One-day tropisetron treatment improves cognitive deficits and P50 inhibition deficits in schizophrenia

Abstract

The core features of schizophrenia (SCZ) include cognitive deficits and impaired sensory gating represented by P50 inhibition deficits, which appear to be related to the α7 nicotinic acetylcholine receptor (nAChR). An agonist of nAChR receptor may improve these defects. This study aimed to investigate how administering multiple doses of tropisetron, a partial agonist of nAChR, for 1 day would affect cognitive deficits and P50 inhibition deficits in SCZ patients. We randomized 40 SCZ non-smokers into a double-blind clinical trial with four groups: placebo, 5 mg/d, 10 mg/d, and 20 mg/d of oral tropisetron. Their P50 ratios were all more than 0.5 and they took risperidone at 3–6 mg/day for at least a month before participating in the experiment. We measured the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and P50 inhibition before and one day after treatment. After one day of treatment, the total RBANS scores of the 20 mg and 5 mg tropisetron groups, and the immediate memory of the 10 mg group were significantly higher than placebo group. The P50 ratio was smaller in the 5 mg and 10 mg groups than in the placebo group (both p < 0.05) after treatment. Furthermore, the improvement in RBANS total score was correlated with increased S1 latency (p < 0.05), and the increase in immediate memory score was correlated with decreased S2 amplitude. One day of treatment with tropisetron improved both cognitive and P50 inhibition deficits, suggesting that longer term treatment with α7 nAChR agonists for these deficits in SCZ may be promising.

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Fig. 1: Association between the improvement in the total score of RBANS and the change in the latency of S1 after treatment.
Fig. 2: Changes in P50 Gating Ratio in Patients With Schizophrenia After 1-Day Treatment With Tropisetron or Placeboa.

References

  1. 1.

    Kanchanatawan B, Hemrungrojn S, Thika S, Sirivichayakul S, Ruxrungtham K, Carvalho AF, et al. Changes in Tryptophan Catabolite (TRYCAT) pathway patterning are associated with mild impairments in declarative memory in schizophrenia and deficits in semantic and episodic memory coupled with increased false-memory creation in deficit schizophrenia. Mol Neurobiol. 2018;55:5184–201.

    CAS  PubMed  Google Scholar 

  2. 2.

    Vohringer PA, Barroilhet SA, Amerio A, Reale ML, Alvear K, Vergne D, et al. Cognitive impairment in bipolar disorder and schizophrenia: a systematic review. Front Psychiatry. 2013;4:87.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Khalil AH, El-Meguid MA, Bastawy M, Rabei S, Ali R, Abd Elmoneam MHE. Correlating cognitive functions to symptom domains and insight in Egyptian patients with schizophrenia. Int J Soc Psychiatry. 2020;66:240–248.

  4. 4.

    Simonsen C, Sundet K, Vaskinn A, Birkenaes AB, Engh JA, Faerden A, et al. Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. Schizophr Bull. 2011;37:73–83.

    PubMed  Google Scholar 

  5. 5.

    Giraldo-Chica M, Rogers BP, Damon SM, Landman BA, Woodward ND. Prefrontal-thalamic anatomical connectivity and executive cognitive function in schizophrenia. Biol Psychiatry. 2018;83:509–17.

    PubMed  Google Scholar 

  6. 6.

    Hoonakker M, Doignon-Camus N, Bonnefond A. Sustaining attention to simple visual tasks: a central deficit in schizophrenia? A systematic review. Ann N. Y Acad Sci. 2017;1408:32–45.

    PubMed  Google Scholar 

  7. 7.

    Paquin K, Wilson AL, Cellard C, Lecomte T, Potvin S. A systematic review on improving cognition in schizophrenia: which is the more commonly used type of training, practice or strategy learning? BMC Psychiatry. 2014;14:139.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Schreiber R, Newman-Tancredi A. Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT(1A) receptor activation. Neurobiol Learn Mem. 2014;110:72–80.

    CAS  PubMed  Google Scholar 

  9. 9.

    Neu P, Gooren T, Niebuhr U, Schlattmann P. Cognitive impairment in schizophrenia and depression: a comparison of stability and course. Appl Neuropsychol Adult. 2019;26:215–28.

    PubMed  Google Scholar 

  10. 10.

    Peralta V, Cuesta MJ. Social cognition in schizophrenia: the relevance of early detection and intervention. Sist Sanit Navar. 2017;40:173–75.

    CAS  Google Scholar 

  11. 11.

    Dziwota E, Stepulak MZ, Wloszczak-Szubzda A, Olajossy M. Social functioning and the quality of life of patients diagnosed with schizophrenia. Ann Agric Environ Med. 2018;25:50–5.

    PubMed  Google Scholar 

  12. 12.

    Davidson M. Cognitive impairment as a diagnostic criterion and treatment target in schizophrenia. World Psychiatry. 2019;18:171.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Hamling KR, Schoppik D. Sensory gating: cellular substrates of surprise. Curr Biol. 2018;28:R871–3.

    CAS  PubMed  Google Scholar 

  14. 14.

    Lei Y, Ozdemir RA, Perez MA. Gating of sensory input at subcortical and cortical levels during grasping in humans. J Neurosci. 2018;38:7237–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Toyomaki A, Hashimoto N, Kako Y, Tomimatsu Y, Koyama T, Kusumi I. Different P50 sensory gating measures reflect different cognitive dysfunctions in schizophrenia. Schizophr Res Cogn. 2015;2:166–9.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Xia L, Yuan L, Du XD, Wang D, Wang J, Xu H, et al. P50 inhibition deficit in patients with chronic schizophrenia: relationship with cognitive impairment of MATRICS consensus cognitive battery. Schizophr Res. 2020;215:105–12.

    PubMed  Google Scholar 

  17. 17.

    Schubring D, Popov T, Miller GA, Rockstroh B. Consistency of abnormal sensory gating in first-admission and chronic schizophrenia across quantification methods. Psychophysiology. 2018;55:1–13.

    Google Scholar 

  18. 18.

    Chien YL, Hsieh MH, Gau SS. P50-N100-P200 sensory gating deficits in adolescents and young adults with autism spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2019;95:109683.

    PubMed  Google Scholar 

  19. 19.

    Karkal R, Goyal N, Tikka SK, Khanande RV, Kakunje A, Khess CR. Sensory gating deficits and their clinical correlates in drug-free/drug-naive patients with schizophrenia. Indian J Psychol Med. 2018;40:247–56.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Koukouli F, Rooy M, Tziotis D, Sailor KA, O’Neill HC, Levenga J, et al. Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nat Med. 2017;23:347–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Jones C. alpha7 nicotinic acetylcholine receptor: a potential target in treating cognitive decline in schizophrenia. J Clin Psychopharmacol. 2018;38:247–49.

    CAS  PubMed  Google Scholar 

  22. 22.

    Wadenberg MG, Manetti D, Romanelli MN, Arias HR. Significance of the nicotinic alpha7 receptor in cognition and antipsychotic-like behavior in the rat. Behav Brain Res. 2017;333:129–34.

    CAS  PubMed  Google Scholar 

  23. 23.

    Shiina A, Shirayama Y, Niitsu T, Hashimoto T, Yoshida T, Hasegawa T, et al. A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann Gen Psychiatry. 2010;9:27.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Hashimoto K. Targeting of α7 nicotinic acetylcholine receptors in the treatment of schizophrenia and the use of auditory sensory gating as a translational biomarker. Curr Pharm Des. 2015;21:3797–806.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Noroozian M, Ghasemi S, Hosseini SM, Modabbernia A, Khodaie-Ardakani MR, Mirshafiee O, et al. A placebo-controlled study of tropisetron added to risperidone for the treatment of negative symptoms in chronic and stable schizophrenia. Psychopharmacology (Berl). 2013;228:595–602.

    CAS  Google Scholar 

  26. 26.

    Poddar I, Callahan PM, Hernandez CM, Yang X, Bartlett MG, Terry AV Jr. Tropisetron enhances recognition memory in rats chronically treated with risperidone or quetiapine. Biochem Pharm. 2018;151:180–7.

    CAS  PubMed  Google Scholar 

  27. 27.

    Spilman P, Descamps O, Gorostiza O, Peters-Libeu C, Poksay KS, Matalis A, et al. The multi-functional drug tropisetron binds APP and normalizes cognition in a murine Alzheimer’s model. Brain Res. 2014;1551:25–44.

    CAS  PubMed  Google Scholar 

  28. 28.

    Hashimoto K, Iyo M, Freedman R, Stevens KE. Tropisetron improves deficient inhibitory auditory processing in DBA/2 mice: role of alpha 7 nicotinic acetylcholine receptors. Psychopharmacol (Berl). 2005;183:13–9.

    CAS  Google Scholar 

  29. 29.

    Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, et al. Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Schizophr Res. 2005;76:67–72.

    PubMed  Google Scholar 

  30. 30.

    Zhang XY, Liu L, Liu S, Hong X, Chen DC, Xiu MH, et al. Short-term tropisetron treatment and cognitive and P50 auditory gating deficits in schizophrenia. Am J Psychiatry. 2012;169:974–81.

    PubMed  Google Scholar 

  31. 31.

    Chopko TC, Lindsley CW. Classics in chemical neuroscience: risperidone. ACS Chem Neurosci. 2018;9:1520–29.

    CAS  PubMed  Google Scholar 

  32. 32.

    Hong X, Chan RC, Zhuang X, Jiang T, Wan X, Wang J, et al. Neuroleptic effects on P50 sensory gating in patients with first-episode never-medicated schizophrenia. Schizophr Res. 2009;108:151–7.

    PubMed  Google Scholar 

  33. 33.

    de Wilde OM, Bour L, Dingemans P, Koelman J, Linszen D. A meta-analysis of P50 studies in patients with schizophrenia and relatives: differences in methodology between research groups. Schizophr Res. 2007;97:137–51.

    PubMed  Google Scholar 

  34. 34.

    Dolu N, Suer C, Ozesmi C. A comparison of the different interpair intervals in the conditioning-testing P50 paradigms. Int J Psychophysiol. 2001;41:265–70.

    CAS  PubMed  Google Scholar 

  35. 35.

    Sánchezmorla EM, Santos JL, Aparicio A, Garcíajiménez MÁ, Soria C, Arango C. Neuropsychological correlates of P50 sensory gating in patients with schizophrenia. Schizophr Res. 2013;143:102–6.

    Google Scholar 

  36. 36.

    Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998;20:310–9.

    CAS  Google Scholar 

  37. 37.

    Zhang BH, Tan YL, Zhang WF, Wang ZR, Yang GG, Shi C, et al. Repeatable battery for the assessment of neuropsychological status as a screening test in Chinese: reliability and validity. Chin Ment Health J. 2008;22:865–69.

    Google Scholar 

  38. 38.

    Cheng Y, Wu W, Wang J, Feng W, Wu X, Li C. Reliability and validity of the Repeatable Battery for the Assessment of Neuropsychological Status in community-dwelling elderly. Arch Med Sci. 2011;7:850–7.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Team RDC. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing. 2015.

  40. 40.

    Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry. 2008;165:1040–7.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Ishikawa M, Hashimoto K. α7 nicotinic acetylcholine receptor as a potential therapeutic target for schizophrenia. Curr Pharm Des. 2011;17:121–29.

    CAS  PubMed  Google Scholar 

  42. 42.

    Boggs DL, Carlson J, Cortes-Briones J, Krystal JH, D’Souza DC. Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia. Curr Pharm Des. 2014;20:5077–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Hamilton HK, D’Souza DC, Ford JM, Roach BJ, Kort NS, Ahn KH, et al. Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: implications for schizophrenia. Schizophr Res. 2018;191:87–94.

    PubMed  Google Scholar 

  44. 44.

    Hashimoto K, Ishima T, Fujita Y, Matsuo M, Kobashi T, Takahagi M, et al. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron: role of α 7 nicotinic receptors. Biol Psychiatry. 2008;553:191–5.

    Google Scholar 

  45. 45.

    Hashimoto K, Ishima T, Fujita Y, Matsuo M, Kobashi T, Takahagi M, et al. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective alpha7 nicotinic receptor agonist SSR180711. Biol Psychiatry. 2008;63:92–7.

    CAS  PubMed  Google Scholar 

  46. 46.

    Ishikawa M, Sakata M, Toyohara J, Oda K, Ishii K, Wu J, et al. Occupancy of α7 nicotinic acetylcholine receptors in the brain by tropisetron: a positron emission tomography study using [(11)C]CHIBA-1001 in healthy human subjects. Clin Psychopharmacol Neurosci. 2011;9:111–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Sagud M, Vuksan-Cusa B, Jaksic N, Mihaljevic-Peles A, Rojnic Kuzman M, Pivac N. Smoking in Schizophrenia: an Updated Review. Psychiatr Danub. 2018;30(Suppl 4):216–23.

    PubMed  Google Scholar 

  48. 48.

    Fond G, Berna F, Andrianarisoa M, Godin O, Leboyer M, Brunel L, et al. Chronic low-grade peripheral inflammation is associated with severe nicotine dependence in schizophrenia: results from the national multicentric FACE-SZ cohort. Eur Arch Psychiatry Clin Neurosci. 2017;267:465–72.

    CAS  PubMed  Google Scholar 

  49. 49.

    Dickerson F, Origoni A, Schroeder J, Adamos M, Katsafanas E, Khushalani S, et al. Natural cause mortality in persons with serious mental illness. Acta Psychiatr Scand. 2018;137:371–79.

    CAS  PubMed  Google Scholar 

  50. 50.

    Dickerson F, Stallings CR, Origoni AE, Vaughan C, Khushalani S, Schroeder J, et al. Cigarette smoking among persons with schizophrenia or bipolar disorder in routine clinical settings, 1999–2011. Psychiatr Serv. 2013;64:44–50.

    PubMed  Google Scholar 

  51. 51.

    Zhang XY, Rao WW, Yu Q, Yu Y, Kou C, Tan YL, et al. Association of the manganese superoxide dismutase gene Ala-9Val polymorphism with age of smoking initiation in male schizophrenia smokers. Am J Med Genet Part B Neuropsychiatr Genet. 2016;171:243–49.

    CAS  Google Scholar 

  52. 52.

    Zhang XY, Li CB, Li M, Zheng YL, Zhang CX, Yan QZ, et al. Smoking initiation and schizophrenia: a replication study in a Chinese Han population. Schizophr Res. 2010;119:110–4.

    PubMed  Google Scholar 

  53. 53.

    Heishman SJ, Kleykamp BA, Singleton EG. Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacol (Berl). 2010;210:453–69.

    CAS  Google Scholar 

  54. 54.

    Campos MW, Serebrisky D, Castaldelli-Maia JM. Smoking and cognition. Curr Drug Abus Rev. 2016;9:76–9.

    CAS  Google Scholar 

  55. 55.

    Hong L, Schroeder M, Ross T, Buchholz B, Salmeron B, Wonodi I, et al. Nicotine enhances but does not normalize visual sustained attention and the associated brain network in schizophrenia. Schizophr Bull. 2011;37:416–25.

    PubMed  Google Scholar 

  56. 56.

    Zhang XY, Tan YL, Chen DC, Tan SP, Yang FD, Zunta-Soares GB, et al. Effects of cigarette smoking and alcohol use on neurocognition and BDNF levels in a Chinese population. Psychopharmacol (Berl). 2015;233:435–45.

    Google Scholar 

  57. 57.

    Tan SP, Jie-Feng C, Fan FM, Zhao YL, Chen N, Fan HZ, et al. Smoking, MATRICS consensus cognitive battery and P50 sensory gating in a Han Chinese population. Drug Alcohol Depend. 2014;143:51–7.

    PubMed  Google Scholar 

  58. 58.

    Choueiry J, Blais CM, Shah D, Smith D, Fisher D, Illivitsky V, et al. Combining CDP-choline and galantamine: Effects of a selective alpha7 nicotinic acetylcholine receptor agonist strategy on P50 sensory gating of speech sounds in healthy volunteers. J Psychopharmacol. 2019;33:688–99.

    CAS  PubMed  Google Scholar 

  59. 59.

    Leon JD, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res. 2005;76:135–57.

    PubMed  Google Scholar 

  60. 60.

    Turan T, Dolu N, Ozsoy S, Kılıç C, BeşİRli̇ A, Esel E. Effects of smoking on P50 waveform in schizophrenic patients. Klin Psikofarmakol Bul. 2009;19:227–35.

    Google Scholar 

  61. 61.

    Winterer G. Why do patients with schizophrenia smoke? Curr Opin Psychiatry. 2010;23:112.

    PubMed  Google Scholar 

  62. 62.

    Liu H, Luo Q, Du W, Li X, Zhang Z, Yu R, et al. Cigarette smoking and schizophrenia independently and reversibly altered intrinsic brain activity. Brain Imaging Behav. 2018;12:1457–65.

    PubMed  Google Scholar 

  63. 63.

    Pesko MF, Baum CF. The self-medication hypothesis: evidence from terrorism and cigarette accessibility. Econ Hum Biol. 2016;22:94–102.

    PubMed  Google Scholar 

  64. 64.

    Kodaka F, Ito H, Takano H, Takahashi H, Arakawa R, Miyoshi M, et al. Effect of risperidone on high-affinity state of dopamine D2 receptors: a PET study with agonist ligand [11C](R)-2-CH3O-N-n-propylnorapomorphine. Int J Neuropsychopharmacol. 2011;14:83–9.

    CAS  PubMed  Google Scholar 

  65. 65.

    Hecht EM, Landy DC. Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis. Schizophr Res. 2012;134:202–6.

    PubMed  Google Scholar 

  66. 66.

    Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, Todd L, Patel RC, et al. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry. 2007;64:1115.

    CAS  PubMed  Google Scholar 

  67. 67.

    Liu DT, Zhuo KM, Song ZH, Yan WU, Chen XS, Wang JJ, et al. Effect of risperidone on sensory gating P50 deficit in patients with schizophrenia. J Shanghai Jiaotong Univ. 2010;30:1525–29.

    CAS  Google Scholar 

  68. 68.

    Xu L, Song L, Zhang M, Chen X, Wu R, Tang J. A study on the effect of risperidone on PPI and P50 Deficit in FirstEpisode and chronic patients with schizophrenia. J Int Psychl. 2016;4:577–80.

    Google Scholar 

  69. 69.

    Hashimoto K. Tropisetron and its targets in Alzheimer’s disease. Expert Opin Ther Targets. 2015;19:1–5.

    CAS  PubMed  Google Scholar 

  70. 70.

    Rahimian R, Fakhfouri G, Ejtemaei Mehr S, Ghia JE, Genazzani AA, Payandemehr B, et al. Tropisetron attenuates amyloid-beta-induced inflammatory and apoptotic responses in rats. Eur J Clin Invest. 2013;43:1039–51.

    CAS  PubMed  Google Scholar 

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LX and XYZ performed analysis, made interpretation of data and drafted the manuscript. LL and XH made contributions to the acquisition of clinical and P50 data for the work. DW, GW, JW, HZ, HX, YT, QD, and LW helped draft the work and revise it critically. HEW, CC, and TRK helped to interpret the data and revised the paper significantly. All authors made significant contributions to the paper to assess the important intellectual content, read and approved the paper.

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Correspondence to Xiang Yang Zhang.

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Xia, L., Liu, L., Hong, X. et al. One-day tropisetron treatment improves cognitive deficits and P50 inhibition deficits in schizophrenia. Neuropsychopharmacol. 45, 1362–1368 (2020). https://doi.org/10.1038/s41386-020-0685-0

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