Clozapine's Superiority for Resistant Schizophrenia Challenged

Megan Brooks

February 18, 2016

There is insufficient evidence from blinded, randomized controlled trials (RCTs) to prove that clozapine (multiple brands), the standard for treatment-resistant schizophrenia, works better than some second-generation antipsychotics for treatment-refractory schizophrenia, a new analysis shows.

"This is the first network meta-analysis that integrates blinded evidence from all available antipsychotics in treatment-resistant schizophrenia and allows the simultaneous comparison of their efficacy, acceptability, and tolerability," Myrto Samara, MD, from the Department of Psychiatry and Psychotherapy, Technische Universitat Munchen, Munich, Germany, told Medscape Medical News.

The results "challenge the superiority" of clozapine over some other second-generation antipsychotics, such as olanzapine (Zyprexa, Eli Lilly and Company) and risperidone (Risperdal, Janssen Pharmaceuticals, Inc). "Based on our results, we feel that treatment attempts with olanzapine or risperidone could be warranted before moving on to clozapine," she added.

The study was published online February 3 in JAMA Psychiatry.

"Few Significant Differences"

The researchers analyzed data from 40 blinded RCTs that compared any antipsychotic ― at any dose and in any form of administration ― with another antipsychotic or placebo in a total of 5172 adult patients (mean age, 38.8 years) with treatment-resistant schizophrenia. Most participants were men (71.5%). The trials lasted a median of 11 weeks, and the average dropout rate was 30.2%.

For all outcomes, "few significant differences" emerged, the researchers report. "The most surprising finding was that clozapine was not significantly better than most other drugs," they write.

For the primary outcome of efficacy, as measured by overall change in symptoms of schizophrenia, olanzapine was more effective than quetiapine (Seroquel, AstraZeneca Pharmaceuticals LP) (standardized mean difference [SMD], -0.29; 95% confidence interval [CI], -0.56 to -0.02), haloperidol (Haldol, Janssen Pharmaceuticals, Inc) (SMD, -0.29; 95% CI, -0.44 to -0.13), and sertindole (Serdolect, Lundbeck, Inc) (SMD, -0.46; 95% CI, -0.80 to -0.06); clozapine was more effective than haloperidol (SMD, -0.22; 95% CI, -0.38 to -0.07) and sertindole (SMD, -0.40; 95% CI, -0.74 to -0.04); and risperidone was more effective than sertindole (SMD, -0.32; 95% CI, -0.63 to -0.01).

Clozapine, haloperidol, olanzapine, and risperidone are the most-studied antipsychotics, with relatively few data from RCTs for other antipsychotics, the researchers point out.

There is a "pattern of superiority for olanzapine, clozapine, and risperidone in various efficacy outcomes," such as mean change in overall and positive symptoms, response rates, and dropouts due to inefficacy, said Dr Samara. But the results were inconsistent, and the effect sizes were usually small. "Owing to insufficient blinded evidence, a definite recommendation could not be provided, and more trials are needed," she said.

The investigators point out in their article that clozapine was superior to other second-generation antipsychotics in three large, unblinded effectiveness studies that were not included in their analysis of only blinded studies. One possible explanation for this, they say, is that patients who could benefit from clozapine the most (ie, those patients with the most treatment- resistant cases) are rarely included in blinded RCTs, leading to sampling bias. The dosing regimen in clozapine trials and the "likely underdosing" in industry-funded trials could could also have affected the results.

The investigators also acknowledge that network meta-analysis, which they used, is a "relatively new method that has been criticized even more than conventional meta-analysis because it includes indirect evidence, which adds another level of complexity and assumptions."

"Our analysis suggests that more trials comparing clozapine with other SGAs [second-generation antidepressants] in patients with more severe illness and using high clozapine doses are warranted," Dr Samara and colleagues conclude.

Confusion, Concerns, Caveats

The coauthors of an editorial published with the study note that many guidelines promoted by national agencies and professional societies recommend clozapine when other drugs fail, and clozapine remains the only medication with regulatory approval for patients with treatment-refractory schizophrenia (and for reducing suicidal behavior).

"The meta-analysis by Samara and colleagues questions the unique role of clozapine for patients who have not responded to other antipsychotics by concluding that few blinded data support clozapine's superiority over olanzapine and risperidone in this patient population," write John M. Kane, MD, and Christoph Correll, MD, of Zucker Hills Hospital, Glen Oaks, New York.

But they are "concerned" that the results of this analysis will be confusing to clinicians, patients, and families, for a number of reasons. First, the findings are in direct opposition to those of a 2013 meta- analysis of antipsychotic efficacy in the short-term treatment of patients with nonrefractory schizophrenia.

"In that meta-analysis, which also used the multiple-treatment meta-analytic approach of ranking antipsychotics by using not only direct but also indirect comparisons via common comparators, clozapine was significantly superior to all other antipsychotics, including risperidone and olanzapine," Dr Kane and Dr Correll point out.

The fact that the studies with positive results were unblinded and mostly nonrandomized could be interpreted in two ways, they say. "The positive findings are due to bias on the part of the treating clinicians, patients, and raters, or the patients in open studies are more representative of the severely ill patients who benefit most from clozapine but are less likely to enroll in complex and demanding RCTs," they explain in their editorial.

Their biggest concern about the validity of the findings of this new meta-analysis centers on the generalizability of the samples that were enrolled into the blinded RCTs, they write.

Dr Kane and Dr Correll agree with the authors that more study is needed to clarify the efficacy and effectiveness of clozapine. "Because data suggest that, even in naturalistic, nationwide studies, clozapine's efficacy and effectiveness might diminish as it is used later in the illness, we urge the field to conduct large, pragmatic RCTs that are designed to include patients who are as representative as possible of the target population to provide high-quality generalizable data that can address the current uncertainty around the role of clozapine in patients with treatment- resistant schizophrenia," they conclude.

The study was supported by a grant from the German Federal Ministry of Education and Research. Dr Samara has disclosed no relevant financial relatinships. Principal investigator Stefan Leucht, MD, has disclosed several relationships with Eli Lilly, Pfizer, Janssen, and other pharmaceutical companies. Dr Kane's disclosures include relationships with Eli Lilly, Janssen, Merck, Otsuka, Teva, and others.

JAMA Psychiatry. Published online February 3, 2016. Abstract, Editorial


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