Where to position clozapine: re-examining the evidence.
OBJECTIVE
To review clozapine's position in treatment algorithms for schizophrenia.


METHODS
Clozapine's status is reviewed in the context of its initial discovery and unique clinical and (or) pharmacological profile, withdrawal and link with hematologic concerns, reintroduction with monitoring guidelines, prototype for atypicality, positioning in treatment algorithms, and current evidence regarding efficacy, effectiveness, and side effects.


RESULTS
The hematologic monitoring implemented with clozapine's reintroduction here in North America has proven successful in preventing clozapine-related deaths secondary to agranulocytosis. While its other side effects are not without concern, present evidence does not link clozapine to increased mortality rates; indeed, it appears better than other antipsychotics in this regard. Moreover, its clinical superiority compared with all other antipsychotics has been confirmed both in efficacy and in effectiveness trials.


CONCLUSIONS
Schizophrenia continues to represent a treatment challenge, with many people demonstrating suboptimal response and poor functional outcome. Clozapine is routinely positioned as a third-line treatment in schizophrenia, but in light of existing evidence this warrants re-examination.
Agid
Ofer
O
Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario. Ofer_agid@camh.net
Foussias
George
G
Singh
Shayna
S
Remington
Gary
G
D000380:Agranulocytosis / Q000139:chemically induced / Q000175:diagnosis / Q000401:mortality; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics; D003024:Clozapine / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics; D003362:Cost-Benefit Analysis; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D009656:North America; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D003024:Clozapine