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Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis

  • Dan Siskind (a1), Lara McCartney (a2), Romi Goldschlager (a3) and Steve Kisely (a4)



Although clozapine is the ‘gold standard’ for treatment-refractory schizophrenia, meta-analyses of clozapine for this condition are lacking.


We conducted a systematic review and meta-analysis of clozapine treatment for people with treatment-refractory schizophrenia.


We searched the Cochrane Schizophrenia Group's trial register, PubMed and EMBASE and hand-searched key papers for randomised controlled trials of clozapine for treatment-refractory schizophrenia.


Twenty-one papers with 25 comparisons were included. The number needed to treat was 9. Clozapine was superior for positive symptoms in both the short and long term. In the short term only clozapine was superior for total and negative symptoms, with higher response rates. Both funding source and dosage affected results. Higher baseline psychosis scores predicted better outcomes for clozapine in a meta-regression.


Clozapine is superior for treatment-refractory disorder but if there is no response by 6 months medications with lower adverse reactions should be considered.

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Corresponding author

Dan Siskind, MIRT, 519 Kessels Road, MacGregor, Queensland 4109, Australia. Email:


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1 Idanpaan-Heikkila, J, Alhava, E, Olkinuora, M, Palva, IP. Agranulocytosis during treatment with chlozapine. Eur J Clin Pharmacol 1977; 11: 193–8.
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: 789–96.
3 Leucht, S, Cipriani, A, Spineli, L, Mavridis, D, Orey, D, Richter, F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–62.
4 Lehman, AF, Lieberman, JA, Dixon, LB, McGlashan, TH, Miller, AL, Perkins, DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004; 161 (suppl 2): 156.
5 National Institute for Health and Care Excellence. Psychosis and Schizophrenia in Adults: Prevention and Management. CG 178. NICE, 2014.
6 Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for the Treatment of Schizophrenia and Related Disorders. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders. Aust NZ J Psychiatry 2005; 39: 130.
7 Warnez, S, Alessi-Severini, S. Clozapine: a review of clinical practice guidelines and prescribing trends. BMC Psychiatry 2014; 14: 102.
8 Forrester, T, Siskind, D, Winckel, K, Wheeler, A, Hollingworth, S. Increasing clozapine dispensing trends in Queensland, Australia 2004–2013. Pharmacopsychiatry 2015; 48: 164–9.
9 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: 481–5.
10 Moncrieff, J Clozapine, V. conventional antipsychotic drugs for treatment-resistant schizophrenia: a re-examination. Br J Psychiatry 2003; 183: 161–6.
11 Booth, A, Clarke, M, Dooley, G, Ghersi, D, Moher, D, Petticrew, M, et al. The nuts and bolts of PROSPERO: an international prospective register of systematic reviews. Syst Rev 2012; 1: 2.
12 Moher, D, Liberati, A, Tetzlaff, J, Altman, DG. The PRISMA group (2009) preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097.
13 Andreasen, NC, Pressler, M, Nopoulos, P, Miller, D, Ho, BC. Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biol Psychiatry 2010; 67: 255–62.
14 Leucht, S, Samara, M, Heres, S, Patel, MX, Furukawa, T, Cipriani, A, et al. Dose equivalents for second-generation antipsychotic drugs: the classical mean dose method. Schizophr Bull 2015; 41: 1397–402.
15 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.
16 Overall, JE, Gorham, DR. The brief psychiatric rating scale. Psychol Rep 1962; 10: 799812.
17 Kay, SR, Fiszbein, A, Opler, LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–76.
18 Higgins, JPT, Green, S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Cochrane Collaboration, 2011.
19 Andreasen, NC. The Scale for the Assessment of Positive Symptoms (SAPS). University of Iowa, 1984.
20 Andreasen, NC. The Scale for the Assessment of Negative Symptoms (SANS). University of Iowa, 1983.
21 Leucht, S, Rothe, P, Davis, JM, Engel, RR. Equipercentile linking of the BPRS and the PANSS. Eur Neuropsychopharmacol 2013; 23: 956–9.
22 Azorin, JM, Spiegel, R, Remington, G, Vanelle, JM, Pere, JJ, Giguere, M, et al. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry 2001; 158: 1305–13.
23 Bitter, I, Dossenbach, MR, Brook, S, Feldman, PD, Metcalfe, S, Gagiano, CA, et al. Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 173–80.
24 Bondolfi, G, Dufour, H, Patris, M, May, JP, Billeter, U, Eap, CB, et al. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry 1998; 155: 499504.
25 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.
26 Cao, HJ, You, HF, Fan, FL, Zhang, J. The control study of risperidone and clozapine for the treatment-resistant schizophrenia. J Chinese Med Res 2003; 4: 316–9.
27 Hong, CJ, Chen, JY, Chiu, HJ, Sim, CB. A double-blind comparative study of clozapine versus chlorpromazine on Chinese patients with treatment-refractory schizophrenia. Int Clin Psychopharmacol 1997; 12: 123–30.
28 Kane, JM, Marder, SR, Schooler, NR, Wirshing, WC, Umbricht, D, Baker, RW, et al. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison. Arch Gen Psychiatry 2001; 58: 965–72.
29 Kumra, S, Frazier, JA, Jacobsen, LK, McKenna, K, Gordon, CT, Lenane, MC, et al. Childhood-onset schizophrenia. A double-blind clozapine–haloperidol comparison. Arch Gen Psychiatry 1996; 53: 1090–7.
30 Kumra, S, Kranzler, H, Gerbino-Rosen, G, Kester, HM, Thomas, C, Kafantaris, V, et al. Clozapine and ‘high-dose’ olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. Biol Psychiatry 2008; 63: 524–9.
31 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.
32 Meltzer, HY, Bobo, WV, Roy, A, Jayathilake, K, Chen, Y, Ertugrul, A, et al. A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry 2008; 69: 274–85.
33 Moresco, RM, Cavallaro, R, Messa, C, Bravi, D, Gobbo, C, Galli, L, et al. Cerebral D2 and 5-HT2 receptor occupancy in schizophrenic patients treated with olanzapine or clozapine. J Psychopharmacol 2004; 18: 355–65.
34 Naber, D, Riedel, M, Klimke, A, Vorbach, EU, Lambert, M, Kuhn, KU, et al. Randomized double blind comparison of olanzapine vs. clozapine on subjective well-being and clinical outcome in patients with schizophrenia. Acta Psychiatr Scand 2005; 111: 106–15.
35 Rosenheck, R, Cramer, J, Xu, W, Thomas, J, Henderson, W, Frisman, L, et al. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med 1997; 337: 809–15.
36 Sacchetti, E, Galluzzo, A, Valsecchi, P, Romeo, F, Gorini, B, Warrington, L, et al. Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study. Schizophr Res 2009; 110: 80–9.
37 Shaw, P, Sporn, A, Gogtay, N, Overman, GP, Greenstein, D, Gochman, P, et al. Childhood-onset schizophrenia: a double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry 2006; 63: 721–30.
38 Tollefson, GD, Birkett, MA, Kiesler, GM, Wood, AJ. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol Psychiatry 2001; 49: 5263.
39 Volavka, J, Czobor, P, Sheitman, B, Lindenmayer, JP, Citrome, L, McEvoy, JP, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 2002; 159: 255–62
40 Wahlbeck, K, Cheine, M, Tuisku, K, Ahokas, A, Joffe, G, Rimon, R. Risperidone versus clozapine in treatment-resistant schizophrenia: a randomized pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24: 911–22.
41 Wang, RZ, Geng, YY, Pan, DH, Zhang, SJ. A comparative trial of efficacy of risperidone vs clozapine in treatment of refractory schizophrenia. Chinese J Pharmacoepidemiol 2002; 5: 230–1.
42 Turner, EH, Matthews, AM, Linardatos, E, Tell, RA, Rosenthal, R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252–60.
43 Lexchin, J, Bero, LA, Djulbegovic, B, Clark, O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167–70.
44 Stark, A, Scott, J. A review of the use of clozapine levels to guide treatment and determine cause of death. Aust NZ J Psychiatry 2012; 46: 816–25.
45 Potkin, SG, Bera, R, Gulasekaram, B, Costa, J, Hayes, S, Jin, Y, et al. Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 1994; 55 (suppl B): 133–6.
46 Citrome, L, Ketter, TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract 2013; 67: 407–11.
47 Dixon, LB, Dickerson, F, Bellack, AS, Bennett, M, Dickinson, D, Goldberg, RW, et al. The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements. Schizophr Bull 2010; 36: 4870.
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Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis

  • Dan Siskind (a1), Lara McCartney (a2), Romi Goldschlager (a3) and Steve Kisely (a4)
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Clozapine in treatment-refractory schizophrenia meta-analyses

Dan J Siskind, Clinical Academic Psychiatrist, Metro South Addiction and Mental Health Service & UQ School of Medicine, Brisbane, Australia
Lara McCartney, Psychiatry Registrar, Melbourne Health, Melbourne, Victor
Steve Kisely, Professor of Psychiatry, Metro South Addiction and Mental Health Service & UQ School of Medicine, Brisbane, Australia
10 March 2017

We agree with Samara and Leucht that clinicians can feel overwhelmed by the vast quantity of published meta-analyses and variety of methodologies. It is therefore important that protocols for potential meta-analyses are published on open access repositories such as PROSPERO to reduce the risk of duplication. Unfortunately, we were unaware of the Samara et al (2016) (1) meta-analysis at the time of conducting ours, as they did not register their protocol on PROSPERO, only including a protocol as a supplementary document at the time of the publication.

The results of the two meta-analyses were broadly similar(1, 2). Our primary outcome, difference in total psychotic symptoms over short and long term, showed that clozapine was not superior to other antipsychotics in long term studies, which corresponds to the results of Samara et al (2016). We did find that clozapine was superior to other antipsychotics for positive symptoms in the short and long term, an important finding for clinicians, patients and their carers.

There are several key differences between the meta-analyses. Firstly, Samara et al (2016) did not divide by study duration. We separated studies that reported data before 3 months from those that reported data after 3 months. We feel that it is inappropriate to include results from a 6-week study with those from a 78-week study. Secondly, unlike Samara et al, we conducted sensitivity analyses on the effect of pharmaceutical funding, and found that studies without such funding favoured clozapine more strongly.

There remains debate as to the validity of network meta-analyses. They are at higher risk of bias, and require an underlying assumption that all included interventions should be jointly randomisable (3). This is clearly not the case for people with treatment-refractory schizophrenia, as some will have previously been on the same antipsychotics that are the intervention arm of other trials.

We identified and excluded four of the five of the papers listed as “missed” by Leucht as they did not have usable data. The other, Honigfeld 1984, provided 4-week data for total psychotic symptoms, which, when included, did not alter the short-term results. We note that Samara et al did not include Honigfeld 1984 in their analysis. Similarly, excluding McEvoy’s partially-blinded study made little difference.

Samara and Leucht were inaccurate in what was included in our meta-analysis. Although we included studies from different age groups, children were excluded on sensitivity analyses, making no difference to the results. We also reported sensitivity analyses of comparisons with first and second generation anti-psychotics as well as specific anti-psychotics in our original article.

Samara and Leucht are dismissive of Chinese data, even though their original protocol stated they would be included in their meta-analysis. Furthermore, there are increasing calls to include such data (4). In a review of PubMed English-language articles published 2000 and 2010, 11% or retractions were from China, while 33% were from the USA. Both Chinese studies in our meta-analysis were identified in the Cochrane database and analysed for risk of bias.

Acknowledgements: Romi Goldschlager

1.Samara MT, Dold M, Gianatsi M, Nikolakopoulou A, Helfer B, Salanti G, et al. Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: a network meta-analysis. JAMA psychiatry. 2016;73(3):199-210.

2.Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first-and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. The British Journal of Psychiatry. 2016:bjp. bp. 115.177261.

3.Li T, Puhan MA, Vedula SS, Singh S, Dickersin K. Network meta-analysis-highly attractive but more methodological research is needed. BMC medicine. 2011;9(1):79.

4.Cohen JF, Korevaar DA, Wang J, Spijker R, Bossuyt PM. Should we search Chinese biomedical databases when performing systematic reviews? Systematic reviews. 2015;4(1):1.
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Conflict of interest: None Declared

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Clozapine in treatment-resistant schizophrenia

Myrto Samara, MD, Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
Stefan Leucht, Professor, Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
07 December 2016

In an era when 11 meta-analyses are published every day, there are sometimes two on the same topic which do not agree. As such a situation can be very confusing, systematic reviewers should discuss their findings in the light of existing reviews to make the differences understandable for readers.(1) In a pairwise meta-analysis by Siskind et al.(2), clozapine was shown to be superior to other first- and second-generation antipsychotics in treatment-resistant schizophrenia which is in sharp contrast to our recently published network meta-analysis on the same topic.(3) As the publication of the two studies overlapped, the authors could not discuss the results of the other. Thus, readers might find themselves confused and unable to understand where the discrepancies lie.

First of all, there are differences in included trials. Siskind et al. included studies in children and adolescents (i.e. Kumra 1996, 2008) whereas we did not because we considered that this population requires different pharmacological treatment from adult patients. They included Chinese studies (i.e. Cao 2003, Shaw 2006, Wang 2002) whereas we did not because it has been reported that studies from mainland China are often not reliable.(4) Moreover, Siskind et al. included the study by McEvoy et al. (from CATIE phase II) assuming that it was a blind trial, but this did not hold true for the crucial clozapine arm which was open label. Last but not least, five studies (i.e. Breier 1999, Conley 2003, Daniel 1996, Honigfeld 1984, and McGurk 2005) were missed by our colleagues. There are also differences in the use of endpoint or change data and the handling of short-term and long-term studies.

Finally, a major difference lies in the statistics applied in the two meta-analyses. Siskind et al. conducted a pairwise meta-analysis whereas Samara et al. conducted both a network and a pairwise meta-analysis. But even in the pairwise meta-analysis alone, results differed. Siskind at al. combined all comparator drugs versus clozapine, ignoring possible efficacy differences between the various comparators which may explain the significant heterogeneity in many outcomes limiting the robustness of the results. In our pairwise meta-analysis of all clozapine trials (figure 5), even lumping the other antipsychotics and comparing them with clozapine revealed no significant difference in overall symptoms. We found clozapine to be better than the first-generation antipsychotics chlorpromazine and haloperidol, but not than the second-generation antipsychotics olanzapine, risperidone and ziprasidone

Whether the superiority of clozapine has been sufficiently proven by blinded trials is essential for clinical practice. Therefore, our Australian colleagues and ourselves plan a joint re-analysis of these meta-analytic data.


1.Helfer B, Prosser A, Samara MT, Geddes JR, Cipriani A, Davis JM, et al. Recent meta-analyses neglect previous systematic reviews and meta-analyses about the same topic: a systematic examination. BMC Med. 2015; 13: 82.

2.Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016; 209(5): 385-92.

3.Samara MT, Dold M, Gianatsi M, Nikolakopoulou A, Helfer B, Salanti G, et al. Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis. JAMA Psychiatry. 2016; 73(3): 199-210.

4.Woodhead M. 80% of China's clinical trial data are fraudulent, investigation finds. BMJ. 2016; 355: i5396.
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Conflict of interest: Dr Samara has no competing interests. In the last 3 years, Prof. Leucht reports receiving honoraria for lectures from Eli Lilly, Lundbeck (Institute), Pfizer, Janssen, BMS, Johnson and Johnson, Otsuka, Roche, Sanofi, ICON, AbbVie, AOP Orphan, and Servier; for consulting/advisory boards from Roche, Janssen, Lundbeck, Eli Lilly, Otsuka, and TEVA; and for the preparation of educational material and publications from Lundbeck Institute and Roche. Eli Lilly has provided medication for a clinical trial led by Prof. Leucht as the principal investigator.

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