Український вісник ПСИХОНЕВРОЛОГІЇ

Науково-практичний медичний журнал
ISSN 2079-0325
DOI 10.36927/2079-0325

КЛІНІКО-ПАТОГЕНЕТИЧНА ФЕНОТИПІЗАЦІЯ ТРИВОЖНО-ДЕПРЕСИВНИХ РОЗЛАДІВ ПРИ ВОЄННОМУ ДИСТРЕСІ ЯК ОСНОВА ПЕРСОНАЛІЗОВАНОЇ ПСИХІАТРІЇ: ТЕОРЕТИЧНЕ ОБҐРУНТУВАННЯ ТА ТЕРАПЕВТИЧНІ ПЕРСПЕКТИВИ

Індекс УДК:

Анотація

Повномасштабна збройна агресія російської федерації проти України зумовила масштабну кризу психічного здоров’я населення. За прогнозами ВООЗ, близько 9,6 мільйонів українців можуть страждати на  психічні розлади, серед яких провідне місце посідають тривожно-депресивні розлади (ТДР). Патогенетична гетерогенність ТДР зумовлює недостатню ефективність уніфікованої фармакотерапії та потребу переходу до персоналізованої психіатрії. Метою огляду є теоретичне обґрунтування моделі клініко-патогенетичних фенотипів ТДР при  воєнному дистресі та  визначення терапевтичних перспектив фенотип-орієнтованого підходу. На  підставі аналізу сучасних наукових даних описано п’ять патогенетичних фенотипів, зокрема нейрозапальний, окислювально-метиляційний, нейротрофічно-дисрегуляторний, стрес-дисрегуляторний та нейромедіаторно-дисрегуляторний. Для кожного фенотипу охарактеризовано провідні нейробіологічні механізми, специфічні біомаркери та диференційовані терапевтичні підходи. Обґрунтовано переваги фенотипорієнтованого підходу, а  саме підвищення частоти терапевтичної відповіді, скорочення часу до  ремісії, об’єктивний моніторинг ефективності лікування, стратифікація ризику несприятливого перебігу та  фармакогеномне прогнозування. Запропонована модель клініко-патогенетичних фенотипів ТДР при  воєнному дистресі створює наукову основу для впровадження персоналізованої психіатричної допомоги постраждалому населенню України.

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  1. Charlson F, van Ommeren M, Flaxman A, Cornett J, Whiteford H, Saxena S. New WHO prevalence estimates of mental disorders in conflict settings: a systematic review and metaanalysis. Lancet. 2019;394(10194):240-248. doi:10.1016/S0140- 6736(19)30934-1
  2. World Health Organization. Scaling-up mental health and psychosocial services in war-affected regions: best practices from Ukraine. Geneva : WHO, 2022. URL: https://www.who.int/news-room/feature-stories/detail/scaling-up-mental-health-andpsychosocial-services-in-war-affected-regions–best-practicesfrom-ukraine
  3. Yasenok V, Neumann E, Raineri A, Kopp J, Rüegger S, Ballouz T, Kaufmann M, Loboda A, Smiianov V, Baumer AM, Seifritz E, Königstein HF, Frei A, Von Wyl V, Kriemler S, Kostenko A and Puhan MA. Mental Health Assessment of the Population: Study Protocol of the MAP Research Program in Ukraine (MAP U) and in Zurich (MAP-Z). International Journal of Public Health. 2025;69:1607271. doi:10.3389/ijph.2024.1607271
  4. Baker LD, Ponder WN, Carbajal J, Norton R, Price M, Cassiello-Robbins C, Roberge EM. Network analysis of PTSD, depression, and anxiety symptom co-occurrence among U.S. veterans seeking treatment. European Journal of Trauma & Dissociation. 2024. Vol. 8, No. 4. Article 100447. doi:10.1016/j.ejtd.2024.100447
  5. Lei AA, Phang VWX, Lee YZ, Kow ASF, Tham CL, Ho Y-C, Lee MT. Chronic Stress-Associated Depressive Disorders: The Impact of HPA Axis Dysregulation and Neuroinflammation on the Hippocampus—A Mini Review. International Journal of Molecular Sciences. 2025; 26(7):2940. doi:10.3390/ijms26072940
  6. Krasner H, Ong CV, Hewitt P, Vida TA. From Stress to Synapse: The Neuronal Atrophy Pathway to Mood Dysregulation. International Journal of Molecular Sciences. 2025;26(7):3219. doi:10.3390/ijms26073219
  7. Jensen KHR, Dam VH, Ganz M, et al. Deep phenotyping towards precision psychiatry of first-episode depression – the Brain Drugs-Depression cohort. BMC Psychiatry. 2023;23(1):151. Published 2023 Mar 9. doi:10.1186/s12888-023-04618-x
  8. Schork N. Personalized medicine: Time for one-person trials. Nature. 2015;520:609-611. doi:10.1038/520609a
  9. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. doi:10.1176/ajp.2006.163.11.1905
  10. Belanger HG, Lee C, Poliacoff Z, Gupta CT, Winsberg M. Early Response to Antidepressant Medications in Adults With Major Depressive Disorder: A Naturalistic Study and Odds of Remission at 14 Weeks. J Clin Psychopharmacol. 2023;43(1):46-54. doi:10.1097/JCP.0000000000001638
  11. Turner M. Neurobiological and psychological factors to depression. Int J Psychiatry Clin Pract. 2024;28(2):114-127. doi:10.1080/13651501.2024.2382091
  12. Clementz BA, Sweeney JA, Hamm JP, et al. Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers. Am J Psychiatry. 2016;173(4):373-384. doi:10.1176/appi.ajp.2015.14091200
  13. Kas MJH, Penninx BWJH, Knudsen GM, et al. Precision psychiatry roadmap: towards a biology-informed framework for mental disorders. Mol Psychiatry. 2025;30(8):3846-3855. doi:10.1038/s41380-025-03070-5
  14. Stolfi F, Abreu H, Sinella R, et al. Omics approaches open new horizons in major depressive disorder: from biomarkers to precision medicine. Front Psychiatry. 2024;15:1422939. Published 2024 Jun 13. doi:10.3389/fpsyt.2024.1422939
  15. Sălcudean A, Bodo CR, Popovici RA, et al. Neuroinflammation—A Crucial Factor in the Pathophysiology of Depression—A Comprehensive Review. Biomolecules. 2025;15(4):502. Published 2025 Mar 30. doi:10.3390/biom15040502
  16. Correia AS, Vale N. Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways. Int J Mol Sci. 2022;23(15):8493. Published 2022 Jul 31. doi:10.3390/ijms23158493
  17. Chen C-H, Wu N-L, Tsai T-F. How Cells Die in Psoriasis? International Journal of Molecular Sciences. 2025; 26(8):3747. doi:10.3390/ijms26083747
  18. Dudek KA, Dion-Albert L, Kaufmann FN, Tuck E, Lebel M, Menard C. Neurobiology of resilience in depression: immune and vascular insights from human and animal studies. Eur J Neurosci. 2021;53(1):183-221. doi:10.1111/ejn.14547
  19. Li Y, Zhang H, Kosturakis AK, et al. MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy. Brain Behav Immun. 2015;49:255-266. doi:10.1016/j.bbi.2015.06.00
  20. Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry. 2014;71(10):1121-1128. doi:10.1001/jamapsychiatry.2014.1332
  21. Jha MK, Minhajuddin A, Gadad BS, et al. Can C reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology. 2017. 2017;78:105-113. doi:10.1016/j.psyneuen.2017.01.023
  22. Savitz J. The kynurenine pathway: a finger in every pie Mol Psychiatry. 2020;25(1):131-147. doi:10.1038/s41380-019-0414-4
  23. Mikhalitskaya EV, Vyalova NM, Ermakov EA, et al. Association of single nucleotide polymorphisms of cytokine genes with depression, schizophrenia and bipolar disorder. Genes (Basel). 2023;14(7):1460. Published 2023 Jul 17. doi: 10.3390/genes14071460. PMID: 37510364
  24. Wang X, Zhang H, Cao X, et al. Gene-disease association study of tumor necrosis factor-α G-308A gene polymorphism with risk of major depressive disorder: a systematic review and meta-analysis. Brain Behav. 2020;10(6):e01628. doi:10.1002/brb3.1628
  25. Chen Y, Shen YQ. Role of reactive oxygen species in regulating epigenetic modifications. Cell Signal. 2025;125:111502. doi:10.1016/j.cellsig.2024.111502
  26. Yuan M, Yang B, Rothschild G, et al. Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential. Signal Transduct Target Ther. 2023;8(1):309. Published 2023 Aug 30. doi:10.1038/s41392-023-01519-z
  27. Vaváková M, Ďuračková Z, Trebatická J. Markers of Oxidative Stress and Neuroprogression in Depression Disorder. Oxid Med Cell Longev. 2015;2015:898393. doi:10.1155/2015/898393
  28. Cui L, Lu J, Shen Z, et al. Oxidative stress markers predict treatment outcomes in patients with generalized anxiety disorder treated with selective serotonin reuptake inhibitors. medRxiv. 2024. doi:10.1101/2024.09.07.24313247
  29. Hemmings SMJ, Malan-Müller S, van den Heuvel LL, et al. The Microbiome in Posttraumatic Stress Disorder and Trauma-Exposed Controls: An Exploratory Study. Psychosom Med. 2017;79(8):936-946. doi:10.1097/PSY.0000000000000512
  30. Dee G, Ryznar R, Dee C. Epigenetic Changes Associated with Different Types of Stressors and Suicide. Cells. 2023;12(9):1258. doi:10.3390/cells12091258
  31. Wang L, Lv B, Ma Z. Multilayered regulation of BDNF DNA methylation in PTSD: a review from molecular mechanisms to transgenerational inheritance. Front Psychiatry. 2026;17:1734160. Published 2026 Jan 22. doi: 10.3389/fpsyt.2026.1734160
  32. Yang R, Xu C, Bierer LM, et al. Longitudinal genomewide methylation study of PTSD treatment using prolonged exposure and hydrocortisone. Transl Psychiatry. 2021;11(1):398. Published 2021 Jul 13. doi:10.1038/s41398-021-01513-5
  33. Wan L, Li Y, Zhang Z, Sun Z, He Y, Li R. Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry. 2018;8(1):242. Published 2018 Nov 5. doi:https://doi.org/10.1038/s41398-018-0276-6
  34. Zhang YX, Yang LP, Gai C, et al. Association between variants of MTHFR genes and psychiatric disorders: A metaanalysis. Front Psychiatry. 2022;13:976428. Published 2022 Aug 18. doi:10.3389/fpsyt.2022.976428
  35. Mech AW, Farah A. Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2016;77(5):668-671. doi:10.4088/JCP.15m10166
  36. Yuan B, Sun X, Xu Z, Pu M, Yuan Y, Zhang Z. Influence of genetic polymorphisms in homocysteine and lipid metabolism systems on antidepressant drug response. BMC Psychiatry. 2020;20(1):408. doi:10.1186/s12888-020-02798-4
  37. Lima Giacobbo B, Doorduin J, Klein HC, Dierckx RAJO, Bromberg E, de Vries EFJ. Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation. Mol Neurobiol. 2019;56(5):3295-3312. doi:10.1007/s12035-018-1283-6
  38. Schmaal L, Hibar DP, Sämann PG, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 international cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22(6):900-909. doi:10.1038/mp.2016.60
  39. Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-Scale Network Dysfunction in Major Depressive Disorder: A Meta-analysis of Resting-State Functional Connectivity. JAMA Psychiatry. 2015;72(6):603-611. doi:10.1001/jamapsychiatry.2015.0071
  40. Li Y, Ma J, Zhang WX, Cao YL, Lei C. Serum Brain-derived Neurotrophic Factor Levels as a Biomarker of Treatment Response in Patients With Depression: Systematic Review and Metaanalysis. Actas Esp Psiquiatr. 2025;53(4):857-867. doi:10.62641/aep.v53i4.1967
  41. McEwen, B., Nasca, C. & Gray, J. Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex. Neuropsychopharmacology. 2016;41(1):3-23. doi:10.1038/npp.2015.171
  42. Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N = 9484). Mol Psychiatry. 2014;19(7):791-800. doi:10.1038/mp.2013.105
  43. Segi-Nishida E. The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors. Front Cell Neurosci. 2017;11:142. Published 2017 May 16. doi:10.3389/fncel.2017.00142
  44. Wang Y, Li O, Li N, Sha Z, Zhao Z, Xu J. Association between the BDNF Val66Met polymorphism and major depressive disorder: a systematic review and meta-analysis. Front Psychiatry. 2023;14:1143833. Published 2023 Jun 21. doi:10.3389/fpsyt.2023.1143833
  45. Kishi T, Yoshimura R, Ikuta T, Iwata N. Brain-Derived Neurotrophic Factor and Major Depressive Disorder: Evidence from Meta-Analyses. Front Psychiatry. 2018;8:308. Published 2018 Jan 17. doi:10.3389/fpsyt.2017.00308
  46. Lei AA, Phang VWX, Lee YZ, et al. Chronic Stress-Associated Depressive Disorders: The Impact of HPA Axis Dysregulation and Neuroinflammation on the Hippocampus — A Mini Review. Int J Mol Sci. 2025;26(7):2940. Published 2025 Mar 24. doi:10.3390/ijms26072940
  47. Azevedo PL, Rezende M, Felix M, Corrêa S, Abdelhay E, Binato R. SAA1 Protein: A Potential Biomarker for Acute Myeloid Leukemia. Biomedicines. 2025; 13(4):880. doi:10.3390/biomedicines13040880
  48. Arancibia M, Manterola M, Ríos U, Moya PR, MoranKneer J, Bustamante ML. The rs1360780 Variant of FKBP5: Genetic Variation, Epigenetic Regulation, and Behavioral Phenotypes. Genes (Basel). 2025;16(3):325. Published 2025 Mar 11. doi:10.3390/genes16030325
  49. Fani N, King TZ, Shin J, et al. Structural and Functional Connectivity in Posttraumatic Stress Disorder: Associations with FKBP5. Depress Anxiety. 2016;33(4):300-307. doi:10.1002/da.22483
  50. Sippel LM, Han S, Watkins LE, et al. Oxytocin Receptor Gene Polymorphisms, Attachment, and PTSD: Results from the National Health and Resilience in Veterans Study. J Psychiatr Res. 2017;94:139-147. doi:10.1016/j.jpsychires.2017.07.008
  51. Carmassi C, Marazziti D, Mucci F, et al. Decreased Plasma Oxytocin Levels in Patients With PTSD. Front Psychol. 2021;12:612338. Published 2021 Jul 1. doi:10.3389/fpsyg.2021.612338
  52. Zhao T, Liu T, Wang L, Xie K, Tang H, Tang M. Dysfunction of neurotransmitter metabolism is associated with the severity of depression in first-diagnosed, drug-naïve depressed patients. J Affect Disord. 2024;349:332-341. doi:10.1016/j.jad.2024.01.023
  53. Opmeer EM, Kortekaas R, van Tol MJ, et al. Influence of COMT val158met genotype on the depressed brain during emotional processing and working memory. PLoS One. 2013;8(9):e73290. Published 2013 Sep 12. doi:10.1371/journal.pone.0073290
  54. Baune BT, Hohoff C, Berger K, et al. Association of the COMT val158met variant with antidepressant treatment response in major depression. Neuropsychopharmacology. 2008;33(4):924- 932. doi:10.1038/sj.npp.1301462
  55. Hanna S, Faiz M, Ahmed S, et al. The interplay between SLC6A4 and HTR1A genetic variants that may lead to antidepressant failure. Pharmacogenomics J. 2025;25(3):13. Published 2025 May 7. doi:10.1038/s41397-025-00370-5
  56. Stein K, Maruf AA, Müller DJ, Bishop JR, Bousman CA. Serotonin Transporter Genetic Variation and Antidepressant Response and Tolerability: A Systematic Review and MetaAnalysis. J Pers Med. 2021;11(12):1334. Published 2021 Dec 9. doi:10.3390/jpm11121334
  57. Lin J, Liu W, Guan J, et al. Latest updates on  the serotonergic system in depression and anxiety. Front Synaptic Neurosci. 2023;15:1124112. Published 2023 May 9. doi:10.3389/fnsyn.2023.1124112
  58. Zhu W, Bu Y, Wu L, Li J, Song C, Hao Y. Association between 5-HT1A receptor C-1019G, 5-HTTLPR polymorphisms and panic disorder: a meta-analysis. Aging (Albany NY). 2024;16(17):12293- 12311. doi:10.18632/aging.206087
  59. Yuan H, Qing L, Zou T, Cheng T, Zhou C, Guo X, Li Y, Hu L, Nie S, Liu L. A review of the relationship between the SLC6A4 gene and mental disorders. J Transl Genet Genom. 2025;9:286-303. doi:10.20517/jtgg.2025.52
  60. Cutler AJ, Mattingly GW, Maletic V. Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder. Transl Psychiatry. 2023;13(1):228. Published 2023 Jun 26. doi:10.1038/s41398-023-02514-2
  61. Epperson CN, Rubinow DR, Meltzer-Brody S, et al. Effect of brexanolone on depressive symptoms, anxiety, and insomnia in women with postpartum depression: Pooled analyses from 3 double-blind, randomized, placebo-controlled clinical trials in the HUMMINGBIRD clinical program. J Affect Disord. 2023;320:353-359. doi:10.1016/j.jad.2022.09.143
  62. Qiao J, Tao S, Sun Y, et al. The  Effects of Variation in the GABAA Receptor Gene on Anxious Depression are Mediated by the Functional Connectivity Between the Amygdala and Middle Frontal Gyrus. Neuropsychiatr Dis Treat. 2024;20:1781- 1796. Published 2024 Sep 24. doi:10.2147/NDT.S468290