Skip to main content
    • Aa
    • Aa

Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from a systematic review and meta-analyses

  • Juliano S Souza (a1) (a2), Monica Kayo (a1), Ivson Tassell (a1), Camila Bertini Martins (a3) and Helio Elkis (a1) (a2)...

Clozapine is considered the gold standard for the treatment of patients with treatment-resistant schizophrenia (TRS); however, randomized controlled trials (RCT) of olanzapine showed efficacy similar to clozapine in patients with TRS.


A systematic review was conducted comparing clozapine with olanzapine in patients with TRS. Meta-analyses were performed for single outcome measures. Response to treatment was measured by the percentage of responders, or mean change or endpoint values of psychotic symptoms scales. Effect sizes were shown as relative risks (RR), or standardized mean differences, with 95% confidence intervals.


Seven RCT were included, comprising 648 patients. Five meta-analyses were performed. Olanzapine and clozapine had similar effects on dropout rates (RR = 0.93, CI95% = 0.77–1.12), PANSS total endpoints (SMD = 0.21, CI95% = –0.04–0.46), and PANSS total mean changes (SMD = 0.08, CI95% = –0.01–0.027). Clozapine was superior to olanzapine for PANSS positive (SMD = 0.51, CI95% = 0.17–0.86) and negative (SMD = 0.50, CI95% = 0.16–0.85) subscales. There was a trend toward high doses of olanzapine producing higher effect sizes for this drug.


The results of this study suggest that clozapine is significantly more efficacious than olanzapine in improving positive and negative symptoms in TRS patients.

Corresponding author
*Address for correspondence: Juliano Santos Souza, University of São Paulo Medical School, Projesq–Schizophrenia Program, Rua Ovidio Pires de Campos 785, São Paulo SP-05403-010, Brazil. Email
Hide All

The authors would like to thank Dr. Carlos B. Pereira, Dr. Ricardo Moreno, and Dr. Orestes Forlenza for their valuable critical comments and suggestions for the manuscript, and also Carolina Rehem, for her library assistance.

Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1.KT Mueser , SR McGurk . Schizophrenia. Lancet. 2004; 363(9426): 20632072.

3.H Elkis . Treatment-resistant schizophrenia. Psychiatr Clin North Am. 2007; 30(3): 511533.

5.H Elkis , HY Meltzer . [Refractory schizophrenia]. Rev Bras Psiquiatr. 2007; 29(Suppl 2): S41S47.

6.P Brambilla , F Barale , F Caverzasi , G Tognoni , C Barbui . Clozapine-treated subjects with treatment-resistant schizophrenia: a systematic review of experimental and observational studies. Int. Clin. Psychopharmcol. 2002; 17: 189195.

7.M Chakos , J Lieberman , E Hoffman , D Bradford , B Sheitman . Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry. 2001; 158: 518526.

8.JM Davis , N Chen , ID Glick . A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003; 60(6): 553564.

10.S Leucht , C Corves , D Arbter , etal. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009; 373(9657): 3141.

11.J Moncrieff . Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: a re-examination. Br J Psychiatry. 2003; 183: 161166.

13.MJ Sernyak , RA Rosenheck . Antipsychotic use in the treatment of outpatients with schizophrenia in the VA from fiscal years 1999 to 2006. Psychiatr Serv. 2008; 59(5): 567569.

15.RW Buchanan , J Kreyenbuhl , DL Kelly , JM Noel , DL Boggs , BA Fischer , etal. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010; 36(1): 7193.

16.G Bondolfi , H Dufour , M Patris , etal. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. the Risperidone Study Group. Am J Psychiatry. 1998; 155: 499504.

19.S Leucht , K Komossa , C Rummel-Kluge , etal. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry. 2009; 166(2): 152163.

20.S Lewis , T Barnes , L Davies , etal. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006; 32: 715723.

21.J McEvoy , J Lieberman , T Stroup , etal. 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: 600610.

22.E Johnsen , HA Jorgensen . Effectiveness of second generation antipsychotics: a systematic review of randomized trials. BMC Psychiatry. 2008; 8: 3145.

23.JM Davis , N Chen . Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol. 2004; 24(2): 192208.

25.H Meltzer , W Bobo , A Roy , etal. A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry. 2008; 69(2): 274285.

26.L Citrome , VL Stauffer , L Chen , etal. Olanzapine plasma concentrations after treatment with 10, 20, and 40 mg/d in patients with schizophrenia: an analysis of correlations with efficacy, weight gain, and prolactin concentration. J Clin Psychopharmacol. 2009; 29(3): 278283.

27.BJ Kinon , J Volavka , V Stauffer , etal. Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, fixed-dose study. J Clin Psychopharmacol. 2008; 28(4): 392400.

28.L Citrome , RI Holt , DJ Walker , VP Hoffmann . Weight gain and changes in metabolic variables following olanzapine treatment in schizophrenia and bipolar disorder. Clin Drug Investig. 2011; 31(7): 455482.

30.SR Kay , A Fiszbein , LA Opler . The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13(2): 261276.

31.J Overall , D Gorham . The Brief Psychiatric Rating Scale. Psychol Rep. 1962; 10: 799812.

35.M Egger , GD Smith , DG Altman , Eds. Systematic Reviews in Health Care. Meta-Analysis in Context. London: BMJ Books; 2001.

37.SW Woods . Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003; 64(6): 663667.

38.J Azorin , R Spiegel , G Remington , etal. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry. 2001; 158: 13051313.

39.I Bitter , M Dossenbach , S Brook , etal. Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 28: 173180.

40.RR Conley , DL Kelly , CM Richardson , CA Tamminga , WT Carpenter Jr. The efficacy of high-dose olanzapine versus clozapine in treatment-resistant schizophrenia: a double-blind, crossover study. J Clin Psychopharmacol. 2003; 23(6): 668671.

41.R Moresco , R Cavallaro , C Messa , etal. Cerebral D2 and 5-HT2 receptor occupancy in schizophrenic patients treated with olanzapine or clozapine. J Psychopharmacol. 2004; 18(3): 355365.

42.D Naber , M Riedel , A Klimke , etal. Randomized double blind comparison of olanzapine vs. clozapine on subjective wellbeing and clinical outcome in patients with schizophrenia. Acta Psychiatr Scand. 2005; 111: 106115.

43.E Sacchetti , A Galluzzo , P Valsecchi , etal. Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study. Schizophr Res. 2009; 110(1–3): 8089.

44.G Tollefson , M Birkett , G Kiesler , A Wood . Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol Psychiatry. 2001; 49: 5263.

45.J Volavka , P Czobor , B Sheitman . Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry. 2002; 159: 255262.

46.A Fanous , J Lindenmayer . Schizophrenia and schizoaffective disorder treated with high doses of olanzapine. J Clin Psychopharmacol. 1999; 19: 275276.

47.S Kumra , H Kranzler , G Gerbino-Rosen , etal. Clozapine versus “high-dose” olanzapine in refractory early-onset schizophrenia: an open-label extension study. J Child Adolesc Psychopharmacol. 2008; 18(4): 307316.

48.S Kumra , H Kranzler , G Gerbino-Rosen , etal. Clozapine and “high-dose” olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. Biol Psychiatry. 2008; 63: 524529.

50.J Lindenmayer , J Volavka , J Lieberman , etal. Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial. J Clin Psychopharmacol. 2001; 21(4): 448453.

51.C Mountjoy , A Baldacchino , J Stubbs . British experience with high-dose olanzapine for treatment-refractory schizophrenia. Am J Psychiatry. 1999; 156: 158159.

53.B Sheitman , J Lindgren , J Early , M Sved . High-dose olanzapine for treatment-refractory schizophrenia. Am J Psychiatry. 1997; 154(11): 1626 (letter).

54.DL Kelly , CM Richardson , Y Yu , RR Conley . Plasma concentrations of high-dose olanzapine in a double-blind crossover study. Hum Psychopharmacol. 2006; 21(6): 393398.

55.PJ Perry , TR Argo , RM Carnahan , etal. The association of weight gain and olanzapine plasma concentrations. J Clin Psychopharmacol. 2005; 25(3): 250254.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score