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.