The Underuse of Clozapine and Long-Acting Injectable Antipsychotics

Clozapine became available in the United States in 1989 and is the gold standard among antipsychotics. A meta-analysis reported that it is almost twice as effective as other antipsychotics (6). Clozapine is the only antipsychotic approved by the U.S. Food and Drug Administration (FDA) for decreasing suicidal ideation, has the lowest mortality rate among antipsychotics, and was reported to be more effective than other antipsychotics in decreasing hostility and aggression among patients with schizophrenia (7, 8). Despite its superior properties, only 4% of individuals treated with antipsychotic medication in the United States receive clozapine, compared with rates of 20%–38% in countries such as Germany, Australia, Taiwan, and China (9). What percentage of people with schizophrenia should be treated with clozapine? Dr. John Kane, an expert on the treatment of schizophrenia, suggested that “10% is a bare minimum and 20% would be more appropriate” (10).

The major reasons for the low use of clozapine are side effects. Of primary concern is agranulocytosis, which requires monitoring with periodic blood testing. Myocarditis, seizures, and weight gain are other potential issues that contribute to patients’ reluctance to use the drug. The possible side effects may also contribute to clinicians’ overestimation of patients’ reluctance to use clozapine and clinicians’ fears of legal liability (9, 10).

Similarly, LAIs have been available in the United States since 1972. Currently in the United States, 11 formulations of seven antipsychotics with dosing intervals ranging from 2 to 24 weeks are approved for use (see the online supplement to this Open Forum). Studies comparing the efficacy of LAIs with the efficacy of oral antipsychotics have consistently shown the superiority of the former for medication adherence, rate and duration of hospitalizations, and emergency department visits, especially for patients who are typically medication nonadherent (11). Some LAIs may decrease hostility and aggression among individuals with schizophrenia (8).

Despite these useful properties, a 2018 survey of Medicaid beneficiaries with schizophrenia reported that only 15% were receiving an LAI (12). This contrasts with LAI use rates in other developed countries, such as 30% in the United Kingdom (13). A survey of 9,433 U.S. psychiatric outpatient clinics reported that 70% of them did not prescribe LAIs at all, including 40% of clinics that had treatment programs specifically for patients with severe mental illness (14).

Given the clear rationale for using the best treatments available for schizophrenia and related psychotic disorders, we are surprised that clozapine and LAIs are underused. If the most effective drugs were being underused for other medical conditions such as diabetes, hypertension, or cancer, a great outcry would arise among those affected. For schizophrenia, several stakeholders, noted next, should have some responsibility for correcting the current underuse of clozapine and LAIs.

Schizophrenia is among the most devastating and costly human diseases, and patients need better treatment options. Clozapine and LAIs are among the most effective treatments for this disease but are markedly underused. All government and nongovernment stakeholders are responsible for correcting this situation.