Clozapine Underutilization in the Treatment of Schizophrenia: How Can Clozapine Prescription Rates Be Improved?

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 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. Approximately 20% to 30% of patients with schizophrenia are thought to be treatment refractory and therefore eligible for clozapine treatment, but with drug monitoring, at least 60% of these patients respond to clozapine. 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, aggressiveness, and substance abuse, 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. 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. 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, 7.0% in Singapore, 10.2% in Denmark, 11.0% in Hong Kong, 12.7% in India and in Korea, and 2% to 4% in the United States. 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%. 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. Unquestionably, delayed initiation of clozapine unnecessarily prolongs patients' suffering and impedes their recovery. Moreover, there are data showing that a delay may even diminish the effectiveness of clozapine. It is not clear why clozapine is underprescribed, but doctors and patients may be concerned about, or unfamiliar with, the unusual and hazardous adverse effects of clozapine. There has been a steady flow of publications about the potentially lethal complications of clozapine treatment and calls for more intensive monitoring of adverse effects. Although agranulocytosis is the best-known adverse effect, there is an impressive list of other, mostly rare, complications, such as thromboembolism, thrombocytopenia, myocarditis, cardiomyopathy, pericarditis, acute cardiac arrest, apnea, ileus, polyserositis, convulsions, neuroleptic malignant syndrome, rhabdomyolysis, diabetic ketoacidosis, colitis, and interstitial nephritis. These reports have undoubtedly led to clozapine having the reputation as a useful but potentially harmful medicine, a reputation that is probably the most important reason for the drug's worldwide underprescription. Weight gain, especially in maintenance treatment, obesity, metabolic abnormalities, somnolence, hypersalivation, and urine incontinence are also common and wellknown adverse effects of clozapine. These adverse effects adversely affect the quality of life of patients