The Effect of Race-Ethnicity on the

Comparative Effectiveness of Clozapine

Among Medicaid Beneficiaries
Marcela Horvitz-Lennon, M.D., M.P.H.
Julie M. Donohue, Ph.D.
Judith R. Lave, Ph.D.
Margarita Alegra, Ph.D.
Sharon-Lise T. Normand, Ph.D.

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

PSYCHIATRIC SERVICES

he second-generation antipsychotic clozapine is the only antipsychotic drug approved by

the U.S. Food and Drug Administration for the management of treatmentresistant symptoms and recurrent
suicidal behavior, two severe complications of schizophrenia (1,2). Furthermore, among all antipsychotics,
clozapine has the lowest rate of
suicide-related and all-cause mortality
(3,4). Despite these advantages, clozapine is underused in the routine
care of U.S. patients with schizophrenia (57). Consistent with a body of
evidence suggesting that patterns of
schizophrenia care are influenced by
patients race-ethnicity (79), studies
have shown that use of clozapine is
lower among patients from minority
groups than among white patients
(10).
Although clozapines superior efficacy has been long established (11,12),
evidence about its superior effectiveness had lagged behind until publication in the mid-2000s of results from
the publicly funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (13). The studys
primary measure of effectiveness was
time to drug discontinuation for any
causea synthesis of clinician and patient judgments on a drugs efficacy
and tolerability (14). Use of time to
discontinuation for any cause as
a measure of effectiveness is supported by evidence that has shown
that longer time to discontinuation is

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associated with greater clinical and

functional improvement (15,16). Unfortunately, like efficacy researchers
before them, CATIE researchers did
not report on whether the comparative
effectiveness of clozapine and the
other antipsychotics varies by racialethnic group. We know of two inpatient studies that assessed whether
black and white patients differed in
their response to clozapine; one
study found no differences, and the
other had mixed findings (17,18).
However, we are not aware of any study
that has assessed clozapine treatment
response by Latino ethnicity.
The purpose of this study was to fill
this evidentiary gap. Using time to
discontinuation for any cause as our
measure of effectiveness, we examined the effect of race-ethnicity on the
comparative effectiveness of clozapine and other antipsychotics among
patients in maintenance antipsychotic
treatment. The paucity of evidence
on racial-ethnic differences in antipsychotic effectiveness precluded us
from formulating hypotheses.

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
PSYCHIATRIC SERVICES

filled for any of the eight study drugs

beyond an initial three-month period
(representing acute-phase treatment).
Episodes were excluded if during the
three-month period preceding the
date when the antipsychotic prescription was first filled, the beneficiary
had fewer than three months of continuous fee-for-service enrollment or
any health maintenance organization
(HMO) or Medicare coverage. When
more than one qualifying maintenance antipsychotic treatment episode was observed for a beneficiary,
we selected the first episode. Episodes that were ongoing at the end of
the study period were observed for
one additional year.
Outcome variables
Our primary outcome variable was
time to discontinuation of medication
for any cause among beneficiaries receiving maintenance treatment with
clozapine versus other antipsychotics.
We operationalized discontinuation as
a break in prescription fills of 45 or
more days. We selected this interval
to allow for dose reductions or shortlived treatment interruptions attributable to refill delays stemming from
less than optimal adherence or other
treatment barriers commonly encountered by this population (7). We
sought to capture a broader set of
poor outcomes through a secondary
outcome variable that measured either time to antipsychotic discontinuation or time to hospitalization for
schizophrenia.
Explanatory variables
Our main explanatory variables were
antipsychotic drug treatment, raceethnicity, and their interaction. Antipsychotic drug treatment categories
were clozapine versus a group of seven
antipsychotic drugs (other antipsychotics). The group of other antipsychotics comprised all then-available
second-generation antipsychotics (olanzapine, quetiapine, risperidone,
ziprasidone, and aripiprazole) and
two first-generation antipsychotics
(haloperidol and perphenazine). We
included haloperidol because of its
dominance in the first-generation antipsychotic market and its prominent
role in antipsychotic outcomes research, and we included perphenazine

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because it was the first-generation

drug included in the CATIE trial.
Because fewer studies have assessed
the comparative effectiveness of clozapine versus other second-generation
agents, we conducted additional analyses that compared only clozapine to
the second-generation agents in the
other antipsychotic group.
Race-ethnicity was defined as black,
Latino, and non-Latino white, and it
was assessed as of the date when the
study drug prescription was first filled.
The Florida Medicaid program uses
a racial classification that describes beneficiaries as white, black, Hispanic,
Oriental, American Indian, or other.
We excluded the small proportion of
beneficiaries (less than 1%) otherwise
meeting inclusion criteria who during
the study period were classified as
Oriental or American Indian. While
the percentage of beneficiaries who
were classified as black or white varied
little during the study period, the
percentage classified as other and
Hispanic varied dramatically because
of changes in data recording. For example, an analysis of beneficiaries
present in the data in both FY 2005
and FY 2006 showed that 92% of
those who were classified as Hispanic
in FY 2006 had been classified as
other in FY 2005. In addition,
individuals classified as other in FY
2005 who were also present in the FY
2006 data indicated that 71% were
reclassified as Hispanic in FY 2006.
Most of the remaining 29% remained
other in 2006, which may indicate
that that they too were Hispanic.
Therefore, because most beneficiaries who were classified as other
during our study period were classified as Hispanic in previous or subsequent years, we reclassified the
other group as ever categorized as
Hispanic and we included these
patients and all those classified as
Hispanic in a group that we labeled
Latinos. As a result of this decision,
we have some minor misclassification
in our racial-ethnic groups.
Other explanatory variables included several need-related variables that
may have an impact on the decision to
use clozapine over other antipsychotics. These were age (a continuous
variable), sex, and four measures of
illness severity: psychiatric disorder
231

comorbidity, substance use disorder

comorbidity, intensity of use of inpatient services for schizophrenia, and
Supplemental Security Income (SSI)
status (further described below). Because patients general medical status
and geographic location may influence
prescriber decision making, additional
explanatory variables were metabolic
comorbidity and other general medical comorbidity and a geographic
variable indicating 11 multicounty
areas used by the Florida Medicaid
program to administer benefits. [A
table listing the counties in each of the
11 areas is available in an online data
supplement to this article.] Age, sex,
and area of residence were assessed as
of the date when the antipsychotic
drug prescription was first filled. The
measures of comorbidity, intensity of
inpatient use, and SSI status were
constructed with data observed during the three-month period before the
date when the antipsychotic prescription was first filled (baseline period).
The binary comorbidity measures required the observation of one or more
claims with selected ICD-9 diagnoses.
These diagnoses were major depression, dysthymia, and anxiety disorders
(psychiatric comorbidity); abuse of
and dependence on alcohol or drugs
other than tobacco (substance use
disorder comorbidity); diabetes, dyslipidemias, and obesity (metabolic
comorbidity); and all chronic general
medical disorders (other general
medical comorbidity). Intensity of
inpatient service use was defined as
the total number of inpatient days
with a primary diagnosis of schizophrenia. SSI status, a severity indicator because SSI eligibility suggests
a more disabling illness, was operationalized as SSI, Temporary Assistance
for Needy Families (TANF), or other.
To account for possible secular
trends, we also created a categorical
variable indicating the quarter in
which the antipsychotic prescription
was first filled.
Statistical analysis
Propensity score models for clozapine
use. We used propensity score matching to address potential selection
bias in medications received (19). We
modeled the log-odds of receiving
clozapine versus other antipsychotics
232

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
PSYCHIATRIC SERVICES

estimated Kaplan-Meier curves of

time to antipsychotic discontinuation
or to hospitalization for schizophrenia
and considered withdrawal and administrative censoring as censored
events. Final model estimates were
based on Cox proportional hazard
regression models that accounted for
the matched sets and included a clozapine dummy variable, a set of raceethnicity dummy variables, and a set of
interaction terms between antipsychotic drug treatment and raceethnicity. We assessed differences
in risk of discontinuation among the
groups (that is, the proportionality assumption) through graphical summaries of Schoenfeld residuals plotted
against log(time), chi square tests
for each covariate (drug treatment
and race-ethnicity), and a chi square
global test. Statistical models were
estimated using the S-PLUS software
system, version 8.0. Statistical significance was set at p#.05. We report
comparisons in the form of relative
risks (RRs) and 95% confidence
intervals (CIs).
Our study was granted exempt status
by the University of Pittsburgh Institutional Review Board because we used
data free of personal identifiers.

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

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Table 1

Characteristics of adult Medicaid beneficiaries with schizophrenia, by drug treatment

Total sample
(N=20,122)
Variablea
Race-ethnicity
Black
Latino
White
Age (mean6SD)
Female
Comorbid disorder
Psychiatric
Substance use
Metabolic
Other general medical
SSI beneficiary
Geographic areac
1
2
3
4
5
6
7
8
9
10
11
Quarter
1 (JulySept. 2000)
2 (Oct.Dec. 2000)
3 (Jan.March 2001)
4 (AprilJune 2001)
5 (JulySept. 2001)
6 (Oct.Dec. 2001)
7 (Jan.March 2002)
8 (AprilJune 2002)
9 (JulySept. 2002)
10 (Oct.Dec. 2002)
11 (Jan.March 2003)
12 (AprilJune 2003)
13 (JulySept. 2003)
14 (Oct.Dec. 2003)
15 (Jan.March 2004)
16 (AprilJune 2004)
17 (JulySept. 2004)
18 (Oct.Dec. 2004)
19 (Jan.March 2005)
20 (AprilJune 2005)
a

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.

includes Miami-Dade and Monroe

counties (41%) and occurred in the
first six quarters of the study period
(50%, N=10,125).
Clozapine was used in 3.7% of the
person-episodes (N=749). The proportions of blacks (2.3%) and Latinos
(2.1%) using clozapine were lower than
PSYCHIATRIC SERVICES

the proportion of whites (5.9%).

For the other 19,373 episodes, the
index antipsychotic drug was a
second-generation
antipsychotic
other than clozapine in 87% of the
cases (N=16,903); risperidone (28%,
N=5,398) and olanzapine (35%,
N=6,692) were the most frequently

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used drugs. On the basis of standardized differences, clozapine users

differed from users of other antipsychotics on most of the variables included in our multivariate models.
With few exceptions, these differences
were also observed within each racialethnic group.
233

Table 2

Unadjusted analysis of antipsychotic treatment discontinuation among

Medicaid beneficiaries with schizophrenia (N=20,122), by race-ethnicity
and drug treatment
Discontinuation for any cause
Drug and outcomea
Clozapine
Sample N
Median days to discontinuation
Rate (%)
Other antipsychotics
Sample N
Median days to discontinuation
Rate (%)b
a
b

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)

and twice as many users of other

antipsychotics (N=1,498). Our propensity score model generated wellbalanced groups, as evidenced by
the fact that with just one exception, standardized differences for
all variables were smaller than 10%.
The exception was time and only
for the 20th quarter (standardized
difference=10.4%).
Adjusted analyses confirmed most
of the unadjusted results (Table 3). [A
figure in the online data supplement
presents results of this analysis.]
Clozapine users had a lower risk of
discontinuation than users of other
antipsychotics (RR=.45). This effect
was not moderated by race-ethnicity.
Overall risk of discontinuation, however, was higher for blacks than for
whites (RR=1.56) and higher for

Table 3

Adjusted risk of antipsychotic treatment discontinuation among Medicaid

beneficiaries with schizophrenia, by drug treatment and race-ethnicitya
Model covariate
Main analysisb
Clozapine treatment (reference: other antipsychotics)
Race-ethnicity (reference: whites)
Blacks
Latinos
Interactions (reference: whites)c
Blacks
Latinos
a

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

PSYCHIATRIC SERVICES

Latinos than for whites (RR=1.23).

Although assessment of the proportionality assumption suggested some
nonconstant hazards (global x2=9.53;
p=.021), with blacks having a slightly
higher overall risk of earlier discontinuation than whites (x2=6.06, p=.014),
the (log) hazard ratio was small (,1.0).
In keeping with the Cox model results,
clozapine users had longer times to
discontinuation than users of other
antipsychotics (Table 4).
Results did not change when we
examined time to discontinuation or
to hospitalization or when clozapine
was compared only with secondgeneration antipsychotics. [Three
figures in the online data supplement
present results of these analyses.]

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

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of hospital days (18). A study that used

a longitudinal statewide data set comprising all inpatient episodes during
which patients received clozapine
found that blacks experienced more
robust early improvements on some
but not all the standardized scales that
were used to assess response (17).
Time to discontinuation for any
cause is influenced by a drugs efficacy
and tolerability, by patient adherence
behavior, and by prescriber behavior
(13). It is therefore notable that we
did not find racial-ethnic differences
in the effectiveness of clozapine relative to that of other antipsychotics
given evidence that black patients
treated with clozapine receive lower
doses (17), experience more weight
gain (22), and are more likely to have
clozapine unnecessarily discontinued
by their physicians (17,23,24).
Our finding that blacks and Latinos had a higher risk than whites
of discontinuing maintenance antipsychotic treatment is in keeping
with a study of California Medicaid
beneficiaries that found that black
race was associated with time to
antipsychotic discontinuation; the
study looked at use of three secondgeneration antipsychotics other than
clozapine and a first-generation antipsychotic (25). What may underlie this
result? Although it has been conjectured that racial-ethnic differences in
antipsychotic efficacy may exist (26),
there is no evidence from a randomized controlled trial to support this
possibility. There is evidence that
persons from racial-ethnic minority
groups may be more prone to certain
side effects (27), a phenomenon that
may be driven by inadequate matching of drugs to patients or excessive
dosing (28). Finally, some adherence
studies (2932) but not all (33) have
found that blacks and Latinos are
more likely to exhibit poor adherence
to antipsychotics.
Only a small fraction of patients in
our study were on maintenance treatment with clozapine. Although all
major schizophrenia treatment guidelines call for the use of clozapine to
manage severe presentations (34),
rates of any clozapine use remain
low in the United States (57). Clozapine treatment requires periodic blood
draws to monitor the patient for
PSYCHIATRIC SERVICES

Table 4

Days to antipsychotic treatment discontinuation among Medicaid

beneficiaries with schizophrenia, by drug treatment and race-ethnicitya
Drug and group
Clozapine
Blacks
Latinos
Whites
Other antipsychotics
Blacks
Latinos
Whites
All antipsychotics
Blacks
Latinos
Whites
a

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

' ps.psychiatryonline.org ' March 2013 Vol. 64 No. 3

nonresponsive to other drugs, with

persons receiving treatment with other
antipsychotics who were likely to
exhibit greater degrees of treatment
responsiveness. Second, unlike CATIE
researchers, we were unable to differentiate between discontinuation due
to lack of efficacy, intolerability, or
patient factors associated with adherence behavior. However, because
we assessed discontinuation among
patients in maintenance treatment
a population that had already shed
many persons most likely to discontinue because of intolerability or
treatment nonadherenceour anycause discontinuation results are
more likely to reflect discontinuation
due to lack of efficacy than to other
causes. In addition, we evaluated
incidence of concurrent antipsychotic
polypharmacy because polypharmacy
can lead to discontinuation of the
entire drug regimen due to a higher
incidence of side effects. Our analyses
showed that rates of polypharmacy
were similar for clozapine users and
other antipsychotic users for all racialethnic groups combined and for whites
(results not shown). Among blacks and
Latinos, rates of polypharmacy were
higher for clozapine users than for
users of other antipsychotics. However, if differences in polypharmacy
had any impact, they would have
worked to attenuate our findings
by increasing the likelihood of
235

clozapine discontinuation among minority groups. Third, our analyses may

have been underpowered to detect the
racial-ethnic differences in the comparative effectiveness of clozapine and
other antipsychotics that were suggested by the unadjusted analyses.
Last, the generalizability of our findings is limited by the fact that Florida
differs from other state Medicaid
programs because of its racial-ethnic
diversity and restrictive eligibility
requirements.

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.

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