the National Alliance for Research on Schizophrenia and Depression, and the Dana Foundation; Dr. Carter is supported by the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression. The present work was supported by a Seed grant from the Conte Center for the Neuroscience of Mental Disorders (PI D Lewis MD) to Dr Carter.
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Department of Psychiatry and Psychology, University of California at Davis.