Modulowanie funkcji układu cholinergicznego w leczeniu schizofrenii – dziś i jutro

Frątczak, Anna; Kula, Katarzyna; Rabe-Jabłońska, Jolanta; Strzelecki, Dominik

Journal

Psychiatria i Psychologia Kliniczna

2013 | 13 | 2 | 108–115

Article title

Modulowanie funkcji układu cholinergicznego w leczeniu schizofrenii – dziś i jutro

Authors

Anna Frątczak , Katarzyna Kula , Jolanta Rabe-Jabłońska , Dominik Strzelecki

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108-115 Psychiatria 2.2013 Fratczak Modulowanie.pdf

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Modulation of the cholinergic system function in the treatment of schizophrenia – today and tomorrow

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Abstracts

W ostatnim czasie rośnie zainteresowanie rolą układu cholinergicznego w patogenezie schizofrenii. Od wielu lat obserwowano zaburzenia funkcji tego układu, głównie w postaci efektów niepożądanych wywołanych lekami przeciwpsychotycznymi. Postrzeganie układu acetylocholiny ewoluuje, co wynika z założenia, że wpływ na przekaźnictwo w jego obrębie może nie tylko wywoływać albo eliminować wspomniane objawy niepożądane, ale też bezpośrednio modyfikować symptomatologię schizofrenii. Celem niniejszego artykułu jest przegląd aktualnego piśmiennictwa dotyczącego nowych opcji modulowania funkcji układu cholinergicznego. Obecnie badania koncentrują się na poszukiwaniu selektywnych agonistów i allosterycznych modulatorów receptorów muskarynowych, które mogą redukować ryzyko skutków ubocznych tradycyjnej terapii przeciwpsychotycznej i jednocześnie mieć swój własny terapeutyczny potencjał antypsychotyczny. Zastosowanie substancji mniej selektywnych nie prowadzi do takich korzyści. W kręgu zainteresowań psychofarmakologów pozostają również modulatory receptorów nikotynowych α4β2 i α7, które korzystnie wpływają między innymi na funkcjonowanie poznawcze chorych na schizofrenię, co potwierdzono w wielu niezależnych badaniach. Jak wiadomo, u większości pacjentów mimo leczenia utrzymują się objawy negatywne, deficyty poznawcze, często też resztkowe objawy pozytywne. Z klinicznego punktu widzenia istotne pozostają także objawy niepożądane, które bardzo często komplikują leczenie, ograniczają możliwości terapeutyczne i pogarszają współpracę chorego w farmakoterapii. Badania nowych, bardziej selektywnych substancji cholinergicznych dają nadzieję na udoskonalenie terapii schizofrenii poprzez zwiększenie skuteczności i wyeliminowanie objawów niepożądanych.

Recently, the interest in the cholinergic system in the pathogenesis of schizophrenia has increased. For many years the disorders in the function of this system, mainly as adverse effects induced by antipsychotics, have been observed. Perception of acetylcholine system evolves, which results from the assumption that the impact on the transmission through it may not only induce or eliminate the mentioned adverse effects but also directly modify symptomatology of schizophrenia. This article is aimed at a survey of the current literature on new options of the modulation of the cholinergic system functions. Presently the studies are focussed on searching for selective agonists and allosteric modulators of muscarinic receptors which can reduce the risk of side effects of the traditional antipsychotic therapy and simultaneously have their own therapeutic antipsychotic potential. The use of less selective substances does not yield such benefits. Psychopharmacologists’ interests cover also the modulators of nicotinic receptors α4β2 and α7, which favourably affect, among others, the cognitive functioning in patients with schizophrenia, as has been confirmed by many independent studies. Admittedly, in most of the patients, despite the treatment, adverse symptoms, cognitive deficits and often also residual positive symptoms persist. From the clinical point of view, significant are also adverse effects which often complicate the treatment, confine therapeutic abilities, and hamper the patient’s cooperation in pharmacotherapy. The studies on new, more selective cholinergic substances give some hope for improvements in schizophrenia therapy through increased efficacy and elimination of adverse symptoms.

Keywords

acetyl cholinesterase inhibitors allosteric modulators cholinergic system inhibitory acetylocholinesterazy ksanomelina modulatory allosteryczne schizofrenia schizophrenia układ cholinergiczny xanomeline

Discipline

MEDICINE: MEDICINE

Publisher

Medical Communications

Journal

Psychiatria i Psychologia Kliniczna

Year

2013

Volume

Issue

Pages

108–115

Physical description

Contributors

author

Anna Frątczak

Klinika Zaburzeń Afektywnych i Psychotycznych, I Katedra Psychiatrii Uniwersytetu Medycznego w Łodzi, Centralny Szpital Kliniczny

author

Katarzyna Kula

Klinika Zaburzeń Afektywnych i Psychotycznych, I Katedra Psychiatrii Uniwersytetu Medycznego w Łodzi, Centralny Szpital Kliniczny

author

Jolanta Rabe-Jabłońska

Klinika Zaburzeń Afektywnych i Psychotycznych, I Katedra Psychiatrii Uniwersytetu Medycznego w Łodzi, Centralny Szpital Kliniczny

author

Dominik Strzelecki

dominik.strzelecki@umed.lodz.pl

Klinika Zaburzeń Afektywnych i Psychotycznych, I Katedra Psychiatrii Uniwersytetu Medycznego w Łodzi, Centralny Szpital Kliniczny

References

1. Correll C.U.: Adjunctive therapy for schizophrenia: current and emerging directions faculty and disclosures. Medscape Education Psychiatry & Mental Health, CME Released: 03/17/2011.
2. Keshavan M.S., Tandon R., Buotros N.N., Nasrallah H.A.: Schizophrenia, “just the facts”: what we know in 2008. Part 3: neurobiology. Schizophr. Res. 2008; 106: 89–107.
3. Dencker D., Wörtwein G., Weikop P. i wsp.: Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline. J. Neurosci. 2011; 31: 5905–5908.
4. Buchanan R.W., Kreyenbuhl J., Kelly D.L. i wsp.: The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr. Bull. 2010; 36: 71–93.
5. Gauthier S.: Advances in the pharmacotherapy of Alzheimer’s disease. CMAJ 2002; 166: 616–623.
6. Stahl S.M.: Podstawy psychofarmakologii. Tom 4, Via Medica, Gdańsk 2010: 155.
7. Stahl S.M.: Podstawy psychofarmakologii. Tom 1, Via Medica, Gdańsk 2010: 212–213.
8. Mierzejewski P., Kostowski W.: Rola hipokampa w patogenezie uzależnień i działaniu pozytywnie wzmacniającym substancji psychoaktywnych. Alkohol. Narkom. 2002; 15: 207–219.
9. Newman E.L., Gupta K., Climer J.R. i wsp.: Cholinergic modulation of cognitive processing: insights drawn from computational models. Front. Behav. Neurosci. 2012; 6: 24.
10. Bennouna M., Greene V.B., Defranoux L.: [Cholinergic hypothesis in psychosis following traumatic brain injury and cholinergic hypothesis in schizophrenia: a link?]. Encephale 2007; 33: 616–620.
11. Stahl S.M.: Podstawy psychofarmakologii. Tom 4, Via Medica, Gdańsk 2010: 152–153.
12. Abrams P., Andersson K.E., Buccafusco J.J. i wsp.: Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br. J. Pharmacol. 2006; 148: 565–578.
13. Sobkowiak R., Lesicki A.: Komórkowe szlaki sygnalizacyjne aktywowane przez nikotynę. Postępy Biol. Komórki 2011; 38: 581–596.
14. Forchuk C., Norman R., Malla A. i wsp.: Schizophrenia and the motivation for smoking. Perspect. Psychiatr. Care 2002; 38: 41–49.
15. Booij L.H.D.J., Drobnik L.: Anatomia i fizjologia przewodnictwa nerwowo-mięśniowego – część I. Anestezjologia i Ratownictwo 2010; 4: 49–80.
16. Pfeiffer C.C., Jenney E.H.: The inhibition of the conditioned response and the counteraction of schizophrenia by muscarinic stimulation of the brain. Ann. NY Acad. Sci. 1957; 66: 753–764.
17. Sullivan R.J., Allen J.S., Otto C. i wsp.: Effects on chewing betel nut (Areca catechu) on the symptoms of people with schizophrenia in Palau, Micronesia. Br. J. Psychiatry 2000; 177: 174–178.
18. Bridges T.M., LeBois E.P., Hopkins C.R. i wsp.: The antipsychotic potential of muscarinic allosteric modulation. Drug News Perspect. 2010; 23: 229–240.
19. Wilkinson J.A.: Side effects of transdermal scopolamine. J. Emerg. Med. 1987; 5: 389–392.
20. Clarke L.A., Cassidy C.W., Catalano G. i wsp.: Psychosis induced by smoking cessation clinic administered anticholinergic overload. Ann. Clin. Psychiatry 2004; 16: 171–175.
21. Marchlewski M.B.: Anticholinergic syndrome. Avoiding misdiagnosis. J. Psychosoc. Nurs. Ment. Health Serv. 1994; 32: 22–24.
22. Johnstone E.C., Crow T.J., Ferrier I.N. i wsp.: Adverse effects of anticholinergic medication on positive schizophrenic symptoms. Psychol. Med. 1983; 13: 513–527.
23. Tandon R., Shipley J.E., Greden J.F. i wsp.: Muscarinic cholinergic hyperactivity in schizophrenia. Relationship to positive and negative symptoms. Schizophr. Res. 1991; 4: 23–30.
24. Neubauer H., Sundland D.M., Gershon S.: Sernyl, ditran, and their antagonists: succinate and THA. Int. J. Neuropsychiatry 1966; 2: 216–222.
25. Edelstein P., Schultz J.R., Hirschowitz J. i wsp.: Physostigmine and lithium response in the schizophrenias. Am. J. Psychiatry 1981; 138: 1078–1081.
26. Janowsky D.S., el-Yousef M.K., Davis J.M., Sekerke H.J.: Antagonistic effects of physostigmine and methylphenidate in man. Am. J. Psychiatry 1973; 130: 1370–1376.
27. Coyle J.T., Balu D., Benneyworth M. i wsp.: Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia. Dialogues Clin. Neurosci. 2010; 12: 359–382.
28. Dean B., McLeod M., Keriakous D. i wsp.: Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol. Psychiatry 2002; 7: 1083–1091.
29. Freedman R., Hall M., Adler L.E., Leonard S.: Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol. Psychiatry 1995; 38: 22–33.
30. Terry A.V. Jr: Role of the central cholinergic system in the therapeutics of schizophrenia. Curr. Neuropharmacol. 2008; 6: 286–292.
31. Dencker D., Wörtwein G., Weikop P. i wsp.: Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline. J. Neurosci. 2011; 31: 5905–5908.
32. Tzavara E.T., Bymaster F.P., Davis R.J. i wsp.: M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies. FASEB J. 2004; 18: 1410–1412.
33. Dasari S., Gulledge A.T.: M1 and M4 receptors modulate hippocampal pyramidal neurons. J. Neurophysiol. 2011; 105: 779–792.
34. Watson J., Brough S., Coldwell M.C. i wsp.: Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. Br. J. Pharmacol. 1998; 125: 1413–1420.
35. Bodick N.C., Offen W.W., Levey A.I. i wsp.: Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behaviour symptoms in Alzheimer disease. Arch. Neurol. 1997; 54: 465–473.
36. Bymaster F.P., Felder C., Ahmed S., McKinzie D.: Muscarinic receptors as a target for drugs treating schizophrenia. Curr. Drug Targets CNS Neurol. Disord. 2002; 1: 163–181.
37. Bymaster F.P., Shannon H.E., Rasmussen K. i wsp.: Potential role of muscarinic receptors in schizophrenia. Life Sci. 1999; 64: 527–534.
38. Walter H., Kammerer H., Frasch K. i wsp.: Altered reward functions in patients on atypical antipsychotic medication in line with the revised dopamine hypothesis of schizophrenia. Psychopharmacology (Berl.) 2009; 206: 121–132.
39. Baker S., Chin C.L., Basso A.M. i wsp.: Xanomeline modulation of the blood oxygenation level-dependent signal in awake rats: development of pharmacological magnetic resonance imaging as a translatable pharmacodynamic biomarker for central activity and dose selection. J. Pharmacol. Exp. Ther. 2012; 341: 263–273.
40. Andersen M.B., Fink-Jensen A., Peacock L. i wsp.: The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic- like activity in Cebus apella monkeys. Neuropsychopharmacology 2003; 28: 1168–1175.
41. Shekhar A., Potter W.Z., Lightfoot J. i wsp.: Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am. J. Psychiatry 2008; 165: 1033–1039.
42. Shannon H.E., Rasmussen K., Bymaster F.P. i wsp.: Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr. Res. 2000; 42: 249–259.
43. Michal P., Lysíková M., El-Fakahany E.E., Tucek S.: Clozapine interaction with the M2 and M4 subtypes of muscarinic receptors. Eur. J. Pharmacol. 1999; 376: 119–125.
44. Maehara S., Hikichi H., Ohta H.: Behavioral effects of N-desmethylclozapine on locomotor activity and sensorimotor gating function in mice – possible involvement of muscarinic receptors. Brain Res. 2011; 1418: 111–119.
45. ACADIA Pharmaceuticals Inc. announces results from ACP-104 Phase IIb schizophrenia trial. Adres: http://news.acadia- pharm.com/phoenix.zhtml?c=125180&p=irolnewsArticle& ID=1166151&highlight=.
46. Chan W.Y., McKinzie D.L., Bose S. i wsp.: Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc. Natl Acad. Sci. USA 2008; 105: 10978–10983.
47. Farrell M., Roth B.L.: Allosteric antipsychotics: M4 muscarinic potentiators as novel treatments for schizophrenia. Neuropsychopharmacology 2010; 35: 851–852.
48. Gannon R.L., Millan M.J.: LY2033298, a positive allosteric modulator at muscarinic M4 receptors, enhances inhibition by oxotremorine of light-induced phase shifts in hamster circadian activity rhythms. Psychopharmacology (Berl.) 2012; 224: 231–240.
49. Leach K., Loiacono R.E., Felder C.C. i wsp.: Molecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic properties. Neuropsychopharmacology 2010; 35: 855–869.
50. Suratman S., Leach K., Sexton P. i wsp.: Impact of species variability and ‘probe-dependence’ on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptor. Br. J. Pharmacol. 2011; 162: 1659–1670.
51. Jones C.K., Brady A.E., Davis A.A. i wsp.: Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. J. Neurosci. 2008; 28: 10422–10433.
52. Ratschen E., Britton J., McNeill A.: Implementation of smokefree policies in mental health in-patient settings in England. Br. J. Psychiatry 2009; 194: 547–551.
53. Mukherjee S., Mahadik S.P., Korenovsky A. i wsp.: Serum antibodies to nicotinic acetylcholine receptors in schizophrenic patients. Schizophr. Res. 1994; 12: 131–136.
54. Sacco K.A., Termine A., Selay A. i wsp.: Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch. Gen. Psychiatry 2005; 62: 649–659.
55. Adler L.E., Hoffer L.D., Wiser A., Freedman R.: Normalization of auditory psychology by cigarette smoking in schizophrenic patients. Am. J. Psychiatry 1993; 150: 1856–1861.
56. Węgrzyn J.: Disordered sensory gating of the P50 component of the auditory evoked potentials (AEP). Psychiatr. Pol. 2004; 38: 833–845.
57. Ishikawa M., Hashimoto K.: α7 nicotinic acetylcholine receptor as a potential therapeutic target for schizophrenia. Curr. Pharm. Des. 2011; 17: 121–129.
58. Olincy A., Stevens K.E.: Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men. Biochem. Pharmacol. 2007; 74: 1192–1201.
59. Wildeboer K.M., Zheng L., Choo K.S., Stevens K.E.: Ondansetron results in improved auditory gating in DBA/2 mice through a cholinergic mechanism. Brain Res. 2009; 1300: 41–50.
60. Shiina A., Shirayama Y., Niitsu T. i wsp.: A randomised, double- blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann. Gen. Psychiatry 2010; 9: 27.
61. Toyohara J., Hashimoto K.: α7 nicotinic receptor agonists: potential therapeutic drugs for treatment of cognitive impairments in schizophrenia and Alzheimer’s disease. Open Med. Chem. J. 2010; 4: 37–56.
62. Na podstawie danych opublikowanych na stronie ClinicalTrials.gov.
63. Pohanka M.: Alpha7 nicotinic acetylcholine receptor is a target in pharmacology and toxicology. Int. J. Mol. Sci. 2012; 13: 2219–2238.
64. McEvoy J.P., Freundenreich O., Wilson W.: Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol. Psychiatry 1999; 46: 125–129.
65. Williams D.K., Wang J., Papke R.L.: Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations. Biochem. Pharmacol. 2011; 82: 915–930.
66. Gill J.K., Dhankher P., Sheppard T.D. i wsp.: A series of α7 nicotinic acetylcholine receptor allosteric modulators with close chemical similarity but diverse pharmacological properties. Mol. Pharmacol. 2012; 81: 710–718.
67. Barron S.C., McLaughlin J.T., See J.A. i wsp.: An allosteric modulator of α7 nicotinic receptors, N-(5-chloro-2,4- dimethoxyphenyl)-N’-(5-methyl-3-isoxazolyl)-urea (PNU- 120596), causes conformational changes in the extracellular ligand binding domain similar to those caused by acetylcholine. Mol. Pharmacol. 2009; 76: 253–263.
68. Malysz J., Grønlien J.H., Anderson D.J. i wsp.: In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)- 2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), exhibiting unique pharmacological profile. J. Pharmacol. Exp. Ther. 2009; 330: 257–267.
69. Kaufer D.: Beyond the cholinergic hypothesis: the effect of metrifonate and other cholinesterase inhibitors on neuropsychiatric symptoms in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 1998; 9 supl. 2: 8–14.
70. Sharma T., Reed C., Aasen I., Kumari V.: Cognitive effects of adjunctive 24-weeks rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, doubleblind investigation. Schizophr. Res. 2006; 85: 73–83.
71. Gray J.A., Roth B.L.: Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr. Bull. 2007; 33: 1100–1119.
72. Bora E., Veznedaroğlu B., Kayahan B.: The effect of galantamine added to clozapine on cognition of five patients with schizophrenia. Clin. Neuropharmacol. 2005; 28: 139–141.
73. Lee S.W.: 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: 63–68.
74. Schubert M.H., Young K.A., Hicks P.B.: Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biol. Psychiatry 2006; 60: 530–533.
75. Singh J., Kour K., Jayaram M.B.: Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database Syst. Rev. 2012; 1: CD007967.

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