CPCP: Clozapine Duck or Rabbit?

There was this recent story about one of those ambiguous drawings which look like one thing or another and both depending on your ability to sort of switch your view…and your viewpoint. This one happened to be a drawing of a duck…or a rabbit. If you can see them both (or not) it may say something about how creative you are. The story makes it seem like this is a totally new thing but I can recall the image of the old lady and the young lady, which preceded the duck/rabbit trick by a few years. For laughs you can try stretching your mind’s eye:

Young lady or old lady?




Duck or Rabbit
Duck or rabbit?







Now, is Clozapine a Duck or a Rabbit? I’ll bet you didn’t see that one coming but a new study was just published in which clozapine seemingly comes off as not the champion drug for treatment-resistant schizophrenia [1]. This is a stretch because many studies seem to show just the opposite. This prompted a different sort of Clinical Problems in Consultation Psychiatry (CPCP) pesentation delivered by Dr. Adam Wood, a senior psychiatry resident who will soon graduate. He presented the study by Samara and colleagues succinctly–which is good because I got a little dizzy reading it, mainly because of the statistical mumbo-jumbo.

CPCP Clozapine by Dr. Adam Wood

And what made this even more interesting was Dr. John Kane’s editorial which seemed to dispute the findings and uphold the view that clozapine is the go-to drug for treatment-resistant schizophrenia [2].

We also invited a senior faculty member, Dr. Del Miller, MD, to comment because he’s our departmental Clozapine guru. Del is one of those guys who can inspire anyone to higher levels of scholarship.

The discussion seemed to flip back and forth between go and no-go for clozapine. So which is it, Duck or Rabbit? Turns out it’s not so easy to decide, partly because of the statistical model but also because of study methodologies over the years since Kane published his landmark study seemingly clearly demonstrating the superiority of clozapine over the first generation antipsychotic chlorpromazine.

The key points box in the Samara paper are:

“Key Points
Question: What is the most effective and acceptable antipsychotic for treatment-resistant schizophrenia?
Findings: A certain pattern of superiority was found for olanzapine, clozapine, and risperidone in various efficacy outcomes, such as mean change in overall and positive symptoms, response rates, and dropouts owing to inefficacy, but treatment efficacy differences were not definitive and clozapine was no more efficacious than most other second-generation antipsychotics. Although substantial evidence was available for clozapine, haloperidol, olanzapine, and risperidone, data on the other included antipsychoticswere limited.
Meaning: Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia.”

On the other hand, Kane says:

“…in contrast to the studies included in the meta-analysis by Samara and colleagues, those showing superiority of clozapine, including randomized clinical trials
(RCTs), were all open-label studies.Whereas the blinded, randomized studies failed to show a difference between clozapine and other second-generation antipsychotics in treatment resistant schizophrenia, the fact that the studies with positive results were unblinded and mostly nonrandomized could be interpreted in 2 ways. 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.
Thus, the biggest concern about the validity of the findings from the meta-analysis by Samara et al is the question regarding the generalizability of the samples that were enrolled into the blinded RCTs.”

Most of us in the discussion believe that clozapine is an effective antipsychotic for those with treatment-resistant schizophrenia (even though “treatment-resistant” has not been consistently defined).

It’s still underutilized and that’s because it’s difficult to titrate and has many side effects far beyond that of severe neutropenia including weight gain, hyperglycemia, seizures, tachycardia, myocarditis, neuroleptic malignant syndrome, sialorrhea, constipation and bowel obstruction, and sedation.

While the FDA has endorsed the Clozapine REMS Program partly in response to suggestions of some experts who believed that an effort at consolidating the many clozapine registries into a single centralized registry would make it easier for prescribers to manage the blood monitoring feature–it has been described as a fiasco by many, including me. It still takes some clinicians a month to register and there are still many problems with the web site itself, including the necessity to enroll and re-enroll patients sometimes just to enter lab data as well as having to carry patients on one’s list that are not one’s own.

And our residents by policy still can’t independently enroll patients into the Clozapine REMS Program despite the newly established departmental requirement that all prescribers, including trainees, register with the program. It’s a mixed message, driven mainly by the side effect risks which can be difficult to bear in mind if you don’t often see patients who are taking clozapine. For that matter, faculty can have a little trouble keeping up. “You’re not experienced enough to sign off on clozapine.” How and when are they going to learn? And how will that encourage more clinicians to use clozapine?

Food for your head.


  1. Samara, M. T., et al. (2016). “Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: A network meta-analysis.” JAMA Psychiatry.

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.

2. Kane, J. M. and C. U. Correll (2016). “THe role of clozapine in treatment-resistant schizophrenia.” JAMA Psychiatry.

In this issue of JAMA Psychiatry, the study by Samara et al provides an important update on the evidence surrounding clozapine as the treatment of choice for those individuals with schizophrenia that is considered resistant to other medications. The authors indicate that as many as one-third of patients with schizophrenia experience persistent psychotic symptoms despite adequate treatment with antipsychotics. Therefore, the management of schizophrenia in these patients represents a major public health challenge in human and economic terms.