Consortium PSYCHIATRICUMConsortium PSYCHIATRICUMConsortium PSYCHIATRICUM2712-76722713-2919Eco-Vector1560310.17816/CP15603REVIEWОБЗОРReview ArticleAssociation of the COMT gene polymorphism rs4680 with cognitive impairment in schizophrenia: a narrative reviewАссоциации функционального варианта гена COMT rs4680 с когнитивными нарушениями при шизофрении: нарративный обзорMaksimenkoTatiana V.МаксименкоТатьяна Владимировна
Russian Federation

Resident Physician

zorkina.ya@serbsky.ruhttps://orcid.org/0000-0003-0247-271754584719100H-2424-20133017-3328ZorkinaYana A.ЗоркинаЯна Александровна
Russian Federation

Cand. Sci (Biolog.), Senior Researcher, Mental-health clinic No. 1 named after N.A. Alexeev; V. Serbsky National Medical Research Centre of Psychiatry and Narcology of the Ministry of Health of the Russian Federation

zorkina.ya@serbsky.ruhttps://orcid.org/0000-0003-0842-3203158365705003427-8085EfimovaOlga I.ЕфимоваОльга Игоревна
Russian Federation

Junior Researcher, V. Zelman Center for Neurobiology and Brain Restoration

zorkina.ya@serbsky.ruhttps://orcid.org/0000-0002-7702-6343AndriushchenkoAlisa V.АндрющенкоАлиса Владимировна
Russian Federation

MD, Dr. Sci (Med.), Head of the Department of Mental Disorders in Neurodegenerative Brain Diseases, Mental-health Clinic No. 1 named after N.A. Alexeev; Professor, Department of Mental Health and Clinical Psychiatry, Faculty of Psychology, Lomonosov Moscow State University

zorkina.ya@serbsky.ruhttps://orcid.org/0000-0002-3073-6305572000818843424-4544KostyukGeorge P.КостюкГеоргий Петрович
Russian Federation

MD, Dr. Sci (Med.), Professor, Director, Mental-health Clinic No. 1 named after N.A. Alexeev; Head of the Department of Mental Health and Clinical Psychiatry, Faculty of Psychology, Lomonosov Moscow State University; Professor, BIOTECH University

zorkina.ya@serbsky.ruMental-health clinic No. 1 named after N.A. AlexeevГБУЗ «Психиатрическая клиническая больница № 1 им. Н.А. Алексеева Департамента здравоохранения города Москвы»V. Serbsky National Medical Research Centre of Psychiatry and Narcology of the Ministry of Health of the Russian FederationФГБУ «Национальный медицинский исследовательский центр психиатрии и наркологии им. В.П. Сербского» Минздрава РоссииSkolkovo Institute of Science and TechnologyАНОО ВО «Сколковский институт науки и технологий»Lomonosov Moscow State UniversityФГБОУ ВО «Московский государственный университет имени М.В. Ломоносова»BIOTECH UniversityФГБОУ ВО «Российский биотехнологический университет (РОСБИОТЕХ)22092025260920256362700912202410092025Copyright ©; 2025, Maksimenko T.V., Zorkina Y.A., Efimova O.I., Andriushchenko A.V., Kostyuk G.P.Copyright ©; 2025, Максименко Т.В., Зоркина Я.А., Ефимова О.И., Андрющенко А.В., Костюк Г.П.2025Maksimenko T.V., Zorkina Y.A., Efimova O.I., Andriushchenko A.V., Kostyuk G.P.Максименко Т.В., Зоркина Я.А., Ефимова О.И., Андрющенко А.В., Костюк Г.П.https://creativecommons.org/licenses/by-nc-nd/4.0https://consortium-psy.com/jour/article/view/15603

BACKGROUND: Cognitive impairment in schizophrenia patients is characterized by decreased functioning, reduced quality of life, and is a predictor of a more severe course of the disease. The rs4680 variant of the COMT gene (Val158Met), which encodes catechol-O-methyltransferase, affects dopamine metabolism in the prefrontal cortex and is a key genetic modifier of cognitive endophenotypes. However, the associations of the rs4680 alleles with the severity of cognitive impairment remain unclear. This review summarizes and critically re-evaluates the evidence on the role of rs4680 in the development of cognitive deficits in schizophrenia.

AIM: To explore the associations of the rs4680 variant of the COMT gene with cognitive functions in schizophrenia.

METHODS: A literature search of the PubMed database for the last 10 years (2014–2024) was performed with the search query “rs4680 schizophrenia cognition”. The review included 11 studies.

RESULTS: In the majority of studies (9 out of 11), carriers of the Met allele demonstrated better cognitive parameters, such as verbal and visual memory, information processing speed, and regulatory functions (especially in men). Individuals with the Val/Val genotype demonstrated worse attention. Women in the Russian population with Met allele had better conceptualization and inhibitory control results, and men in the Han population with Met allele had a better association with memory and attention.

CONCLUSION: The results of this review confirm the association between the rs4680 variant of the COMT gene and cognitive function. Although the quality of the studies included in this review was low, the overall results indicate that further investigation of this association is promising. The identification of a stable association between the COMT genotype and the severity of cognitive deficit provides the basis for a personalized approach in the management of patients with schizophrenia. Further studies on the validation of genetic markers in independent cohorts and the development of algorithms for the integration of genetic data with complex neurocognitive assessments and clinical endophenotypes are needed to make the clinical implementation of this approach successful.

ВВЕДЕНИЕ: Когнитивные нарушения при шизофрении приводят к снижению функционирования и ухудшению качества жизни, а также служат предикторами более тяжелого течения заболевания. Вариант rs4680 гена COMT (Val158Met), кодирующего катехол-О-метилтрансферазу, определяет метаболизм дофамина в префронтальной коре и является ключевым генетическим модификатором когнитивных эндофенотипов. Однако ассоциации аллелей rs4680 с выраженностью когнитивных нарушений остаются недостаточно ясными. В обзоре обобщены и критически переосмыслены сведения о роли rs4680 в формировании когнитивного дефицита при шизофрении.

ЦЕЛЬ: Изучить ассоциации варианта rs4680 гена COMT с когнитивными функциями при шизофрении.

МЕТОДЫ: Проведен поиск литературы по базе данных PubMed за последние 10 лет (2014–2024) по запросу «rs4680 schizophrenia cognitive». В обзор было включено 11 исследований.

РЕЗУЛЬТАТЫ: В большинстве исследований (в 9 из 11) носители аллеля Met демонстрировали лучшие когнитивные показатели, такие как вербальная и зрительная память, скорость обработки информации, регуляторные функции (особенно у мужчин). Для группы лиц с генотипом Val/Val наблюдалось снижение внимания. У женщин-носителей аллеля Met российской популяции были выше показатели концептуализации и тормозного контроля, а у мужчин-носителей аллеля Met популяции хань были выше показатели памяти и внимания.

ЗАКЛЮЧЕНИЕ: По результатам данного обзора подтверждена взаимосвязь между вариантом rs4680 гена COMT и когнитивными функциями. Несмотря на то что качество исследований, включенных в данный обзор, было низким, суммарный результат указывает на перспективность дальнейшего изучения данной связи. Выявление устойчивой связи между генотипом COMT и выраженностью когнитивного дефицита создает основу для персонализированного подхода в ведении пациентов с шизофренией. Для успешной клинической реализации этого подхода необходимы дальнейшие исследования по валидации генетических маркеров в независимых когортах и разработка алгоритмов интеграции генетических данных с комплексной нейрокогнитивной оценкой и клиническими эндофенотипами.

schizophreniaCOMTVal158Metcognitive functionsrs4680шизофренияCOMTVal158Metкогнитивные функцииrs4680Russian Science FoundationРоссийский научный фонд22-15-00474McCutcheon RA, Keefe RSE, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28(5):1902–1918. doi: 10.1038/s41380-023-01949-9Solmi M, Seitidis G, Mavridis D, et al. Incidence, prevalence, and global burden of schizophrenia – data, with critical appraisal, from the Global Burden of Disease (GBD) 2019. Mol Psychiatry. 2023;28(12):5319–5327. doi: 10.1038/s41380-023-02138-4Korkmaz C, Durat G, Tarsuslu B. An evaluation of the disability, insight and self-care agency of schizophrenia patients. Perspect Psychiatr Care. 2022;58(3):919–927. doi: 10.1111/ppc.12877Bosia M, Buonocore M, Bechi M, et al. Cognitive remediation and functional improvement in schizophrenia: is it a matter of size? Eur Psychiatry. 2017;40:26–32. doi: 10.1016/j.eurpsy.2016.06.007Kuperberg G, Heckers S. Schizophrenia and cognitive function. Curr Opin Neurobiol. 2000;10(2):205–210. doi: 10.1016/s0959-4388(00)00068-4Romanov DV, Andryushchenko AV. [Epidemiology of schizophrenia]. In: Smulevich AB, editor. [Schizophrenia and schizophrenia spectrum disorders]. Moscow: Gorodec; 2024. p. 47–77. Russian.Gebreegziabhere Y, Habatmu K, Mihretu A, et al. Cognitive impairment in people with schizophrenia: an umbrella review. Eur Arch Psychiatry Clin Neurosci. 2022;272(7):1139–1155. doi: 10.1007/s00406-022-01416-6Penadés R, Forte MF, Mezquida G, et al. Treating Cognition in Schizophrenia: A Whole Lifespan Perspective. Healthcare (Basel). 2024;12(21):2196. doi: 10.3390/healthcare12212196Brisch R, Saniotis A, Wolf R, et al. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front Psychiatry. 2014;5:47. doi: 10.3389/fpsyt.2014.00047Yang KC, Yang BH, Liu MN, et al. Cognitive impairment in schizophrenia is associated with prefrontal-striatal functional hypoconnectivity and striatal dopaminergic abnormalities. J Psychopharmacol. 2024;38(6):515–525. doi: 10.1177/02698811241257877McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms. Trends Neurosci. 2019;42(3):205–220. doi: 10.1016/j.tins.2018.12.004Schacht JP. COMT val158met moderation of dopaminergic drug effects on cognitive function: a critical review. Pharmacogenomics J. 2016;16(5):430–438. doi: 10.1038/tpj.2016.43Zhang T, Liu C, Zhong N, et al. Advances in the Treatment of Cognitive Impairment in Schizophrenia: Targeting NMDA Receptor Pathways. Int J Mol Sci. 2024;25(19):10668. doi: 10.3390/ijms251910668Laruelle M. Schizophrenia: from dopaminergic to glutamatergic interventions. Curr Opin Pharmacol. 2014;14:97–102. doi: 10.1016/j.coph.2014.01.001Lachman HM, Papolos DF, Saito T, et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6(3):243–250. doi: 10.1097/00008571-199606000-00007Lotta T, Vidgren J, Tilgmann C, et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry. 1995;34(13):4202–4210. doi: 10.1021/bi00013a008Palmatier MA, Kang AM, Kidd KK. Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry. 1999;46(4):557–567. doi: 10.1016/s0006-3223(99)00098-0Zai G, Robbins TW, Sahakian BJ, et al. A review of molecular genetic studies of neurocognitive deficits in schizophrenia. Neurosci Biobehav Rev. 2017;72:50–67. doi: 10.1016/j.neubiorev.2016.10.024Geller S, Wilhelm O, Wacker J, et al. Associations of the COMT Val158Met polymorphism with working memory and intelligence — A review and meta-analysis. Intelligence. 2017;65:75–92. doi: 10.1016/j.intell.2017.09.002Bondrescu M, Dehelean L, Farcas SS, et al. Cognitive Impairments Related to COMT and Neuregulin 1 Phenotypes as Transdiagnostic Markers in Schizophrenia Spectrum Patients. J Clin Med. 2024;13(21):6405. doi: 10.3390/jcm13216405Loch AA, van de Bilt MT, Bio DS, et al. Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission. Braz J Psychiatry. 2015;37(3):235–241. doi: 10.1590/1516-4446-2014-1553Sun Z, Zhang Z, Mao P, et al. Association between COMT gene polymorphisms, clinical symptoms, and cognitive functions in Han Chinese patients with schizophrenia. Psychiatr Genet. 2018;28(3):47–54. doi: 10.1097/YPG.0000000000000194Nkam I, Ramoz N, Breton F, et al. Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia. PLoS One. 2017;12(1):e0170147. doi: 10.1371/journal.pone.0170147Matsuzaka CT, Christofolini D, Ota VK, et al. Catechol-O-methyltransferase (COMT) polymorphisms modulate working memory in individuals with schizophrenia and healthy controls. Braz J Psychiatry. 2017;39(4):302–308. doi: 10.1590/1516-4446-2016-1987Luck SJ, Gold JM. The construct of attention in schizophrenia. Biol Psychiatry. 2008;64(1):34–39. doi: 10.1016/j.biopsych.2008.02.014Lindenmayer JP, Khan A, Lachman H, et al. COMT genotype and response to cognitive remediation in schizophrenia. Schizophr Res. 2015;168(1–2):279–284. doi: 10.1016/j.schres.2015.07.037Sagud M, Tudor L, Nedic Erjavec G, et al. Genotypic and Haplotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Gene Polymorphisms with Particular Clinical Symptoms in Schizophrenia. Genes (Basel). 2023;14(7):1358. doi: 10.3390/genes14071358Bosia M, Bechi M, Pirovano A, et al. COMT and 5-HT1A-receptor genotypes potentially affect executive functions improvement after cognitive remediation in schizophrenia. Health Psychol Behav Med. 2014;2(1):509–516. doi: 10.1080/21642850.2014.905206Syamsuddin S, Rakhmawati TA, Limoa E, et al. Catechol-O-methyltransferase (COMT) Val158Met polymorphism in schizophrenia patients: response to antipsychotic treatment and cognitive function. J Popul Ther Clin Pharmacol. 2023;30(16):49–58. doi: 10.47750/jptcp.2023.30.16.006Xu H, Zhou Y, Xiu M, et al. The inconsistent mediating effect of catechol O methyl transferase Val158Met polymorphism on the sex difference of cognitive impairment in schizophrenia patients. Front Psychiatry. 2022;13:993859. doi: 10.3389/fpsyt.2022.993859Morozova A, Zorkina Y, Pavlov K, et al. Association of rs4680 COMT, rs6280 DRD3, and rs7322347 5HT2A With Clinical Features of Youth-Onset Schizophrenia. Front Psychiatry. 2019;10:830. doi: 10.3389/fpsyt.2019.00830Zorkina Y, Morozova A, Abramova O, et al. Sex differences in social functioning of patients with schizophrenia depending on the age of onset and severity of the disease. Early Interv Psychiatry. 2021;15(5):1197–1209. doi: 10.1111/eip.13063de Castro-Catala M, Barrantes-Vidal N, Sheinbaum T, et al. COMT-by-sex interaction effect on psychosis proneness. Biomed Res Int. 2015;2015:829237. doi: 10.1155/2015/829237Lachance J. Hardy-Weinberg Equilibrium and Random Mating. In: Kliman RM, editor. Encyclopedia of Evolutionary Biology. Cambridge: Academic Press; 2016. p. 208–211.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text revision (DSM-IV-TR®). Washington: APA; 2010.Singh A, Kumar V, Pathak H, et al. Effect of antipsychotic dose reduction on cognitive function in schizophrenia. Psychiatry Res. 2022;308:114383. doi: 10.1016/j.psychres.2021.114383