Clozaril® efficacy in TRS

Clozapine has demonstrated superior clinical efficacy over typical and atypical antipsychotics in TRS patients

Clinical data show that clozapine significantly reduces the overall symptom score, and positive and negative symptoms of schizophrenia in TRS patients,1-10 with significant improvement seen as soon as 6 weeks from the start of treatment1,4 (see Figures 1 and 2).

Figure 1. Clozapine significantly improves the Brief Psychiatric Rating Scale (BPRS) total score compared with the typical antipsychotic chlorpromazine (with benztropine) over 6 weeks

Adapted from Kane, et al. 1988.4

Figure 2. Clozapine significantly improves the Clinical Global Impressions (CGI) severity of iIIness scale total score compared with chlorpromazine (with benztropine)

Adapted from Kane,et al. 1988.4

As well as superiority over typical antipsychotics, clozapine has also demonstrated greater clinical efficacy than atypical antipsychotics in TRS patients.3,6 Trends for greater improvement in positive and negative syndrome scale (PANSS) scores are supported by significant reductions in total PANSS score6 (see Figure 3).

Figure 3. Clozapine shows greater reduction in symptoms scores than other atypical antipsychotics in total score and positive and negative syndrome scores

Adapted from data in McEvoy, et al. 2006.6

High rates of clinical response to Clozaril®

A large proportion of patients on clozapine show a clinical response to treatment, defined as at least 20% improvement in BPRS score.1-3 In clinical studies, the proportion of responders ranges from 56.6% (at 29 weeks, mean dose 523 mg/day2) to 86% (at 12 weeks, mean dose 600 mg/day3), and is higher than that seen in typical antipsychotics (see Table 1).

A meta-analysis has shown that clozapine-treated patients are nearly 2.5 times more likely to experience a 20-30% decrease from baseline in total BPRS score compared with those treated with typical antipsychotics (p=0.001).7

Table 1. Significantly more patients respond to treatment with clozapine than with typical antipsychotics

% Responders (≥20% improvement in BPRS score)


Typical antipsychotic

Kane, et al. 1988
267 patients at 6 weeks

30% 4%



Kane, et al. 2001
71 patients at 29 weeks

56.6% 24.8%



Some patients achieve at least 50% improvement in symptoms score.1 In a 6-week study of 51 patients with TRS, 1 in 10 (10.5%) of the 38 patients who remained on clozapine achieved at least a 50% decrease in BPRS score.1

Low rates of treatment withdrawal with Clozaril® (clozapine)

In clinical studies, fewer patients with TRS on clozapine discontinue treatment due to lack of efficacy compared with those on typical2,5 and atypical3,6 antipsychotics.2

Examples include:

  • A large study of 423 patients: 6.3% of patients on clozapine discontinued due to lack of efficacy, compared with 36.7% on the typical antipsychotic, haloperidol (p<0.001)5

  • A study of 273 patients: drop-out rates due to poor efficacy were 0.7% for clozapine compared with 6.7% for the atypical antipsychotic, risperidone (p<0.01)3

Treatment withdrawal due to adverse events is similar for patients on clozapine and those on some typical and atypical antipsychotics:

  • In a study of 71 patients with TRS randomised to clozapine or haloperidol, 2/37 patients discontinued due to adverse events on clozapine, compared with 3/34 on haloperidol2

  • A large study of 423 TRS patients randomised to clozapine or haloperidol found withdrawal rates due to adverse events of 12.7% and 12.4%, respectively5

  • In a study of 273 patients with TRS randomised to clozapine or risperidone, withdrawal rates due to adverse events were 11.6% for those on clozapine and 8.9% for those on risperidone (this difference was not statistically significant)3

As an indicator of tolerability, the overall dropout rates from long-term antipsychotic treatment are also lower for clozapine compared with typical antipsychotics. Two meta-analyses of clinical studies show discontinuation rates of 33% and 39% for clozapine and 56% and 70% for conventional agents.8,9

Fewer hospitalisation days with clozapine

For outpatients with TRS, treatment with clozapine results in fewer days in hospital for schizophrenia symptoms compared with typical and atypical antipsychotics: 14.4% fewer and 27.3% fewer, respectively.5,11

Clozaril® improves quality of life in patients with TRS

Clinical data in patients with TRS followed-up for 12 months show that clozapine significantly improves the total score and all 21 item scores of the quality of life scale (QLS).1

Significant improvement can occur from as early as 6 weeks into treatment,5 and improvements in social and occupational functioning have been seen during long-term therapy.10


  1. Meltzer HY, Bastani B, Kwon KY, Ramirez LF, Burnett S, Sharpe J. A prospective study of clozapine in treatment-resistant schizophrenic patients. Preliminary report. Psychopharmacology (Berl). 1989; 99 Suppl: S68-72.
  2. Kane J, Marder S, Schooler N, Wirshing W, Umbricht D, Baker R, et al. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month nrandomized double-blind comparison. Arch Gen Psychiatry 2001; 58: 965-72.
  3. Azorin JM, Spiegel R, Remington G, Vanelle JM, Pere JJ, Giguere M, Bourdeix I. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry 2001;158: 1305-13.
  4. Kane JM, Honigfeld G, Singer J, Meltzer H. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull 1988; 24: 62-7.
  5. Rosenheck R, Cramer J, Xu W, Thomas J, Henderson W, Frisman L, et al for the Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med 1997; 337: 809-15.
  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: 600-10.
  7. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001; 158: 518-26.
  8. Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry 1999; 156: 990-9.
  9. Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev 2009 Jan 21; (1): CD000059.pub2.
  10. Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT. Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry 1998; 155: 751-60.
  11. Misawa F, Suzuki T, Fujii Y. Effect of clozapine vs other second-generation antipsychotics on hospitalization and seclusion: a retrospective mirror-image study in a Japanese public psychiatric hospital. J Clin Psychopharmacol 2017; 37: 664-8.


CLZ-2022-0099 May 2023

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