Monoaminergic Treatment of Schizophrenia
By Eran Chemerinski, MD, and Larry J. Siever, MD |
February 1, 2006
Dr. Chemerinski is assistant professor of psychiatry in the department of psychiatry at Mt. Sinai School of Medicine and the Bronx Veterans Affairs Medical Center (VAMC).
Dr. Siever is professor of psychiatry in the department of psychiatry at Mt. Sinai School of Medicine and the Bronx VAMC.
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 α2a-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(Drug information on clonidine) (Catapres), an α2 adrenergic receptor agonist (Arnsten and Goldman-Rakic, 1985).
It has been proposed that moderate levels of norepinephrine(Drug information on norepinephrine) enhance prefrontal cortex functions through actions at postsynaptic α2 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(Drug information on guanfacine) (Tenex), by enhancing signals at postsynaptic α2-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 α2 adrenergic receptors are potential targets for cognitive enhancement in psychiatric disorders. Similarly, atomoxetine(Drug information on 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-HT1A receptor that enhances cognition (Roth et al., 2004). For example, both atypical antipsychotic drugs with 5-HT1A partial agonist action and antagonist action have been shown to enhance cognition (Newman-Tancredi et al., 1998). Additionally, tandospirone, a compound with 5-HT1A 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-HT1A 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-HT2A antagonism improves cognition in schizophrenia. Most atypical antipsychotics have significant 5-HT2A antagonist actions and, while cognitive improvement was seen in patients with schizophrenia after the administration of mianserin(Drug information on mianserin), a drug with 5-HT2A/2C antagonist activity (Poyurovsky et al., 2003), the reverse was observed in healthy volunteers after the administration of psilocybin, a 5-HT2A agonist (Vollenweider et al., 1998). (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-HT2A agonist (Williams et al., 2002). However, findings from immunocytochemical studies suggest that beneficial effects of 5-HT2A antagonism might be secondary to normalization of N-methyl-D-aspartate receptor functioning (Varty et al., 1999). Since most atypical antipsychotics have potent 5-HT2A 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(Drug information on 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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