Should clozapine be a first-line treatment for schizophrenia? The rationale for a double-blind clinical trial in first-episode patients.

Recent studies suggest that clozapine is more effective than typical neuroleptics for patients with treatment-resistant schizophrenia. Although other investigations suggest that clozapine may also be at least as effective, and probably more so, than typical neuroleptics for individuals with acute psychosis, the toxicity of this drug has caused its use to be restricted to patients who have demonstrated resistance to previous treatment. The hypothesis behind this article, however, is that clozapine may not only be more effective than typical neuroleptics for individuals with "first-episode" schizophrenia but may also lead to a better long-term course in such patients. This hypothesis is based on the clinical literature concerning clinical and biological response to typical and atypical neuroleptic drugs, as well as on preliminary findings from studies of clinical, neuroendocrine, and biochemical effects that occur during treatment with haloperidol but not with clozapine. When examined in light of Wyatt's recent proposal that each period of symptom exacerbation may lay the groundwork for further symptoms and for increasing syndrome severity, the data suggest that clozapine, despite its disturbing side-effect profile, should be studied in controlled double-blind clinical trials during patients' first episode of schizophrenia. If such investigations show that clozapine is more effective than typical neuroleptics for patients with first-episode schizophrenia and results in a better long-term course, then its benefits and risk as a routine first-line treatment for schizophrenia can be considered. The findings of these studies may also lead us to the regular clinical use of new agents that are less toxic than clozapine but have similar clinical and biological profiles.