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Evolution of the Concept of Treatment-Resistant Schizophrenia

https://doi.org/10.52667/2712-9179-2025-5-2-37-48

Abstract

Therapy-resistant schizophrenia and its subtype, ultra-resistant schizophrenia, remain one of the most serious socially significant psychiatric disorders. The lack of unified diagnostic criteria complicates the interpretation of research data in this area and reduces the effectiveness of therapy in real clinical practice. The development of standardised approaches and in-depth study of resistance mechanisms remain priority tasks of modern psychiatry. The analysis of the literature shows that ideas about therapy-resistant schizophrenia have changed significantly over the last decades. This narrative review considers the criteria for treatment-resistant schizophrenia from the first criteria proposed by Kane et al. to the current ones, including TRRIP, which take into account the duration of therapy, the dose of the drug, the form of its administration, and the patient's compliance. Special attention is paid to the criteria for ultra-resistant schizophrenia in the absence of therapeutic response to clozapine. Currently, there are significant differences in the definition of therapy-resistant schizophrenia, which underline the need to unify its diagnostic criteria.

About the Authors

Anna S. Shumilova
St. Petersburg State Psychiatric Hospital of St. Nicholas the Wonderworker
Russian Federation

St. Petersburg 190121.



Alla V. Kidyaeva
St. Petersburg State Psychiatric Hospital of St. Nicholas the Wonderworker; V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology
Russian Federation

St. Petersburg 190121;

St. Petersburg 192019. 

 



Regina F. Nasyrova
St. Petersburg State Psychiatric Hospital of St. Nicholas the Wonderworker; V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology
Russian Federation

St. Petersburg 190121;

St. Petersburg 192019. 



References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5), 5th ed.; American Psychiatric Publishing: Arlington, VA, USA, 2013.

2. Case, M.; Stauffer, V.L.; Ascher-Svanum, H.; Conley, R.; Kapur, S.; Kane, J.M.; Kollack-Walker, S.; Jacob, J.; Kinon, B.J. The heterogeneity of antipsychotic response in the treatment of schizophrenia. Psychol. Med. 2011, 41:1291–1300. doi: 10.1017/S0033291710001893.

3. Kane, J.M.; Agid, O.; Baldwin, M.L.; Howes, O.; Lindenmayer, J.P.; Marder, S.; Olfson, M.; Potkin, S.G.; Correll, C.U. Clinical Guidance on the Identification and Management of Treatment-Resistant Schizophrenia. J. Clin. Psychiatry 2019, 80:18com12123. doi: 10.4088/JCP.18com12123.

4. Iasevoli, F.; Giordano, S.; Balletta, R.; Latte, G.; Formato, M.V.; Prinzivalli, E.; De Berardis, D.; Tomasetti, C.; de Bartolomeis, A. Treatment resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016, 65:34–48. doi: 10.1016/j.pnpbp.2015.08.010.

5. Galderisi, S.; Rossi, A.; Rocca, P.; Bertolino, A.; Mucci, A.; Bucci, P.; Rucci, P.; Gibertoni, D.; Aguglia, E.; Amore, M. The influence of illness-related variables, personal resources and context-related factors on real-life functioning of people with schizophrenia. World Psychiatry 2014, 13:275–287. doi: 10.1002/wps.20167.

6. Hill, K.; Startup, M. The relationship between internalized stigma, negative symptoms and social functioning in schizophrenia: The mediating role of self-efficacy. Psychiatry Res. 2013, 206:151–157. doi: 10.1016/j.psychres.2012.09.056.

7. Kennedy, J.L.; Altar, C.A.; Taylor, D.L.; Degtiar, I.; Hornberger, J.C. The social and economic burden of treatment-resistant schizophrenia: A systematic literature review. Int. Clin. Psychopharmacol. 2014, 29:63–76. doi: 10.1097/YIC.0b013e32836508e6.

8. Kane, J.; Honigfeld, G.; Singer, J.; Meltzer, H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry 1988, 45:789–796. doi: 10.1001/archpsyc.1988.01800330013001.

9. Meltzer, H.Y.; McGurk, S.R. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr. Bull. 1999, 25:233–255. doi: 10.1093/oxfordjournals.schbul.a033376.

10. Gammon, D.; Cheng, C.; Volkovinskaia, A.; Baker, G.B.; Dursun, S.M. Clozapine: Why Is It So Uniquely Effective in the Treatment of a Range of Neuropsychiatric Disorders? Biomolecules 2021, 11:1030. doi: 10.3390/biom11071030.

11. Li, Y.; Ang, M.S.; Yee, J.Y.; See, Y.M.; Lee, J. Predictors of functioning in treatment-resistant schizophrenia: the role of negative symptoms and neurocognition. Front. Psychiatry 2024, 15:1444843. doi: 10.3389/fpsyt.2024.1444843.

12. Suzuki, Y.; Watanabe, K.; Kanno-Nozaki, K.; Horikoshi, S.; Ichinose, M.; Hirata, Y.; Kobayashi, Y.; Takeuchi, S.; Osonoe, K.; Hoshino, S.; et al. Factors associated with cognitive dysfunction in treatment-responsive and -resistant schizophrenia: A pilot cross-sectional study. J. Psychiatr. Res. 2024, 178:228–235. doi: 10.1016/j.jpsychires.2024.08.012.

13. Correll, C.U.; Brevig, T.; Brain, C. Patient characteristics, burden and pharmacotherapy of treatment-resistant schizophrenia: results from a survey of 204 US psychiatrists. BMC Psychiatry 2019, 19:362. doi: 10.1186/s12888-019-2318-x.

14. Sosin, D.N.; Ivaschenko, D.V.; Otmakhov, A.P.; Yanushko, M.G.; Grishina, E.A.; Sychev, D.A.; Ivanov, M.V. Associations of polymorphic variants of the DRD2, DRD3, HTR2A, BDNF genes with cognitive impairment in patients with treatment-resistant schizophrenia. Psychiatry and psychopharmacotherapy 2019, 21:4–10.

15. Howes, O.D.; McCutcheon, R.; Agid, O.; de Bartolomeis, A.; van Beveren, N.J.; Birnbaum, M.L.; Bloomfield, M.A.; Bressan, R.A.; Buchanan, R.W.; Carpenter, W.T.; et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. Am. J. Psychiatry 2017, 174:216–229. doi: 10.1176/appi.ajp.2016.16050503.

16. Dold, M.; Leucht, S. Pharmacotherapy of treatment-resistant schizophrenia: a clinical perspective. Evid. Based Ment. Health 2014, 17:33–37. doi: 10.1136/eb-2014-101813.

17. Samara, M.T.; Dold, M.; Gianatsi, M.; Nikolakopoulou, A.; Helfer, B.; Salanti, G.; Leucht, S. Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: A network meta-analysis. JAMA Psychiatry 2016, 73:199–210. doi: 10.1001/jamapsychiatry.2015.2955.

18. Aubel, T. Cariprazine: Patients with Treatment-Resistant Schizophrenia. Neuropsychiatr. Dis. Treat. 2021, 17:2327–2332. doi: 10.2147/NDT.S315653.

19. Mazo, G.E.; Gorobets, L.N. Antipsychotic replacement as a method of preventing the formation of resistance in schizophrenia. Review of Psychiatry and Medical Psychology named after V.M. Bekhterev 2017, (3):74–80.

20. Pandey, A.; Kalita, K.N. Treatment-resistant schizophrenia: How far have we traveled? Front. Psychiatry 2022, 13:994425. doi: 10.3389/fpsyt.2022.994425.

21. Siskind, D.; Sharma, M.; Pawar, M.; Pearson, E.; Wagner, E.; Warren, N.; Kisely, S. Clozapine levels as a predictor for therapeutic response: A systematic review and meta-analysis. Acta Psychiatr. Scand. 2021, 144:422–432. doi: 10.1111/acps.13361.

22. Faden, J.; Citrome, L. Resistance is not futile: treatment-refractory schizophrenia—overview, evaluation and treatment. Expert Opin. Pharmacother. 2019, 20:11–24. doi: 10.1080/14656566.2018.1543409.

23. American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia; American Psychiatric Publishing: Arlington, VA, USA, 2020. doi: 10.1176/appi.books.9780890424841.

24. Barnes, T.R.; Drake, R.; Paton, C.; et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology. J. Psychopharmacol. 2019, 34:3–78. doi: 10.1177/0269881119889296.

25. National Institute for Clinical Excellence. Schizophrenia: The NICE Guideline on Core Interventions in the Treatment and Management of Schizophrenia in Primary and Secondary Care; National Clinical Practice Guidelines No. CG82; NICE: London, UK, 2014.

26. Hasan, A.; Falkai, P.; Wobrock, T.; Lieberman, J.; Glenthoj, B.; Gattaz, W.F.; Thibaut, F.; Möller, H.J.; WFSBP Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J. Biol. Psychiatry 2012, 13:318–378. doi: 10.3109/15622975.2012.696143.

27. Galletly, C.; Castle, D.; Dark, F.; Humberstone, V.; Jablensky, A.; Killackey, E.; Kulkarni, J.; McGorry, P.; Nielssen, O.; Tran, N. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust. N. Z. J. Psychiatry 2016, 50:410–472. doi: 10.1177/0004867416641195.

28. Arnold, M.J. Management of First-Episode Psychosis and Schizophrenia: Guidelines From the VA/DoD. Am. Fam. Physician 2024, 109:482–483.

29. Remington, G.; Addington, D.; Honer, W.; Ismail, Z.; Raedler, T.; Teehan, M. Guidelines for the Pharmacotherapy of Schizophrenia in Adults. Can. J. Psychiatry 2017, 62:604–616. doi: 10.1177/0706743717720448.

30. Russian Society of Psychiatrists. Clinical guidelines. Schizophrenia; Russian Society of Psychiatrists: Moscow, Russia, 2024.

31. Williams, L.; Newton, G.; Roberts, K.; Finlayson, S.; Brabbins, C. Clozapine-resistant schizophrenia: a positive approach. Br. J. Psychiatry 2002, 181:184–187. doi: 10.1192/bjp.181.3.184.

32. Tranulis, C.; Mouaffak, F.; Chouchana, L.; Stip, E.; Gourevitch, R.; Poirier, M.F.; Olié, J.P.; Lôo, H.; Gourion, D. Somatic augmentation strategies in clozapine resistance—what facts? Clin. Neuropharmacol. 2006, 29:34–44. doi: 10.1097/00002826-200601000-00010.

33. Remington, G.; Saha, A.; Chong, S.A.; Shammi, C. Augmentation strategies in clozapine-resistant schizophrenia. CNS Drugs 2005, 19:843–872. doi: 10.2165/00023210-200519100-00004.

34. Mouaffak, F.; Tranulis, C.; Gourevitch, R.; Poirier, M.F.; Douki, S.; Olié, J.P.; Lôo, H.; Gourion, D. Augmentation strategies of clozapine with antipsychotics in the treatment of ultraresistant schizophrenia. Clin. Neuropharmacol. 2006, 29:28–33. doi: 10.1097/00002826-200601000-00009.

35. Kontaxakis, V.P.; Ferentinos, P.P.; Havaki-Kontaxaki, B.J.; Roukas, D.K. Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review. Eur. Psychiatry 2005, 20: 409–415. doi: 10.1016/j.eurpsy.2004.12.007.

36. Tikhonov, D.V.; Pomytkin, A.N.; Kaleda, V.G. Modern aspects of therapeutic resistance in schizophrenia. Mental Health 2021, (12):79–89. doi: 10.25557/2074-014X.2021.12.79-89.

37. Tseng, P.T.; Chen, M.H.; Liang, C.S. Difference between treatment-resistant schizophrenia and clozapine-resistant schizophrenia. World J. Psychiatry 2022, 12:1102–1104. doi: 10.5498/wjp.v12.i8.1102.

38. Chakrabarti, S. Clozapine resistant schizophrenia: Newer avenues of management. World J. Psychiatry 2021, 11:429–448. doi: 10.5498/wjp.v11.i8.429.

39. Wagner, E.; Kane, J.M.; Correll, C.U.; Howes, O.; Siskind, D.; Honer, W.G.; Lee, J.; Falkai, P.; Schneider-Axmann, T.; Hasan, A.; TRRIP Working Group. Clozapine combination and augmentation strategies in patients with schizophrenia—recommendations from an International Expert Survey Among the Treatment Response and Resistance in Psychosis (TRRIP) Working Group. Schizophr. Bull. 2020, 46:1459–1470. doi: 10.1093/schbul/sbaa060.

40. Vasiliu, O. Third-generation antipsychotics in patients with schizophrenia and non-responsivity or intolerance to clozapine regimen: What is the evidence? Front. Psychiatry 2022, 13:1069432. doi: 10.3389/fpsyt.2022.1069432.

41. Remington, G.; Addington, D.; Honer, W.; Ismail, Z.; Raedler, T.; Teehan, M. Guidelines for the Pharmacotherapy of Schizophrenia in Adults. Can. J. Psychiatry 2017, 62:604–616. doi: 10.1177/0706743717720448.

42. Kreyenbuhl, J.; Buchanan, R.W.; Dickerson, F.B.; Dixon, L.B.; Schizophrenia Patient Outcomes Research Team (PORT). The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr. Bull. 2010, 36:94–103. doi: 10.1093/schbul/sbp130.

43. Campana, M.; Falkai, P.; Siskind, D.; Hasan, A.; Wagner, E. Characteristics and definitions of ultra-treatment-resistant schizophrenia—A systematic review and meta-analysis. Schizophr. Res. 2021, 228:218–226. doi: 10.1016/j.schres.2020.12.002.

44. Luykx, J.J.; Gonzalez-Diaz, J.M.; Guu, T.W.; van der Horst, M.Z.; van Dellen, E.; Boks, M.P.; Guloksuz, S.; DeLisi, L.E.; Sommer, I.E.; Cummins, R.; et al. An international research agenda for clozapine-resistant schizophrenia. Lancet Psychiatry 2023, 10:644–652. doi: 10.1016/S2215-0366(23)00109-8.

45. Yeh, T.C.; Correll, C.U.; Yang, F.C.; Chen, M.H.; Tseng, P.T.; Hsu, C.W.; Carvalho, A.F.; Stubbs, B.; Thompson, T.; Chu, C.S.; et al. Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment. Asian J. Psychiatr. 2023, 79:103375. doi: 10.1016/j.ajp.2022.103375.

46. Zubov, D.S.; Ivanov, M.V.; Khalchitsky, S.E.; Sogoyan, M.V.; Shchedrina, L.V. Relationship between rs6265 gene polymorphism and serum BDNF level in patients with treatment-resistant schizophrenia in the dynamics of the treatment process. Siberian Bulletin of Psychiatry and Narcology 2020, 2(107):60–66. doi: 10.26617/1810-3111-2020-2(107)-60-66.

47. Oleneva, E.V.; Ryvkin, P.V.; Mosolov, S.N. Clinical predictors of the effectiveness of electroconvulsive therapy in treatment-resistant schizophrenia. Modern Therapy of Mental Disorders 2021, (2):11–18. doi: 10.21265/PSYPH.2021.57.2.002.

48. Stanovaya, V.V.; Guseinova, Z.T.; Ivanov, M.V.; Bigday, E.V. The phenomenon of therapeutic resistance in the treatment of schizophrenia: the possibilities of modern diagnostics and methods of anti-resistant effects. Review of Psychiatry and Medical Psychology named after V.M. Bekhterev 2023, 57(4):120–130. doi: 10.31363/2313-7053-2023-4-893.

49. Correll, C.U.; Rubio, J.M.; Inczedy-Farkas, G.; Birnbaum, M.L.; Kane, J.M.; Leucht, S. Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: Systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry 2017, 74:675–684. doi: 10.1001/jamapsychiatry.2017.0624.

50. Sun, J.; Yee, J.Y.; See, Y.M.; Tang, C.; Zheng, S.; Ng, B.T.; Lee, J. Association between treatment resistance and cognitive function in schizophrenia. Singapore Med. J. 2024, 65:552–557. doi: 10.4103/singaporemedj.SMJ-2024-143.


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Shumilova A.S., Kidyaeva A.V., Nasyrova R.F. Evolution of the Concept of Treatment-Resistant Schizophrenia. Personalized Psychiatry and Neurology. 2025;5(2):37-48. https://doi.org/10.52667/2712-9179-2025-5-2-37-48

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