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Muscarinic Agonists for the Treatment of Cognition in Schizophrenia

Published online by Cambridge University Press:  07 November 2014

Angela K. Sellin ,
Mujeeb Shad  and
Carol Tamminga
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Abstract

It is widely accepted that cholinergic activity at muscarinic receptors is required to maintain cognitive functions, including learning and memory. Memory domains are especially impaired in schizophrenia, which may explain difficulties in psychosocial rehabilitation of individuals with this illness. However, little is known about the mechanism of this impairment. To understand our current knowledge, we reviewed the literature since 1990 via a PubMed search for the terms “muscarinic”, “schizophrenia” “cognition,” “memory,” “learning,” and “agonist” in combination. We found 89 basic science/laboratory studies, case reports/series, case-control studies, cross-sectional studies, standardized controlled animal trials, standardized controlled human trials, and reviews. Although further research is required to fully understand the neuropharmacology of the cholinergic system in cognitive function in schizophrenia, we have examined the data currently available. In general, these data suggest that agonist activity at acetylcholine muscarinic type 1 (M1) receptors would enhance memory and learning in schizophrenia. We present an overview of likely side effects of muscarinic agonists. We outline the anticholinergic activity of several available antipsychotics and review the available M1 muscarinic agonists.

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Type
Review Articles
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CNS Spectrums , Volume 13 , Issue 11 , November 2008 , pp. 985 - 996
Copyright
Copyright © Cambridge University Press 2008

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References

REFERENCES

1.Hyman, SE, Fenton, WS. Medicine: what are the right targets for psychopharmacology? Science. 2003;299:350–351.Google Scholar
2.Green, MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996;153:321–330.Google ScholarPubMed
3.Mohs, RC. Assessing cognitive function in schizophrenics and patients with Alzheimer's disease. Schizophr Res. 1995;17(1):115–121.Google Scholar
4.Saykin, AJ, Gur, RC, Gur, RE, et al.Neuropsychological function in schizophrenia. Selective impairment in memory and learning. Arch Gen Psychiatry. 1991;48(7):618–624.Google Scholar
5.Saykin, AJ, Shtasel, DL, Gur, RE, et al.Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry. 1994;51(2):124–131.CrossRefGoogle ScholarPubMed
6.Weickert, TW, Goldberg, TE. First- and second-generation antipsychotic medication and cognitive processing in schizophrenia. Curr Psychiatry Rep. 2005;7(4):304–310.CrossRefGoogle ScholarPubMed
7.Carter, CS, Braver, TS, Barch, DM, et al.Anterior cingulate cortex, error detection, and the online monitoring of performance. Science. 1998;280(5364):747–749.CrossRefGoogle ScholarPubMed
8.Carter, CS, Perlstein, W, Ganguli, R, et al.Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry. 1998;155(9):1285–1287.CrossRefGoogle ScholarPubMed
9.Friedman, JI, Adler, DN, Howanitz, E, et al.A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry. 2002;51:349–357.CrossRefGoogle ScholarPubMed
10.Peuskens, J, Demily, C, Thibaut, F. Treatment of cognitive dysfunction in schizophrenia. Clin Ther. 2005;27(suppl 1):S25–S37.Google Scholar
11.Keefe, RS, Bilder, RM, Davis, SM, et al;CATIE Investigators; Neurocognitive Working Group. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry. 2007;64(6):633–647.Google Scholar
12.Keefe, RS, Eesley, CE, Poe, MP. Defining a cognitive function decrement in schizophrenia. Biol Psychiatry. 2005;15;57(6):688–691.Google Scholar
13.Keefe, RS, Bilder, RM, Harvey, PD, et al.Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology. 2006;31(9):2033–2046.CrossRefGoogle ScholarPubMed
14.Marder, SR. The NIMH-MATRICS project for developing cognition-enhancing agents for schizophrenia. Dialogues Clin Neurosci. 2006;8(1):109–113.Google Scholar
15.Kern, RS, Nuechterlein, KH, Green, MF, et al.The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization. Am J Psychiatry. 2008;165(2):214–220.Google Scholar
16.Nuechterlein, KH, Barch, DM, Gold, JM, et al.Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004;72(1):29–39.Google Scholar
17.Nuechterlein, KH, Green, MF, Kern, RS, et al.The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008;65(2):203–213.Google Scholar
18.Buchanan, RW, Summerfelt, A, Tek, C, Gold, J. An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia. Schizophr Res. 2002;59:29–33.Google Scholar
19.Friedman, JI. Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists. Psychopharmacology (Berl). 2004;174(1):45–53.Google Scholar
20.Eglen, RM. Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function. Auton Autacoid Pharmacol. 2006;26(3):219–233.CrossRefGoogle ScholarPubMed
21.Dean, B, McLeod, M, Keriakous, D, McKenzie, J, Scarr, E. Decreased muscarinic receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2002;7:1083–1091.CrossRefGoogle ScholarPubMed
22.Li, Z, Huang, M, Ichikawa, J, Dai, J, Meltzer, HY. N-Desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors. Neuropsychopharmacology. 2005;30(11):1986–1995.Google Scholar
23.Anagnostaras, SG, Murphy, GG, Hamilton, SE, et al.Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci. 2003;6(1):51–58.Google Scholar
24.Wess, J. Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications. Annu Rev Pharmacol Toxicol. 2004;44(1):423–450.Google Scholar
25.Bymaster, FP, Felder, CC, Tzavara, E, et al.Muscarinic mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(7):1125–1143.Google Scholar
26.Wess, J, Eglen, RM, Gautam, D. Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov. 2007;6:721–733.CrossRefGoogle ScholarPubMed
27.Pinkas-Kramarski, R, Stein, R, Undenboim, L, Sokolovsky, M. Growth factor-like effects mediated by muscarinic receptors in PC12M1 cells. J Neurochem. 1992;59(6):2158–2166.CrossRefGoogle ScholarPubMed
28.Lindenboim, L, Pinkas-Kramarski, R, Sokolovsky, M, Stein, R. Activation of muscarinic receptors inhibits apoptosis in PC12M1 cells. J Neurochem. 1995;64:2491–2499.Google Scholar
29.Van Der Zee, EA, Luiten, PGM. Muscarinic acetycholine receptors in the hippocampus, neocortex and amygdala: A review of immunocytochemical localization in relation to learning and memory. Prog Neurobiol. 1999;58:409–471.Google Scholar
30.Aura, J, Sirvio, J, Riekkinen, P Jr.Methoctramine moderately improves memory but pirenzepine disrupts performance in delayed non-matching to position test. Eur J Pharmacol. 1997;333:129–134.CrossRefGoogle ScholarPubMed
31.McDonald, MP, Willard, LB, Wenk, GL, Crawley, JN. Coadministration of galanin antagonist M40 with a muscarinic M1 agonist improves delayed nonmatching to position choice accuracy in rats with cholinergic lesions. J Neurosci. 1998;18:5078–5085.Google Scholar
32.Terry, AV, Buccafusco, JJ, Borsini, F, Leusch, A. Memory-related task performance by aged rhesus monkeys administered the muscarinic M1-preferring agonist, talsaclidine. Psychopharmacology. 2002;162(3):292–300.CrossRefGoogle Scholar
33.Fisher, A, Brandeis, R, Chapman, S, Pittel, Z, Michaelson, DM, (). M1 muscarinic agonist treatment reverses cognitive and cholinergic impairments of apolipoprotein E-deficient mice. J Neurochem. 1998;70:1991–1997.Google Scholar
34.Ruske, AC, White, KG. Facilitation of memory performance by a novel muscarinic agonist in young and old rats. Pharmacol Biochem Behav. 1999;63(4):663–667.Google Scholar
35.Brandeis, R, Sapir, M, Hafif, N, et al.AF150(S): A new functionally selective M1 agonist improves cognitive performance in rats. Pharmacol Biochem Behav. 1995;51(4):667–674.Google Scholar
36.Hyde, TM, Crook, JM. Cholinergic systems and schizophrenia: primary pathology or epiphenomena? J Chem Neuroanat. 2001;22:53–63.Google Scholar
37.Levey, AI, Edmunds, SM, Koliatsps, V, Wiley, RG, Heilman, CJ. Expression of m1-m4 muscarinic acetycholine receptor proteins in rat hippocampus and regulation by cholinergic innervation. J Neurosci. 1995;15(5):4077–4092.Google Scholar
38.Bymaster, FP, Felder, C, Ahmed, S, McKinzie, D. Muscarinic receptors as a target for drugs treating schizophrenia. Curr Drug Targets CNS Neurol Disord. 2002;1(2):163–181.Google Scholar
39.Crook, JM, Tomaskovic-Crook, E, Copolov, DL, Dean, B. Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biol Psychiatry. 2000;48:381–388.CrossRefGoogle ScholarPubMed
40.Eglen, RM, Choppin, A, Dillon, MP, Hegde, S. Muscarinic receptor ligands and their therapeutic potential. Curr Opin Chem Biol. 1999;3(4):426–432.Google Scholar
41.Friedman, JI, Temporini, H, Davis, KL. Pharmacologic strategies for augmenting cognitive performance in schizophrenia. Biol Psychiatry. 1999;45:1–16.Google Scholar
42.Mancama, D, Arranz, MJ, Landau, S, Kerwin, R. Reduced expression of the muscarinic 1 receptor cortical subtype in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2003l119B:2–6.Google Scholar
43.Scarr, E, Keriakous, D, Crossland, N, Dean, B. No change in cortical muscarinic M2, M3 receptors or [35S]GTPgammaS binding in schizophrenia. Life Sci. 2006;78(11):1231–1237.Google Scholar
44.Yeomans, JS. Role of tegmental cholinergic neurons in dopaminergic activation, anti-muscarinic psychosis and schizophrenia. Neuropsychopharmacogy. 1995;12(1):3–16.Google Scholar
45.Zavitsanou, K, Katsifis, A, Manner, F, Huang, XF. Investigation of m1/m4 muscarinic receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression disorder. Neuropsychopharmacogy. 2004;29(3):619–625.Google Scholar
46.Raedler, TJ, Knable, MB, Jones, DW, et al.In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia. Am J Psychiatry. 2003;160(1):118–27.Google Scholar
47.Han, M, Newell, K, Zavitsanou, K, Deng, C, Huang, XF. Effects of antipsychotic medication on muscarinic M1 receptor mRNA expression in the rat brain. J Neurosci Res. 2008;86(2):457–64.Google Scholar
48.Sarter, M, Bruno, JP. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev. 1997;23(1–2):28–46.Google Scholar
49.Liao, DL, Hong, CH, Chen, HM, et al.Association of muscarinic m1 receptor genetic polymorphisms with psychiatric symptoms and cognitive function in schizophrenic patients. Neuropsychobiology. 2003;48(2):72–76.Google Scholar
50.Zakzanis, KK, Andrikopoulos, J, Young, DA, Campbell, Z, Sethian, T. Neuropsychological differentiation of late-onset schizophrenia and dementia of the Alzheimer's type. Appl Neuropsychol. 2003;10(2):105–114.CrossRefGoogle ScholarPubMed
51.Barch, DM, Carter, CS, Braver, TS, et al.Selective deficits in prefrontal cortex function in medicationnaive patients with schizophrenia. Arch Gen Psychiatry. 2001;58:280–288.Google Scholar
52.Harvey, PD, Keefe, RS. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry. 2001;158(2):176–184.Google Scholar
53.Brown, JH, Taylor, P. Muscarinic receptor agonists and antagonists. In: Hardman, JG, Limbird, LE, Gilman, AG, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill Professional; 2001;10(7):155–174.Google Scholar
54.Minzenberg, MJ, Poole, JH, Benton, C, Vinogradov, S. Association of anticholinergic load with impairment of complex attention and memory in schizophrenia. Am J Psychiatry. 2004;161:116–124.CrossRefGoogle ScholarPubMed
55.Davies, MA, Compton-Toth, BA, Hufeisen, SJ, Meltzer, HY, Roth, BL. The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine's actions? Psychiopharmacology. 2005;178(4):451–460.CrossRefGoogle ScholarPubMed
56.Abi-Dargham, A, Laruelle, M. Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies. Eur Psychiatry. 2005;20(1):15–27.Google Scholar
57.Kanba, SSuzuki, E, Nomura, S, et al.Affinity of neuroleptics for D1 receptor of human brain striatum. J Psychiatry Neurosci. 1994;19(4):265–269.Google ScholarPubMed
58.Weiner, DM, Meltzer, HY, Veinbergs, I, et al.The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology. 2004;177(1–2):207–216.CrossRefGoogle ScholarPubMed
59.Wagner, AD, Davachi, L. Cognitive neuroscience: forgetting of things past. Curr Biol. 2001;11(23):R964–R967.Google Scholar
60.Ellis, JR, Ellis, KA, Bartholomeusz, CF, et al.Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans. Int J Neuropsychopharmacol. 2006;9(2): 175–189.Google Scholar
61.Drimer, T, Shahal, B, Barak, Y. Effects of discontinuation of long-term anticholinergic treatment in elderly schizophrenia patients. Int Clin Psychopharmacol. 2004;19:27–29.Google Scholar
62.Goldsmith, SK, Joyce, JN. Alterations in hippocampal mossy fiber pathway in schizo-phrenia and alzheimer's disease. Biol Psychiatry. 1995;37:122–126.Google Scholar
63.White, KE, Cummings, JL. Schizophrenia and Alzheimer's disease: clinical and pathophysiologic analogies. Compr Psychiatry. 1996;37(3):188–195.Google Scholar
64.Stryjer, R, Bar, F, Straus, RD, Baruch, Y, Rabey, JM. Donepezil management of schizophrenia with associated dementia. J Clin Psychopharmacol. 2002;22(2):226-229.CrossRefGoogle ScholarPubMed
65.MacEwan, GW, Ehmann, TS, Khanbhai, I, Wrixon, C. Donepezil in schizophrenia–is it helpful? An experimental design case study. Acta Psychiatr Scand. 2001;104(6):469–472.Google Scholar
66.Allen, TB, McEvoy, JP. Galantamine for treatment-resistant schizophrenia. Am J Psychiatry. 2002;159:1244–1245.Google Scholar
67.Buchanan, RW, Conley, RR, Dickinson, D, et al.Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am J Psychiatry. 2008;165(1):82–89.Google Scholar
68.Kohler, CG, Martin, EA, Kujawski, E, Bilker, W, Gur, RE, Gur, RC. No Effect of donepezil on neurocognition and social cognition in young persons with stable schizophrenia. Cognit Neuropsychiatry. 2007;12(5):412–421.Google Scholar
69.Stip, E, Sepehery, AA, Chouinard, S. Add-on therapy with acetylcholinesterase inhibitors for memory dysfunction in schizophrenia: a systematic quantitative review, Part 2. Clin Neuropharmacol. 2007;30(4):218–229.Google Scholar
70.Nahas, Z, George, MS, Horner, MD, et al.Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study. Neurocase. 2003;9(3):274–282.Google Scholar
71.Schubert, MH, Young, KA, Hicks, PB. Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biol Psychiatry. 2006;60(6):530–533.CrossRefGoogle ScholarPubMed
72.Lee, SW, Lee, JG, Lee, BJ, Kim, YH. A 12-week, double-blind, placebo-controlled trial of galantamine adjunctive treatment to conventional antipsychotics for the cognitive impairments in chronic schizophrenia. Int Clin Psychopharmacol. 2007;22(2):63–68.Google Scholar
73.Raedler, TJ, Knable, MB, Jones, DW, Urbina, RA, Egan, MF, Weinberger, DR. Central muscarinic acetylcholine receptor availability in patients treated with clozapine. Neuropsychopharmacogy. 2003;28:1531–1537.Google Scholar
74.Kay, GG, Abou-Donia, MB, Messer, WS, Murphy, DG, Tsao, JW, Ouslander, JG. Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients. J Am Geriatr Soc. 2005;53(12):2195–2201.Google Scholar
75.Bartolomeo, AC, Morris, H, Buccafusco, JJ, et al.The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist. J Pharmacol Exp Ther. 2000;292(2):584–596.Google Scholar
76.Bodick, NC, Offen, WW, Levey, AI, et al.Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol. 1997;54(4):465–473.Google Scholar
77.Guitton, C, Abbar, M, Kinowski, J-M, Chabrand, P, Bressolle, F. Multiple-dose pharmacokinetics of clozapine in patients with chronic schizophrenia. J Clinical Psychopharmacology. 1998;18(6):470–476.Google Scholar
78.Sauerberg, P, Jeppesen, L, Olesen, PH, et al.Muscarinic agonists with antipsychotic-like activity: structure-activity relationships of 1,2,5-thiadiazole analogues with functional dopamine antagonist activity. J Med Chem. 1998;41(22):4378–4384.Google Scholar
79.Shannon, HE, Rasmussen, K, Bymaster, Fet al.Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res. 2000;42:249–259.Google Scholar
80.Sur, C, Mallorga, PJ, Wittmann, M, et al.N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci U S A. 2003;100(23):13674–13679.Google Scholar
81. Safety Study of ACP-104: To Demonstrate the Safety, Tolerability, and Pharmacokinetics. Available at: http://clinicaltrials.gov/ct2/show/NCT00628420?term=NCT00628420&rank=1. Accessed September 15, 2008.Google Scholar
82.Thal, LJ, Forrest, M, Loft, H, Mengel, H. Lu 25-109, a muscarinic agonist, fails to improve cognition in Alzheimer's disease. Neurology. 2000;54(2):421.CrossRefGoogle ScholarPubMed
83.Young, CD, Meltzer, HY, Deutch, AY. Effects of desmethylclozapine on fos protein expression in the forebrain: in vivo biological activity of the clozapine metabolite. Neuropsychopharmacogy. 1998;19(1):99–103.Google Scholar
84.Mirza, NR, Peters, D, Sparks, RG. Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. CNS Drug Rev. 2003;9(2):159–186.CrossRefGoogle ScholarPubMed
85.Jakubík, J, Michal, P, Machová, E, Doležal, V. Importance and prospects for design of selective muscarinic agonists. Physiol Res. 2008 May 13 [Epub ahead of print].Google Scholar
86.Shekhar, A, Potter, WZ, Lightfoot, J, et al.Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165(8):1033–1039Google Scholar
87.Burstein, ES, Ma, JN, Wong, S, et al.Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. J Pharmacol Exp Ther. 2005;315(3):1278–1287.Google Scholar
88.Natesan, S, Reckless, GE, Barlow, KB, Nobrega, JN, Kapur, S. of N-desmethylclozapine as a potential antipsychotic–preclinical studies. Neuropsychopharmacology. 2007;32(7):1540–1549.CrossRefGoogle ScholarPubMed
89.Lameh, J, Burstein, ES, Taylor, E, Weiner, DM, Vanover, KE, Bonhaus, DW. Pharmacology of N-desmethylclozapine. Pharmacol Ther. 2007;115(2):223–231.Google Scholar