Catechol-O-methyltransferase (COMT) Val158Met polymorphism in schizophrenia patients: response to antipsychotic treatment and cognitive function
Main Article Content
Keywords
COMT Val158Met polymorphism, risperidone, schizophrenia, treatment response, cognitive function
Abstract
Schizophrenia is a complex and severe mental disorder, suggesting genetic factors involvement. The role of Catechol-O-methyltransferase (COMT) gene in the degradation of dopamine could be related to treatment response to antipsychotics and cognitive functions in schizophrenia. This study investigated the association between genotypic polymorphisms of COMT Val158Met and treatment response to risperidone and cognitive function in schizophrenia patients. By using cross-sectional study, this study recruited 200 subjects and later divided them into 2 groups. The first group consisted of 100 subjects with schizophrenia and the second group consisted of 100 healthy volunteers. Clinical improvement of schizophrenia group assessed thrice in 4 weeks (on admission, on the 2nd, and 4th week) using the PANSS Score. The cognitive test in the schizophrenia group was assessed in the 4th week using TMT. The results found that individuals with the Met allele have a 3.353 times risk for schizophrenia. PANSS positive score tends to higher in schizophrenia with Met allele whereas PANSS negative score tends to higher in Val/Val genotype on admission. Schizophrenia with Met allele tends to finish the test faster TMT A and TMT B than to Val / Val genotype. Even though no significant association, schizophrenia with Met allele tends to have a better treatment response and cognitive function compared to Val/Val genotype. This study concluded that COMT Val158Met polymorphism has an influence on treatment response to risperidone and cognitive function in schizophrenia.
References
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10. Illi A, Mattila KM, Kampman O, Anttila S, Roivas M, Lehtimäki T, Leinonen E. Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia. J Clin Psychopharmacol. 2003;23(5):429-34.
11. Molero P, Ortuño F, Zalacain M, Patiño-García A. Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment. Pharmacogenomics J. 2007;7(6):418-26.
12. Yamanouchi Y, Iwata N, Suzuki T, Kitajima T, Ikeda M, Ozaki N. Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. Pharmacogenomics J. 2003;3(6): 356-61.
13. Galderisi S, Maj M, Kirkpatrick B, Piccardi P, Mucci A, Invernizzi G, Rossi A, Pini S, Vita A, Cassano P, Stratta P, Severino G, Del Zompo M. Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment. Neuropsychobiology. 2005;52(2):83-9.
14. Ehlis AC, Reif A, Herrmann MJ, Lesch KP, Fallgatter AJ. Impact of catechol-O-methyltransferase on prefrontal brain functioning in schizophrenia spectrum disorders. Neuropsychopharmacology. 2007;32(1):162-70.
15. Szöke A, Schürhoff F, Méary A, Mathieu F, Chevalier F, Trandafir A, Alter C, Roy I, Bellivier F, Leboyer M. Lack of influence of COMT and NET genes variants on executive functions in schizophrenic and bipolar patients, their first-degree relatives and controls. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(5): 504-12.
16. Ira E, Zanoni M, Ruggeri M, Dazzan P, Tosato S. COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation. J Psychiatry Neurosci. 2013;38(6): 366-80.
17. Hosmer DW, Lemeshow S. Applied survival analysis: time-to-event. Wiley-Interscience; 1999.
18. Gaudino EA, Geisler MW, Squires NK. Construct validity in the Trail Making Test: what makes Part B harder? J Clin Exp Neuropsychol. 1995;17(4): 529-35.
19. Wan CL, Zainal NZ, Lian LH, Mohamed Z. Association of the functional polymorphism in the catechol-O-methyltransferase gene with schizophrenia in the three ethnic groups of the Malaysian population. Psychiatry Res. 2011;189 (1):67-71.
20. Al-Asmary S, Kadasah S, Arfin M, Tariq M, Al-Asmari A. Genetic association of catechol-O-methyltransferase val(158)met polymorphism in Saudi schizophrenia patients. Genet Mol Res. 2014;13(2): 3079-88.
21. Sazci A, Ergul E, Kucukali I, Kilic G, Kaya G, Kara I. Catechol-O-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women. Brain Res Mol Brain Res. 2004;132(1): 51-6.
22. Costas J, Sanjuán J, Ramos-Ríos R, Paz E, Agra S, Ivorra JL, Páramo M, Brenlla J, Arrojo M. Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis. J Psychiatr Res. 2011;45(1): 7-14.
23. Stahl SM. (2013). Stahl’s Essential Psychopharmacology. Fourth Edition. Cambridge University Press. New York.
24. Han DH, Kee BS, Min KJ, Lee YS, Na C, Park DB, Lyoo IK. Effects of catechol-O-methyltransferase Val158Met polymorphism on the cognitive stability and aggression in the first-onset schizophrenic patients. Neuroreport. 2006;17(1):95-9.
25. Kim YR, Kim JH, Kim SJ, Lee D, Min SK. Catechol-O-methyltransferase Val158Met polymorphism in relation to aggressive schizophrenia in a Korean population. Eur Neuropsychopharmacol. 2008;18(11):820-5.
26. Bhakta SG, Zhang JP, Malhotra AK. The COMT Met158 allele and violence in schizophrenia: a meta-analysis. Schizophr Res. 2012;140 (1-3):192-7.
27. Pelayo-Terán JM, Pérez-Iglesias R, Vázquez-Bourgon J, Mata I, Carrasco-Marín E, Vázquez-Barquero JL, Crespo-Facorro B. Catechol-O-methyltransferase Val158Met polymorphism and negative symptoms after acute antipsychotic treatment in first-episode non-affective psychosis. Psychiatry Res. 2011;185(1-2):286-9.
28. Mao Q, Tan YL, Luo XG, Tian L, Wang ZR, Tan SP, Chen S, Yang GG, An HM, Yang FD, Zhang XY. Association of catechol-O-methyltransferase Val(108/158) Met genetic polymorphism with schizophrenia, P50 sensory gating, and negative symptoms in a Chinese population. Psychiatry Res. 2016;242: 271-276.
29. Gupta M, Bhatnagar P, Grover S, Kaur H, Baghel R, Bhasin Y, Chauhan C, Verma B, Manduva V, Mukherjee O, Purushottam M, Sharma A, Jain S, Brahmachari SK, Kukreti R. Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment. Pharmacogenomics. 2009;10(3):385-97
30. Huang E, Zai CC, Lisoway A, Maciukiewicz M, Felsky D, Tiwari AK, Bishop JR, Ikeda M, Molero P, Ortuno F, Porcelli S, Samochowiec J, Mierzejewski P, Gao S, Crespo-Facorro B, Pelayo-Terán JM, Kaur H, Kukreti R, Meltzer HY, Lieberman JA, Potkin SG, Müller DJ, Kennedy JL. Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis. Int J Neuropsychopharmacol. 2016;19(5): 132.
31. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005;8(5):594-6
32. Nikolac Perkovic, M., Sagud, M., Zivkovic, M. et al. Catechol-O-methyltransferase rs4680 and rs4818 haplotype association with treatment response to olanzapine in patients with schizophrenia. Sci Rep. 2020;10:10049.
33. Rajagopal VM, Rajkumar AP, Jacob KS, Jacob M. Gene-gene interaction between DRD4 and COMT modulates clinical response to clozapine in treatment-resistant schizophrenia. Pharmacogenet Genomics. 2018;28(1):31-35.
34. Kaneko H, Miura I, Kanno-Nozaki K, Horikoshi S, Hino M, Yabe H. COMT Val 108/158 Met polymorphism and treatment response to aripiprazole in patients with acute schizophrenia. Neuropsychiatr Dis Treat. 2018;14:1657-1663.
35. Sánchez-Cubillo I, Periáñez JA, Adrover-Roig D, Rodríguez-Sánchez JM, Ríos-Lago M, Tirapu J, Barceló F. Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc. 2009;15(3): 438-50.
36. Nkam I, Ramoz N, Breton F, Mallet J, Gorwood P, Dubertret C. Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia. PLoS One. 2017;12(1): e0170147.
37. Bertolino A, Caforio G, Blasi G, De Candia M, Latorre V, Petruzzella V, Altamura M, Nappi G, Papa S, Callicott JH, Mattay VS, Bellomo A, Scarabino T, Weinberger DR, Nardini M. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry. 2004;161(10): 1798-805.
38. Weickert TW, Goldberg TE, Mishara A, Apud JA, Kolachana BS, Egan MF, Weinberger DR. Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry. 2004;56(9): 677-82.
39. Durstewitz D, Seamans JK. The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-o-methyltransferase genotypes and schizophrenia. Biol Psychiatry. 2008;64(9): 739-49.
40. Schacht JP. COMT val158met moderation of dopaminergic drug effects on cognitive function: a critical review. Pharmacogenomics J. 2016;16(5):430-8.
41. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci. 2002;22(9): 3708-19.
2. Angelo Barbato. Schizophrenia and public health. Division of Mental Health and Prevention of Substance Abuse. 1998. WHO/MSA/NAM/97.6
3. Arranz MJ, de Leon J. (2007). Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry. 2007;8:707-47.
4. Hwang R, Shinkai T, De Luca V, Ni X, Potkin SG, Lieberman JA, Meltzer HY, Kennedy JL. (2007). Association study of four dopamine D1 receptor gene polymorphisms and clozapine treatment response. J Psychopharmacol. 2007;7:718-27.
5. Syamsuddin S, Yusuf I , Tanra J, Idris I. The Polymorphisms of DRD2 141-C Ins/Del Receptor Influenced the Treatment Responses of Schizophrenia Patients. Neuropsychiatry (London). 2019;9(5):2467–2470.
6. Li J, Hashimoto H, Meltzer HY. (2009). Association of Serotonin2c Receptor Polymorphisms With Antipsychotic Drug Response in Schizophrenia. Front Psychiatry. 2009;10:58.
7. McGurk SR, Mueser KT, DeRosa TJ, Wolfe R. Work, recovery, and comorbidity in schizophrenia: a randomized controlled trial of cognitive remediation. Schizophr Bull. 2009;35(2):319-35.
8. Bilder RM, Volavka J, Lachman HM, Grace AA. The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology. 2004;29(11):1943-61.
9. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6(3):243-50.
10. Illi A, Mattila KM, Kampman O, Anttila S, Roivas M, Lehtimäki T, Leinonen E. Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia. J Clin Psychopharmacol. 2003;23(5):429-34.
11. Molero P, Ortuño F, Zalacain M, Patiño-García A. Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment. Pharmacogenomics J. 2007;7(6):418-26.
12. Yamanouchi Y, Iwata N, Suzuki T, Kitajima T, Ikeda M, Ozaki N. Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. Pharmacogenomics J. 2003;3(6): 356-61.
13. Galderisi S, Maj M, Kirkpatrick B, Piccardi P, Mucci A, Invernizzi G, Rossi A, Pini S, Vita A, Cassano P, Stratta P, Severino G, Del Zompo M. Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment. Neuropsychobiology. 2005;52(2):83-9.
14. Ehlis AC, Reif A, Herrmann MJ, Lesch KP, Fallgatter AJ. Impact of catechol-O-methyltransferase on prefrontal brain functioning in schizophrenia spectrum disorders. Neuropsychopharmacology. 2007;32(1):162-70.
15. Szöke A, Schürhoff F, Méary A, Mathieu F, Chevalier F, Trandafir A, Alter C, Roy I, Bellivier F, Leboyer M. Lack of influence of COMT and NET genes variants on executive functions in schizophrenic and bipolar patients, their first-degree relatives and controls. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(5): 504-12.
16. Ira E, Zanoni M, Ruggeri M, Dazzan P, Tosato S. COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation. J Psychiatry Neurosci. 2013;38(6): 366-80.
17. Hosmer DW, Lemeshow S. Applied survival analysis: time-to-event. Wiley-Interscience; 1999.
18. Gaudino EA, Geisler MW, Squires NK. Construct validity in the Trail Making Test: what makes Part B harder? J Clin Exp Neuropsychol. 1995;17(4): 529-35.
19. Wan CL, Zainal NZ, Lian LH, Mohamed Z. Association of the functional polymorphism in the catechol-O-methyltransferase gene with schizophrenia in the three ethnic groups of the Malaysian population. Psychiatry Res. 2011;189 (1):67-71.
20. Al-Asmary S, Kadasah S, Arfin M, Tariq M, Al-Asmari A. Genetic association of catechol-O-methyltransferase val(158)met polymorphism in Saudi schizophrenia patients. Genet Mol Res. 2014;13(2): 3079-88.
21. Sazci A, Ergul E, Kucukali I, Kilic G, Kaya G, Kara I. Catechol-O-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women. Brain Res Mol Brain Res. 2004;132(1): 51-6.
22. Costas J, Sanjuán J, Ramos-Ríos R, Paz E, Agra S, Ivorra JL, Páramo M, Brenlla J, Arrojo M. Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis. J Psychiatr Res. 2011;45(1): 7-14.
23. Stahl SM. (2013). Stahl’s Essential Psychopharmacology. Fourth Edition. Cambridge University Press. New York.
24. Han DH, Kee BS, Min KJ, Lee YS, Na C, Park DB, Lyoo IK. Effects of catechol-O-methyltransferase Val158Met polymorphism on the cognitive stability and aggression in the first-onset schizophrenic patients. Neuroreport. 2006;17(1):95-9.
25. Kim YR, Kim JH, Kim SJ, Lee D, Min SK. Catechol-O-methyltransferase Val158Met polymorphism in relation to aggressive schizophrenia in a Korean population. Eur Neuropsychopharmacol. 2008;18(11):820-5.
26. Bhakta SG, Zhang JP, Malhotra AK. The COMT Met158 allele and violence in schizophrenia: a meta-analysis. Schizophr Res. 2012;140 (1-3):192-7.
27. Pelayo-Terán JM, Pérez-Iglesias R, Vázquez-Bourgon J, Mata I, Carrasco-Marín E, Vázquez-Barquero JL, Crespo-Facorro B. Catechol-O-methyltransferase Val158Met polymorphism and negative symptoms after acute antipsychotic treatment in first-episode non-affective psychosis. Psychiatry Res. 2011;185(1-2):286-9.
28. Mao Q, Tan YL, Luo XG, Tian L, Wang ZR, Tan SP, Chen S, Yang GG, An HM, Yang FD, Zhang XY. Association of catechol-O-methyltransferase Val(108/158) Met genetic polymorphism with schizophrenia, P50 sensory gating, and negative symptoms in a Chinese population. Psychiatry Res. 2016;242: 271-276.
29. Gupta M, Bhatnagar P, Grover S, Kaur H, Baghel R, Bhasin Y, Chauhan C, Verma B, Manduva V, Mukherjee O, Purushottam M, Sharma A, Jain S, Brahmachari SK, Kukreti R. Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment. Pharmacogenomics. 2009;10(3):385-97
30. Huang E, Zai CC, Lisoway A, Maciukiewicz M, Felsky D, Tiwari AK, Bishop JR, Ikeda M, Molero P, Ortuno F, Porcelli S, Samochowiec J, Mierzejewski P, Gao S, Crespo-Facorro B, Pelayo-Terán JM, Kaur H, Kukreti R, Meltzer HY, Lieberman JA, Potkin SG, Müller DJ, Kennedy JL. Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis. Int J Neuropsychopharmacol. 2016;19(5): 132.
31. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005;8(5):594-6
32. Nikolac Perkovic, M., Sagud, M., Zivkovic, M. et al. Catechol-O-methyltransferase rs4680 and rs4818 haplotype association with treatment response to olanzapine in patients with schizophrenia. Sci Rep. 2020;10:10049.
33. Rajagopal VM, Rajkumar AP, Jacob KS, Jacob M. Gene-gene interaction between DRD4 and COMT modulates clinical response to clozapine in treatment-resistant schizophrenia. Pharmacogenet Genomics. 2018;28(1):31-35.
34. Kaneko H, Miura I, Kanno-Nozaki K, Horikoshi S, Hino M, Yabe H. COMT Val 108/158 Met polymorphism and treatment response to aripiprazole in patients with acute schizophrenia. Neuropsychiatr Dis Treat. 2018;14:1657-1663.
35. Sánchez-Cubillo I, Periáñez JA, Adrover-Roig D, Rodríguez-Sánchez JM, Ríos-Lago M, Tirapu J, Barceló F. Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc. 2009;15(3): 438-50.
36. Nkam I, Ramoz N, Breton F, Mallet J, Gorwood P, Dubertret C. Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia. PLoS One. 2017;12(1): e0170147.
37. Bertolino A, Caforio G, Blasi G, De Candia M, Latorre V, Petruzzella V, Altamura M, Nappi G, Papa S, Callicott JH, Mattay VS, Bellomo A, Scarabino T, Weinberger DR, Nardini M. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry. 2004;161(10): 1798-805.
38. Weickert TW, Goldberg TE, Mishara A, Apud JA, Kolachana BS, Egan MF, Weinberger DR. Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry. 2004;56(9): 677-82.
39. Durstewitz D, Seamans JK. The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-o-methyltransferase genotypes and schizophrenia. Biol Psychiatry. 2008;64(9): 739-49.
40. Schacht JP. COMT val158met moderation of dopaminergic drug effects on cognitive function: a critical review. Pharmacogenomics J. 2016;16(5):430-8.
41. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci. 2002;22(9): 3708-19.
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Jun 23, 2023
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Saidah Syamsuddin, Tri Anny Rakhmawati, Erlyn Limoa, Kristian Liaury, Burhanuddin Bahar, Firdaus Hamid, Irfan Idris, & Sonny T Lisal. (2023). Catechol-O-methyltransferase (COMT) Val158Met polymorphism in schizophrenia patients: response to antipsychotic treatment and cognitive function. Journal of Population Therapeutics and Clinical Pharmacology, 30(16), 49–58. https://doi.org/10.47750/jptcp.2023.30.16.006
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