Korean J Schizophr Res.  2021 Oct;24(2):52-59. 10.16946/kjsr.2021.24.2.52.

Effect of Delayed Clozapine Initiation on Acute Treatment Response in Treatment-Resistant Schizophrenia

• Yang SY
• Choi JK
• Park S
• Park J

• KMID: 2522031
• DOI: http://doi.org/10.16946/kjsr.2021.24.2.52

Abstract

Objectives
Recent studies have reported that delayed initiation of clozapine can affect clinical response in patients with treatment-resistant schizophrenia (TRS). This study aimed to explore the relationship between delayed initiation of clozapine and acute treatment response.
Methods
Sixty-five inpatients with TRS who started clozapine for the first time were included through a retrospective chart review. Acute treatment response was defined as a 30% reduction in the Positive and Negative Syndrome Scale score or a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) at 4 weeks after initiating clozapine.
Results
After meeting the TRS criteria, the mean delay for initiating clozapine was approximately 13.8 months. The delay was shorter in patients who showed a better response to clozapine in logistic regression analysis (p=0.037).
Conclusion
Our findings suggest that reducing the delay in initiating clozapine increases the effectiveness of clozapine in patients with TRS.

Keyword

Clozapine; Treatment delay; Treatment resistant schizophrenia; Treatment response; 조현병; 치료 반응; 치료저항성 치료지연; 클로자핀

Figure

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  Fig. 1. Methodology for the inclusion of study subjects. TD, Tardive dyskinesia.

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  Fig. 2. The example of schematic treatment course of multiple episode patients[33]. Definitions of delay in initiating clozapine in this study was demonstrated. ‘Onset of treatment-resistant schizophrenia (TRS)’ refers to a state which treatment resistance has developed intrinsically in the patients. This condition is difficult to recognize until failure of a 2nd antipsychotic drug is demonstrated in the hospital. ‘Diagnosis of TRS’ refers to non-response to 2nd antipsychotics trial at adequate dose and more than 4 weeks of duration. AP, antipsychotics; DUP, duration of untreated psychosis.

Reference

1. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2004; 161(2 Suppl):1–56.

2. Lally J, Gaughran F. Treatment resistant schizophrenia-review and a call to action. Ir J Psychol Med. 2019; 36:279–291.

3. Howes OD, McCutcheon R, Agid O, De Bartolomeis A, Van Beveren NJ, Birnbaum ML, 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.

4. Gillespie AL, Samanaite R, Mill J, Egerton A, MacCabe JH. Is treatment-resistant schizophrenia categorically distinct from treatmentresponsive schizophrenia? A systematic review. BMC Psychiatry. 2017; 17:1–14.

5. National Collaborating Centre for Mental Health (UK). Psychosis and schizophrenia in adults: treatment and management. London: National Institute for Health and Care Excellence (UK);2014.

6. Lee K. Treatment-Resistant Schizophrenia: terminology and Clinical Features. Korean J Schizophr Res. 2020; 23:45–50.

7. Kinon BJ. The group of treatment resistant schizophrenias. Heterogeneity in treatment resistant schizophrenia (TRS). Front Psychiatry. 2019; 9:757.

8. Meltzer HY, Rabinowitz J, Lee MA, Cola PA, Ranjan R, Findling RL, et al. Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. Am J Psychiatry. 1997; 154:475–482.

9. Schennach R, Riedel M, Musil R, Möller HJ. Treatment response in first-episode schizophrenia. Clin Psychopharmacol Neurosci. 2012; 10:78.

10. 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.

11. Kane JM, Leucht S, Carpenter D, Docherty JP. The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry. 2003; 64:5–19.

12. Meltzer HY, Bobo WV, Roy A, Jayathilake K, Chen Y, Ertugrul A, et al. A randomized, double-blind comparison of clozapine and highdose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry. 2008; 69:274–285.

13. Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013; 382:951–962.

14. Wheeler A, Humberstone V, Robinson G. Outcomes for schizophrenia patients with clozapine treatment: how good does it get? J Psychopharmacol. 2009; 23:957–965.

15. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. 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.

16. Norman R, Lecomte T, Addington D, Anderson E. Canadian treatment guidelines on psychosocial treatment of schizophrenia in adults. Can J Psychiatry. 2017; 62:617–623.

17. Taylor DM, Paton C. Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review. J Clin Psychiatry. 2003; 64:30–34.

18. Howes OD, Vergunst F, Gee S, McGuire P, Kapur S, Taylor D. Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Br J Psychiatry. 2012; 201:481–485.

19. Kim SH. Current status of clozapine for treatment-resistant schizophrenia. Korean J Schizophr Res. 2021; 24:1–7.

20. Wheeler AJ, Feetam CL, Harrison J. Pathway to clozapine use: a comparison between a patient cohort from New Zealand and a cohort from the United Kingdom. Clin Drug Investig. 2014; 34:203–211.

21. Kang SH, Lee HW. Prescribing pattern of clozapine and clinical factors associated with discontinuation of clozapine. Korean J Schizophr Res. 2019; 22:1–7.

22. Okhuijsen-Pfeifer C, Sterk A, Horn I, Terstappen J, Kahn R, Luykx J. Demographic and clinical features as predictors of clozapine response in patients with schizophrenia spectrum disorders: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2020; 111:246–252.

23. Griffiths K, Millgate E, Egerton A, MacCabe JH. Demographic and clinical variables associated with response to clozapine in schizophrenia: a systematic review and meta-analysis. Psychol Med. 2021; 51:376–386.

24. Altamura A, Bassetti R, Sassella F, Salvadori D, Mundo E. Duration of untreated psychosis as a predictor of outcome in first-episode schizophrenia: a retrospective study. Schizophr Res. 2001; 52:29–36.

25. Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry. 2005; 162:1785–1804.

26. Shah P, Iwata Y, Plitman E, Brown EE, Caravaggio F, Kim J, et al. The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: a systematic review. Psychiatry Res. 2018; 268:114–122.

27. Shah P, Iwata Y, Brown EE, Kim J, Sanches M, Takeuchi H, et al. Clozapine response trajectories and predictors of non-response in treatment-resistant schizophrenia: a chart review study. Eur Arch Psychiatry Clin Neurosci. 2020; 270:11–22.

28. Üçok A, Çikrikçili U, Karabulut S, Salaj A, Öztürk M, Tabak Ö, et al. Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia. Int Clin Psychopharmacol. 2015; 30:290–295.

29. Lee JS, Yun JY, Kang SH, Lee SJ, Choi JH, Nam B, et al. Korean Medication Algorithm for Schizophrenia 2019, second revision: treatment of psychotic symptoms. Clin Psychopharmacol Neurosci. 2020; 18:386–394.

30. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13:261.

31. Guy W. ECDEU assessment manual for psychopharmacology. Rockville: U. S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs;1976.

32. Leucht S, Kane JM, Etschel E, Kissling W, Hamann J, Engel RR. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacology. 2006; 31:2318–2325.

33. Yoshimura B, Yada Y, So R, Takaki M, Yamada N. The critical treatment window of clozapine in treatment-resistant schizophrenia: secondary analysis of an observational study. Psychiatry Res. 2017; 250:65–70.

34. Thien K, O’Donoghue B. Delays and barriers to the commencement of clozapine in eligible people with a psychotic disorder: a literature review. Early Interv Psychiatry. 2019; 13:18–23.

35. Cho JW, Kim WH, Shin JH, Kim JH, Lee JS, Bae JN, et al. Reason for clozapine discontinuation. Korean J Schizophr Res. 2016; 19:17–24.

36. Hayhurst KP, Brown P, Lewis SW. Postcode prescribing for schizophrenia. Br J Psychiatry. 2003; 182:281–283.

37. Cirulli G. Clozapine prescribing in adolescent psychiatry: survey of prescribing practice in in-patient units. Psychiatr Bull. 2005; 29:377–380.

38. Farooq S, Choudry A, Cohen D, Naeem F, Ayub M. Barriers to using clozapine in treatment-resistant schizophrenia: systematic review. B J Psych Bull. 2019; 43:8–16.

39. Gee S, Vergunst F, Howes O, Taylor D. Practitioner attitudes to clozapine initiation. Acta Psychiatr Scand. 2014; 130:16–24.

40. Iqbal MM, Rahman A, Husain Z, Mahmud SZ, Ryan WG, Feldman JM. Clozapine: a clinical review of adverse effects and management. Ann Clin Psychiatry. 2003; 15:33–48.

41. Laker M, Duffett R, Cookson J. Long-term outcome with clozapine: comparison of patients continuing and discontinuing treatment. Int Clin Psychopharmacol. 1998; 13:75–78.

42. Young CR, Bowers Jr MB, Mazure CM. Management of the adverse effects of clozapine. Schizophr Bull. 1998; 24:381.

43. Jeon YH, Jung MY. The determinants of the length of stay in hospital for schizophrenic patients: using from the Health Insurance Claim Data of inpatients. J Digit Converg. 2020; 18:257–263.

44. Conley RR, Carpenter WT Jr, Tamminga CA. Time to clozapine response in a standardized trial. Am J Psychiatry. 1997; 154:1243–1247.