Eran Chemerinski, MD

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 D

 receptors in the prefrontal cortex. This hypothesis is supported by studies of nonhuman primates with reduced stimulation of prefrontal cortex D

 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 D

 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 D

C]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 D

 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 D

 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 D

 agonist available for human use. Several pharmacologic agents with a high ratio of D

 activity are being evaluated for use as cognitive function enhancers in patients with schizophrenia. Pergolide (Permax) is an ergot derivative D

 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 D

 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 D

 antagonist activity (Cussac et al., 2004), several ongoing studies are evaluating the use of D

 agonist agents as add-on therapy to atypical antipsychotics in patients with schizophrenia, in order to improve their cognitive deficit.

The noradrenaline system has been implicated in cognitive functions, such as memory, consolidation/learning (McDowell, 1996) and selective attention (Aston-Jones et al., 1999; Lange et al., 1992). The dorsal noradrenergic bundle is composed of axons of the locus ceruleus' noradrenergic cell bodies. This bundle innervates the prefrontal cortex, which has a high density of α

-adrenergic subtype receptors (Aoki et al., 1994).

Animal studies have shown that noradrenergic depletion of the prefrontal cortex, by means of surgical ablation, toxin exposure or aging, leads to spatial working memory deficits (Brozoski et al., 1979; Cai and Arnsten, 1997). These deficits are improved by clonidine (Catapres), an α

 adrenergic receptor agonist (Arnsten and Goldman-Rakic, 1985).

It has been proposed that moderate levels of norepinephrine enhance prefrontal cortex functions through actions at postsynaptic α

 adrenoceptors, while the release of high levels of norepinephrine activates a1 adrenoceptors, leading to cognitive dysfunction (Arnsten et al., 1999; Birnbaum et al., 1999; Mao et al., 1999). Guanfacine (Tenex), by enhancing signals at postsynaptic α

-adrenergic receptors, has been shown to improve working memory performance in animal models (Arnsten and Goldman-Rakic, 1985; Marjamaki et al., 1993; Schneider and Kovelowski, 1990; Uhlen et al., 1995) and healthy individuals (Jakala et al., 1999).

In our ongoing studies, participants with schizophrenia spectrum personality disorders, tested after four weeks of guanfacine administration, showed significant improvements in tests of cognitive processing (i.e., Paced Auditory Serial Addition Test [PASAT], Letter-Number Sequence and Trail-Making Test B [TMT-B]). These results, while preliminary, support the hypothesis that α

 adrenergic receptors are potential targets for cognitive enhancement in psychiatric disorders. Similarly, atomoxetine (Strattera), a norepinephrine reuptake inhibitor that indirectly increases DA concentration in the prefrontal cortex, is presently being tested as a potential therapy for the cognitive deficits of schizophrenia (Friedman et al., 2004).

Serotonin (5-HT) is implicated in the modulation of cognition, emotion and perception (Azmitia, 2001; Williams et al., 2002). Moreover, cognitive deficits and impulsivity in psychiatric disorders such as schizophrenia and depression have been correlated with dysregulation of this neurotransmitter system. The relationship between 5-HT and preservative behavior observed in schizophrenia was suggested by reports of cognitive inflexibility in animals after prefrontal 5-HT depletion with the use of the selective neurotoxin 5,7-DHT (Clarke et al., 2004).

At least 15 distinct 5-HT receptors have been identified. The preclinical and human literature are not in agreement as to whether it is activation or antagonism of the 5-HT

 receptor that enhances cognition (Roth et al., 2004). For example, both atypical antipsychotic drugs with 5-HT

 partial agonist action and antagonist action have been shown to enhance cognition (Newman-Tancredi et al., 1998). Additionally, tandospirone, a compound with 5-HT

 partial agonist action, has been shown to enhance verbal memory in schizophrenia (Sumiyoshi et al., 2001) and to impair explicit memory function in patients with dementia (Yasuno et al., 2003). (

Tandospirone is not approved for use in the United States--Ed.

) Furthermore, it has been hypothesized that compounds with a high degree of 5-HT

 agonist action, such as NAE-086, carry a significant risk of exacerbating symptoms in patients with schizophrenia (Renyi et al., 2001).

Multiple lines of evidence suggest that 5-HT

 antagonism improves cognition in schizophrenia. Most atypical antipsychotics have significant 5-HT

 antagonist actions and, while cognitive improvement was seen in patients with schizophrenia after the administration of mianserin, a drug with 5-HT

 antagonist activity (Poyurovsky et al., 2003), the reverse was observed in healthy volunteers after the administration of psilocybin, a 5-HT

Mianserin and psilocybin are not approved for use in the United States--Ed.

Moreover, worsening working memory was also reported in primates after the use of a 5-HT

 agonist (Williams et al., 2002). However, findings from immunocytochemical studies suggest that beneficial effects of 5-HT

 antagonism might be secondary to normalization of N-methyl-D-aspartate receptor functioning (Varty et al., 1999). Since most atypical antipsychotics have potent 5-HT

 antagonist activity, it is unlikely that the introduction of an agent with specific antagonist activity in this receptor will provide significant added cognitive improvement in patients with schizophrenia (Silver, 2003).

Additionally, reports from studies of selective serotonin reuptake inhibitor augmentation of atypical antipsychotics are contradictory. Although earlier studies have reported improvement in negative symptoms (Silver et al., 1995; Szegedi et al., 1995) and cognitive deficits (Lammers et al., 1999) in schizophrenia, a more recent study by Friedman et al. (2005) found that adding citalopram (Celexa) to atypical antipsychotics did not produce improvements in clinical symptoms or cognitive performance in these patients when compared with placebo treatment. Thus, further research on alternative serotonergic approaches for the treatment of cognitive deficits in schizophrenia is warranted.

Despite 50 years of pharmacological intervention, schizophrenia remains one of the top causes of disability across cultures (Murray and Lopez, 1997). Meta-analytic reviews clearly demonstrate a correlation between cognitive impairment and several domains of functional outcome (Green, 1996) and have led to the hypothesis that cognitive-enhancing treatments (Hyman and Fenton, 2003) in schizophrenia may result in improved functional outcomes. An important goal for future studies is the development of novel agents with specific activity on promising targets to enhance cognition in patients with schizophrenia.

Drs. Chemerinski and Siever have indicated they have nothing to disclose.

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Although several clinical studies suggest that cognitive impairments in schizophrenia are associated with reduced stimulation of dopamine receptors in the prefrontal cortex, mounting evidence suggests that other monoaminergic neurotransmitter systems may also be involved. We provide an overview of neurotransmitters that hold promise as therapeutic interventions for the cognitive deficit in schizophrenia.

Eran Chemerinski, MD

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