Outcomes of Medicaid Beneficiaries With Schizophrenia Receiving Clozapine Only or Antipsychotic Combinations

The study was a retrospective observational analysis of data from the Medicaid MarketScan database, which contains integrated administrative claims and eligibility data for approximately 30 million Medicaid beneficiaries located throughout the United States. Data fields for pharmacy claims included national drug code numbers, fill dates, and days’ supply. Medical claims included ICD-9-CM codes for up to 15 diagnoses, current procedural terminology and revenue codes, and Healthcare Common Procedure Coding System codes. Data were collected as part of normal business operations and deidentified before delivery to the investigators in accordance with HIPAA requirements. For this reason, institutional review board approval was not sought.

A total of 3,376 patients were treated with at least one second-generation antipsychotic and met the sampling criteria. Of these, 457 were treated with antipsychotic polypharmacy that included clozapine, and these patients were removed from the sample. Of the 2,919 remaining patients, 479 were treated with clozapine monotherapy, and 2,440 were treated with antipsychotic polypharmacy containing an antipsychotic other than clozapine (Table 1). The most common combination was risperidone and quetiapine (N=499), followed by risperidone and aripiprazole (N=272) (Table 2). Combinations of the top four antipsychotic drugs used by sample patients (aripiprazole, quetiapine, risperidone, and ziprasidone) accounted for 65% (N=1,584) of antipsychotic polypharmacy cases.

Patients treated with clozapine monotherapy differed at baseline from those treated with antipsychotic polypharmacy, both demographically and clinically (all differences significant at p<.001) (Table 1). Clozapine-treated patients were, on average, 3.4 years younger (36.3 versus 39.7 years, respectively) and had lower CCI scores (means of .3 versus .8). Among patients in the clozapine group, the proportion of white patients was smaller than in the polypharmacy group (52% versus 61%), as was the proportion of female patients (41% versus 51%).

Baseline comorbidity rates were lower for the clozapine group than for the polypharmacy group: 12% versus 31%, respectively, for substance abuse; 12% versus 35% for depression; and 3% versus 14% for anxiety (Table 1). In both all-cause and disease-specific preperiod utilization categories, patients in the clozapine group were approximately one-half as likely as those in the polypharmacy group to use medical services. For example, the percentages with at least one all-cause hospitalization and one emergency department visit, were 17% and 29%, respectively, for the clozapine group, compared with 37% and 57% for the polypharmacy group. Schizophrenia-related hospitalization and schizophrenia-related emergency department use occurred for 15% and 17%, respectively, of patients in the clozapine group, compared with 29% and 30% of those in the polypharmacy group.

When the analysis controlled for these baseline differences (Table 3), patients treated with clozapine monotherapy were less likely than those treated with antipsychotic polypharmacy to have mental disorder–related use of the emergency department (odds ratio [OR]=.75, 95% confidence interval [CI]=.60–.95) or schizophrenia-related use of the emergency department (OR=.70, CI=.54–.90) in the postperiod; however, the clozapine group was not significantly less likely to be hospitalized or have an all-cause emergency department visit in the postperiod. This pattern of results was similar for all antipsychotic polypharmacy combinations, but it was statistically significant only for the groups with polypharmacy involving quetiapine, risperidone, and ziprasidone. The number of all-cause hospital days for the clozapine group and the polypharmacy group did not significantly differ, either overall or for any specific polypharmacy combination (Table 4).

As shown in Table 5, in all utilization and drug categories, total Medicaid payments were significantly lower for clozapine-treated patients than for patients treated with antipsychotic polypharmacy, with all-cause costs reduced on average by $21,233, mental disorder–related costs reduced by $17,457, and schizophrenia-related costs reduced by $10,582. Across all antipsychotic polypharmacy categories, costs for clozapine-treated patients were on average $20,365–$26,557 lower for all-cause medical services, $15,530–$22,745 lower for mental disorder–related services, and $8,172–$11,923 lower for schizophrenia-related services.

In a large, observational, 12-month study of Medicaid beneficiaries with a diagnosis of schizophrenia, those treated with clozapine monotherapy were less likely than those treated with antipsychotic polypharmacy to have a disease-related emergency department visit but not significantly less likely to have an all-cause emergency department visit or an all-cause hospitalization. Compared with antipsychotic polypharmacy, clozapine monotherapy was associated with disease-specific and all-cause Medicaid cost reductions of approximately 40%−45%.

These findings are generally consistent with treatment guideline recommendations that discourage the use of antipsychotic polypharmacy (1–3). Furthermore, although previous observational research did not directly compare antipsychotic polypharmacy with clozapine monotherapy, it has generally found benefits associated with monotherapy, even though polypharmacy is increasingly prescribed (25). For example, one study found that 69% of patients who switched to monotherapy remained on that therapy and that these patients experienced a loss in body mass index with no worsening of symptom control and no increase in hospitalizations (26). Another study found that switching from polypharmacy to monotherapy was associated with improvements in attention, which was associated with improvements in work skills (27). Finally, a naturalistic study conducted in Hungary found that monotherapy was associated with a longer time to discontinuation, although polypharmacy was associated with a lower likelihood of mortality and hospitalization (28). The authors concluded that the superiority of monotherapy for long-term sustained treatment, combined with the advantage of polypharmacy for mortality and psychiatric hospitalizations, suggests that combination treatments may be more efficacious during exacerbation of psychotic symptoms (28).

The potential economic and clinical implications of our findings should be considered in light of two main factors. First, our sample consisted of Medicaid beneficiaries, a population in which cost containment pressures are intensifying, the rate of antipsychotic polypharmacy is high (8,9), and the rate of clozapine use is generally low, estimated at only 2% of New York Medicaid beneficiaries with schizophrenia who initiated antipsychotic pharmacotherapy in 2009 (29). Although our results should not be viewed as definitive because of the study’s observational design, they suggest that efforts to increase conformity with guidelines for schizophrenia treatment have the potential to decrease Medicaid costs.

The second factor is the degree of unmet therapeutic need among patients with schizophrenia regardless of payment source. For example, Pickar and colleagues (5) conducted a cross-sectional survey of a community-based convenience sample of patients with a diagnosis of schizophrenic disorder (N=200), of whom 48% reported at least one involuntary hospitalization, 48% reported at least one suicide attempt, 49% reported previous incarceration, and 57% were in a supervised living arrangement or shelter. Overall, 43% were taking more than one antipsychotic medication, 70% were using an off-label regimen, and only 26% were using U.S. Food and Drug Administration–approved monotherapy. Pickar and colleagues commented that the “real world pharmacotherapy of schizophrenia has developed its own established practice that may have outstripped current data support” and argued that off-label use is partially attributable to a lack of effective treatments. In the first phase of the Clinical Antipsychotic Trials of Intervention Effectiveness study (CATIE), 74% of patients discontinued the study medication to which they were originally randomly assigned (30).

In light of the severe functional impairments that schizophrenia imposes on patients, as well as the prevalence of antipsychotic polypharmacy, it appears reasonable to intensify efforts both to identify more effective treatments and to encourage the use of treatments with demonstrated efficacy, such as clozapine, when clinically appropriate. Such efforts might target factors associated in previous research with reluctance to prescribe clozapine. These include concerns about side effects and comorbidities, lack of experience in prescribing clozapine, and reluctance to commit patients to ongoing blood level monitoring for agranulocytosis (31,32). Treatment inertia—that is, the failure to make a change in therapy even when clinically indicated—may also contribute to antipsychotic polypharmacy. For example, a semistructured-interview study conducted by Correll and colleagues (33) with 44 prescribers of combination antipsychotic therapy indicated that many “had inherited most of” their antipsychotic polypharmacy users “and were reluctant to convert patients to antipsychotic monotherapy.”

Given these concerns, educational efforts highlighting the results of pragmatic controlled trials may be helpful. For example, Essock and colleagues (34) randomly assigned patients with schizophrenia who were receiving antipsychotic polypharmacy to switch from polypharmacy to monotherapy (N=65) or to continue with antipsychotic polypharmacy (N=62). At a six-month follow-up, 86% of patients in the antipsychotic polypharmacy group were still taking the same medications and 69% of patients in the monotherapy group were still taking the same medication, with no significant group differences in symptom scores. Body mass index declined by .5 points in the monotherapy group and increased by .3 points in the antipsychotic polypharmacy group (p<.05 for group × time interaction). Although noting the limitations of their open-label design, Essock and colleagues (34) concluded that “most patients with continuing psychopathology while taking two antipsychotic medications are well able to tolerate switching from polypharmacy to monotherapy, and they reap the metabolic benefits associated with weight loss while avoiding the side effects and other burdens of taking an additional medication.” The generally favorable results observed for patients using clozapine in CATIE, the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, and the International Suicide Prevention Trial may also support educational efforts (14,35,36).

The limitations of this study should be noted. First, the substantial differences in the baseline characteristics of the antipsychotic polypharmacy and clozapine monotherapy cohorts suggest the possibility of confounding by indication. For example, physicians may be reluctant to prescribe clozapine for patients who appear to be particularly unlikely to adhere to blood monitoring requirements. The lower rates of substance abuse and depression among clozapine users compared with those in the polypharmacy group are consistent with that possibility. Manuel and colleagues (29) found that the odds of clozapine use were reduced by more than half for Medicaid beneficiaries with a diagnosis of substance abuse. Because of the possibility of drug-drug interactions, physicians may also be concerned about prescribing clozapine to patients with comorbidities, consistent with our finding of lower CCI scores among clozapine users. These results, combined with lower resource utilization in the preperiod, suggest that the clozapine cohort may have been more stable or may have been earlier in their course of treatment, compared with the antipsychotic polypharmacy cohort. However, the analyses controlled for observable differences between the two cohorts. Second, cohorts were defined on an intent-to-treat basis, and it is possible that treatment choices made after the initial cohort classification could have affected study outcomes. Third, the study sample consisted of Medicaid beneficiaries age 18 to 64, and results may not be generalizable to Medicare beneficiaries or commercially insured patients. Finally, the analyses focused on clozapine monotherapy and thus are not generalizable to all users of clozapine.

In a sample of adult Medicaid beneficiaries with schizophrenia, treatment with clozapine rather than antipsychotic polypharmacy was associated with reduced use of the emergency department for mental disorder or schizophrenia diagnoses and with reduced disease-specific and all-cause health care costs.

This study was funded by Teva Pharmaceuticals, which manufactures generic clozapine.

Dr. Carroll owns stock in Teva. The other authors were consultants to Teva for this study.