Monoaminergic Treatment of Schizophrenia

February 1, 2006

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.

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.


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 (Catapres), an α2 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 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 (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 (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, 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 (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.




Abi-Dargham A, Mawlawi O, Lombardo I et al. (2002), Prefrontal dopamine D


receptors and working memory in schizophrenia. J Neurosci 22(9):3708-3719.


Aoki C, Go CG, Venkatesan C, Kurose H (1994), Perikaryal and synaptic localization of alpha 2A-adrenergic receptor-like immunoreactivity. Brain Res 650(2):181-204.


Arnsten AF, Goldman-Rakic PS (1985), Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230(4731):1273-1276.


Arnsten AF, Mathew R, Ubriani R et al. (1999), Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function. Biol Psychiatry 45(1):26-31.


Aston-Jones G, Rajkowski J, Cohen J (1999), Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 46(9):1309-1320.


Azmitia EC (2001), Modern views on an ancient chemical: serotonin effects on cell proliferation, maturation, and apoptosis. Brain Res Bull 56(5):413-424.


Birnbaum S, Gobeske KT, Auerbach J et al. (1999), A role for norepinephrine in stress-induced cognitive deficits: alpha-1-adrenoceptor mediation in the prefrontal cortex. Biol Psychiatry 46(9):1266-1274.


Blanchet PJ, Fang J, Gillespie M et al. (1998), Effects of the full dopamine D


receptor agonist dihydrexidine in Parkinson's disease. Clin Neuropharmacol 21(6):339-343.


Breier A, Su TP, Saunders R et al. (1997), Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 94(6):2569-2574.


Brozoski TJ, Brown RM, Rosvold HE, Goldman PS (1979), Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205(4409):929-932.


Cai JX, Arnsten AF (1997), Dose-dependent effects of the dopamine D


receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther 283(1):183-189.


Carlsson A, Lindqvist M (1963), Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 20:140-144.


Carter CS, Mintun M, Nichols T, Cohen JD (1997), Anterior cingulate gyrus dysfunction and selective attention deficits in schizophrenia: [15O]H2O PET study during single-trial Stroop task performance. Am J Psychiatry 154(12):1670-1675 [see comment].


Carter CS, Perlstein W, Ganguli R et al. (1998), Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry 155(9):1285-1287.


Clarke HF, Dalley JW, Crofts HS et al. (2004), Cognitive inflexibility after prefrontal serotonin depletion. Science 304(5672):878-880.


Cussac D, Pasteau V, Millan MJ (2004), Characterisation of Gs activation by dopamine D


receptors using an antibody capture assay: antagonist properties of clozapine. Eur J Pharmacol 485(1-3):111-117.


Daniel DG, Weinberger DR, Jones DW et al. (1991), The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia. J Neurosci 11(7): 1907-1917.


Davis KL, Kahn RS, Ko G, Davidson M (1991), Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148(11):1474-1486 [see comments].


Egan MF, Goldberg TE, Kolachana BS et al. (2001), Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 98(12):6917-6922.


Fici GJ, Wu H, VonVoigtlander PF, Sethy VH (1997), D


dopamine receptor activity of anti-parkinsonian drugs. Life Sci 60(18):1597-1603.


Friedman JI, Ocampo R, Elbaz Z et al. (2005), The effect of citalopram adjunctive treatment added to atypical antipsychotic medications for cognitive performance in patients with schizophrenia. J Clin Psychopharmacol 25(3):237-242.


Friedman JI, Stewart DG, Gorman JM (2004), Potential noradrenergic targets for cognitive enhancement in schizophrenia. CNS Spectr 9(5):350-355.


Goldman-Rakic PS, Muly EC 3rd, Williams GV (2000), D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev 31(2-3):295-301.


Green ME (1996), What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153(3):321-330 [see comment].


Hyman SE, Fenton WS (2003), Medicine. What are the right targets for psychopharmacology? Science 299(5605):350-351.


Jakala P, Riekkinen M, Sirvio J et al. (1999), Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology 20(5):460-479.


Kimberg DY, D'Esposito M (2003), Cognitive effects of the dopamine receptor agonist pergolide. Neuropsychologia 41(8):1020-1027.


Kulisevsky J, Garcia-Sanchez C, Berthier ML et al. (2000), Chronic effects of dopaminergic replacement on cognitive function in Parkinson's disease: a two-year follow-up study of previously untreated patients. Mov Disord 15(4):613-626.


Lammers CH, Deuschle M, Weigmann H et al. (1999), Coadministration of clozapine and fluvoxamine in psychotic patients-clinical experience. Pharmacopsychiatry 32(2):76-77.


Lange KW, Robbins TW, Marsden CD et al. (1992), L-dopa withdrawal in Parkinson's disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychophamocology (Berl) 107(2-3):394-404.


Mao ZM, Arnsten AF, Li BM (1999), Local infusion of an alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biol Psychiatry 46(9):1259-1265.


Marjamaki A, Luomala K, Ala-Uotila S, Scheinin M (1993), Use of recombinant human alpha 2-adrenoceptors to characterize subtype selectively of antagonist binding. Eur J Pharmacol 246(3):219-226.


McDowell SK (1996), Update on pharmacology. A role for dopamine in executive function deficits. J Head Trauma Rehabil 11(6):89-92.


Mitropoulou VD, Harvey PD, Iskander EG et al. (2005), Amphetamine, psychosis and cognition in the schizophrenia spectrum. Current Psychosis and Therapeutics Reports 3(4):176-181.


Muller U, von Cramon DY, Pollmann S (1998), D


- versus D


-receptor modulation of visuospatial working memory in humans. J Neurosci 18(7):2720-2728.


Murray CJ, Lopez AD (1997), Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 349(9063):1436-1442 [see comment].


Newman-Tancredi A, Gavaudan S, Conte C et al. (1998), Agonist and antagonist actions of antipsychotic agents at 5-HT


receptors: a [35S]GTPgammaS binding study. Eur J Pharmacol 355(2-3):245-256.


Poyurovsky M, Koren D, Gonopolsky I et al. (2003), Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia patients: an add-on, double-blind placebo-controlled study. Eur Neuropsychopharmacol 13(2):123-128.


Renyi L, Evenden JL, Fowler CJ et al. (2001), The pharmacological profile of (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a selective 5-hydroxytryptamine(1A) receptor agonist. J Pharmacol Exp Ther 299(3):883-893.


Roth BL, Hanizavareh SM, Blum AE (2004), Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology (Berl) 174(1):17-24.


Schneider JS, Kovelowski CJ 2nd (1990), Chronic exposure to low doses of MPTP. I. Cognitive deficits in motor asymptomatic monkeys. Brain Res 519(1-2):122-128.


Siever LJ, Kalus OF, Keefe RS (1993), The boundaries of schizophrenia. Psychiatr Clin North Am 16(2):217-244.


Silver H (2003), Selective serotonin reuptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia. Int Clin Psychopharmacol 18(6):305-313.


Silver H, Kaplan A, Jahjah N (1995), Fluvoxamine augmentation for clozapine-resistant schizophrenia. Am J Psychiatry 152(7):1098 [see comment].


Stevens AA, Goldman-Rakic PS, Gore JC et al. (1998), Cortical dysfunction in schizophrenia during auditory word and tone working memory demonstrated by functional magnetic resonance imaging. Arch Gen Psychiatry 55(12):1097-1103.


Sumiyoshi T, Matsui M, Nohara S et al. (2001), Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am J Psychiatry 158(10):1722-1725.


Szegedi A, Wiesner J, Hiemke C (1995), Improved efficacy and fewer side effects under clozapine treatment after addition of fluvoxamine. J Clin Psychopharmacol 15(2):141-143 [letter].


Uhlen S, Muceniece R, Rangel N et al. (1995), Comparison of the binding activities of some drugs on alpha 2A, alpha 2B and alpha 2C-adrenoceptors and non-adrenergic imidazoline sites in the guinea pig. Pharmacol Toxicol 76(6):353-364.


Varty GB, Bakshi VP, Geyer MA (1999), M100907, a serotonin 5-HT


receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats. Neuropsychopharmacology 20(4):311-321.


Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A et al. (1998), Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9(17):3897-3902.


Walters AS, Mandelbaum DE, Lewin DS et al. (2000), Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD. Dopaminergic Therapy Study Group. Pediatr Neurol 22(3):182-186.


Weinberger DR (1987), Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44(7):660-669.


Williams GV, Rao SG, Goldman-Rakic PS (2002), The physiological role of 5-HT


receptors in working memory. J Neurosci 22(7):2843-2854.


Yasuno F, Suhara T, Nakayama T et al. (2003), Inhibitory effect of hippocampal 5-HT


receptors on human explicit memory. Am J Psychiatry 160(2):334-340 [see comment].