Journal List > Korean J Schizophr Res > v.19(1) > 1122205

Cho, Kim, Shin, Kim, Lee, and Kim: Reason for Clozapine Discontinuation



Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant schizophrenia. Clozapine is underutilized in the management of treatment-resistant schizophrenia. To understand contributing factors, we analyzed the time course and causes of clozapine discontinuations that occurred over a 20-year period in a clinical setting.


The reasons for discontinuation and duration of clozapine treatment from a retrospective database of 138 patients with schizophrenia who had prescribed clozapine at least a month were reviewed, with the motives for discontinuation coded. The causes for termination were analyzed.


Over two-thirds of the patient had ceased clozapine. The two most common causes for discontinuation were side-ef-fects (50%), and own decision (30%). Somnolence accounted for 34% of all side-effects induced discontinuations. Hematologi-cal problems accounted for 23% of side-effect. The Maximal treatment dose of clozapine was higher in continuation group (442.36 mg) than in discontinuation group (397.26 mg). The CGI-S score when prescribing clozapine last was higher in discontinuation group than in continuous group. The patients who took atypical antipsychotics before clozapine tended to cease clozapine because of side-effects than who took typical agent.


Future studies should seek various methods to relieve side-effects of clozapine. Prospective researches using more objective tools are needed to clarify the reason for clozapine discontinuation.


1). Levine SZ, Rabinowitz J, Faries D, Lawson AH, Scher-Svanum H. Treatment response trajectories and antipsychotic medications: examination of up to 18 months of treatment in the CATIE chronic schizophrenia trial. Schizophr Res. 2012; 137:141–146.
2). 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.
3). Meltzer HY, Bartani B, Kwon KY, Ramirez LF, Burnett S, Sharpe J. A prospective study of clozapine in treatment-resistant schizophrenia patients. I. Preliminary report. Psychopharmacology. 1989; 99:S68–S72.
4). Glick ID, Correll CU, Altamura AC, Marder SR, Csemansky JG, Weiden PJ, et al. Mid-term and longterm efficacy and effectiveness of antipsychotic medications for schizophrenia: a data-driv-en, personalized clinical approach. J Clin Psychiatry. 2011; 72:1616–1627.
5). Lewis SW, Barnes TR, Davies L, Murray RM, Dunn G, Hayhurst KP, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006; 32:715–723.
6). McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006; 163:600–610.
7). Lieberman JA, Kane JM, Johns CA. Clozapine: Guidelines for clonical management. J Clin Psychiatry. 1989; 50:329–338.
8). Wheeler A, Humberstone V, Robinson G. Outcomes for schizophrenia patients with clozapine treatment: how good does it get? J Psychopharmacol. 2009; 23:957–965.
9). Pai NB, Vella SC. Reason for clozapine cessation. Acta Psychiatr Scand. 2012; 125:39–44.
10). Henneen J, Baldessarini R. Suicidal risk during treatment with clozapine: a metaanalysis. Schizophr Res. 2005; 73:139–145.
11). Howes OD, Vergunst F, Gee S, McGuire P, Kapur S, Taylor D. Adherence to treatment guidelines in clinical practice: study of anti-psychotic treatment prior to clozapine initiation. Br J Psychiatry. 2012; 201:481–485.
12). Nielsen J, Damkier P, Lublin H, Taylor D. Optimizing clozapine treatment. Acta Psychiatr Scand. 2011; 123:411–422.
13). Meltzer HY. Clozapine: balancing safety with superior antipsychotic efficacy. Clin Schizophr Relat Psychoses. 2012; 6:134–144.
14). Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005; 19(Suppl 1):1–93.
15). Tuunainen A, Wahlbeck K, Gilbody SM. Newer atypical antipsychotic medication versus clozapine for schizophrenia. Cochrane Database Syst Rev. 2000. CD000966.
16). Fitzsimons J, Berk M, Lambert T, Bourin M, Dodd S. A review of clozapine safety. Expert Opin Drug Saf. 2005; 4:731–744.
17). Davis MC, Fuller MA, Strauss ME, Konicki PE, Jaskiw GE. Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients. Acta Psychiatr Scand. 2014; 130:30–39.
18). Patel M, de Zoysa N, David A. Cross-sectional study of patients per-spectives on adherence to antipsychotic medication: depot versus oral. J Clin Psychiatry. 2008; 69:1548–1556.
19). Zygmunt A, Olfson M, Boyer C, Mechanic D. Interventions to im-prove medication adherence in schizophrenia. Am J Psychiatry. 2002; 159:1653–1654.
20). Taylor D, Douglas-Hall P, Olofinjana B, Whiskey E, Thomas A. Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-lasting injection. Br J Psychiatry. 2009; 94:165–167.
21). Munro J, O'Sullivan D, Andrews C, Arana A, Mortimer A, Ker-win R. Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Br J Psychiatry. 1999; 175:576–580.
22). Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005; 353:1209–1223.
23). Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Davis JM. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev. 2012; 5:CD008016.
24). Kahn RS, Fleischhacker WW, Boter H, Davidson M, Verqouwe Y, Keet IP, et al. Effectiveness of antipsychotic drugs in firstepisode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008; 371:1085–1097.
25). Szymanski SR, Cannon TD, Gallacher F, Erwin RJ, Gur RE. Course of treatment response in firstepisode and chronic schizophrenia. Am J Psychiatry. 1996; 153:519–525.
26). Ciudad A, Haro JM, Alonso J, Bousono M, Suarez D, Novick D, et al. The Schizophrenia Outpatient Health Outcomes (SOHO) study: 3-year results of antipsychotic treatment discontinuation and related clinical factors in Spain. Eur Psychiatry. 2008; 23:1–7.
27). Taylor M, Shajahan P, Lawrie SM. Comparing the use and discontinuation of antipsychotics in clinical practice: an observation-al study. J Clin Psychiatry. 2008; 69:240–245.
28). Hodgson R, Belgamwar R, Al Tawarah Y, Mackenzie G. The use of atypical antipsychotics in the treatment of schizophrenia in North Staffordshire. Hum Psychopharmacol. 2005; 20:141–147.
29). Haro JM, Novick D, Belger M, Jones PB. Antipsychotic type and correlates of antipsychotic treatment discontinuation in the outpatient treatment of schizophrenia. Eur Psychiatry. 2006; 21:41–47.
30). Ciapparelli A, Dell'Osso L, Bandettini PA, Carmassi C, Cecconi D, Fenzi M, et al. Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-month followup study. J Clin Psychiatry. 2003; 64:451–458.
31). Laker MK, Duffett RS, Cookson JC. Longterm outcome with clozapine: comparison of patients continuing and discontinuing treatment. Int Clin Psychopharmacol. 1998; 13:75–78.
32). Seabourne A, Thomas CS. The use of clozapine in South Man-chester. Psychiatric Bull. 1994; 18:618–619.
33). Krivoy A, Malka L, Fischel T, Weizman A, Valevski A. Predictors of clozapine discontinuation in patients with schizophrenia. Int Clin Psychopharmacol. 2011; 26:311–315.
34). Atkinson JM, Douglas-Hall P, Fischetti C, Sparshatt A, Taylor DM. Outcome following clozapine discontinuation: a retrospective analysis. J Clin Psychiatry. 2007; 68:1027–1030.
35). Fenton WS, Blyler CR, Heinssen RK. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull. 1997; 23:637–651.
36). Hudson TJ, Owen RR, Thrush CR, Han X, Pyne JM, Thapa P, et al. A pilot study of barriers to medication adherence in schizophrenia. J Clin Psychiatry. 2004; 65:211–216.
37). 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.
38). Young C, Bowers M, Mazure C. Management of the adverse effects of clozapine. Schizophr Bull. 1998; 24:381–390.
39). Longden E, Read J. Assessing and reporting the adverse effects of antipsychotic medication: A Systematic Review of clinical studies, and prospective retrospective, and cross-sectional research. Clin Neuropharmacol. 2016; 39:29–39.
40). Scheepers FE, de Wied CC, Hulshoff Pol HE, van de Flier W, van der Linden JA, Kahn RS. The effect of clozapine on caudate nucle-us volume in schizophrenic patients previously treated with typical antipsychotics. Neuropsychopharmacol. 2001; 24:47–54.
41). Leung JG, Chengappa KN, Ivanov E, Gandotra G, Kahn CE, Weber JS, et al. Antipsychotic agents used to augment clozapine during longterm inpatient hospitalizations. Pharmacopsychiatry. 2014; 47:263–267.
42). Clarke LA, Lindenmayer JP, Kaushik S. Clozapine augmentation with aripiprazole for negative symptoms. J Clin Psychiatry. 2006; 67:675–676.
43). Benedetti A, Di Paolo A, Lastella M, Casamassima F, Candiracci C, Litta A, et al. Augmentation of clozapine with aripiprazole in severe psychotic bipolar and schizoaffective disorders: a pilot study. Clin Pract Epidemiol Ment Health. 2010; 6:30–35.

Fig. 1.
Kaplan-Meier Survival plot for time to discontinuation.
Fig. 2.
Number of patients ceasing clozapine by general reason and treatment duration.
Fig. 3.
Number of patients ceasing clozapine for medical reasons by treatment duration.
Table 1.
Factors for clozapine discontinuation
Factors for clozapine discontinuation Operational description
Own decision The patient's decision to cease treatment without apparent reason
Side effect Ceasing treatment owing to medical complications induced by clozapine
Hospital transfer To move the hospital by the convenience of the patient
Treatment failure Failure to make an adequate clinical improvement
Pregnancy To discontinue the medication for fetal safety
Death To stop treatment owing to death
Table 2.
Sociodemographic and clinical characteristics of the subjects
Total Continuation, n (%) Discontinuation, n (%) χ2 p-value
Whole Sample 137 41 (30.4) 96 (69.6)
 Male 73 23 (56.1) 50 (52.1) 0.186 0.666
 Female 64 19 (43.9) 46 (47.9)
 0-12 75 24 (64.9) 51 (60.7) 0.188 0.665
>12 47 13 (35.1) 33 (39.3)
 Single 102 30 (73.2) 72 (76.6) 0.528 0.768
 Married 25 9 (22.0) 16 (17.0)
 Divorced 8 2 (4.9) 6 (6.4)
Living arrangement
Living alone 17 3 (7.3) 14 (15.1) 1.538 0.215
Living with family 117 39 (92.7) 79 (84.9)
 No 86 23 (57.5) 63 (66.3) 0.946 0.331
 Yes 49 17 (42.5) 32 (33.7)
Economic status
 Low 37 10 (25.6) 27 (30.0) 0.253 0.615
 High 92 29 (74.4) 63 (70.0)
Concomitant antipsychoti ics
 No 74 13 (31.7) 61 (63.5) 11.722 0.001
 Yes 63 28 (68.3) 35 (36.5)

: full-time, part-time, homemaker, student

Table 3.
Comparison between continuation group and discontinuation group
Continuation, Mean (SD) Discontinuation, Mean (SD) t p
Age of onset 21.13 (7.53) 22.80 (8.04) -1.124 0.263
Age at clozapine start 29.85 (12.52) 29.52 (10.74) 0.158 0.875
Duration of untreatment 10.19 (32.26) 9.79 (19.48) 0.082 0.935
Hospitalization number before using clozapine 2.93 (3.28) 2.13 (2.54) 1.377 0.174
Hospitalization number in the use of clozapine 0.63 (1.75) 0.50 (0.88) 0.553 0.581
Body mass index (BMI) 23.37 (3.01) 24.15 (4.56) -1.054 0.295
Clozapine maximal dose 442.36 (90.40) 397.26 (95.34) 2.362 0.020
Clozapine last prescription dose 279.29 (137.00) 260.27 (127.06) 0.710 0.480
Clinical Global Impression-Severity (CGI-S) scale before starting clozapine 5.71 (1.12) 5.75 (1.18) -0.201 0.842
Clinical Global Impression-Severity (CGI-S) scale when prescribing clozapine last 3.12 (0.78) 3.93 (1.06) -4.356 <0.001

: the subjects was excluded prescribed less than 300 mg of clozapine maximal dose

Table 4.
Clinical characteristics of the subjects
Total Side effect, n (%) Other reason, n (%) χ2 p-value
Number of previous antipsychotics
 0 27 11 (40.7) 16 (59.3) 4.228 0.472
 1 41 24 (58.5) 17 (41.5)
 2 16 8 (50.0) 8 (50.0)
 3 7 3 (42.9) 4 (57.1)
 4 3 1 (33.3) 2 (66.7)
 5 2 2 (100.0) 0 (0)
Previous antipsychotics
 Typical Antipsychotics 20 4 (20.0) 16 (80.0) 13.263 <0.001
 Atypical Antipsychotics 50 34(68.0) 16 (32.0)    
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