Clozapine’s Role in the Treatment of First-Episode Schizophrenia

Shortly after its release in the early 1970s, clozapine was linked to a risk, albeit a low one, of agranulocytosis (1). As a result, its use was markedly curtailed and a requirement for mandatory blood monitoring was established in most countries. A seminal study in the late 1980s demonstrating clozapine’s clinical superiority in refractory schizophrenia (3) established its position in North America as a treatment of “last resort,” permitted only after the failure of other antipsychotics and only in conjunction with routine hematological monitoring.

Despite the introduction of a number of newer atypical antipsychotics over the past two decades, clozapine remains the treatment of choice in refractory schizophrenia, a position endorsed by various guidelines (4–7). As a rule, clozapine is recommended only after incomplete response to two adequate antipsychotic trials, which is reflected in some product monographs. For example, in Canada clozapine can be prescribed only as a third-line treatment (8), although in the United States it is permitted (although not recommended) as a second-line treatment (9).

The criteria that define treatment resistance have been modified to reflect changes in recommended antipsychotic dosing guidelines that now advocate somewhat lower dosages (10). Also, treatment criteria have been proposed for “ultraresistant schizophrenia,” applicable to patients who demonstrate a suboptimal response to clozapine (11).

It is noteworthy that there remains a hesitancy in prescribing clozapine for individuals with refractory schizophrenia. For example, a review of the Veterans Affairs databases for 1999–2006 indicated that while the atypical antipsychotics were rapidly supplanting their conventional counterparts, clozapine use remained flat at 2%–3% (12). Other researchers have reported an average delay of 5 years in moving to clozapine in the face of treatment resistance (13).

Schizophrenia is characterized by a differential response to antipsychotic treatment based on stage of illness, with evidence that shorter duration of untreated psychosis is associated with greater antipsychotic response (14). Notwithstanding the different trial designs and thresholds that define clinical response, as well as nonpharmacological variables such as adherence problems, studies of patients with first-episode schizophrenia report response rates in the range of 40%–90% (15–26), although time to response increases and likelihood of response declines substantially in subsequent trials (27). In the largest study of its sort, our group followed 244 individuals with first-episode schizophrenia in a naturalistic design across two atypical antipsychotic trials before a switch to clozapine (15). The response rate was 75.4% the first trial, and it decreased to 16.7% in the second. Once again confirming clozapine’s efficacy in refractory schizophrenia, the response rate increased to 75% in the third trial, when patients were switched to clozapine. A smaller (N=58) open study of first-episode schizophrenia patients who were switched to olanzapine after a failed risperidone trial (28) reported a response rate of 29.3%, which parallels the 25.7% response rate we observed for the same switch in our larger naturalistic trial (15). A second such study (N=51) reported a response rate of 35.3% in switching from olanzapine to risperidone (29).

Unfortunately, there is a paucity of research systematically evaluating response rates across multiple antipsychotic trials. This may reflect current limitations that we face in terms of biological markers and differential treatment strategies, in sharp contrast with other areas of medicine, such as infectious diseases. In the seminal trial establishing clozapine’s superiority in treatment-resistant schizophrenia (N=319), patients were entered into a 6-week trial of haloperidol prior to random assignment to receive either clozapine or chlorpromazine; however, less than 2% met criteria for haloperidol response (3).

Taken together, the evidence suggests that repeated antipsychotic trials, except those of clozapine, are met with a progressive decrease in likelihood of response, leading some to call into question the benefit of switching antipsychotics in the populations with more chronic illness (30–33).

Only four published trials have examined the use of clozapine as first-line treatment. An open 12-week trial (N=30) in China evaluating clozapine in first-episode schizophrenia found it to be both efficacious and safe, leading to the conclusion that clozapine should be used in this population (34). In a larger controlled study (N=160), also carried out in China, patients with first-episode schizophrenia were randomly assigned to receive clozapine or chlorpromazine and assessed over a 1-year follow-up period (35). While those receiving clozapine showed greater symptom improvement and attained remission sooner, as evaluated at 12 weeks, these differences were lost at endpoint, with remission rates of 81% and 79% for clozapine and chlorpromazine, respectively. Attrition was higher in the group treated with chlorpromazine (22.5% compared with 15%), indicating greater patient retention with clozapine. A follow-up study with 9-year data offers further confirmation of the 1-year findings (36). Remission rates (78%) and relapse rates (14%) were essentially identical in the two treatment groups, while significantly greater attrition occurred in the chlorpromazine group. Median time to discontinuation was 39 months for clozapine, compared with 23 months for chlorpromazine, with significantly more patients on clozapine at endpoint (26%) compared with chlorpromazine (10%). Finally, a U.S. study followed 38 patients with first-episode schizophrenia who were treated with clozapine; there was no control group, but results were compared with those of a previous study of first-episode schizophrenia treated with fluphenazine (37). The cumulative response rate in clozapine-treated patients was 66.4% at 13 weeks, with none responding thereafter, a response rate in keeping with that reported for fluphenazine (38). The median time to response was 11 weeks with clozapine, compared with 9 weeks for fluphenazine.

Research has approached the issue of clozapine as first-line treatment in schizophrenia from two perspectives. The first addresses whether longer-term outcome is influenced differentially by use of clozapine as first-line treatment compared with other antipsychotics. The evidence gathered to date, albeit limited, suggests that this is not the case. More patients stay on clozapine, and in the early stages of treatment they may also show a more robust response compared with patients treated with other antipsychotics. However, the evidence indicates that in the longer term, most patients will not continue on clozapine, and over time the group will not look any different from those started on another antipsychotic (36).

The second perspective addresses whether outcome differs over the longer term between patients who receive clozapine and those who receive other antipsychotics as first-line treatment but continue on the same treatment. To date, only two studies have addressed this question. One was an open trial that retrospectively compared improvement with clozapine and improvement with fluphenazine in an earlier study, concluding that clozapine was not clinically superior (37). The other, a randomized controlled trial, compared clozapine and chlorpromazine over 1 year and found comparable results at endpoint (35). These findings may not be so surprising. Response rates are relatively robust in first-episode schizophrenia, as high as almost 90% (21), which establishes a ceiling effect that minimizes the chances of distinguishing between different agents.

In summary, it is difficult to make a case for clozapine as a first-line treatment. As noted, there is a high response rate in the first-episode population regardless of the choice of antipsychotic. Existing evidence does not support increased concerns about safety, but the practical demands of routine hematological monitoring make clozapine an unlikely choice without evidence of clear superiority. That said, there is insufficient evidence to determine whether outcomes differ over the longer term between individuals started and maintained on clozapine and those treated with other antipsychotics. There are simply not enough data, and potentially important outcome measures (e.g., suicidality) have not yet been assessed on a larger scale. Thus, it is premature to discount the benefits of clozapine as a first-line treatment, and further studies are warranted. Whether positive findings would translate to changes in clinical practice is open to debate.

In contrast, the case can readily be made that clozapine should at least be considered as second-line treatment, and we strongly advocate research that can shed light on this issue. Various key findings fuel this argument: 1) While there is a high response rate to the first antipsychotic, the rate markedly drops off among patients who require a second trial and appears to decrease even further with subsequent trials, except with clozapine. 2) Clozapine reinstates a higher response rate, even as a third-line treatment, raising the question of whether this effect might be enhanced with clozapine used as a second-line treatment. 3) A longer duration of untreated psychosis diminishes the likelihood of remission. 4) Treatment with clozapine leads to earlier and longer remission intervals.

Whether shifting clozapine from third-line to second-line treatment would favorably affect outcome is not clear based on available evidence. What makes this question so important and clinically relevant, though, is the current state of the art. Despite the introduction of numerous new medications in the past two decades, many individuals with schizophrenia continue to do poorly, and for these patients clozapine represents the most effective alternative available. It may well turn out that there are no added benefits to the use of clozapine as a second-line treatment, but to avoid the question because of safety concerns neither can be substantiated nor is in the best interest of efforts to enhance outcomes in schizophrenia.