This article addresses the Core Competency of Practice-Based Learning and Improvement

ARTICLES

Outcomes of Medicaid Beneficiaries With Schizophrenia Receiving Clozapine Only or Antipsychotic Combinations Dawn I. Velligan, Ph.D., Cathy Carroll, Ph.D., Maureen J. Lage, Ph.D., Kathleen Fairman, M.A.

Objective: Patients with treatment-resistant schizophrenia commonly receive nonrecommended drug regimens, including antipsychotic polypharmacy, sometimes in lieu of clozapine. This analysis compared utilization and cost outcomes for cohorts of Medicaid beneficiaries treated with clozapine monotherapy and with antipsychotic polypharmacy. Methods: Data were from the Medicaid MarketScan database. Patients (age 18–64) initiated second-generation antipsychotic polypharmacy or clozapine monotherapy between July 2006 and January 2009, had continuous Medicaid coverage from six months before (preperiod) through 12 months after (postperiod) treatment initiation, and had a diagnosis of schizophrenic disorder (ICD-9-CM code 295.XX). Study outcomes included disease-specific and all-cause hospitalization, emergency department use, and Medicaid payments. Logistic regression analyses and generalized linear models controlled for demographic factors, preperiod utilization, and comorbidities. Results: Characteristics associated with use of clozapine monotherapy (N=479) instead of antipsychotic polypharmacy

Antipsychotic polypharmacy, defined as prescribing two or more antipsychotic agents simultaneously, has little evidentiary support in the treatment of patients with schizophrenia and is generally discouraged by practice guidelines and consensus statements (1–3). Nonetheless, the practice of using antipsychotic polypharmacy for schizophrenic disorder is common and increasing. Although an antipsychotic polypharmacy rate of only 13.7% was reported in a Department of Veterans Affairs study of second-generation antipsychotic use in 2004 (4), rates of 40% or more have been documented in studies of a wide variety of settings, time periods, and drugs (5–7). One naturalistic study of U.S. patients initiating treatment for schizophrenic disorder with a second-generation antipsychotic (olanzapine, quetiapine, or risperidone) from 1997–2003 found that 58% had at least one period of antipsychotic polypharmacy exceeding 60 days (7). In samples of Medicaid beneficiaries with schizophrenia, Clark and colleagues (8) Psychiatric Services 66:2, February 2015

(N=2,440) included younger age, fewer comorbidities, lower preperiod utilization rates, nonwhite race, and male sex. When the analysis controlled for baseline differences, clozapine monotherapy was associated with lower odds of mental disorder–related (odds ratio [OR]=.75, 95% confidence interval [CI]=.60–.95) or schizophrenia-related (OR=.70, CI=.54–.90) emergency department use but not with hospitalization or all-cause emergency department use. Total Medicaid payments were significantly lower for the clozapine group than for the polypharmacy group: reductions of $21,315 for all-cause, $17,457 for mental disorder–related, and $10,582 for schizophrenia-related payments. Conclusions: Among nonelderly adult Medicaid beneficiaries with schizophrenia, treatment with clozapine instead of antipsychotic polypharmacy was associated with reduced disease-specific emergency department use and with reduced disease-specific and all-cause health care costs. Psychiatric Services 2015; 66:127–133; doi: 10.1176/appi.ps.201300085

found that the rate of antipsychotic polypharmacy increased from 5.7% in 1995 to 24.3% in 1999. Ganguly and colleagues (9) documented an antipsychotic polypharmacy rate increase from 32% in 1998 to 41% in 2000. Ganguly and colleagues also found that the mean duration of antipsychotic polypharmacy was 149 days overall, with 23% of patients receiving long-term antipsychotic polypharmacy (more than two months) for a mean duration of 236 days. Treatment resistance (that is, suboptimal response to at least one adequate trial of antipsychotic monotherapy) is a commonly cited justification for antipsychotic polypharmacy (10–13). However, two pragmatic randomized controlled trials have shown clozapine to be a first-line agent of choice in treatment-resistant schizophrenia (14,15). American Psychiatric Association guidelines for the treatment of schizophrenia (updated in May 2011) recommend that monotherapy with clozapine be considered “for a patient who has had no response ps.psychiatryonline.org 127

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or partial and suboptimal response to two trials of antipsychotic medication” (16). Thus it has been suggested that reluctance to prescribe clozapine when clinically indicated for treatmentresistant disease may contribute to antipsychotic polypharmacy (17–19). Research evidence indicating that antipsychotic polypharmacy is often tried before clozapine provides support for this view. For example, Taylor and colleagues (20) reviewed medical histories for inpatients with schizophrenia who were prescribed clozapine for the first time and found that 65% had prior antipsychotic polypharmacy. In a more recent study of a sample that included both inpatient and outpatient clozapine users, Howes and colleagues (21) found a 36% rate of previous antipsychotic polypharmacy. Despite the widespread use of antipsychotic polypharmacy, often in lieu of clozapine monotherapy, we are aware of no research comparing these regimens in the treatment of patients with schizophrenia. This study addressed that information gap by examining all-cause and disease-specific health care utilization rates and costs in a large, recent sample of Medicaid beneficiaries treated for schizophrenic disorder with either clozapine monotherapy or second-generation antipsychotic polypharmacy. METHODS 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. Sample The data set delivered to the investigators represented a sample consisting of all Medicaid beneficiaries who had at least one pharmacy claim for a second-generation antipsychotic (aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone) or at least one diagnosis of schizophrenic disorder (ICD-9-CM code 295.XX) in the Medicaid MarketScan database from January 2005 through December 2009. From this data set (N=611,622), all patients who initiated second-generation antipsychotic treatment between July 1, 2006, and January 1, 2009 (identification period) were selected. The clozapine monotherapy cohort consisted of patients with at least one claim for clozapine during the identification period and no claims for any other second-generation antipsychotic from 90 days before through 90 days after the first clozapine 128

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claim fill (index) date. The antipsychotic polypharmacy cohort consisted of patients with two or more overlapping secondgeneration antipsychotic claims, defined on the basis of fill date plus days’ supply. For example, a patient with 30-day supply claims for aripiprazole on July 1 and August 1 who filled prescriptions for olanzapine on July 15 and August 15 was defined as receiving an aripiprazole-olanzapine combination. All cohorts were defined on an intent-to-treat basis; that is, the earliest drug (clozapine) or drug combination (antipsychotic polypharmacy) in the identification period was used to classify the patient throughout the study regardless of subsequent treatment augmentation or switching. Patients whose index regimen was antipsychotic polypharmacy with clozapine (that is, clozapine plus any other second-generation antipsychotic) were excluded from the sample (N=457). From this group, study patients were selected if they were age 18 to 64 as of the index date (first second-generation antipsychotic claim), had continuous Medicaid coverage with both medical and drug benefits from six months before (preperiod) through 12 months after (postperiod) the index date, and had a diagnosis of schizophrenia or schizoaffective disorder, defined as having at least one medical claim with a diagnosis of a schizophrenic disorder (ICD-9-CM code 295.XX) in any diagnosis field in either the preperiod or postperiod. Outcome Measures Postperiod outcome measures included costs, use of inpatient care, and use of the emergency department. Costs were defined as gross payments to a provider for a service. This payment is equal to the amount eligible for payment under the medical plan terms after applying rules such as discounts, but before applying coordination of benefits, copayments, and deductibles. Inpatient care and the emergency department were measured as binomials. Each of these measures was reported in three diagnosis categories based on ICD-9-CM codes in any field: all cause (any diagnosis), mental disorder related (290. XX–319.XX), and schizophrenia related (295.XX). Mental disorder–related costs and schizophrenia-related costs were defined as all inpatient, outpatient, drug, and laboratory costs with an accompanying diagnosis of a mental disorder or schizophrenia, respectively. Total number of all-cause hospital inpatient days was an additional outcome measure. Statistical Analyses The primary study analyses were multivariate. Logistic regression analyses were used to model the binomial measures of emergency department and inpatient use, generalized linear models (GLMs) with gamma distribution and log link to model costs, and GLMs with negative binomial distribution and log link to model hospital days. All analyses controlled for demographic characteristics (age, sex, and race), preperiod Charlson Comorbidity Index (CCI) (22) score, and indicators of preperiod comorbidities common in schizophrenia. These indicators were based on ICD-9-CM diagnosis codes in any field and included substance abuse (303.XX, alcohol dependence; 304.XX, drug dependence; and 305.XX, nondependent abuse of drugs) (23,24), depression Psychiatric Services 66:2, February 2015

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Polypharmacy column labels indicate at least 1 drug in the combination; for example, aripiprazole indicates treatment with any combination that included aripiprazole. To mitigate the degree of cumulative type 1 error and to enhance readability of the table, no statistical tests for individual polypharmacy combinations are shown. All tests compared total polypharmacy (N=2,440) with clozapine monotherapy (N=479) using Pearson chi square tests for nominal-scale variables and t tests for age and CCI. c Polypharmacy group significantly different from clozapine group (p,.001) d Charlson Comorbidity Index. Possible scores range from 0 to 17, with higher scores indicating poorer health. b

a

52 41 28 1,529 1,204 825 57 45 30 1,390 1,098 742 59 46 29 410 319 200 59 47 33 753 605 423 61 48 32 728 576 381 62 48 35 123 95 69 49 40 29 328 272 198 53 40 26 29 22 17 139 106 83

438 329 213

34 33 27 980 958 773 37 36 29 898 876 699 36 35 28 253 244 192 38 37 31 492 480 399 39 38 30 464 458 357 39 38 33 78 76 66 35 34 27 233 227 184 34 33 24 17 17 15 82 82 74

276 267 200

28 32 12 .761.3 807 919 361 31 35 14 .861.4 748 860 348 31 36 14 .961.4 213 248 96 30 34 13 .861.3 388 440 173 32 37 17 .861.3 399 446 199 36 37 12 .861.4 72 74 24 30 29 12 .861.5 202 197 83 28 38 15 .961.4 233 315 122 12 12 3 .36.1 59 59 13

52 27 19 250 130 92

Age (M6SD) Femalec Racec White Black Other

Preperiod health status CCI (M6SD)c,d Substance abusec Depressionc Anxietyc Hospitalization All causec Mental disorder relatedc Schizophrenia relatedc Emergency department visit All causec Mental disorder relatedc Schizophrenia relatedc

60 30 9 1,745 866 271 61 30 7 1,495 736 179 63 27 8 440 191 58 57 34 8 732 439 106 61 31 7 737 368 81 55 37 8 109 73 15 62 29 7 421 198 47 67 25 6

39.7612.5 1,242 57 39.3612.2 396 49 39.7612.6 634 52 39.6612.5 629 46 38.3612.5 92 43 40.9612.5 291 54 39.5612.7 442 41 36.3612.4 198

551 203 61

49 51

39.1612.6 1,440

% N % N % N % N % N % N % N % N N

% c

Characteristic

Total (N=2,440)b Ziprasidone (N=698) Risperidone (N=1,286) Quetiapine (N=1,201) Paliperidone (N=200) Olanzapine (N=675)

Antipsychotic polypharmacya

Aripiprazole (N=820)

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,

Clozapine monotherapy (N=479)

RESULTS

TABLE 1. Characteristics of Medicaid beneficiaries with schizophrenia treated with clozapine monotherapy or antipsychotic polypharmacy

(300.4, dysthymic disorder; 309.XX, adjustment reaction; 296.2 and 296.3, major depressive disorder; and 311, depressive disorder not elsewhere classified) (23), and anxiety (300.0X, anxiety states; 300.2X, phobic disorders; and 300.83, somatoform disorders). In addition, the resource utilization models controlled for preperiod resource utilization. In all analyses, antipsychotic polypharmacy was the reference category, and the coefficients represented clozapine monotherapy. For each study outcome, seven separate equations were run, one for antipsychotic polypharmacy overall and one for each antipsychotic polypharmacy cohort (aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone), compared with clozapine monotherapy (for example, aripiprazole polypharmacy versus clozapine monotherapy, olanzapine polypharmacy versus clozapine monotherapy, and so forth). Antipsychotic polypharmacy cohorts were not mutually exclusive; for example, a patient who used aripiprazole and olanzapine was included in both the antipsychotic polypharmacy aripiprazole and antipsychotic polypharmacy olanzapine cohorts. All analyses were conducted using SAS version 9.3, and an a priori significance level of .05 was specified.

Total sample (N=2,919)

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to have mental disorder–related use of the emergency departAripiprazole Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone ment (odds ratio [OR]=.75, 95% confidence interval [CI]=.60–.95) Antipsychotic N % N % N % N % N % N % or schizophrenia-related use Aripiprazole 176 7.2 27 1.1 248 10.2 272 11.2 97 4.0 of the emergency department Olanzapine 176 7.2 19 .8 151 6.2 216 8.9 113 4.6 (OR=.70, CI=.54–.90) in the Paliperidone 27 1.1 19 .8 61 2.5 73 3.0 20 .8 Quetiapine 248 10.2 151 6.2 61 2.5 499 20.4 242 9.9 postperiod; however, the cloRisperidone 272 11.2 216 8.9 73 3.0 499 20.5 226 9.3 zapine group was not sigZiprasidone 97 4.0 113 4.6 20 .8 242 9.9 226 9.3 nificantly less likely to be hospitalized or have an allboth demographically and clinically (all differences significause emergency department visit in the postperiod. This patcant at p,.001) (Table 1). Clozapine-treated patients were, on tern of results was similar for all antipsychotic polypharmacy average, 3.4 years younger (36.3 versus 39.7 years, respectively) combinations, but it was statistically significant only for the and had lower CCI scores (means of .3 versus .8). Among groups with polypharmacy involving quetiapine, risperidone, patients in the clozapine group, the proportion of white and ziprasidone. The number of all-cause hospital days for the patients was smaller than in the polypharmacy group (52% clozapine group and the polypharmacy group did not signifiversus 61%), as was the proportion of female patients (41% cantly differ, either overall or for any specific polypharmacy versus 51%). combination (Table 4). Baseline comorbidity rates were lower for the clozapine As shown in Table 5, in all utilization and drug categories, group than for the polypharmacy group: 12% versus 31%, total Medicaid payments were significantly lower for clozapinerespectively, for substance abuse; 12% versus 35% for detreated patients than for patients treated with antipsychotic pression; and 3% versus 14% for anxiety (Table 1). In both polypharmacy, with all-cause costs reduced on average by all-cause and disease-specific preperiod utilization categories, $21,233, mental disorder–related costs reduced by $17,457, and patients in the clozapine group were approximately one-half as schizophrenia-related costs reduced by $10,582. Across likely as those in the polypharmacy group to use medical all antipsychotic polypharmacy categories, costs for clozapineservices. For example, the percentages with at least one alltreated patients were on average $20,365–$26,557 lower for allcause hospitalization and one emergency department visit, cause medical services, $15,530–$22,745 lower for mental were 17% and 29%, respectively, for the clozapine group, disorder–related services, and $8,172–$11,923 lower for compared with 37% and 57% for the polypharmacy group. schizophrenia-related services. Schizophrenia-related hospitalization and schizophreniarelated emergency department use occurred for 15% and DISCUSSION 17%, respectively, of patients in the clozapine group, compared with 29% and 30% of those in the polypharmacy In a large, observational, 12-month study of Medicaid bengroup. eficiaries with a diagnosis of schizophrenia, those treated When the analysis controlled for these baseline differences with clozapine monotherapy were less likely than those (Table 3), patients treated with clozapine monotherapy were treated with antipsychotic polypharmacy to have a diseaseless likely than those treated with antipsychotic polypharmacy related emergency department visit but not significantly less TABLE 2. Second-generation antipsychotic combinations prescribed to a sample of 2,440 Medicaid beneficiaries with schizophrenia

TABLE 3. Logistic regression analyses of postperiod hospital and emergency department utilization and polypharmacy type among 2,440 Medicaid beneficiariesa Hospitalization

Polypharmacy typeb Aripiprazole Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone All

All cause

Mental disorder related

Emergency department visit Schizophrenia Related

All cause

Mental disorder related

Schizophrenia related

Nc

OR

95% CI

OR

95% CI

OR

95% CI

OR

95% CI

OR

95% CI

OR

95% CI

1,299 1,154 679 1,680 1,765 1,177 2,919

.82 .83 .66 .89 .85 .87 .84

.61–1.10 .61–1.12 .44–.99 .68–1.18 .65–1.11 .65–1.80 .66–1.08

.80 .81 .64 .89 .83 .85 .82

.60–1.08 .60–1.09 .43–.97 .67–1.17 .63–1.01 .63–1.15 .64–1.06

.84 .77 .69 .80 .81 .85 .80

.62–1.15 .56–1.05 .45–1.07 .60–1.07 .61–1.08 .61–1.16 .62–1.04

.86 1.00 .76 .89 .80 .77 .85

.67–1.12 .77–1.31 .52–1.12 .70–1.14 .64–1.02 .59–1.01 .69–1.06

.76 .84 .80 .76 .74 .71 .75

.58–1.00 .64–1.11 .54–1.18 .59–.98 .58–.95 .54–.93 .60–.95

.79 .76 .75 .69 .69 .67 .70

.58–1.06 .56–1.04 .50–1.15 .52–.91 .53–.91 .49–.90 .54–.90

a

Values are for comparison of clozapine monotherapy (dummy coded as 1) with each polypharmacy group (dummy coded as 0). All analyses controlled for demographic characteristics (age, sex, and race), preperiod health status (Charlson Comorbidity Index score, depression, substance abuse, and anxiety), and corresponding preperiod utilization measure (for example, preperiod all-cause hospitalization for analyses of postperiod all-cause hospitalization). b Drug name indicates at least 1 drug in the combination; for example, aripiprazole indicates treatment with any combination that includes aripiprazole. c The total N for each equation is 479 (N of patients treated with clozapine monotherapy) plus the number of those treated with any antipsychotic polypharmacy combination including the indicated drug.

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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%245%. 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 Psychiatric Services 66:2, February 2015

TABLE 4. Negative binomial regression analyses of postperiod number of days hospitalized and polypharmacy type among 2,440 Medicaid beneficiariesa Polypharmacy type Aripiprazole Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone All a

Exponentiated coefficient

95% CI

1.30 1.27 1.17 1.22 1.13 1.22 1.21

.86–1.97 .83–1.93 .62–2.19 .85–1.75 .80–1.60 .81–1.83 .89–1.64

Values are for comparison of clozapine monotherapy (dummy coded as 1) with each polypharmacy group (dummy coded as 0). Analyses controlled for demographic characteristics (age, sex, and race), preperiod health status (Charlson Comorbidity Index score, depression, substance abuse, and anxiety), and corresponding preperiod utilization measure (for example, preperiod all-cause hospitalization for analyses of postperiod all-cause hospitalization).

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 semistructuredinterview 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 sixmonth 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 3 time interaction). Although noting the limitations of their open-label design, Essock and colleagues (34) concluded that “most patients with continuing ps.psychiatryonline.org 131

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TABLE 5. Medical cost reductions (in dollars) for Medicaid beneficiaries with schizophrenia treated with clozapine monotherapy compared with those treated with antipsychotic polypharmacya Cost category and polypharmacy comparator

Cost reduction for clozapine group M

SD

Total costs Aripiprazole Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone All polypharmacy types

20,365 23,158 26,557 23,588 20,462 20,583 21,233

8,199 10,228 8,586 6,413 7,080 9,900 7,463

Mental disorder–related costs Aripiprazole Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone All polypharmacy types

17,225 19,512 22,745 19,264 17,171 15,530 17,457

6,063 7,168 7,043 5,441 4,987 5,398 4,958

Schizophrenia-related costsb Aripiprazole Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone All polypharmacy types

10,652 11,632 11,923 10,938 11,657 8,172 10,582

2,844 2,762 3,033 2,362 2,378 2,012 1,802

a

Estimated costs from a generalized linear model with gamma distribution and log link, which controlled for age; sex; race; preperiod Charlson Comorbidity Index score; preperiod diagnosis of depression, substance abuse, or anxiety; and intent-to-treat drug or drugs. All cost reductions for the clozapine group were significant (p,.001). b Data for some patients were removed from the analyses because of invalid values: polypharmacy with aripiprazole, 1 (N=1,298); with olanzapine, 1 (N=1,153); with risperidone, 2 (N=1,763); and all polypharmacy, 2 (N=2,917).

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 132

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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. CONCLUSIONS 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.

AUTHOR AND ARTICLE INFORMATION Dr. Velligan is with the Department of Psychiatry, University of Texas Health Science Center at San Antonio. Dr. Carroll is with Xcenda, Charlotte, North Carolina, and completed work on this project while employed at Teva Pharmaceuticals, Kansas City, Missouri. Dr. Lage is with HealthMetrics Outcomes Research, Bonita Springs, Florida. Ms. Fairman is with Kathleen Fairman, LTD, Phoenix, Arizona. Send correspondence to Dr. Lage (e-mail: [email protected]). 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.

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Outcomes of medicaid beneficiaries with schizophrenia receiving clozapine only or antipsychotic combinations.

Patients with treatment-resistant schizophrenia commonly receive nonrecommended drug regimens, including antipsychotic polypharmacy, sometimes in lieu...
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