Revisiting an Old Friend

December 14, 2015
Brian Miller, MD, PhD, MPH

Information about the performance of clozapine compared with other treatment strategies in usual practice may impact on its use in routine clinical settings. Here: findings from US national Medicaid data in a cohort of patients with treatment-resistant schizophrenia.

Despite evidence for superior efficacy in reducing psychotic symptoms,1 only a minority of patients with treatment-resistant schizophrenia in the US are prescribed clozapine.2 Rather than starting clozapine, clinicians often switch to a different, non-clozapine antipsychotic or combine antipsychotic medications. Information about the performance of clozapine compared with other treatment strategies in usual practice may impact on its use in routine clinical settings.

Stroup and colleagues3 compared the effectiveness and safety of initiating clozapine versus other antipsychotic treatment in a retrospective cohort of patients with evidence of treatment-resistant schizophrenia. The authors hypothesized that clozapine would be more effective in reducing the risk of psychiatric hospitalization, treatment discontinuation, and concomitant antipsychotic use.

Using a national (45 states) database from 2001 to 2009, the authors identified Medicaid enrollees aged 18 to 64 years with at least 2 outpatient or 1 inpatient claim for schizophrenia. All subjects were in active treatment (ie, had filled a prescription for an antipsychotic within 30 days prior to study entry) and had not taken clozapine in the past year. Patients using long-acting injectable antipsychotic in the 60 days prior to study entry were excluded. Treatment resistance was defined as at least one psychiatric hospitalization, filling prescriptions for at least 2 antipsychotic medications, and a medication possession ratio of > 0.75 in the year before entering the study.

A cohort was assembled by 1:1 matching of patients with treatment-resistant schizophrenia who were eligible initiators of clozapine (N = 3123) versus standard antipsychotics (N = 3123). Intervention was defined as treatment with clozapine or another oral antipsychotic for which there were no filled prescriptions in the past year. The primary outcome measure was psychiatric hospitalization. Secondary effective outcomes were discontinuation of the initial antipsychotic medication (gap of > 30 days in prescription) and use of an additional antipsychotic medication. Safety outcomes included incident cases of acute myocardial infarction, stroke, self-injurious behavior, myocarditis, agranulocytosis, and intestinal obstruction. Data were analyzed using Cox proportional hazards models.

The majority of the cohort was male (52%) and Caucasian (56%) with a mean age of 39. Patients who initiated clozapine had significantly lower rates of psychiatric hospitalization than those who began taking other antipsychotic medications (hazard ratio [HR] = 0.78, 95% confidence interval [CI] = 0.69-0.88). They also had significantly lower rates of discontinuation of the index antipsychotic medication (HR = 0.60, 95% CI = 0.55-0.65) and first use of additional antipsychotic medication (HR = 0.76, 95% CI 0.70-0.82). Patients initiating clozapine also had a higher incidence of diabetes (HR = 1.63, 95% CI = 0.98-2.70); hyperlipidemia (HR = 1.40, 95% CI = 1.09-1.78) ; and intestinal obstruction (HR = 2.50, 95% CI=0.97-6.44)

The authors concluded that in a national cohort of patients with schizophrenia and evidence of treatment resistance, initiating clozapine was more effective than a standard antipsychotic on risk of hospital admission, antipsychotic discontinuation, and initiation of a new antipsychotic medication. They noted that their definition of treatment resistance required patients to be hospitalized and to initiate new medications; thus, the results are most applicable to this subgroup of patients (versus patients with schizophrenia started on clozapine following a period of stable symptoms in the community.)

The bottom line
Increased, judicious use of clozapine is warranted in routine clinical practice, together with vigilant monitoring to prevent and detect serious medical adverse events associated with initiation of this medication.


Dr Miller is Associate Professor in the department of psychiatry and health behavior at Georgia Regents University in Augusta. He is the Schizophrenia Section Editor for Psychiatric Times. [Full bio]


1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple treatments meta-analysis. Lancet. 2013;382:951–962.

2. Stroup TS, Gerhard T, Crystal S, et al. Geographic and clinical variation in clozapine use in the United States. Psychiatr Serv. 2014;65:186–192.

3. Stroup TS, Gerhard T, Crystal S, et al. Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. Am J Psychiatry 2015; doi: 10.1176/appi.ajp.2015.15030332).