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Original Investigation | Meta-analysis

Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia A Network Meta-analysis

Myrto T. Samara, MD1; Markus Dold, MD2; Myrsini Gianatsi, MSc3; Adriani Nikolakopoulou, MSc3; Bartosz Helfer, MSc1; Georgia Salanti, PhD4,5,6; Stefan Leucht, MD1
[+] Author Affiliations
1Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
2Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
3Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
4Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
5Berner Institut für Hausarztmedizin, University of Bern, Bern, Switzerland
6CTU Bern (Clinical Trials Unit), Department of Clinical Research, University of Bern, Bern, Switzerland
JAMA Psychiatry. 2016;73(3):199-210. doi:10.1001/jamapsychiatry.2015.2955.
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Published online

Importance  In treatment-resistant schizophrenia, clozapine is considered the standard treatment. However, clozapine use has restrictions owing to its many adverse effects. Moreover, an increasing number of randomized clinical trials (RCTs) of other antipsychotics have been published.

Objective  To integrate all the randomized evidence from the available antipsychotics used for treatment-resistant schizophrenia by performing a network meta-analysis.

Data Sources  MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov were searched up to June 30, 2014.

Study Selection  At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form of administration) with another antipsychotic or placebo.

Data Extraction and Synthesis  At least 2 independent reviewers extracted all data into standard forms and assessed the quality of all included trials with the Cochrane Collaboration’s risk-of-bias tool. Data were pooled using a random-effects model in a Bayesian setting.

Main Outcomes and Measures  The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. Secondary outcomes included change in positive and negative symptoms of schizophrenia, categorical response to treatment, dropouts for any reason and for inefficacy of treatment, and important adverse events.

Results  Forty blinded RCTs with 5172 unique participants (71.5% men; mean [SD] age, 38.8 [3.7] years) were included in the analysis. Few significant differences were found in all outcomes. In the primary outcome (reported as standardized mean difference; 95% credible interval), olanzapine was more effective than quetiapine (−0.29; −0.56 to −0.02), haloperidol (−0. 29; −0.44 to −0.13), and sertindole (−0.46; −0.80 to −0.06); clozapine was more effective than haloperidol (−0.22; −0.38 to −0.07) and sertindole (−0.40; −0.74 to −0.04); and risperidone was more effective than sertindole (−0.32; −0.63 to −0.01). A pattern of superiority for olanzapine, clozapine, and risperidone was seen in other efficacy outcomes, but results were not consistent and effect sizes were usually small. In addition, relatively few RCTs were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. The most surprising finding was that clozapine was not significantly better than most other drugs.

Conclusions and Relevance  Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia, and blinded RCTs—in contrast to unblinded, randomized effectiveness studies—provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics. Future clozapine studies with high doses and patients with extremely treatment-refractory schizophrenia might be most promising to change the current evidence.

Figures in this Article

Figures

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Figure 1.
PRISMA Diagram

The diagram illustrates the process of review and exclusion of studies.

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Figure 2.
Network Plot for Mean Change in Overall Symptoms of Schizophrenia

The size of the nodes corresponds to the number of trials that study the treatments. Directly comparable treatments are linked with a line; the thickness of the line corresponds to the number of trials that assess the comparison.

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Figure 3.
Primary Outcome of Mean Score Reduction in Overall Symptoms of Schizophrenia

Pairwise (upper right portion) and network (lower left portion) meta-analytic results are shown for the primary outcome. Drugs are reported in order of efficacy ranking, and outcomes are expressed as standardized mean differences (SMDs) (95% credible intervals). For the pairwise meta-analyses, SMDs of less than 0 indicate that the treatment specified in the row is more efficacious. For the network meta-analysis (NMA), SMDs of less than 0 indicate that the treatment specified in the column is more efficacious. Bold results indicate statistical significance. The overall heterogeneity (τ) is 0.11 for pairwise results and 0.08 for NMA results. To obtain SMDs for comparisons in the opposite direction, negative values should be converted into positive values and vice versa.

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Figure 4.
Secondary Outcome of Response Rates

Pairwise (upper right portion) and network (lower left portion) meta-analytic results are shown for the secondary outcome. Drugs are reported in order of efficacy ranking, and outcomes are expressed as odds ratios (ORs) (95% credible intervals). For the pairwise meta-analyses, ORs of greater than 1 indicate that the treatment specified on the row has more responders. For the network meta-analysis (NMA), ORs of greater than 1 indicate that the treatment specified in the column has more responders than the treatment on the row. Bold results indicate statistical significance. The overall heterogeneity (τ) is 0.27 for pairwise results and 0.30 for NMA results. To obtain ORs for comparisons in the opposite direction, reciprocals should be taken.

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Figure 5.
Pairwise Meta-analysis of All Clozapine Trials per Comparator Drug

The size of squares reflects the weight attributed to each study for every separate pairwise meta-analysis (per drug) and not vs all drugs combined. The diamonds illustrate the summary effect sizes (per separate drug and vs all drugs combined). The middle of each diamond sits on the value for the summary effect size, and the width of the diamond depicts the width of the overall CI. The last comparison (combined) presents the summary effect size for the pairwise meta-analysis of clozapine vs all other antipsychotics. Error bars indicate 95% CI; SMD, standardized mean difference.

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Other Atypicals are Not Equivalent to Clozapine
Posted on April 7, 2016
Jeffrey A. Mattes, M.D.
Psychopharmacology Research Association of Princeton
Conflict of Interest: None Declared
“First do no harm”. But the article by Samara et al (1) suggesting that clozapine may be no better than some other atypicals may do great harm to patients who might benefit from clozapine. At a time when many prominent psychiatrists are decrying inadequate use of clozapine in the U.S. (2), this article is counterproductive.

The authors mention many caveats regarding their study, however, some issues they don’t discuss sufficiently invalidate their conclusions:

1) Companies making other atypicals have at times attempted to show that their drugs are better than typical neuroleptics for refractory patients (references are in the Samara article). Unlike with clozapine, these studies did not show benefit, which is why clozapine is the only drug FDA approved for treatment refractory illness.

2) Companies also tried to show that clozapine was not better than their atypicals. To do a study of this type “properly”, one would have a group assigned to a typical neuroleptic, in addition to groups assigned to clozapine and the other atypical. This would establish “assay sensitivity” since, for the study to be meaningful, it would have to show (as has been shown before) that clozapine is better than the typical agent (similarly, new antidepressants are typically compared both to a standard antidepressant and to placebo; for the study to be meaningful, the standard antidepressant has to be better than placebo). Admittedly, such studies are difficult to do, but a study without a typical neuroleptic, is not particularly meaningful. Apparent (but not true) equivalence can be caused by many factors, e.g., if patients studied are not truly treatment refractory, or if ratings are not sufficiently reliable. High dropout rates, poor compliance, and a multitude of other factors would all tend to increase the chance of finding no difference between groups. A study only comparing clozapine to another atypical which shows equivalence, especially if it is funded by a drug company making the other atypical, should be given little credence. D’Agostino et al. (3) and Kaul et al. (4) discuss the difficulties in interpreting non-inferiority trials.

3) The authors don’t mention the many reports of attempts to change patients from clozapine to other atypicals, which document how difficult this change is, with frequent relapses (5).

4) This article should not be justification for psychiatrists not using clozapine because “there’s no evidence that it’s better than some other atypicals”. Refractory patients should be tried on clozapine.

Sincerely,

Jeffrey A. Mattes, M.D.


References:

(1) Samara MT, Dold M, Gianatsi M, et al. Efficacy, Acceptability, and Tolerability of
Antipsychotics in Treatment-Resistant Schizophrenia. JAMA Psychiatry. 2016;73(3):199-210.

(2) Stroup TS, Gerhard T, Crystal S, et al. Geographic and Clinical Variation in Clozapine Use in
the United States. Psychiatric Services. 2014 Feb;65(2):186-192.

(3) Agostino RB, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues – the encounters of academic consultants in statistics. Statist. Med. 2003;22:169-186.

(4) Kaul S, Diamond GA, Weintraub WS. Trials and Tribulations of Non-Inferiority. J Am Coll
Cardiol. 2005;46(11):1986-1995.

(5) Atkinson JM, Douglas-Hall P, Fischetti C, et al. Outcome following clozapine discontinuation: a retrospective analysis. J Clin Psychiatry. 2007 Jul;68(7):1027-30.

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