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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)
Abstract
Background

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

Aims

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

Method

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.

Results

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.

Conclusions

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: d.siskind@uq.edu.au
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Declaration of interest

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References
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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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eLetters

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.

References

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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