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No. 2 (2025)

GENERAL THERAPY QUESTIONS AND REVIEWS

Current Understanding of the Pathogenesis and Treatment of Generalized Anxiety Disorder

https://doi.org/10.48612/psyph/1xte-3z82-eek1

Published 2025-06-30

  • V.I. Frolova
    • ,
  • D.K. Egiazaryan

V.I. Frolova
Peoples’ Friendship University of Russia (RUDN University)

D.K. Egiazaryan
Peoples’ Friendship University of Russia (RUDN University)

Abstract

Background. Given the high prevalence of generalized anxiety disorder (GAD), as well as the limited efficacy and high incidence of adverse events associated with currently recommended treatments affecting serotonergic and noradrenergic neurotransmission, it is reasonable to assume that other pathophysiological mechanisms are involved in the pathogenesis of GAD. However, the understanding of these mechanisms remains incomplete. This article presents current data on the pathogenic factors of GAD that may help explain the mechanism of action of agomelatine.

Methods. A search and analysis of publications from PubMed and eLIBRARY databases for the period 2019–2025 was conducted using the keywords: generalized anxiety disorder, pathogenesis, pharmacogenetics, gene polymorphism, therapy, agomelatine.

Results. Genetic studies aim to identify neurobiological risk markers for GAD and to predict treatment efficacy and safety in order to develop preventive and individualized therapeutic approaches. These studies have explored both genomic association patterns in GAD and specific genes influencing the severity and duration of anxiety symptoms.

Findings from neuroimaging studies remain inconclusive. They may indicate either a lack of significant morphological brain changes in GAD or limitations in current methods focused on simple linear associations, highlighting the need for more comprehensive analytical approaches.

Immunological research suggests that pro-inflammatory cytokines could serve as potential biomarkers for diagnosing GAD and predicting response to psychopharmacotherapy. The anxiolytic effect of agomelatine may be explained by its anti-inflammatory, immunomodulatory, and anti-cytokine properties.

Data from randomized clinical trials and meta-analyses demonstrate that agomelatine effectively reduces anxiety symptoms in GAD. It shows superiority over placebo in terms of remission rates and comparable tolerability. Additionally, agomelatine is associated with a high remission rate and low discontinuation rate.

Conclusion. Agomelatine can be considered a first-line treatment option for generalized anxiety disorder.

Keywords

generalised anxiety disorder, pathogenesis, pharmacogenetics, gene polymorphism, therapy, agomelatine

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References

  1. World Health Organisation. Depression and Other Common Mental Disorders: Global Health Estimates. – Geneva: WHO, 2017.
  2. Steel Z., Marnane C., Iranpour C. et al. The global prevalence of common mental disorders: a systematic review and meta-analysis 1980–2013 // Int J Epidemiol. – 2014. – Vol. 43(2). – P. 476–493.
  3. Remes O., Brayne C., van der Linde R., Lafortune L. A systematic review of reviews on the prevalence of anxiety disorders in adult populations // Brain Behav. – 2016. – Vol. 6(7):e00497. – doi: 10.1002/brb3.497
  4. . Mohammadi M.R., Pourdehghan P., Mostafavi S.A. et al. Generalized anxiety disorder: Prevalence, predictors, and comorbidity in children and adolescents // J Anxiety Disord. – 2020. – Vol. 73. – 102234. – doi: 10.1016/j.janxdis.2020.102234.
  5. Weisberg R. Overview of generalized anxiety disorder: Epidemiology, presentation, and course // J Clin Psychiatry. – 2009. – Vol. 70(Suppl 2). – P. 4–9.
  6. Ruscio A.M., Hallion L.S., Lim C.C.W. et al. Cross-sectional comparison of the epidemiology of DSM-5 generalized anxiety disorder across the globe // JAMA Psychiatry. – 2017. – Vol. 74(5). – P. 465–475. – doi: 10.1001/jamapsychiatry.2017.0056.
  7. Fagan H.A., Baldwin D.S. Pharmacological treatment of generalized anxiety disorder: current practice and future directions // Expert Rev Neurother. – 2023. – Vol. 23(6). – P. 535–548. – doi: 10.1080/14737175.2023.2211767.
  8. Strawn J.R., Geracioti L., Rajdev N. et al. Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: an evidence-based treatment review // Expert OpinPharmacother. – 2018. – Vol. 19(10). – P. 1057–1070. – doi: 10.1080/14656566.2018.1491966.
  9. Wittchen H.U., Jacobi F. Size and burden of mental disorders in Europe—a critical review and appraisal of 27 studies // EurNeuropsychopharmacol. – 2005. – Vol. 15(4). – P. 357–376.
  10. Незнанов Н.Г., Мартынихин И.А., Мосолов С.Н. Диагностика и терапия тревожных расстройств в Российской Федерации: результаты опроса врачей-психиатров // Современная терапия психических расстройств. – 2017. – № 2. – С. 2–15.
  11. Демчева Н.К., Яздовская А.В., Сидорюк О.В. и др. Эпидемиологические показатели и показатели деятельности психиатрических служб в Российской Федерации (2005–2013 гг.): статистический справочник. – М.: ФГБУ «ФМИЦПН им. В.П. Сербского» Минздрава России, 2015. – 572 с.
  12. Li X.J., He Y.L., Ma H. et al. Prevalence of depressive and anxiety disorders in Chinese gastroenterological outpatients // World J Gastroenterol. – 2012. – Vol. 18(20). – P. 2561–2568. – doi: 10.3748/wjg.v18.i20.2561.
  13. Fava G.A., Porcelli P., Rafanelli C. et al. The spectrum of anxiety disorders in the medically ill // J Clin Psychiatry. – 2010. – Vol. 71(7). – P. 910–914. – doi: 10.4088/JCP.10m06000blu.
  14. JyothiKantipudi S., Kannan G.K., Viswanathan S. et al. Antenatal Depression and Generalized Anxiety Disorder in a Tertiary Hospital in South India // Indian J Psychol Med. – 2020. – Vol. 42(6). – P. 513–518. – doi: 10.1177/0253717620928440.
  15. Sideeq K., Ayub T., Nazir U. Prevalence of Generalized Anxiety Disorder among the Patients Attending a Peripheral Health Center in Kashmir Valley // J Med Sci Clin Res. – 2017. – Vol. 5. – P. 26478–26481.
  16. Revicki D.A., Travers K., Wyrwich K.W. et al. Humanistic and economic burden of generalized anxiety disorder in North America and Europe // J Affect Disord. – 2012. – Vol. 140(2). – P. 103–112. – doi: 10.1016/j.jad.2011.11.014.
  17. Bentley K.H., Franklin J.C., Ribeiro J.D. et al. Anxiety and its disorders as risk factors for suicidal thoughts and behaviors: a meta-analytic review // Clin Psychol Rev. – 2016. – Vol. 43. – P. 30–46. – doi: 10.1016/j.cpr.2015.11.008.
  18. Norton P.J., Temple S.R., Pettit J.W. Suicidal ideation and anxiety disorders: elevated risk or artifact of comorbid depression? // J BehavTherExp Psychiatry. – 2008. – Vol. 39(4). – P. 515–525. – doi: 10.1016/j.jbtep.2007.10.010.
  19. Медведев В.Э. Агомелатин в терапии генерализованного тревожного расстройства // Современная терапия психических расстройств. – 2024. – № 4. – С. 55–65. – doi: 10.21265/PSYPH.2024.47.73.006.
  20. Костюкова Е.Г. Генерализованное тревожное расстройство: основы диагностики, терапии и специфические для России проблемы // Современная терапия психических расстройств. – 2024. – № 2. – С. 23–31. – doi: 10.21265/PSYPH.2024.31.31.003.
  21. Мосолов С.Н., Алфимов П.В. Алгоритм биологической терапии генерализованного тревожного расстройства // Современная терапия психических расстройств. – 2015. – № 2. – С. 24–28.
  22. Генерализованное тревожное расстройство // Клинические рекомендации. 2021–2023. – URL: https://cr.minzdrav.gov.ru/recomend/457_2 (дата обращения 12.03.2024).
  23. BaldwinD.S., AndersonI.M., NuttD.J. etal. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British association for psychopharmacology // J Psychopharmacol. – 2014. – Vol. 28(5). – P. 403–439. – doi: 10.1177/0269881114525674.
  24. Mamun-Or-RashidA., Roknuzzaman A.S.M., Sarker R. et al. Altered serum interleukin-17A and interleukin-23A levels may be associated with the pathophysiology and development of generalized anxiety disorder // Sci Rep. – 2024. – Vol. 14(1):15097. – doi: 10.1038/s41598-024-66131-9.
  25. Ansara ED. Management of treatment-resistant generalized anxiety disorder. MentHealthClin. 2020;5(6):326–34. doi: 10.9740/mhc.2020.11.326.
  26. Салахова А.И., Ягубов М.И. Сексуальная дисфункция при применении антидепрессантов у пациентов с тревожными и депрессивными расстройствами (алгоритм ведения и коррекции) // Современная терапия психических расстройств. — 2024. — No 2. — С. 56–67. — DOI: 10.21265/PSYPH.2024.31.31.006
  27. Zheyu Zhang A Comprehensive Overview on the Generalized Anxiety Disorder – Etiology and Treatment SHS Web of Conferences 193, 03008 (2024) https://doi.org/10.1051/shsconf/202419303008
  28. Levey D.F., Gelernter J., Polimanti R. et al. Reproducible genetic risk loci for anxiety: results from approximately 200,000 participants in the million veteran program // Am J Psychiatry. – 2020. – Vol. 177. – P. 223–232. – doi: 10.1176/appi.ajp.2019.19030256.
  29. Woodward D.J., Thorp J.G., Akosile W. et al. Identification of drug repurposing candidates for the treatment of anxiety: A genetic approach // Psychiatry Res. – 2023. – Vol. 326:115343. – doi: 10.1016/j.psychres.2023.115343.
  30. Roseberry K., Le-Niculescu H., Levey D.F. et al. Towards precision medicine for anxiety disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs // Mol Psychiatry. – 2023. – Vol. 28(7). – P. 2894–2912. – doi: 10.1038/s41380-023-01998-0.
  31. He Q, Shen Z, Ren L, Wang X, Qian M, Zhu J, Shen X. The association of catechol-O-methyltransferase (COMT) rs4680 polymorphisms and generalized anxiety disorder in the Chinese Han population. Int J ClinExpPathol. 2020 Jul 1;13(7):1712-1719. PMID: 32782694; PMCID: PMC7414458.
  32. Liu H, Hao Z, et al. Grey matter structural alterations in anxiety disorders: a voxel-based meta-analysis. Brain Imaging Behav. 2024;18(2):456-474. DOI: 10.1007/s11682-023-00842-x;
  33. Shan X, Yan H, Li H, Liu F, Xie G, Li P, Zhao J, Guo W. Abnormal causal connectivity of prefrontal-limbic circuit by structural deficits in drug-naive anxiety disorders. J Psychiatr Res. 2023 Jul;163:14-23. doi: 10.1016/j.jpsychires.2023.05.010. Epub 2023 May 9. PMID: 37196516.
  34. Schienle A, Wabnegger A. Chapter 8- structural and functional neuroanatomy of generalized anxiety disorder. In: Gerlach A Gloster A, editors. Generalized anxiety disorder and worrying: a comprehensive handbook for clinicians and researchers. Hoboken (NJ): John Wiley & Sons; 2020. p. 151–171.
  35. Carnevali L, Mancini M, Koenig J, Makovac E, Watson DR, Meeten F, Critchley HD, Ottaviani C. Cortical morphometric predictors of autonomic dysfunction in generalized anxiety disorder. AutonNeurosci. 2019 Mar;217:41-48. doi: 10.1016/j.autneu.2019.01.001. Epub 2019 Jan 4. PMID: 30704974
  36. Maggioni E, Delvecchio G., Grottaroli M., Garzitto M., Piccin S., Bonivento C., Brambilla P.Common and different neural markers in major depression and anxiety disorders: a pilot structural magnetic resonance imaging studyPsychiatry Res.: Neuroimaging, 290 (2019), pp. 42-50).
  37. M. Sobral, S. Morgado, H. Moreira, R. Guiomar, A. Ganho-Ávila Association between cortical thickness and anxiety measures: a scoping reviewPsychiatry Res.: Neuroimaging, 319 (2022), Article 111423
  38. Dobson, Croarkin P., Schroeder H., VarneyS. , Mossman S., CecilK. , Strawn J. Bridging anxiety and depression: a network approach in anxious adolescentsJ. Affect. Disord., 280 (2021), pp. 305-314
  39. Harrewijn A, et al. Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group. Transl Psychiatry.2021;11(1):502. DOI: 10.1038/s41398-021-01622-1],Yoo C, Kim MJ. Topographical similarity of cortical thickness represents generalized anxiety symptoms in adolescence. Brain Res Bull. 2023 Oct 1;202:110728. doi: 10.1016/j.brainresbull.2023.110728. Epub 2023 Aug 7. PMID: 37558098).
  40. Yoo C, Kim MJ. Topographical similarity of cortical thickness represents generalized anxiety symptoms in adolescence. Brain Res Bull. 2023 Oct 1;202:110728. doi: 10.1016/j.brainresbull.2023.110728. Epub 2023 Aug 7. PMID: 37558098).Harrewijn A, et al. Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group. Transl Psychiatry.2021;11(1):502. DOI: 10.1038/s41398-021-01622-1],
  41. Duman R.S., Sanacora G., Krystal J.H. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments // Neuron. – 2019. – Vol. 102(1). – P. 75–90.
  42. Nagy E.E., Frigy A., Szasz J.A., Horvath E. Neuroinflammation and microglia/macrophage phenotype modulate the molecular background of post-stroke depression: a literature review // ExpTher Med. – 2020. – Vol. 20(3). – P. 2510–2523.
  43. Troubat R., Barone P., Leman S. et al. Neuroinflammation and depression: a review // Eur J Neurosci. – 2021. – Vol. 53(1). – P. 151–171.
  44. Lu H., Yang Q., Zhang Y. The relation of common inflammatory cytokines with anxiety and depression and their values in estimating cardiovascular outcomes in coronary heart disease patients // J Clin Lab Anal. – 2022. – Vol. 36(6):e24404.
  45. Sarmin N., Roknuzzaman A.S.M., Sarker R. et al. Association of interleukin-2 and interleukin-10 with the pathophysiology and development of generalized anxiety disorder: a case-control study // BMC Psychiatry. – 2024. – Vol. 24(1):462. – doi: 10.1186/s12888-024-05911-z.
  46. Costello H., Gould R.L., Abrol E., Howard R. Systematic review and meta-analysis of the association between peripheral inflammatory cytokines and generalised anxiety disorder // BMJ Open. – 2019. – Vol. 9(7):e027925. – doi: 10.1136/bmjopen-2018-027925.
  47. Shen Z. et al. Combining S100B and cytokines as neuro-inflammatory biomarkers for diagnosing generalized anxiety disorder: A proof-of-concept study based on machine learning // Front Psychiatry. – 2022. – doi: 10.3389/fpsyt.2022.881241.
  48. Gandarela L., de A. Sampaio T.P., Marçal L. et al. Inflammatory markers changes following acceptance-based behavioral psychotherapy in generalized anxiety disorder patients: Evidence from a randomized controlled trial // Brain BehavImmun Health. – 2024. – Vol. 38:100779. – doi: 10.1016/j.bbih.2024.100779.
  49. Lu J., Liang W., Cui L. et al. Identifying neuro-inflammatory biomarkers of generalized anxiety disorder from lymphocyte subsets based on machine learning approaches // Neuropsychobiology. – 2025. – Vol. 84(2). – P. 74–85. – doi: 10.1159/000543646.
  50. Mirzaei E., Mirjalili M., Jahangard L. et al. Influence of simvastatin as augmentative therapy in the treatment of generalized anxiety disorder: a pilot randomized, placebo-controlled study // Neuropsychobiology. – 2021. – Vol. 80. – P. 242–252.
  51. Kim S.-W., Kang H.-J., Jhon M. et al. Statins and inflammation: new therapeutic opportunities in psychiatry // Front Psychiatry. – 2019. – Vol. 10:103.
  52. Millan M.J. Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action // TherAdvPsychopharmacol. – 2022. – Vol. 12:20451253221105128. – doi: 10.1177/20451253221105128.
  53. Gupta K., Gupta R., Bhatia M.S. et al. Effect of agomelatine and fluoxetine on HAM-D score, serum brain-derived neurotrophic factor, and tumor necrosis factor-α level in patients with major depressive disorder with severe depression // J ClinPharmacol. – 2017. – Vol. 57(12). – P. 1519–1526. – doi: 10.1002/jcph.963.
  54. Медведев В.Э., Боголепова А.Н., Морозов Д.П., Квасников Б.Б. Антидепрессивная и противотревожная эффективность и переносимость агомелатина при лечении депрессии после перенесенного COVID-19 в повседневной клинической практике (неинтервенционное исследование TELESPHOR) // Неврология, нейропсихиатрия, психосоматика. – 2024. – Т. 16(6). – С. 61–70. – doi: 10.14412/2074-2711-2024-6-61-70.
  55. Hyeon J.Y., Choi E.Y., Choe S.H. et al. Agomelatine, a MT1/MT2 melatonergic receptor agonist with serotonin 5-HT2C receptor antagonistic properties, suppresses Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages // Arch Oral Biol. – 2017. – Vol. 82. – P. 11–18. – doi: 10.1016/j.archoralbio.2017.05.015.
  56. Kalkman H.O., Feuerbach D. Antidepressant therapies inhibit inflammation and microglial M1-polarization // PharmacolTher. – 2016. – Vol. 163. – P. 82–93. – doi: 10.1016/j.pharmthera.2016.04.001.
  57. Stein D.J., Khoo J.P., Picarel-Blanchot F. et al. Efficacy of agomelatine 25–50 mg for the treatment of anxious symptoms and functional impairment in generalized anxiety disorder: a meta-analysis of three placebo-controlled studies // AdvTher. – 2021. – Vol. 38(3). – P. 1567–1583. – doi: 10.1007/s12325-020-01583-9.
  58. Kong W., Deng H., Wan J. et al. Comparative remission rates and tolerability of drugs for generalized anxiety disorder: a systematic review and network meta-analysis of double-blind randomized controlled trials // Front Pharmacol. – 2020. – Vol. 11:580858. – doi: 10.3389/fphar.2020.580858.
  59. Hood S.D., Odufowora-Sita O., Briere J.B. et al. Systematic review and network meta-analysis of agomelatine for the treatment of generalized anxiety disorder in adult patients // IntClinPsychopharmacol. – 2025. – Vol. 40(2). – P. 62–74. – doi: 10.1097/YIC.0000000000000551.
  60. Генерализованное тревожное расстройство // Клинические рекомендации. 2024–2026 (19.09.2024). – URL: https://cr.minzdrav.gov.ru/view-cr/457_3 (дата обращения 24.12.2024).

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