Studies in humans and nonhuman primates have identified the prefrontal cortex as a structure that plays a central role in many aspects of cognition. Results from preclinical studies of prefrontal cortex dysfunction suggest that monoaminergic neurotransmitters exert a modulatory role on its intrinsic circuitry. Findings from several studies suggest that, in patients with schizophrenia and one of the schizophrenia spectrum disorders, cognitive impairments are associated with reduced stimulation of the prefrontal cortex dopamine (DA) receptors. However, mounting evidence suggests that dysregulation in other monoaminergic neurotransmitter systems might also be involved. After treatment with antipsychotic medication, functional deficits in social, occupational and independent living activities in patients with schizophrenia often persist--even in the presence of only residual psychotic symptoms. Since these functional deficits are believed to be strongly associated with the negative symptoms and cognitive deficits present in patients with schizophrenia, new psychopharmacological therapies are being developed to improve cognition in this disorder.
This overview will focus on monoaminergic neurotransmitters that hold promise as therapeutic interventions for the cognitive deficit in schizophrenia (Table).
Evidence from multiple studies suggests that dysregulation of DA plays a critical role in the pathophysiology of schizophrenia. An early hypothesis of this relationship (the "classical" DA hypothesis) postulated that hyperactivity of mesolimbic DA projections to subcortical areas results in positive symptoms (Carlsson and Lindqvist, 1963). More recently, it has been recognized that the impairment in several cognitive domains in patients with schizophrenia is the best predictor of their social and occupational reintegration.
A "revised" DA hypothesis (Davis et al., 1991; Weinberger, 1987) attributed the cognitive impairments and negative symptoms of schizophrenia to hypoactivity of mesocortical DA projections to D1 receptors in the prefrontal cortex. This hypothesis is supported by studies of nonhuman primates with reduced stimulation of prefrontal cortex D1 receptors that exhibited cognitive impairments similar to the ones observed in schizophrenia (Goldman-Rakic et al., 2000), as well as reports from genetic polymorphism studies of the DA-inactivating enzyme catechol-O-methyl-transferase (COMT). The Val/Val genotype of COMT, which is associated with more efficient metabolism of dopamine than Met/Val or Met/Met genotypes and, thus, reduced dopaminergic availability in prefrontal cortex D1 receptors, has been shown to correlate with poor performance on tests of executive function and working memory (Egan et al., 2001).
Furthermore, reports from functional imaging measurement studies of D1 receptors with PET-[11C]NNC 112 showed excessive expression of these receptors in the dorsolateral prefrontal cortex of drug-free patients with schizophrenia, which predicted poorer working memory performance (Abi-Dargham et al., 2002). The authors proposed that chronic deficit in presynaptic DA function in the dorsolateral prefrontal cortex may be the cause for both the D1 receptor upregulation and the impaired working memory performance reported in their study.
In humans, there is growing evidence that cognitive function improves after the use of dopamine agonists (Kimberg and D'Esposito, 2003). Recent cognitive enhancement studies reported amelioration of working memory (Carter et al., 1998; Stevens et al., 1998) and selective attention impairment (Carter et al., 1997), as well as increase in prefrontal cortex blood flow (Daniel et al., 1991) in patients with schizophrenia after the use of amphetamine. However, the magnitude of DA release and subsequent stimulation of striatal D2 receptors induced by amphetamine in these patients correlates with worsening of their psychotic symptoms (Breier et al., 1997).
In ongoing studies by our group, patients with schizotypal personality disorder, the prototypic disorder of the schizophrenia spectrum, who were given oral administration of 30 mg of a single dose of d-amphetamine showed improvement of visuospatial and auditory working memory (Mitropoulou et al., 2005). Moreover, this improvement occurred without secondary worsening of psychotic-like symptoms. This observation can be explained by the fact that while patients with schizophrenia and schizotypal personality disorder share a hypoactivity of DA receptors in the prefrontal cortex, patients with schizotypal personality disorder do not exhibit the striatal DA hyperactivity present in patients with schizophrenia (Siever et al., 1993). Thus, the study of patients with schizotypal personality disorder, in conjunction with the wealth of data already available regarding schizophrenia, offers a unique opportunity to identify modifying factors contributing to the more serious cognitive/social deficits of chronic schizophrenia in individuals who are relatively free of a history of long-term antipsychotic treatment, institutionalization and chronic psychosis.
Despite its potential benefit, there is presently no specific D1 agonist available for human use. Several pharmacologic agents with a high ratio of D1/D2 activity are being evaluated for use as cognitive function enhancers in patients with schizophrenia. Pergolide (Permax) is an ergot derivative D1/D2 agonist with greatest activity at D1 receptors that has been utilized in Parkinson's disease (PD) (Fici et al., 1997). This compound was reported to improve visuospatial working memory in healthy individuals (Muller et al., 1998) as well as improve scores in tests measuring frontal function and memory in patients with PD (Kulisevsky et al., 2000) and visual memory and attention in patients with sleep disorders and attention-deficit/hyperactivity disorder (Walters et al., 2000).
Because of these findings, it is of interest to evaluate the effects of pergolide on working memory and attention in schizophrenia and the schizophrenia spectrum disorders. In ongoing studies, our group has demonstrated cognitive improvement in patients with schizotypal personality disorder tested after a four-week administration of escalating doses of pergolide. Specifically, participants demonstrated improvement in auditory working memory and information processing, reflecting an overall improvement in context-dependent working memory processing.
Dihydrexidine is another agent with a high ratio of D1/D2 activity that has been extensively studied in animals and more recently in patients with PD (Blanchet et al., 1998). Since recent data demonstrate that atypical antipsychotics, such as clozapine (Clozaril), have D1 antagonist activity (Cussac et al., 2004), several ongoing studies are evaluating the use of D1 agonist agents as add-on therapy to atypical antipsychotics in patients with schizophrenia, in order to improve their cognitive deficit.
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