The interaction of folate cycle enzyme genes and the risk of extrapyramidal side effects of antipsychotics

Personalized medicine means the selection of therapy for patients, taking into account the assessment of genetic risk factors for side effects. A number of studies show that folate metabolism disorders, including single nucleotide polymorphisms (SNPs) in the genes of folate-metabolizing enzymes, are more frequently detected in schizophrenic patients than in the general population. The role of SNPs of the key folate cycle enzymes in developing the extrapyramidal side effects of antipsychotics has not yet been studied, although there is evidence of their association with other movement disorders.

Objective: to analyze the association between the carriage of SNP alleles of MTHFR 677C>T, MTR 2756A>G, and MTRR 66A>G and the severity of extrapyramidal side effects of antipsychotics in patients with schizophrenia.

Patients and methods. The investigation included 61 patients with schizophrenia (according to the criteria for ICD-10 Code F20). All the patients took antipsychotics for at least 7 hospital days were examined using real-time polymerase chain reaction (PCR) with allele-specific primers, followed by detection for the carriage of SNP alleles of MTHFR 677C>T, MTR 2756A>G, and MTRR 66A>G. The standardized Simpson–Angus scale (SAS) was used to evaluate the severity of extrapyramidal symptoms; the PCR test results were unknown during their examination.

Results and discussion. In the patients carrying a low-functional 677 T allele in the gene of the key folate cycle enzyme MTHFR, the severity of extrapyramidal side effects of antipsychotics was statistically significantly higher than in the carriers of the wild-type genotype: 13.27±5.10 versus 9.84±6.03 SAS scores, respectively (t=-2.40; p=0.020). In addition, the carriage of the wild allele A of SNP in the MTRR 66A>G gene (F=3.83; p=0.0283; p_corr.=0.043) is associated with the severity of extrapyramidal symptoms. There was a direct moderate correlation of the number of risk alleles at two loci with the total SAS score (r=0.51; p=0.00017).

Conclusion. The polymorphic allele of MTHFR 677T and the wild allele of MTRR 66A can be regarded as risk alleles for the development of extrapyramidal side effects of antipsychotics.

1. Kibitov AO, Ivashchenko DV, Sychev DA. Pharmacogenetic approach to increase efficacy and safety of schizophrenia treatment with antipsychotics. Sovremennaya terapiya psikhicheskikh rasstroystv. 2017;(1):2-13 (In Russ.).

2. Yadav U, Kumar P, Gupta S, Rai V. Role of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: An updated meta-analysis. Asian J Psychiatry. 2016 Apr;20:41-51. doi: 10.1016/j.ajp.2016.02.002. Epub 2016 Feb 15.

3. Muntjewerff JW, Kahn RS, Blom HJ, et al. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry. 2006 Feb;11(2):143-9. doi: 10.1038/sj.mp.4001746

4. Roffman JL, Weiss AP, Purcell S, et al. Contribution of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms to Negative Symptoms in Schizophrenia. Biol Psychiatry. 2008 Jan 1;63(1):42-8. doi: 10.1016/j.biopsych.2006.12.017. Epub 2007 Jun 1.

5. Boldyrev AA. Molecular mechanisms of homocysteine toxicity. Biochemistry (Moscow). 2009 Jun;74(6):589-98. doi: 10.1134/s000629790906001

6. Liew S-C, Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: Epidemiology, metabolism and the associated diseases. Eur J Med Genet. 2015 Jan;58(1):1-10. doi: 10.1016/j.ejmg.2014.10.004. Epub 2014 Nov 4.

7. Leucht S, Corves C, Arbter D, et al. Second-generation versus firstgeneration antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009 Jan 3;373(9657):31-41. doi: 10.1016/S0140-6736(08)61764-X. Epub 2008 Dec 6.

8. Zhilyaeva TV, Sergeeva AV, Blagonravova AS, Akimova EV, Kasimova LN. Folate metabolism genetic polymorphism MTHFR 677C> T and catatonic symptoms of schizophrenia. Nevrologicheskiy vestnik. 2016;48(2-S):12-6 (In Russ.).

9. Zhilyaeva TV. Disturbances of one-carbon metabolism in schizophrenia. Psikhiatriya i psikhofarmakoterapiya. 2012;14(6):41-6 (In Russ.).

10. Fedorova NV, Vetokhina TN. Diagnostika i lecheniye neyrolepticheskikh ekstrapiramidnykh sindromov: Uchebno-metodicheskoye posobiye [Diagnostics and treatment of neuroleptic extrapyramidal syndromes: Teaching aid]. Moscow: RMAPO; 2006 (In Russ.).

11. Lerner V, Bergman J, Statsenko N, Miodownik C. Vitamin B6 Treatment in Acute Neuroleptic-Induced Akathisia. J Clin Psychiatry. 2004;65(11):1550-4. doi: 10.4088/jcp.v65n1118

12. Lerner V, Miodownik C. Vitamin B6 Treatment for Tardive Dyskinesia. J Clin Psychiatry. 2007;68(11):1648-54. doi: 10.4088/jcp.v68n1103

13. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11-9. doi: 10.1111/j.1600-0447.1970.tb02066.x

14. Lane RD, Glazer WM, Hansen TE, et al. Assessment of tardive dyskinesia using the Abnormal Involuntary Movement Scale. J Nerv Ment Dis. 1985 Jun;173(6):353-7. doi: 10.1097/00005053-198506000-00005

15. Jin H, Cheng H, Chen W, et al. An evidence-based approach to globally assess the covariate-dependent effect of the MTHFR single nucleotide polymorphism rs1801133 on blood homocysteine: a systematic review and meta-analysis. Am J Clin Nutr. 2018 May 1;107(5):817-25. doi: 10.1093/ajcn/nqy035

16. Zhilyaeva TV, Sergeeva AV, Blagonravova AS, Mazo GE. Secondary but not primary negative symptoms of schizophrenia are associated with carriage of minor allele of genetic polymorphism MTHFR677C>T [abstracts of the 27th European Congress of Psychiatry, Poland, Warsaw, 6-9 April 2019; E-Poster Presentation, E-PP1199]. Eur Psychiatry J Eur Psychiatr Assoc. 2019;56 Suppl:S400.

17. Wu Y-L, Ding X-X, Sun Y-H, et al. Methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson's disease: A meta-analysis. J Neurol Sci. 2013 Dec 15;335(1-2):14-21. doi: 10.1016/j.jns.2013.09.006. Epub 2013 Sep 12.

18. Rozycka A, Jagodzinski PP, Kozubski W, et al. Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment. Curr Genomics. 2013;14(8):534-42. doi: 10.2174/1389202914666131210210559

19. Rai V, Yadav U, Kumar P, Yadav SK. Analysis of methionine synthase reductase polymorphism (A66G) in Indian Muslim population. Indian J Hum Genet. 2013;19(2):183-7. doi: 10.4103/0971-6866.116123

20. Fong CS, Shyu HY, Shieh JC, et al. Association of MTHFR, MTR, and MTRR polymorphisms with Parkinson's disease among ethnic Chinese in Taiwan. Clin Chim Acta. 2011 Jan 30;412(3-4):332-8. doi: 10.1016/j.cca.2010.11.004. Epub 2010 Nov 8.

21. Zhilyayeva TV, Sergeyeva AV, Kasimova LN, Blagonravova AS. Dynamics of cognitive functions during augmentation of folate therapy in schizophrenic patients, carriers of the MTHFR677C> T gene polymorphism: a pilot study. Sovremennyye tekhnologii v meditsine. 2015;7(4):147-53 (In Russ.).

22. Zhilyayeva TV, Sergeyeva AV, Blagonravova AS, Kasimova LN. Experience with folic acid augmentation in antipsychotic therapy for schizophrenia. Meditsinskiy al'manakh. 2017;50(5):147-50 (In Russ.).