Psychiatric Times.
No. 2
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.
Noradrenaline
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
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.
Summary
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.
References
1. Abi-Dargham A, Mawlawi O, Lombardo I et al. (2002), Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 22(9):3708-3719.
2. 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.
3. 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.
4. 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.
5. Aston-Jones G, Rajkowski J, Cohen J (1999), Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 46(9):1309-1320.
6. Azmitia EC (2001), Modern views on an ancient chemical: serotonin effects on cell proliferation, maturation, and apoptosis. Brain Res Bull 56(5):413-424.
7. 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.
8. Blanchet PJ, Fang J, Gillespie M et al. (1998), Effects of the full dopamine D1 receptor agonist dihydrexidine in Parkinson's disease. Clin Neuropharmacol 21(6):339-343.
9. 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.
10. 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.
11. Cai JX, Arnsten AF (1997), Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther 283(1):183-189.
12. 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.
13. 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].
14. Carter CS, Perlstein W, Ganguli R et al. (1998), Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry 155(9):1285-1287.
15. Clarke HF, Dalley JW, Crofts HS et al. (2004), Cognitive inflexibility after prefrontal serotonin depletion. Science 304(5672):878-880.
16. Cussac D, Pasteau V, Millan MJ (2004), Characterisation of Gs activation by dopamine D1 receptors using an antibody capture assay: antagonist properties of clozapine. Eur J Pharmacol 485(1-3):111-117.
17. 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.
18. 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].
19. 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.
20. Fici GJ, Wu H, VonVoigtlander PF, Sethy VH (1997), D1 dopamine receptor activity of anti-parkinsonian drugs. Life Sci 60(18):1597-1603.
21. 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.
22. Friedman JI, Stewart DG, Gorman JM (2004), Potential noradrenergic targets for cognitive enhancement in schizophrenia. CNS Spectr 9(5):350-355.
23. 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.
24. Green ME (1996), What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153(3):321-330 [see comment].
25. Hyman SE, Fenton WS (2003), Medicine. What are the right targets for psychopharmacology? Science 299(5605):350-351.
26. 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.
27. Kimberg DY, D'Esposito M (2003), Cognitive effects of the dopamine receptor agonist pergolide. Neuropsychologia 41(8):1020-1027.
28. 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.
29. Lammers CH, Deuschle M, Weigmann H et al. (1999), Coadministration of clozapine and fluvoxamine in psychotic patients-clinical experience. Pharmacopsychiatry 32(2):76-77.
30. 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.
31. 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.
32. 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.
33. McDowell SK (1996), Update on pharmacology. A role for dopamine in executive function deficits. J Head Trauma Rehabil 11(6):89-92.
34. 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.
35. Muller U, von Cramon DY, Pollmann S (1998), D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci 18(7):2720-2728.
36. 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].
37. Newman-Tancredi A, Gavaudan S, Conte C et al. (1998), Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study. Eur J Pharmacol 355(2-3):245-256.
38. 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.
39. 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.
40. 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.
41. 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.
42. Siever LJ, Kalus OF, Keefe RS (1993), The boundaries of schizophrenia. Psychiatr Clin North Am 16(2):217-244.
43. Silver H (2003), Selective serotonin reuptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia. Int Clin Psychopharmacol 18(6):305-313.
44. Silver H, Kaplan A, Jahjah N (1995), Fluvoxamine augmentation for clozapine-resistant schizophrenia. Am J Psychiatry 152(7):1098 [see comment].
45. 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.
46. 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.
47. 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].
48. 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.
49. Varty GB, Bakshi VP, Geyer MA (1999), M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats. Neuropsychopharmacology 20(4):311-321.
50. 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.
51. 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.
52. Weinberger DR (1987), Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44(7):660-669.
53. Williams GV, Rao SG, Goldman-Rakic PS (2002), The physiological role of 5-HT2A receptors in working memory. J Neurosci 22(7):2843-2854.
54. Yasuno F, Suhara T, Nakayama T et al. (2003), Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory. Am J Psychiatry 160(2):334-340 [see comment].
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