C lozapine has a long-standing, unchallenged track record as the only effective and approved medication for treatment-refractory schizophrenia. In their "Lessons to take home from CATIE," Carpenter and Buchanan 1 concluded that "the paradigm should be 2 steps, not 3-that is, failure to respond to 2 antipsychotic drugs, then taking clozapine, rather than failure to respond to one or more first-generation antipsychotics and failure to respond to one or more second-generation antipsychotics, then taking clozapine." Guidelines for the treatment of schizophrenia also suggest that clozapine should be offered as serious treatment option after 2 ineffective trials with any antipsychotic. An analysis of 3 consecutive trials showed that while 75% of patients with a first episode of schizophrenia responded to the first antipsychotic treatment, only 17% of the nonresponders responded when switched to a second antipsychotic drug; however, in the third trial, 75% of the nonresponders responded to clozapine. 2 Approximately 20% to 30% of patients with schizophrenia are thought to be treatment refractory and therefore eligible for clozapine treatment, 3,4 but with drug monitoring, at least 60% of these patients respond to clozapine. 5 Theoretically, therefore, the clozapine prescription rate should be at least 12% to 18% among patients with schizophrenia and even higher if the other indications for clozapine, such as comorbid suicidality, 6 aggressiveness, 7 and substance abuse, 8 are taken into account. Data from England and Wales indicate that the prescription rate is higher in practice (23%), but even so a substantial proportion of patients (32%) who are eligible for clozapine therapy are not receiving it. 9 Another study, performed in a tertiary academic setting, reported that 32% of schizophrenia patients were prescribed clozapine and that, again, a substantial proportion of patients with indications for the drug were not receiving it. 10 Bearing these numbers in mind, a prescription rate of approximately 20% for patients with schizophrenia is rather modest.Unfortunately, clozapine prescription rates are much lower in some countries, such as 4.0% in Malaysia, 11 7.0% in Singapore, 11 10.2% in Denmark, 12 11.0% in Hong Kong, 11 12.7% in India and in Korea, 11 and 2% to 4% in the United States. [13][14][15] In some US studies, clozapine was prescribed mainly for its antisuicidal and antiaggressive properties. A recent study from the Treatment Advocacy Center comparing different states in the United States reported a consistently low clozapine prescribing rate (mean 5%), with most states having a prescribing rate lower than 10%. 16 Not only is the clozapine prescribing rate low, but clozapine initiation is often delayed: 2 studies found that clozapine was prescribed after a mean delay of 47.7 and 29 months, respectively. 17
