bekhterevОбозрение психиатрии и медицинской психологии имени В.М.БехтереваV.M. BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY2313-70532713-055XV. M. BEKHTEREV NATIONAL RESEARCH MEDICAL CENTER FOR PSYCHIATRY AND NEUROLOGY OF THE RUSSIAN FEDERATION MINISTRY OF HEALTH10.31363/2313-7053-2022-56-4-52-62bekhterev-748Research ArticleИССЛЕДОВАНИЯINVESTIGATIONSБиохимические нарушения при шизофрении —«окно возможностей»Biochemical disturbances in schizophrenia — a «window of opportunity»https://orcid.org/0000-0001-6155-1007ЖиляеваТ. В.ZhilyaevaT. V.

Татьяна Владимировна Жиляева, д. м. н., доцент, ведущий научный сотрудник

кафедра психиатрии

отделение трансляционной психиатрии

Нижний Новгород

Санкт-Петербург

Tatyana V. Zhilyaeva

Nizhny Novgorod

St. Petersburg

bizet@inbox.ruhttps://orcid.org/0000-0002-8932-7418ПятойкинаА. С.PiatoikinaA. S.

Анна Сергеевна Пятойкина, врач-психиатр

медико-реабилитационное отделение

603155

ул. Ульянова, д. 41, лит. 3

Нижний Новгород

Anna S. Piatoikina

Nizhny Novgorod

annapiatoikina@yandex.ruhttps://orcid.org/0000-0002-4658-2195КасьяновЕ. Д.KasyanovE. D.

Евгений Дмитриевич Касьянов, младший научный сотрудник

отделение трансляционной психиатрии

Санкт-Петербург

Evgeny D. Kasyanov

St. Petersburg

ohkasyan@yandex.ruhttps://orcid.org/0000-0002-5282-2036РукавишниковГ. В.RukavishnikovG. V.

Григорий Викторович Рукавишников, к. м. н., научный сотрудник

отделение трансляционной психиатрии

Санкт-Петербург

Grigory V. Rukavishnikov

St. Petersburg

grigory_v_r@mail.ruhttps://orcid.org/0000-0001-8816-4357СеменновИ. В.SemennovI. V.

Илья Владимирович Семеннов, врач-психиатр

Нижний Новгород

Ilya V. Semennov

Nizhny Novgorod

semennov.md@gmail.comhttps://orcid.org/0000-0001-7529-2544КостинаО. В.KostinaO. V.

Ольга Владимировна Костина, к. б. н., старший научный сотрудник, врач лабораторной диагностики

отдел лабораторных исследований

группа биохимии

НИИ профилактической медицины

лаборатория биохимии и неотложной диагностики

Нижний Новгород

Olga V. Kostina

Nizhny Novgorod

olkosta@rambler.ruhttps://orcid.org/0000-0002-1467-049XБлагонравоваА. С.BlagonravovaA. S.

Анна Сергеевна Благонравова, доктор медицинских наук, доцент, проректор по научной работе, заведующий кафедрой, профессор

кафедра клинической и лабораторной диагностики

кафедра эпидемиологии, микробиологии и доказательной медицины

Нижний Новгород

Anna S. Blagonravova

Nizhny Novgorod

a.blagonravova@mail.ruhttps://orcid.org/0000-0001-7910-9129МазоГ. Э.MazoG. E.

Галина Элевна Мазо, д. м. н., заместитель директора по инновационному научному развитию, руководитель отделения

отделение трансляционной психиатрии

Санкт-Петербург

Galina E. Mazo

St. Petersburg

galina-mazo@yandex.ruПриволжский исследовательский медицинский университет; Национальный медицинский исследовательский центр психиатрии и неврологии им. В. М. БехтереваРоссияPrivolzhsky Research Medical University; V. M. Bekhterev National Medical Research Center for Psychiatry and NeurologyRussian FederationКлиническая психиатрическая больница № 1РоссияClinical Psychiatric Hospital № 1 of Nizhny NovgorodRussian FederationНациональный медицинский исследовательский центр психиатрии и неврологии им. В. М. БехтереваРоссияV. M. Bekhterev National Medical Research Center for Psychiatry and NeurologyRussian FederationПриволжский исследовательский медицинский университетРоссияPrivolzhsky Research Medical UniversityRussian Federation2022171220225645262Copyright © Жиляева Т.В., Пятойкина А.С., Касьянов Е.Д., Рукавишников Г.В., Семеннов И.В., Костина О.В., Благонравова А.С., Мазо Г.Э., 20222022Жиляева Т.В., Пятойкина А.С., Касьянов Е.Д., Рукавишников Г.В., Семеннов И.В., Костина О.В., Благонравова А.С., Мазо Г.Э.Zhilyaeva T.V., Piatoikina A.S., Kasyanov E.D., Rukavishnikov G.V., Semennov I.V., Kostina O.V., Blagonravova A.S., Mazo G.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.bekhterevreview.com/jour/article/view/748

   В настоящее время имеется большой объем данных о том, что при шизофрении чаще, чем в общей популяции, выявляются воспалительные маркеры, показатели редокс-дисбаланса, нарушения обмена птеринов и другие биохимические отклонения, которые могут играть роль этиопатогенетических факторов, вовлеченных в развитие шизофрении. При этом исследований с оценкой в одной выборке пациентов широкого комплекса корригируемых биохимических отклонений практически не встречается. В клиническую практику до сих пор не внедрены скрининговые алгоритмы выявления и персонифицированной коррекции управляемых биомаркеров.

   Цель

   Цель: оценить частоту наличия ряда биохимических нарушений у пациентов с шизофренией, которые, согласно данным литературы, имеют этиопатогенетическое значение при этом расстройстве, для обоснования целесообразности внедрения биохимического скрининга и коррекции соответствующих нарушений.

   Материалы и методы

   Материалы и методы: у 125 пациентов с шизофренией и 95 здоровых добровольцев в сыворотке крови определялись уровни фолатов и кобаламина (В12) (хемилюминесцентный иммуноанализ на микрочастицах); гомоцистеина (ГЦ, ферментативный анализ), тетрагидробиоптерина (BH4, конкурентный иммуноферментный анализ, ИФА); восстановленного глутатиона (GSH, спектрофотометрия с реактивом Эллмана), интерлейкина-6 (ИЛ-6, ИФА на основе трехстадийного «сэндвич-варианта»); С-реактивного белка (СРБ, иммунотурбодиметрический метод).

   Результаты

   Результаты: У пациентов с шизофренией уровень всех изученных биохимических маркеров сыворотки, кроме В12, статистически значимо отличался от соответствующих показателей здоровых добровольцев. Частота отклонений изученных показателей от нормы у пациентов статистически значимо выше по показателям обмена птеринов (ВН4: p = 0,0000; фолаты: p = 0,0000; ГЦ: p = 0,0094). 29,6 % пациентов являются носителями 4 и более изученных биохимических отклонений, тогда как среди здоровых это встречается в 5,3 % случаев (Хи2 = 19,2; р < 0,001).

   Заключение

   Заключение: Полученные результаты ставят вопрос о необходимости разработки принципов мониторинга ряда биохимических маркеров при шизофрении и их внедрения в клиническую практику.

   Introduction

   Introduction: Currently, there is a large amount of data that inflammatory and oxidative stress biomarkers, pterin metabolism disturbances and other biochemical abnormalities are more often present in schizophrenia compared to general population. They may also play the role of etiopathogenetic factors in schizophrenia mechanisms. At the same time, there are no studies with an assessment of a wide range of correctable biochemical abnormalities in one sample of patients. Moreover, screening algorithms for the detection and personalized correction of controlled biomarkers have not been introduced into clinical practice yet.

   The aim of this work was to evaluate the prevalence of significant etiopathogenetic biochemical disturbances in patients with schizophrenia in order to justify the need for biochemical screening and correction of the corresponding abnormalities.

   Materials and methods

   Materials and methods: in the blood serum of 125 patients with schizophrenia and 95 healthy volunteers the levels of folate and cobalamin (B12) (chemiluminescent immunoassay on microparticles), homocysteine (HC, enzymatic analysis), tetrahydrobiopterin (BH4, competitive enzyme immunoassay, ELISA), reduced glutathione (GSH, spectrophotometry with Ellman’s reagent), interleukin-6 (IL-6, ELISA based on a three-stage «sandwich version») and C-reactive protein (CRP, immunoturbodimetric method) were evaluated.

   Results

   Results: In patients with schizophrenia the level of all studied serum biochemical markers, except for B12, was significantly different compared to healthy volunteers. The deviations levels of the studied parameters from the reference values in patients were statistically significantly higher in the markers of pterin metabolism (VH4: p = 0.0000; folates: p = 0.0000; HC: p = 0.0094). 29.6 % of patients were carriers of 4 or more studied biochemical abnormalities, while among healthy volunteers this occured in 5.3 % of cases (Xi2 = 19.2; p < 0.001).

   Conclusion

   Conclusion: The results obtained raise the question for the need of monitoring principles for a number of biochemical markers in schizophrenia and their implementation in clinical practice.

шизофрениятетрагидробиоптеринфолатывосстановленный глутатионинтерлейкин-6С-реактивный белокschizophreniatetrahydrobiopterinfolateshomocysteinereduced glutathioneinterleukin-6C-reactive proteinИсследование выполнено при финансовой поддержке РФФИ в рамках научного проекта № 20-015-00301_АThe study was carried out with the financial support of the Russian Foundation for Basic Research within the framework of the scientific project No. 20-015-00301_AReferencesВартанян М. Е. О некоторых биологических нарушениях при шизофрении и их понимании на современном этапе исследований / М. Е. Вартанян // Вестник АМН СССР. – 1966. – 3: 11-27.Vartanyan M. E. On some biological disorders in schizophrenia and their understanding at the present stage of research. Vestnik AMN SSSR. 1966; 3: 11-27. (In Russ.).Друцкая М. С. Интерлейкин 6 — от молекулярных механизмов передачи сигнала к физиологическим функциям и терапевтическим мишеням / М. С. Друцкая [и др.] // Молекулярная биология. – 2015. – 49 (6): 937-943.Druckaya M. S., Nosenko M. A., Atrethany K. S. et al. Interlejkin 6 — ot molekulyarnyh mekhanizmov peredachi signala k fiziologicheskim funkciyam i terapevticheskim mishenyam. Molekulyarnaya biologiya. 2015; 49 (6): 937-943. (In Russ.). doi: 10.7868/S0026898415060063Лисицына Т. А. Интерлейкин 6 как патогенетический фактор, опосредующий формирование клинических проявлений, и мишень для терапии ревматических заболеваний и депрессивных расстройств / Т. А. Лисицына [и др.] // Научно-практическая ревматология. – 2019. – 57 (3): 318-327.Lisicyna T. A., Vel’tishchev D. Yu., Lila A. M., Nasonov E. L. Interleukin 6 as a pathogenic factor mediating the formation of clinical manifestations and a target for the treatment of rheumatic diseases and depressive disorders. Nauchno-prakticheskaya revmatologiya. 2019; 57 (3): 318-327. (In Russ.). URL: https://rsp.mediar-press.net/rsp/article/view/2733?locale=ru_RUПятойкина А. С. Двойное слепое рандомизированное плацебо-контролируемое исследование применения N-ацетилцистеина при шизофрении: предварительные результаты / А. С. Пятойкина [и др.] // Журнал неврологии и психиатрии им. C. C. Корсакова. – 2020. – 120 (9): 66-71.Pyatojkina A. S., Zhilyaeva T. V., Semennov I. V. et al. The Double-Blind Randomized Placebo-Controlled Trial Of N-Acetylcysteine Use In Schizophrenia: Preliminary Results. Zhurnal nevrologii i psihiatrii im. S. S. Korsakova. 2020; 120 (9): 66-71. (In Russ.). doi: 10.17116/jnevro202012009166Смирнова Л. П. Результаты поиска биомаркеров шизофрении / Л. П. Смирнова [и др.] // Сибирский вестник психиатрии и наркологии. – 2018. – 2 (99): 33–44.Smirnova L. P., Parshukova D. A., Ermakov E. A. et al. Results of a search for biomarkers of schizophrenia. Sibirskij vestnik psihiatrii i narkologii. 2018; 2 (99): 33–44. (In Russ.). doi: 10.26617/1810-3111-2018-2(99)-33-44.Afanas’ev I. ROS and RNS signaling in heart disorders: could antioxidant treatment be successful?. Oxid Med Cell Longev. 2011; 2011: 293769. doi: 10.1155/2011/293769Afanas’ev I. ROS and RNS signaling in heart disorders: could antioxidant treatment be successful?. Oxid Med Cell Longev. 2011; 2011: 293769. doi: 10.1155/2011/293769Barakauskas V. E. et al. Quantitative mass spectrometry reveals changes in SNAP-25 isoforms in schizophrenia. Schizophr Res. 2016; 177 (1-3): 44-51. doi: 10.1016/j.schres.2016.03.002Barakauskas V. E. et al. Quantitative mass spectrometry reveals changes in SNAP-25 isoforms in schizophrenia. Schizophr Res. 2016; 177 (1-3): 44-51. doi: 10.1016/j.schres.2016.03.002Bentsen H., Osnes K., Refsum H. et al. randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia. Transl Psychiatry. 2013; 3 (12): e335. doi: 10.1038/tp.2013.110Bentsen H., Osnes K., Refsum H. et al. randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia. Transl Psychiatry. 2013; 3 (12): e335. doi: 10.1038/tp.2013.110Berry T., Abohamza E., Moustafa A. A. Treatment-resistant schizophrenia: focus on the transsulfuration pathway. Rev Neurosci. 2020; 31 (2): 219-232. doi: 10.1515/revneuro-2019-0057Berry T., Abohamza E., Moustafa A. A. Treatment-resistant schizophrenia: focus on the transsulfuration pathway. Rev Neurosci. 2020; 31 (2): 219-232. doi: 10.1515/revneuro-2019-0057Borovcanin M. M., Jovanovic I., Radosavljevic G., et al. Interleukin-6 in Schizophrenia-Is There a Therapeutic Relevance? Front Psychiatry. 2017; 8: 221. doi: 10.3389/fpsyt.2017.00221Borovcanin M. M., Jovanovic I., Radosavljevic G., et al. Interleukin-6 in Schizophrenia-Is There a Therapeutic Relevance? Front Psychiatry. 2017; 8: 221. doi: 10.3389/fpsyt.2017.00221Brown H. E., Roffman J. L. Vitamin supplementation in the treatment of schizophrenia. CNS Drugs. 2014; 28 (7): 611-622. doi: 10.1007/s40263-014-0172-4Brown H. E., Roffman J. L. Vitamin supplementation in the treatment of schizophrenia. CNS Drugs. 2014; 28 (7): 611-622. doi: 10.1007/s40263-014-0172-4Cao B., Jin M., Brietzke E., et al. Serum metabolic profiling using small molecular water-soluble metabolites in individuals with schizophrenia: A longitudinal study using a pre-post-treatment design. Psychiatry Clin Neurosci. 2019; 73 (3): 100-108. doi: 10.1111/pcn.12779Cao B., Jin M., Brietzke E., et al. Serum metabolic profiling using small molecular water-soluble metabolites in individuals with schizophrenia: A longitudinal study using a pre-post-treatment design. Psychiatry Clin Neurosci. 2019; 73 (3): 100-108. doi: 10.1111/pcn.12779Cao L., Li L., Zuo Z. N-acetylcysteine reverses existing cognitive impairment and increased oxidative stress in glutamate transporter type 3 deficient mice. Neuroscience. 2012; 220: 85-89. doi: 10.1016/j.neuroscience.2012.06.044Cao L., Li L., Zuo Z. N-acetylcysteine reverses existing cognitive impairment and increased oxidative stress in glutamate transporter type 3 deficient mice. Neuroscience. 2012; 220: 85-89. doi: 10.1016/j.neuroscience.2012.06.044Chia S. C., Henry J., Mok Y. M. et al. Fatty acid and vitamin interventions in adults with schizophrenia: a systematic review of the current evidence. J Neural Transm (Vienna). 2015; 122 (12): 1721-1732. doi: 10.1007/s00702-015-1451-zChia S. C., Henry J., Mok Y. M. et al. Fatty acid and vitamin interventions in adults with schizophrenia: a systematic review of the current evidence. J Neural Transm (Vienna). 2015; 122 (12): 1721-1732. doi: 10.1007/s00702-015-1451-zD’Oria R., Schipani R., Leonardini A. et al. The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor. Oxid Med Cell Longev. 2020; 2020: 5732956. doi: 10.1155/2020/5732956D’Oria R., Schipani R., Leonardini A. et al. The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor. Oxid Med Cell Longev. 2020; 2020: 5732956. doi: 10.1155/2020/5732956Das U. N. Polyunsaturated fatty acids and their metabolites in the pathobiology of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 42: 122-134. doi: 10.1016/j.pnpbp.2012.06.010Das U. N. Polyunsaturated fatty acids and their metabolites in the pathobiology of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 42: 122-134. doi: 10.1016/j.pnpbp.2012.06.010Dean O. M., Mancuso S. G., Bush A. I., et al. Benefits of adjunctive N-acetylcysteine in a sub-group of clozapine-treated individuals diagnosed with schizophrenia. Psychiatry Res. 2015; 230 (3): 982-983. doi: 10.1016/j.psychres.2015.10.037Dean O. M., Mancuso S. G., Bush A. I., et al. Benefits of adjunctive N-acetylcysteine in a sub-group of clozapine-treated individuals diagnosed with schizophrenia. Psychiatry Res. 2015; 230 (3): 982-983. doi: 10.1016/j.psychres.2015.10.037Deepmala, Slattery J., Kumar N., et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 2015; 55: 294-321. doi: 10.1016/j.neubiorev.2015.04.015Deepmala, Slattery J., Kumar N., et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 2015; 55: 294-321. doi: 10.1016/j.neubiorev.2015.04.015Do K. Q., Trabesinger A. H., Kirsten-Krüger M. et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000; 12 (10): 3721–3728. doi: 10.1046/j.1460-9568.2000.00229.xDo K. Q., Trabesinger A. H., Kirsten-Krüger M. et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000; 12 (10): 3721–3728. doi: 10.1046/j.1460-9568.2000.00229.xFarokhnia M., Azarkolah A., Adinehfar F. et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol. 2013; 36 (6): 185-192. doi: 10.1097/WNF.0000000000000001Farokhnia M., Azarkolah A., Adinehfar F. et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol. 2013; 36 (6): 185-192. doi: 10.1097/WNF.0000000000000001Flatow J., Buckley P., Miller B. J.. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013; 74 (6): 400-409. doi: 10.1016/j.biopsych.2013.03.018Flatow J., Buckley P., Miller B. J.. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013; 74 (6): 400-409. doi: 10.1016/j.biopsych.2013.03.018Goff D. C., Bottiglieri T., Arning E. et al. Folate, homocysteine, and negative symptoms in schizophrenia. Am J Psychiatry. 2004; 161 (9): 1705-1708. doi:10.1176/appi.ajp.161.9.1705Goff D. C., Bottiglieri T., Arning E. et al. Folate, homocysteine, and negative symptoms in schizophrenia. Am J Psychiatry. 2004; 161 (9): 1705-1708. doi:10.1176/appi.ajp.161.9.1705Goldsmith D. R., Rapaport M. H., Miller B. J. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016; 21 (12): 1696-1709. doi: 10.1038/mp.2016.3Goldsmith D. R., Rapaport M. H., Miller B. J. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016; 21 (12): 1696-1709. doi: 10.1038/mp.2016.3Golimbet V., Korovaitseva G., Abramova L., Kaleda V. The 844ins68 polymorphism of the cystathionine beta-synthase gene is associated with schizophrenia. Psychiatry Res. 2009; 170 (2-3): 168-171. doi: 10.1016/j.psychres.2008.07.007Golimbet V., Korovaitseva G., Abramova L., Kaleda V. The 844ins68 polymorphism of the cystathionine beta-synthase gene is associated with schizophrenia. Psychiatry Res. 2009; 170 (2-3): 168-171. doi: 10.1016/j.psychres.2008.07.007González-Blanco L., García-Portilla M. P., García-Álvarez L. et al. Oxidative stress biomarkers and clinical dimensions in first 10 years of schizophrenia. Rev Psiquiatr Salud Ment. 2018; 11 (3): 130-140. doi: 10.1016/j.rpsm.2018.03.003González-Blanco L., García-Portilla M. P., García-Álvarez L. et al. Oxidative stress biomarkers and clinical dimensions in first 10 years of schizophrenia. Rev Psiquiatr Salud Ment. 2018; 11 (3): 130-140. doi: 10.1016/j.rpsm.2018.03.003Hill M., Shannahan K., Jasinski S. et al. Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophrenia research. 2011; 127 (1-3): 41–45. doi: 10.1016/j.schres.2010.12.006Hill M., Shannahan K., Jasinski S. et al. Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophrenia research. 2011; 127 (1-3): 41–45. doi: 10.1016/j.schres.2010.12.006Ho P. I., Ashline D., Dhitavat S. et al. Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine. Neurobiol Dis. 2003; 14 (1): 32-42. doi: 10.1016/s0969-9961(03)00070-6Ho P. I., Ashline D., Dhitavat S. et al. Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine. Neurobiol Dis. 2003; 14 (1): 32-42. doi: 10.1016/s0969-9961(03)00070-6Leeming R. J. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990; 336 (8720): 953–954. doi: 10.1016/0140-6736(90)92332-cLeeming R. J. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990; 336 (8720): 953–954. doi: 10.1016/0140-6736(90)92332-cLevine J., Stahl Z., Sela B. A. et al. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biological psychiatry. 2006; 60 (3): 265–269. doi: 10.1016/j.biopsych.2005.10.009Levine J., Stahl Z., Sela B. A. et al. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biological psychiatry. 2006; 60 (3): 265–269. doi: 10.1016/j.biopsych.2005.10.009Li M., Fan Y. L., Tang Z. Y., Cheng X. S. Schizophrenia and risk of stroke: a meta-analysis of cohort studies. Int J Cardiol. 2014; 173 (3): 588–590. doi: 10.1016/j.ijcard.2014.03.101Li M., Fan Y. L., Tang Z. Y., Cheng X. S. Schizophrenia and risk of stroke: a meta-analysis of cohort studies. Int J Cardiol. 2014; 173 (3): 588–590. doi: 10.1016/j.ijcard.2014.03.101Li Y., Huang T., Zheng Y. et al. Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc. 2016; 5 (8): e003768. doi: 10.1161/JAHA.116.003768Li Y., Huang T., Zheng Y. et al. Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc. 2016; 5 (8): e003768. doi: 10.1161/JAHA.116.003768Liu M. L., Zheng P., Liu Z., et al. GC-MS based metabolomics identification of possible novel biomarkers for schizophrenia in peripheral blood mononuclear cells. Mol Biosyst. 2014; 10 (9): 2398-2406. doi: 10.1039/c4mb00157eLiu M. L., Zheng P., Liu Z., et al. GC-MS based metabolomics identification of possible novel biomarkers for schizophrenia in peripheral blood mononuclear cells. Mol Biosyst. 2014; 10 (9): 2398-2406. doi: 10.1039/c4mb00157eMcBean G. J. The transsulfuration pathway: a source of cysteine for glutathione in astrocytes. Amino Acids. 2012; 42 (1): 199-205. doi: 10.1007/s00726-011-0864-8McBean G. J. The transsulfuration pathway: a source of cysteine for glutathione in astrocytes. Amino Acids. 2012; 42 (1): 199-205. doi: 10.1007/s00726-011-0864-8Miller B. J., Buckley P., Seabolt W. et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011; 70 (7): 663–71. doi: 10.1016/j.biopsych.2011.04.013Miller B. J., Buckley P., Seabolt W. et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011; 70 (7): 663–71. doi: 10.1016/j.biopsych.2011.04.013Miller B. J., Culpepper N., Rapaport M. H. C-reactive protein levels in schizophrenia: a review and meta-analysis. Clin Schizophr Relat Psychoses. 2014; 7 (4): 223-230. doi: 10.3371/CSRP.MICU.020813Miller B. J., Culpepper N., Rapaport M. H. C-reactive protein levels in schizophrenia: a review and meta-analysis. Clin Schizophr Relat Psychoses. 2014; 7 (4): 223-230. doi: 10.3371/CSRP.MICU.020813Morellato A. E., Umansky C., Pontel L. B. The toxic side of one-carbon metabolism and epigenetics. Redox Biol. 2021; 40: 101850. doi: 10.1016/j.redox.2020.101850Morellato A. E., Umansky C., Pontel L. B. The toxic side of one-carbon metabolism and epigenetics. Redox Biol. 2021; 40: 101850. doi: 10.1016/j.redox.2020.101850Nishi A., Numata S., Tajima A. et al. Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia. Schizophr Bull. 2014; 40 (5): 1154-1163. doi: 10.1093/schbul/sbt154Nishi A., Numata S., Tajima A. et al. Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia. Schizophr Bull. 2014; 40 (5): 1154-1163. doi: 10.1093/schbul/sbt154Nucifora L. G., Tanaka T., Hayes L. N. et al. Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry. Transl Psychiatry. 2017; 7 (8): e1215. doi: 10.1038/tp.2017.178Nucifora L. G., Tanaka T., Hayes L. N. et al. Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry. Transl Psychiatry. 2017; 7 (8): e1215. doi: 10.1038/tp.2017.178Numata S., Kinoshita M., Tajima A. et al. Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis. BMC Med Genet. 2015; 16: 54. doi: 10.1186/s12881-015-0197-7Numata S., Kinoshita M., Tajima A. et al. Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis. BMC Med Genet. 2015; 16: 54. doi: 10.1186/s12881-015-0197-7Pawełczyk T., Grancow-Grabka M., Kotlicka-Antczak M. et al. A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. J Psychiatr Res. 2016; 73: 34-44. doi: 10.1016/j.jpsychires.2015.11.013Pawełczyk T., Grancow-Grabka M., Kotlicka-Antczak M. et al. A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. J Psychiatr Res. 2016; 73: 34-44. doi: 10.1016/j.jpsychires.2015.11.013Postolache T. T., Del Bosque-Plata L., Jabbour S. et al. Co-shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome. Am J Med Genet B Neuropsychiatr Genet. 2019; 180 (3): 186–203. doi: 10.1002/ajmg.b.32712Postolache T. T., Del Bosque-Plata L., Jabbour S. et al. Co-shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome. Am J Med Genet B Neuropsychiatr Genet. 2019; 180 (3): 186–203. doi: 10.1002/ajmg.b.32712Richardson M. A., Read L. L., Reilly M. A. et al. Analysis of plasma biopterin levels in psychiatric disorders suggests a common BH4 deficit in schizophrenia and schizoaffective disorder. Neurochem Res. 2007; 32 (1): 107-113. doi: 10.1007/s11064-006-9233-5Richardson M. A., Read L. L., Reilly M. A. et al. Analysis of plasma biopterin levels in psychiatric disorders suggests a common BH4 deficit in schizophrenia and schizoaffective disorder. Neurochem Res. 2007; 32 (1): 107-113. doi: 10.1007/s11064-006-9233-5Roffman J. L., Lamberti J. S., Achtyes E., et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. 2013; 70 (5): 481-489. doi: 10.1001/jamapsychiatry.2013.900Roffman J. L., Lamberti J. S., Achtyes E., et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. 2013; 70 (5): 481-489. doi: 10.1001/jamapsychiatry.2013.900Roffman J. L., Petruzzi L. J., Tanner A. S. et al. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial. Mol Psychiatry. 2018; 23 (2): 316-322. doi: 10.1038/mp.2017.41Roffman J. L., Petruzzi L. J., Tanner A. S. et al. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial. Mol Psychiatry. 2018; 23 (2): 316-322. doi: 10.1038/mp.2017.41Rossell S. L., Francis P. S., Galletly C. et al. N-acetyl-cysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms. BMC Psychiatry. 2016; 16 (1): 320. doi: 10.1186/s12888-016-1030-3Rossell S. L., Francis P. S., Galletly C. et al. N-acetyl-cysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms. BMC Psychiatry. 2016; 16 (1): 320. doi: 10.1186/s12888-016-1030-3Trayhurn P., Wood I. S. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004; 92 (3): 347-355. doi: 10.1079/bjn20041213Trayhurn P., Wood I. S. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004; 92 (3): 347-355. doi: 10.1079/bjn20041213Wang D., Zhai J. X., Liu D. W. Serum folate levels in schizophrenia: A meta-analysis. Psychiatry Res. 2016; 235: 83-89. doi: 10.1016/j.psychres.2015.11.045Wang D., Zhai J. X., Liu D. W. Serum folate levels in schizophrenia: A meta-analysis. Psychiatry Res. 2016; 235: 83-89. doi: 10.1016/j.psychres.2015.11.045Zhang P., Li T., Wu X. et al. Oxidative stress and diabetes: antioxidative strategies. Front Med. 2020; 14 (5): 583-600. doi: 10.1007/s11684-019-0729-1Zhang P., Li T., Wu X. et al. Oxidative stress and diabetes: antioxidative strategies. Front Med. 2020; 14 (5): 583-600. doi: 10.1007/s11684-019-0729-1Zhang Y., Hodgson N. W., Trivedi M. S. et al. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLoS One. 2016; 11 (1): e0146797. doi: 10.1371/journal.pone.0146797Zhang Y., Hodgson N. W., Trivedi M. S. et al. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLoS One. 2016; 11 (1): e0146797. doi: 10.1371/journal.pone.0146797Zheng W., Cai D. B., Yang X. H. et al. Adjunctive celecoxib for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials. J Psychiatr Res. 2017; 92: 139-146. doi: 10.1016/j.jpsychires.2017.04.004Zheng W., Cai D. B., Yang X. H. et al. Adjunctive celecoxib for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials. J Psychiatr Res. 2017; 92: 139-146. doi: 10.1016/j.jpsychires.2017.04.004Zhou X., Tian B., Han H. B. Serum interleukin-6 in schizophrenia: A system review and meta-analysis. Cytokine. 2021; 141: 155441. doi: 10.1016/j.cyto.2021.155441Zhou X., Tian B., Han H. B. Serum interleukin-6 in schizophrenia: A system review and meta-analysis. Cytokine. 2021; 141: 155441. doi: 10.1016/j.cyto.2021.155441

The authors declare that there are no conflicts of interest present.