Clozapine (trade name, Clozaril) is a drug that none of us would prescribe if all things were equal. With the potentially catastrophic side effect of agranulocytosis, along with a metabolic side effect profile worse even than Zyprexa’s, the only reason to expose living beings to this medication is that it is reputed to be the most effective antipsychotic under the sun. But is it?

The most widely cited study was published in 1988 by Kane and colleagues (Arch Gen Psychiatry 1988; 45:789-796). In that study, 268 patients with treatment-resistant schizophrenia (that is, they failed at least three different conventional neuroleptic trials, and they failed a prospective six-week trial of Haldol at a mean dose of 61 mg QD) were randomly assigned to clozapine up to 900 mg QD or Thorazine (chlorpromazine) up to 1800 mg QD. The clozapine group had a response rate of 30% vs. a paltry 4% in the Thorazine group. The Age of Clozapine was on its way.

Has clozapine’s glitter rubbed off with the advent of the atypical antipsychotics?

But these findings haven’t held up as well as is generally supposed.

Most reviews of clozapine cite a small handful of studies as evidence that clozapine is superior to conventional neuroleptics. The Kane study mentioned above is one of them, and is compelling, but the others are either very small studies, or are larger controlled studies with more lukewarm results. For example, one frequently cited study (Breier, et al) assigned 19 patients to clozapine and 20 patients to Haldol. Clozapine was superior, but this effect was only robust for positive symptoms of schizophrenia. In another study (Buchanan et al., 1998), the number of subjects was larger (64 patients completed the trial), but clozapine was superior to Haldol only for those patients who completed the trial, and only for positive symptoms of schizophrenia. In the LOCF (last observation carried forward) analysis, which includes data from early dropouts and is the gold standard method today, clozapine was not significantly better than Haldol on any measure.

Nonetheless, taking all the studies together, it’s generally accepted that clozapine is somewhat more effective than conventional neuroleptics--primarily for positive symptoms in treatmentrefractory patients with schizophrenia-- and several meta-analyses have confirmed this (Arch Gen Psychiatry 2003; 60:553-564, BMJ 2000; 321:1371-6). It’s interesting that most psychiatrists have been taught that clozapine’s true claim to fame is superior efficacy for negative symptoms--in fact, the research over the years has demonstrated precisely the opposite.

But all this clozapine vs. Haldol data is largely irrelevant to modern day practice, in which we rarely use conventional neuroleptics. The more interesting question is, how does clozapine stack up against other atypicals?

At this point, several studies have compared clozapine with Risperdal (risperidone) and Zyprexa (olanzapine). According to the most recent metaanalysis of 16 head-to-head studies, clozapine is no more effective than these atypicals (Arch Gen Psychiatry 2003; 60:553-564). Clozapine hasn’t yet been compared with the other atypicals (i.e., Seroquel, Geodon, and Abilify), but we predict that it will perform as well as these drugs, but no better, since there is no good evidence that any of the newer atypicals vary in efficacy (see accompanying article, this issue).

So what are we to make of clozapine? Has its glitter rubbed off with the advent of the newer atypicals? Unfortunately, there’s still no clear answer. Different researchers interpret the existing studies differently, and some continue to argue that clozapine provides an extra “umphh” for those really difficult cases (see, for example, Contemporary Psychiatry, Dec 2002, 1-6).

To muddle issues even more, the FDA recently endorsed clozapine for the prevention of suicide. Clozapine is now FDA-approved for “Reducing the Risk of Recurrent Suicidal Behavior in Patients with Schizophrenia or Schizoaffective Disorder Who are Judged to be at Risk of Re-experiencing Suicidal Behavior.” A mouthful, to be sure! This reflects the results of a huge international trial comparing clozapine with Zyprexa specifically for preventing suicidal behavior (Arch Gen Psychiatry 2003; 60:82 - 91). In that study, 980 patients with schizophrenia or schizoaffective disorder, all of whom were judged to be at unusually high risk for suicide, were randomized to receive either clozapine (mean dose 274 mg QD) or Zyprexa (mean dose 17 mg QD). The main finding was that after two years, the patients randomly assigned to clozapine were about 25% less likely to experience a serious suicide attempt than patients assigned to Zyprexa. This, in addition to several other parallel lines of evidence, especially from registries tracking patients taking clozapine, convinced the FDA that clozapine should be blessed as literally the only medication in the world with good evidence that it reduces suicidality.

If, after evaluating all this confusing evidence, you decide to start a patient on clozapine, note that this drug is not easy on the body. Its package insert contains four--count ‘em, four--black box warnings, for physiological treats like agranulocytosis, myocarditis, seizures, and plain old respiratory and cardiac arrest (i.e., death). But with proper dosing and monitoring, many patients tolerate the agent and, if you believe the recent suicide prevention studies, may find it literally life-saving.

TCR VERDICT:
Efficacy advantage: Marginal
Side effect burden: Extreme