Can we use Clozapine in first episode Schizophrenia?: Am Jl Psy: Feb.2013


Clozapine remains the treatment of choice in resistant schizophrenia and guidelines recommend two antipsychotic trials before starting clozapine.(resistance is defined as incomplete response to two antipsychotics, of which one should be an atypical agent ).  It is permitted as second line in USA, where as in Canada and UK it is third line. Reluctance to use this effective agent is widespread with delays of  5 years or more among those with treatment resistance to start clozapine.

Patients with first-episode schizophrenia report response rates of 40%–90% with the first medication.However, the time to response increases and likelihood of response declines substantially in subsequent trials. If repeated antipsychotic trials, except of clozapine, are met with a progressive decrease in likelihood of response,  why shouldn’t Clozapine be prescribed early on?

 Gary Remington, Ofer Agid,George Foussias, Margaret Hahn, Naren Rao and Mark Sinyor explores this question in this article.

There are only 4 published studies of clozapine as first line treatment. (Yang 1997, Lieberman 2003,Woerner 2003, Girgis, 2011). Only two were controlled studies. The other two are reports of the same cohort at one year and 9 years follow up.  Resonse rates of clozapine is comparable to typical agents used in these trials. Data also suggest that long-term outcome is not dependent on type of antipsychotic used as first line agent. These studies do not show any difference between clozapine and typical agents in side effects.Clozapine show similar rates of remission and no differences on various outcome measures  relative to chlorpromazine.

Currently there is no evidence to suggest that starting clozapine as first line agent improves outcomes in the longterm. Outcomes studied so far do not include important measures like suicidality or quality of life.

The response rate markedly declines in those who require a second trial and only clozapine can provide a high response rate at that stage. The longer the patient remains psychotic, lesser would be the response.The authors argue that these observations should make us consider clozapine as second treatment agent as opposed to third one.


As usual, there is not much data available to make any firm conclusions. One thing is obvious-Clozapine is very much under-utilised. Guidelines recommend it as third agent. But many patients do not get that opportunity even after multiple antipsychotics.

Summary of the article:

Clozapine’s Role in the Treatment of First-Episode Schizophrenia. Remington G, Agid O, Foussias G, Hahn M, Rao N, Sinyor M. Am J Psychiatry. 2013 Feb 1;170(2):146-51

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