Objective: Effectiveness trials have confirmed the superiority of clozapine in schizophrenia treatment, but little is known about whether the
drugs superiority holds across racial-ethnic groups. This study examined
the effectiveness by race-ethnicity of clozapine relative to other antipsychotics among adult patients in maintenance antipsychotic treatment.
Methods: Black, Latino, and white Florida Medicaid beneficiaries with
schizophrenia receiving maintenance treatment with clozapine or other
antipsychotics between July 1, 2000, and June 30, 2005, were identified.
Cox proportional hazard regression models were used to estimate associations between clozapine and race-ethnicity and their interaction; time
to discontinuation for any cause was the primary measure of effectiveness. Results: The 20,122 members of the study cohort accounted for
20,122 antipsychotic treatment episodes; 3.7% were treated with clozapine and 96.3% with other antipsychotics. Blacks accounted for 23% of
episodes and Latinos for 36%. Unadjusted analyses suggested that Latinos continued on clozapine longer than whites and that Latinos and
blacks discontinued other antipsychotics sooner than whites. Adjusted
analyses of 749 propensity scorematched sets of clozapine users and
other antipsychotic users indicated that risk of discontinuation was lower
for clozapine users (risk ratio [RR]=.45, 95% confidence interval [CI]
=.39.52), an effect that was not moderated by race-ethnicity. Times to
discontinuation were longer for clozapine users. Overall risk of antipsychotic discontinuation was higher for blacks (RR=1.56, CI=1.271.91)
and Latinos (RR=1.23, CI=1.021.48). Conclusions: The study confirmed
clozapines superior effectiveness and did not find evidence that raceethnicity modified this effect. The findings highlight the need for efforts
to increase clozapine use, particularly among minority groups. (Psychiatric Services 64:230237, 2013; doi: 10.1176/appi.ps.201200041)
Dr. Horvitz-Lennon is affiliated with the RAND Corporation, 4570 Fifth Ave., Suite 600,
Pittsburgh, PA 15213 (e-mail: mhorvitz@rand.org). When this work was initiated, she was
with the Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
Dr. Donohue and Dr. Lave are with the Graduate School of Public Health, University of
Pittsburgh. Dr. Alegra is with the Center for Multicultural Mental Health Research,
Cambridge Health Alliance, Somerville, Massachusetts. Dr. Normand is with Harvard
Medical School and Harvard School of Public Health, Boston.
230
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Methods
Data sources and sample
To construct the study cohort, we used
enrollment files and medical and pharmacy claims from the Florida Medicaid program for fiscal years 20012005
(July 1, 2000, through June 30, 2005).
Cohort members were adults aged
1864 years who had at least two
claims with a diagnosis of schizophrenia (ICD-9 diagnostic codes 295.xx)
recorded on two different service dates
during each fiscal year (FY) and who
had filled at least one prescription for
an antipsychotic drug during the study
period.
We selected patients receiving maintenance antipsychotic treatment with
clozapine or any of seven antipsychotic drugs (olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole,
haloperidol, and perphenazine). We
focused on patients in maintenance antipsychotic treatment because drug
discontinuation during maintenancephase treatment is less likely than discontinuation during the acute treatment
phase to be influenced by intolerability and patient factors associated with
adherence behavior. We defined maintenance treatment as prescriptions
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as a function of the explanatory variables (age, sex, four comorbidity variables, intensity of inpatient use, SSI
status, geographic area, and quarter of
the year). Our propensity score models
were estimated separately within each
race-ethnicity group. We estimated log-odds of receiving clozapine
versus other antipsychotics and compared probabilities between patients
who received clozapine and those
who received other antipsychotics.
We evaluated the comparability of
clozapine-treated patients and those
treated with other antipsychotic drugs
by assessing the extent to which the
patients overlapped on each variable.
Adequate comparability was defined
a priori as standardized differences of
10% or smaller between the groups
(20). For each clozapine-treated patient, we identified two similar persons of the same race-ethnicity who
were treated with other antipsychotics.
This resulted in matched sets for each
racial-ethnic group of one clozapinetreated person and two persons treated
with other antipsychotics. We assumed
that use of clozapine and raceethnicity might vary widely by geographic area and that medication
discontinuation rates might vary over
time; therefore, we used fine balancing (21) to exactly match clozapine
and other antipsychotic users on the
basis of when they filled their index
prescription (quarter) and where they
lived (area) at that time.
For each matched set of patients,
we assessed number of days from the
start of the antipsychotic episode to
four mutually exclusive outcomes,
whichever was observed first: antipsychotic discontinuation as defined
above, hospitalization for schizophrenia, withdrawal (defined as any discontinuity in Medicaid enrollment or
more than one month of HMO or
Medicare coverage), and administrative censoring (defined as ongoing
use of the study drug by June 1, 2006,
the end of the additional period of
observation).
Discontinuation models. We first
estimated Kaplan-Meier curves of time
to antipsychotic discontinuation and
considered the other three outcomes
(hospitalization for schizophrenia,
withdrawal, and administrative censoring) as censored events. We also
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Results
Characteristics of the study cohort
Over the entire study period, 41,262
persons met diagnostic, age, and
racial-ethnic criteria and also filled
an antipsychotic prescription. Most of
them filled prescriptions for one or
more of the eight study drugs (99%,
N=40,725). Further application of our
inclusion and exclusion criteria reduced the size of the study cohort to
an analytic sample of 20,122 persons,
each contributing one episode of
maintenance antipsychotic treatment.
[A flowchart depicting the cohortbuilding steps is available in the online
data supplement to this article.] As
shown in Table 1, 23% of the patients
were black, 36% were Latino, and
41% were white. The mean age was
42 years, 52% of the patients were
female, and 87% were receiving SSI.
Comorbidity rates ranged between
5% for substance use disorder comorbidity and 29% for other general
medical comorbidity. Most episodes
were observed in area 11, which
Table 1
Clozapine
(N=749)
Other antipsychotics
(N=19,373)
Standardized
differenceb
4,623
7,206
8,293
42.4611.1
10,414
23.0
35.8
41.0
14.3
19.9
65.8
43.4
4,516
7,057
7,800
42.6611.2
10,089
23.3
36.4
40.3
51.8
107
149
493
38.7610.8
325
52.1
223.3
237.4
53.0
.4
217.5
3,854
1,027
2,706
5,816
17,443
19.2
5.1
13.5
28.9
86.7
53
20
39
75
632
7.1
2.7
5.2
10.0
84.4
3,801
1,007
2,667
5,741
16,811
19.6
5.2
13.8
29.6
86.8
237.5
213.0
229.5
237.5
26.8
659
764
1,413
1,815
1,519
942
1,290
635
1,131
1,755
8,199
3.3
3.8
7.0
9.0
7.5
4.7
6.4
3.2
5.6
8.7
40.7
29
18
36
118
101
47
77
58
64
71
130
3.9
2.4
4.8
15.8
13.5
6.3
10.3
7.7
8.5
9.5
17.4
630
746
1,377
1,697
1,418
895
1,213
577
1,067
1,684
8,069
3.3
3.9
7.1
8.8
7.3
4.6
6.3
3.0
5.5
8.7
41.7
3.4
28.3
29.7
21.4
20.3
7.3
14.6
21.3
11.9
2.7
255.3
5,188
1,351
1,055
828
919
784
771
765
765
748
862
785
752
690
721
646
679
632
649
533
25.8
6.7
5.2
4.1
4.6
3.9
3.8
3.8
3.8
3.7
4.3
3.9
3.7
3.4
3.6
3.2
3.4
3.1
3.2
2.6
475
39
38
24
12
13
14
13
21
8
11
12
16
12
10
6
8
8
5
4
63.4
5.2
5.1
3.2
1.6
1.7
1.9
1.7
1.9
1.1
1.5
1.6
2.1
1.6
1.3
.8
1.1
1.1
.7
.5
4,713
1,312
1,017
804
907
771
757
752
744
740
850
773
736
678
711
640
671
624
644
529
24.3
6.8
5.3
4.2
4.7
4.0
3.9
3.9
3.8
3.8
4.4
4.0
3.8
3.5
3.7
3.3
3.5
3.2
3.3
2.7
85.7
26.6
.8
25.0
217.7
213.5
212.2
213.0
25.8
217.9
217.4
214.5
29.8
212.1
215.0
217.7
216.1
214.9
219.1
217.4
Inpatient days, comorbidity variables, and Supplemental Security Income (SSI) status were assessed over the 3-month period preceding the first filled
antipsychotic prescription.
Standardized differences for comparison of clozapine versus other antipsychotics. Differences larger than 10% are statistically significant; positive
values indicate that the measure is higher for clozapine users.
A table listing the counties in each area is available in an online data supplement to this article.
Table 2
All
Blacks
Latinos
Whites
749
740
53.3
107
646
55.1
149
789
48.3
493
736
54.4
.397
19,373
282
73.5
4,516
248
75.5
7,057
281
74.0
7,800
304
71.9
,.001
All rate comparisons between clozapine and other antipsychotics were significant (,.001).
Per Tukeys test, the black-white rate difference and the Latino-white rate difference for other
antipsychotics were statistically significant (p,.05).
Unadjusted analyses
The overall rate of discontinuation
was 72.7% (N=14,634). Mean and median times to discontinuation were 794
days and 548 days, respectively. As
shown in Table 2, clozapine users had
lower rates of discontinuation than
other antipsychotic users regardless
of race-ethnicity. Latinos had lower
rates of discontinuation from clozapine treatment than blacks and
whites, but the differences were not
statistically significant. Whites had
lower rates of discontinuation from
other antipsychotics than blacks and
Latinos. Results for time to discontinuation mirrored the results for rates.
Adjusted analyses
We created 749 matched sets that
included all clozapine users (N=749)
Table 3
b
c
Risk ratio
95% CI
.45
.39.52
1.56
1.23
1.271.91
1.021.48
.77
.83
.531.12
.591.16
Adjusted analyses of 749 propensity scorematched sets of clozapine users and other antipsychotic
users. Adjusted by matching on age, sex, inpatient days for schizophrenia, four measures of comorbidity, Supplemental Security Income status, geographic area, and quarter
Estimates generated by the model without interaction terms
Interactions between clozapine treatment and race-ethnicity
234
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Discussion
In this five-year study of a Medicaid
cohort receiving maintenance treatment for schizophrenia, we did not
observe any significant differences
by race-ethnicity in the effectiveness
of clozapine relative to that of other
antipsychotics. These findings did
not change when we assessed risk
of discontinuation or hospitalization
or when the comparator group included only second-generation antipsychotics other than clozapine. This
is an important set of results given
the paucity of evidence on racial-ethnic
differences in responses to clozapine
and on whether findings of comparative
effectiveness research can be generalized to racial-ethnic minority groups.
Our study replicated the findings of
the CATIE study in a Medicaid population comprising only patients in
maintenance antipsychotic treatment.
Our study expanded on the CATIE
findings by evaluating the influence of
race-ethnicity on outcomes of clozapine
treatment and treatment with other
antipsychotics. We know of only
two studies that have assessed whether
clozapine outcomes vary by race, and
we know of no study that has assessed
whether outcomes vary by Latino
ethnicity. A randomized controlled
trial conducted among hospitalized
veterans with treatment-refractory
symptoms of schizophrenia found
that black race was not predictive
of differential response to clozapine
versus haloperidol, as assessed by
standardized assessments and number
Table 4
Median days
95% CI
107
149
493
1,422
1,659
1,228
9611,840
1,2992,052
1,0701,593
214
298
986
459
566
639
364694
426754
584701
321
447
1,479
720
895
812
569937
7541,038
742883
Adjusted analyses of 749 propensity scorematched sets of clozapine users and other antipsychotic
users. Adjusted by matching on age, sex, inpatient days for schizophrenia, four measures of comorbidity, Supplemental Security Income status, geographic area, and quarter. Estimates generated by
the model without interaction terms
agranulocytosis, a life-threatening condition. It has been posited that underuse stems from patients aversion to
needles, psychiatrists safety concerns,
or the higher burden associated with
clozapine prescribing; however, these
factors are unlikely to fully explain the
underuse phenomenon (35,36). Multiple studies have found that the likelihood of any use of clozapine is even
lower for blacks (7,17) and Latinos
(10,37). The factors driving lower
use of clozapine among racial-ethnic
minority groups are not well understood. It has been suggested that
lower use of clozapine among blacks
may stem from providers expectation
that blacks will have lower response
rates, their perception of blacks as less
treatment adherent, and their unfounded concern that agranulocytosis
may be more likely to occur among
blacks (24).
Our findings should be considered
in light of some limitations. First,
because of the nonexperimental nature of our study design, unmeasured
differences may have existed between
users of clozapine and users of other
antipsychotics. In particular, we were
unable to select patients on the basis
of their treatment response status, an
important confounder. However, this
limitation may have worked to attenuate our findings because we compared clozapine-treated persons, all
of whom were very likely to be
Conclusions
We found that race-ethnicity did not
modify the superior effectiveness of
clozapine compared with that of other
antipsychotics in a population of
Medicaid beneficiaries with schizophrenia. We have thus confirmed and
expanded CATIEs findings, highlighting the need for efforts to understand factors that explain the
underuse of clozapine and to increase
its use, particularly among minority
groups.
Acknowledgments and disclosures
This work was supported by grants R01MH087488 and R34MH082682 from the National Institute of Mental Health and grant
R01HS017695 from the Agency for Healthcare
Research and Quality. The authors are grateful to
Christina Fu, Ph.D., for programming assistance and to Frank Yoon, Ph.D., for statistical
expertise with matching.
The authors report no competing interests.
References
1. Conley RR, Buchanan RW: Evaluation of
treatment-resistant schizophrenia. Schizophrenia Bulletin 23:663674, 1997
2. Cohen LJ, Test MA, Brown RL: Suicide
and schizophrenia: data from a prospective
community treatment study. American
Journal of Psychiatry 147:602607,
1990
3. Walker AM, Lanza LL, Arellano F, et al:
Mortality in current and former users
of clozapine. Epidemiology 8:671677,
1997
4. Tiihonen J, Lnnqvist J, Wahlbeck K, et al:
11-year follow-up of mortality in patients
with schizophrenia: a population-based
cohort study (FIN11 study). Lancet 374:
620627, 2009
5. Wang C-C, Farley JF: Patterns and predictors of antipsychotic medication use
among the U.S. population: findings from
the Medical Expenditure Panel Survey.
Research in Social and Administrative
Pharmacy (Epub ahead of print, Sept 17,
2009)
236
19. DAgostino RB, Jr: Propensity score methods for bias reduction in the comparison of
a treatment to a non-randomized control
group. Statistics in Medicine 17:22652281,
1998
12. Kane J, Honigfeld G, Singer J, et al: Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with
chlorpromazine. Archives of General Psychiatry 45:789796, 1988
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