Recent Trends in Antipsychotic Combination
Therapy of Schizophrenia and Schizoaffective
Disorder: Implications for State Mental
Health Policy
by Robin E. Clark, Stephen J. Bartels, Thomas A. Mellman, and
William J. Peacock
(Davidson 1974; Godleski et al. 1989). More recently,
combination therapy using atypical antipsychotic agents
has gained new currency among clinicians as a means to
optimize outcomes for treatment-resistant or residual
symptoms, including combinations of atypical and typical
antipsychotics or combinations of two atypical antipsychotic drugs (Canales et al. 1999; Stahl 1999a; Meltzer
and Kostakoglu 2000). Despite increasing acceptance of
antipsychotic combination therapy, there is only one controlled study evaluating the effectiveness of this practice
(Shiloh et al. 1997).
The lack of an evidence base for combination therapy
is especially challenging for State mental health authorities and clinical administrators who are responsible for
justifying Medicaid pharmacy costs, one of the most
rapidly growing components of the public health care
budget. In recent years, psychiatric medications, including
atypical antipsychotics and selective serotonin reuptake
inhibitors (SSRIs), have accounted for seven of the ten
most expensive medications purchased through State
Medicaid plans (unpublished New Hampshire Medicaid
data). State mental health authorities around the country
are being asked to develop strategies for controlling
spending on antipsychotics, and some are having such
strategies imposed on them. Data are needed on the trends
and patterns of combination therapy in the treatment of
schizophrenia in order to inform health policy. This article
provides a detailed description of this trend by examining
the use of combination therapy in a cohort of Medicaid
beneficiaries over 5 years of treatment.
Coprescription—sometimes called polypharmacy—is
increasing in clinical practice, although the extent of or
reasons for such a trend are not well documented (Stahl
1999ft; Meltzer and Kostakoglu 2000). A common explanation for the increasing use of combination therapy in
Abstract
Little is known about antipsychotic combination therapy, although this practice is becoming increasingly
common in the treatment of schizophrenia. Medicaid
pharmaceutical claims for a cohort of 836 New
Hampshire beneficiaries with schizophrenia or
schizoaffective disorder were followed from 1995
through 1999. Use of traditional and atypical antipsychotic medications, antidepressants, anxiolytic hypnotics, and mood stabilizers was tracked monthly. The
number of medications, frequency of coprescription,
and Medicaid pharmaceutical costs are described. The
proportion of individuals with schizophrenia and
schizoaffective disorder treated with atypical antipsychotics grew from 43 percent in 1995 to 70 percent in
1999. At the same time, concurrent use of two or more
antipsychotic medications quadrupled, increasing
from 5.7 percent to 24.3 percent. Persons with schizophrenia were also prescribed more antidepressants
(increased from 18.5% in 1995 to 35.6% in 1999),
anxiolytics (increased from 19.9% to 33.5%), and
mood stabilizers (increased from 17.7% to 30.0%).
The increase in multiple agent therapy appears to be
broad-based. Data are needed on the effectiveness and
cost-effectiveness of these practices to inform clinical
decision making and health policy.
Keywords: Schizophrenia, schizoaffective,
polypharmacy, combination therapy, atypical antipsychotics.
Schizophrenia Bulletin, 28(l):75-84, 2002.
Combination therapy with antipsychotic medications is
being embraced as an increasingly common practice by
clinicians in the treatment of schizophrenia, yet there is a
surprising lack of data documenting this trend or supporting its effectiveness. Early reports describe combination
therapy with high- and low-potency neuroleptics as a
strategy to balance side effects while maintaining efficacy
Send correspondence to Dr. R.E. Clark, Dartmouth Medical School,
Department of Community and Family Medicine, Strasenburgh 7250,
Hanover, NH 03755-3862; e-mail: [email protected].
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Schizophrenia Bulletin, Vol. 28, No. 1, 2002
R.E. Clark et al.
schizophrenia treatment is that different types and classes
of agents have different and complementary affinities for
different receptors that play a role in psychosis. For example, the scientific rationale for combining traditional neuroleptics with atypical antipsychotic drugs includes complementing the D2 receptor blockade of neuroleptics with
atypical agents that have varying affinities for different 5HT receptors. A review of three prescription surveys
found that up to one-fourth of patients in outpatient settings (diagnosis not specified) receive two antipsychotics,
usually a neuroleptic and an atypical antipsychotic (Stahl
199%).
Despite reports of the widespread use of antipsychotic combination therapy by clinicians, the evidence
base for this practice (with the exception of a single
study) is limited to anecdotal case reports and small,
uncontrolled studies. These studies include reports of the
addition of thioridazine to risperidone to reduce anxiety
and agitation (Goss 1995); the addition of risperidone to
traditional neuroleptics for treatment-refractory schizophrenia (Bacher and Kaup 1996); and the combination of
low-dose traditional neuroleptics (e.g., haloperidol, trifluoperazine, fluphenazine) with different atypical antipsychotics (risperidone, olanzapine, and quetiapine) for treatment-refractory psychosis (Waring et al. 1999).
Combination therapy, including the addition of parenteral
traditional neuroleptics to atypical antipsychotics, has also
been advocated for crisis management in the treatment of
acute psychosis (Ereshefsky 1999), although this practice
has been criticized for introducing the risk of acute dystonic reactions with minimal (if any) reduction in time to
treatment response (Meltzer and Kostakoglu 2000). The
addition of other atypical antipsychotics to clozapine has
been described as a means of augmentation therapy in a
variety of open trials, including trials combining clozapine with risperidone (McCarthy and Terkelsen 1995;
Henderson and Goff 1996; Morera et al. 1999; Raskin et
al. 2000) and augmenting clozapine with olanzapine
(Gupta et al. 1998). Remarkably, there is only one doubleblind, controlled study of the effectiveness of antipsychotic combination therapy. This study of 28 patients with
a partial treatment response to clozapine found improvement in positive and negative symptoms for augmentation
with sulphide compared to placebo (Shiloh et al. 1997).
Overall, the evidence base for prescribing more than one
antipsychotic has not yet been established, and the potential (but unproven) benefits of this practice should be balanced with the increased risk of adverse side effects, the
greater likelihood of treatment noncompliance, and the
increased pharmacy costs (Lehman and Steinwachs 1998;
Meltzer and Kostakoglu 2000; Sherman 2001).
Despite the benefits of atypical antipsychotics, the
high use and costs of these medications are attracting
attention (Zito 1998; Geddes et al. 2000; Martin et al.
2001). Scrutiny is likely to be further heightened by
trends suggesting that clinical practice is moving toward
combinations of atypical antipsychotics (Sherman 2001)
or combinations of atypical antipsychotics with other relatively expensive agents such as SSRIs. Although costeffectiveness, rather than cost, is the most appropriate
basis for allocating health care expenditures, costly treatments inevitably attract the attention of policy makers
seeking to curb public spending. From a health policy perspective, detailed information is needed by State mental
health authorities on current prescribing trends to help to
define targets for treatment effectiveness research and
clinical practice improvement. The purpose of this article
is to examine trends in combination therapy in the treatment of schizophrenia and to address the following specific questions:
•
•
What are the magnitude and nature of the recent
increase in combination therapy? In view of the long
tradition of combination therapy in schizophrenia
treatment, to what extent is there a recent increase in
this practice, and what combinations are most commonly used by practitioners?
Is the increasing use of combination therapy a selective and targeted practice consisting of one or two
types of antipsychotic combinations? Or is it a trend
toward broad-based polypharmacy, including an
increase in combinations of antipsychotics with a
variety of other antipsychotics, antidepressants, anxiolytics, and mood-stabilizing agents?
Methods
Sample. We used 1995 paid Medicaid claims for New
Hampshire beneficiaries with disabilities to identify a
cohort of persons with schizophrenia and schizoaffective
disorder. Filled prescriptions for this group were then
tracked on a monthly basis over the subsequent 5 years
beginning January 1, 1995, and ending December 31,
1999. This approach allowed us to identify trends in prescription drug use for a fixed group of persons without
risk of bias associated with substantial changes in case
mix. In particular, we were interested in eliminating the
possibility that an increase in the use of combination therapy might be associated with the entry of new individuals
into the treatment system with greater acuity, comorbidity,
and treatment complexity. Changes in prescriptions for a
single treatment cohort over time are most likely to be
associated with evolving treatment practices rather than
fluctuations in the clinical complexity and treatment needs
of the population being served. Inclusion criteria were as
follows: a claims-based diagnosis of schizophrenia or
schizoaffective disorder; absence of recorded diagnoses of
Alzheimer's disease, dementia, or mental retardation; and
76
Recent Trends in Antipsychotic Combination Therapy
Schizophrenia Bulletin, Vol. 28, No. 1, 2002
continuous Medicaid enrollment from 1995 through
1999.
Trends in Antipsychotic Combination Therapy. Figure
1 shows changes in psychiatric medication prescriptions
for individuals with schizophrenia and schizoaffective
disorder from 1995 to 1999. As shown, there were substantial decreases in the number of persons taking traditional neuroleptic antipsychotic medications and
increases in those using atypical antipsychotics. By
December 1999, seven in ten persons were taking an
atypical antipsychotic. In addition, there were substantial
increases in the prescription of antidepressants, anxiolytics, and mood stabilizers over the 5-year period.
Overall, the number of persons taking more than one
antipsychotic of any type increased from 48 (5.7%) in
December 1995 to 203 (24.3%) in December 1999.
Simultaneous use of both traditional neuroleptics and
atypical antipsychotics more than doubled from 1995 to
1999 (up 259.4%). By December 1999, almost 14 percent
of all participants were taking a combination of traditional and atypical antipsychotics. Coprescription of atypical antipsychotics grew even more rapidly, resulting in
10 percent of participants taking two or more atypicals in
December 1999. Among persons with schizophrenia,
multiple atypical antipsychotic use increased from 9 individuals (1.5%) in 1995 to 74 (12.4%) in 1999. In the
schizoaffective group, 2 (0.8%) used more than one atypical antipsychotic in 1995 compared to 19 (8%) in 1999.
Coprescription of traditional medications changed little.
Five persons with schizophrenia (0.8%) took two traditional neuroleptics in 1995 and in 1999. Only one person
with schizoaffective disorder took two traditional medications in 1995, and none used that combination in 1999.
Combination therapy also increased for antipsychotics prescribed with psychiatric medications from
other therapeutic classes. The number of persons with
schizophrenia who used antidepressants increased from
111 (18.5%) in 1995 to 213 (35.6%) in 1999. SSRIs
accounted for more than two-thirds of this change,
increasing from 81 (13.5%) persons with coprescriptions
in 1995 to 151 (25.2%) in 1999. Other novel antidepressant use grew from 12 (2.0%) persons to 41 (6.8%). The
pattern was similar for individuals with schizoaffective
disorder: antidepressant use increased from 48 persons
(20.3%) in 1995 to 115 (48.5%) in 1999. SSRIs
accounted for more than half of the increase, growing
from 27 (11.4%) to 67 (28.3%). Prescriptions of other
novel antidepressants increased from 10 (4.2%) to 33
(13.9%).
Anxiolytic hypnotics and mood stabilizers were used
increasingly during the same period. One in five (19.9%)
persons filled an anxiolytic hypnotic prescription in 1995.
By December 1999, one in three (33.5%) took an anxiolytic hypnotic. Use increased by more than three-quarters (77.1%) among persons with schizophrenia and by
more than half (54.1%) in persons with schizoaffective
Procedures. All paid Medicaid claims in 1995 were used
to identify beneficiaries with schizoaffective disorder or
schizophrenia diagnoses. Persons with both schizophrenia
and schizoaffective disorder during the year were classified as having schizoaffective disorder. Prescription drug
claims were followed for the entire 5 years. Medications
were classified in four major categories and varying numbers of subcategories (in parentheses): antipsychotics (traditional neuroleptics, including chlorpromazine, haloperidol, trifluoperazine, fluphenazine; and atypical
antipsychotics, including clozapine, risperidone, olanzapine, quetiapine), antidepressants (traditional
[monoamine oxidase inhibitors and tricyclics]; SSRIs;
other novel compounds such as bupropion, venlafaxine,
nefazodone, mirtazapine), anxiolytics (e.g., lorazepam,
clonazepam), and mood stabilizers (lithium, valproate,
carbamazepine, gabapentin, lamotrigine, topiramate). Use
of antiparkinsonian drugs to treat extrapyramidal side
effects was also monitored. Filled prescriptions for
patients were summarized monthly for 5 years. We used
point prevalence measures of prescriptions filled in
December of each year to describe changes in medication
treatment patterns from year to year.
We calculated the number of different medications
prescribed in a month and the length of time over which a
given combination of antipsychotic medications was prescribed, choosing a conservative cutoff point of 9 months
to distinguish between within-class coprescription during
a medication change and coprescription as a long-term
therapeutic strategy. Transition from one medication to
another typically takes substantially less than 9 months.
Statistical Analysis. Because our analysis included the
total population of persons with schizophrenia and
schizoaffective disorder, we used only descriptive statistics to explore medication use. The significance of
changes from 1995 to 1999 was analyzed using Wilcoxon
rank sum tests.
Results
A total of 836 persons met inclusion criteria for the full 5
study years: 599 with schizophrenia and 237 with
schizoaffective disorder. The average age for participants
with schizophrenia was 47.7 years (standard deviation
[SD] = 14.9) and for those with schizoaffective disorder
was 43.6 years (SD = 11.6). Slightly more than half
(51.2%) of those with schizophrenia were males, while 46
percent with schizoaffective disorder were males. Most
persons (79.2%) qualified for disability benefits because
of their mental disorder.
77
Schizophrenia Bulletin, Vol. 28, No. 1, 2002
R.E. Clark et al.
Figure 1. Percentage of people with schizophrenia and schizoaffective disorder using various types
of prescribed medications, 1995-1999
80%
60%
a
"a.
I
40%
I«
S.
20%
0% .
1995
1996
1997
1998
1999
• ConventionalAntipsychotics - • • - Atypical Antipsychotics - - ± - Antidepresslnts ^ # ^ - Anxiolytics - - a • • Mood Stabilizers
disorder. Among all persons, the number using mood stabilizers increased from 148 (17.7%) in 1995 to 251
(30.0%) in 1999. In December 1999, 131 persons with
schizophrenia (21.9%) and 120 persons with schizoaffective disorder (50.6%) filled prescriptions for mood stabilizers.
Antiparkinsonian prescriptions declined during the
study period, from 241 persons in 1995 (28.8%) to 173
(20.7%) in 1999. Rates of decline were similar for schizophrenia and for schizoaffective disorder.
and the increased frequency of taking multiple drugs
within a class.
There was a clear trend toward prescribing antipsychotic combinations for longer periods in 1999 than in
1995. The percentages of individuals taking traditional
and atypical antipsychotics simultaneously for 9 or more
months in a given year grew from 15.9 percent in 1995 to
27.7 percent in 1999. The number using atypical antipsychotic combinations for the same duration increased from
22.2 percent to 44.5 percent. Changes in duration were
significantly different for both combinations respectively
(z = 3.54, p < 0.001; z = 2.90, p = 0.004). The number of
persons taking combinations of two or more traditional
antipsychotics declined nonsignificantly from 56 in 1995
to 19 in 1999 (z = 0.57, p = nonsignificant).
Figure 2 shows changes in psychiatric medication
costs for schizophrenia and schizoaffective disorder
from 1995 to 1999. As shown, atypical antipsychotic
medications accounted for the greatest growth in psychiatric medication costs. Total medication payments
(including those for medications for physical disorders
not shown in figure 2) increased 47.5 percent from $328
(SD = $293) per month in 1995 to $484 (SD = $373) in
1999 for persons with schizophrenia, and increased 49.3
percent from $335 (SD = $289) to $500 (SD = $339) for
Medication Treatment Intensity. Combining psychotropic and other medications, the average person with
schizophrenia or schizoaffective disorder filled prescriptions for five different medications in December 1999
(SD = 3.87), one more prescription than in 1995 and one
more than did Medicaid beneficiaries without a schizophrenia-related disorder. Psychotropic medications contributed about half of this change, increasing from a mean
of 2 medications in 1995 to 2.5 in 1999. Atypical antipsychotic use more than doubled (from 0.35 to 0.75 medications per person), antidepressant use increased from 0.24
to 0.37, and traditional antipsychotic use decreased from
0.53 to 0.33. These changes reflect differences in the
number of people using the various drug classifications
78
Recent Trends in Antipsychotic Combination Therapy
Schizophrenia Bulletin, Vol. 28, No. 1, 2002
Figure 2. Mean monthly psychotropic drug costs for people with schizophrenia and schizoaffective
disorder
$300 .
_
.
.
$250
$200 at
» $150 *.
5
•
£
§ $100 -_
n
$50 4- • • •
$0 ;
1995
1996
1997
1998
1999
I- -#- - Conventional Antipsychotics - +-. Atypical Antipsychotics —•— Antidepressants -. A • - Other Psychotropics
1
Adjusted for inflation using the consumer price index for all urban consumers.
Remarkably, both within-therapeutic-class and acrosstherapeutic-class coprescription increased during the 5
study years. The greatest increase was in the practice of
combining two or more antipsychotic medications, which
more than quadrupled over the 5-year period. By the end
of 1999, one-fourth of all persons with schizophrenia or
schizoaffective disorder were taking more than one
antipsychotic. Combination therapy including antipsychotics and antidepressants more than doubled during the
same period, and concurrent prescriptions for anxiolytic
hypnotic medications grew by more than two-thirds.
Growth in the use of antipsychotics combined with mood
stabilizers was similar to that of anxiolytic hypnotics. The
trend toward polypharmacy as a treatment strategy was
further confirmed by measures of medication treatment
intensity. At the end of the study period, persons with
schizophrenia or schizoaffective disorder were taking
more different types of medications and were maintained
on multiple antipsychotic drugs for longer periods of
time. The latter suggests that our point prevalence observations did not simply capture people in the process of
changing from one drug to another but reflected a trend
toward long-term coprescription of antipsychotics as a
therapy.
those with schizoaffective disorder. One-fifth of this cost
(18% and 21%) was for medications used to treat
nonpsychiatric conditions, a proportion that remained
stable from 1995 to 1999. The percentage of overall
medication costs attributable to atypical antipsychotic
medications increased from 58.7 percent to 63.8 percent
among persons with schizophrenia and from 49.8 percent to 56.3 percent for those with schizoaffective disorder. Figure 3 shows the average incremental medication
costs associated with various combinations of antipsychotic medications in 1999. Total drug costs for combinations of atypical antipsychotics, which represented
36.6 percent of all coprescriptions, were three to five
times those of a single traditional antipsychotic. The percentage of total costs contributed by antidepressants and
other psychotropic medications increased less than 1
percent.
Discussion
This analysis of prescribing trends for a cohort of
Medicaid recipients with schizophrenia and schizoaffective disorder shows a clear and substantial increase in the
use of combination therapy between 1995 and 1999.
79
Schizophrenia Bulletin, Vol. 28, No. 1, 2002
R.E. Clark et al.
Figure 3. Total drug costs for people with schizophrenia and schizoaffective disorder, 1999
$1,000
$800
£
o
$600
©
a
§
O
$400
$200
$0
Only One
Conventional
More Than One
Conventional
Only One Atypical Conventional and
Atypical
More Than One
Atypical
Drug Combinations
lAntipsychotics
gAntidepressants
• OtherPsychotropic Drugs
While case reports and uncontrolled clinical studies
suggesting benefits of various drug combinations can be
found in the literature, the evidence base for the benefits
of combining two or more antipsychotics is sparse
(Meltzer and Kostakoglu 2000). In contrast, combining
antipsychotics with antidepressants has been proven to be
effective in the treatment of comorbid depression in schizophrenia (Siris 2000). It is noteworthy that the greatest
increase in antipsychotic and antidepressant combination
therapy was for atypical antipsychotic agents and SSRIs.
Although this combination may be selected with the goal
of maximizing efficacy and minimizing side effects, it
also represents a concurrent prescription of agents that are
among the most expensive in the Medicaid formulary. The
rapid increase in the use of this combination is likely to
attract scrutiny in reviews of Medicaid pharmacy expenditures, raising questions about the indications for use of
this combination in the absence of clearly documented
diagnosis of co-occurring major depression.
Use of anxiolytic hypnotics and mood stabilizers is
more generally accepted, particularly for persons with
schizoaffective disorder. Still, we see no clear explanation
for the utilization rate increases observed in this study.
Unlike atypical antipsychotics and, to a lesser extent,
SSRIs, anxiolytic hypnotics and mood stabilizers have
rjOtherDrugs
been widely available for more than 10 years. Recent articles suggesting the efficacy of these agents in controlling
aggressive behavior may have contributed to their
increased use (Lindenmayer and Kotsaftis 2000). More
frequent use of these agents in combination with antipsychotics is somewhat surprising given published evidence
that atypical agents are more effective than traditional
medications in controlling aggression and mood (Keck et
al. 2000). Finally, the slightly declining use of antiparkinsonian drugs indicates that the switch to atypical antipsychotics may be decreasing extrapyramidal symptoms,
which are a risk factor for later development of tardive
dyskinesia and often associated with traditional antipsychotics.
The trend toward greater coprescription, coupled
with a move to medications that are putatively more
effective than older ones, suggests that physicians may
be making a greater effort to augment or "fine-tune"
treatment response. Availability of more new antipsychotics (two medications were introduced during the
study period) with fewer side effects increases the possible combinations and may encourage both physicians
and their patients to experiment with various drug combinations. However, the effectiveness, safety, and efficiency of these practices are poorly understood. Finally,
80
Recent Trends in Antipsychotic Combination Therapy
Schizophrenia Bulletin, Vol. 28, No. 1, 2002
an analysis of the average incremental medication costs
associated with various combinations of antipsychotic
medications demonstrates that there is a substantial
pharmacy cost associated with combination therapy.
Improvements in functioning and decreased use of highcost acute care services may more than compensate for
this additional cost. However, research has not yet
addressed the effectiveness or cost-effectiveness of this
increasingly common practice.
Despite the clear trends demonstrated in this analysis,
there are several caveats that should be considered in
interpreting the data. First, because this study is limited to
a single State, care should be taken in generalizing these
findings to other areas. Although we have no reason to
believe that practices in that State are any different from
those in other States, we cannot conclusively say that they
are not. Second, readers should note that these observations represent prescribing patterns under full insurance
coverage, without pharmacy benefits management and
with minimal ($0.50) or no cost sharing by beneficiaries.
Prescribing patterns might differ when pharmacy benefits
are managed or when beneficiaries pay out of pocket for
medications. Third, our data do not allow us to identify
prescribing physicians; therefore, we cannot rule out the
possibility that multiple prescriptions could have been due
to multiple providers. Although our data do not allow us
to identify all prescribers, we know of no changes, such as
extension of prescribing privileges to a new group of
providers, that might have significantly changed the number of prescribing practitioners.
(Rosenheck et al. 1998; Essock et al. 2000). Remarkably,
despite a substantial literature supporting the preferential
use of atypical antipsychotics other than clozapine, the collective evidence supporting superior effectiveness and costeffectiveness of these agents compared to traditional neuroleptics is mixed (Geddes et al. 2000; Revicki 2000).
Because most drug trials focus on monotherapy rather
than combination therapy, the benefit of antipsychotic combination therapy is not established. The rapid growth in the
use of antipsychotic combination therapy by clinicians suggests that there is a wide gap between prescribing patterns
and research knowledge. Policy makers are, understandably, skeptical about the value of using expensive medication combinations for which there is no clear scientific evidence of effectiveness. In the best case, these combinations
are prescribed after careful consideration of the different
pharmacological properties of the agents and adequate prior
trials of appropriate single-agent therapy. In addition, the
best case would dictate that the increased cost of combination therapy is accompanied by substantial benefit to consumers in improved functioning, by reduced costs of inpatient and emergency care, or by both. In the worst case, the
trends observed reflect prescribing based on anecdotal data
and an underlying assumption that "more is better" when
more intensive drug treatment could increase the risk of
neurological side effects and waste scarce resources without appreciable benefit to patients.
What can State policy makers do in the absence of
clear guidance from the research literature? One approach
is to develop systems of care that encourage systematic,
rational decision making on the part of prescribing physicians. Evidence-based guidelines or algorithms can
encourage physicians to first employ appropriate alternatives to combination therapy, including changes in dosage
or switches to alternative agents with proven effectiveness
for treatment-refractory psychosis, such as clozapine.
Before implementing a trial of combination therapy,
physicians should pursue a series of trials of agents with
different pharmacological properties. Education and dissemination of guidelines and algorithms alone have generally been unsuccessful in modifying physician prescribing in the absence of changes in the system of care that
provides decision support, reminders, and feedback to
clinicians. For example, providing practice guidelines to
clinicians without additional incentives or practice change
interventions does not result in significant changes in
provider behavior (Grimshaw and Russell 1993; Lin et al.
1995; Oxman et al. 1995). In contrast, when guidelines
are integrated into practices as part of system change
interventions, improvements in quality of care and patient
outcomes have been demonstrated. Effective system
change interventions include interactive physician education, one-on-one academic detailing, patient education,
Implications for State Policy and Practice. The trend
toward using multiple antipsychotics as well as other psychotropic medications raises many questions that are not
answered by current research. Are two antipsychotics
really better than one? If so, which combinations are most
effective? Does combination therapy of antipsychotics
with SSRIs or other antidepressants result in better functioning and symptom relief for more than one-third of all
persons with schizophrenia, including those who do not
have a secondary diagnosis of depression? Is the additional benefit of combination therapy worth the incremental cost for the most costly pharmaceutical combinations,
such as two atypical antipsychotics or atypical antipsychotics combined with SSRIs? What are the long-term
effects of coprescription?
Concerns about coprescribing are both clinical and
policy oriented. The evidence base for the pharmacological
efficacy and cost-effectiveness of antipsychotics is almost
entirely comprised of single-agent comparisons in randomized clinical trials. For example, several studies of moderate length suggest that clozapine may be equally or more
cost-effective than traditional neuroleptics for some groups
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Schizophrenia Bulletin, Vol. 28, No. 1, 2002
R.E. Clark et al.
decision support technologies, care management, and
feedback on clinical outcomes (Davis et al. 1995; Oxman
1998; Soumerai 1998; Hunkeler et al. 2000; Katzelnick et
al. 2000; Simon et al. 2000; Wells et al. 2000).
States can also create learning systems by encouraging a spirit of empiricism among prescribing physicians.
Supporting opportunities for psychiatrists to share information gained from research or practice is one way to foster learning. Claims data, automated clinical records, or
other relevant sources of information can be useful for
monitoring practice patterns and identifying areas for systemwide improvement. States with outcome measurement
systems such as those developed through the Mental
Health Statistics Improvement Program may be able to
link prescription records with individual outcome information to create naturalistic learning tools. In cases where
comprehensive treatment cost data are available, they may
be integrated with outcomes to offer a better understanding of, and perhaps improve, the efficiency of medication
use. New analytic methodologies are needed that more
effectively use observational outcome data to identify
promising treatment strategies. While such efforts cannot
replace rigorous peer-reviewed research and randomized
clinical trials, they provide useful real-time information
that can provide guidance when an evidence base has not
yet been established. In the absence of more definitive
information on the effectiveness and cost-effectiveness of
various coprescription practices, it is inappropriate to
adopt policies that restrict formularies or otherwise
restrict access to new medications. Such practices can not
only prevent consumers from accessing beneficial medications but also increase treatment costs in other areas
(Soumerai et al. 1991; Soumerai et al. 1994).
Canales, P.L.; Olsen, J.; Miller, A.L.; and Crismon, M.L.
Role of antipsychotic polypharmacotherapy in the treatment of schizophrenia. CNS Drugs, 12:179-188, 1999.
Davidson, J. Possible effects of combining phenoth-
iazines. [Letter]. American Journal of Psychiatry,
131(12):1403-1409, 1974.
Davis, D.A.; Thomson, M.A.; Oxman, A.D.; and Haynes,
R.B. Changing physician performance: A systematic
review of the effect of continuing medical education
strategies. Journal of the American Medical Association,
274:700-705, 1995.
Ereshefsky, L. Pharmacological and pharmakokinetic considerations in choosing an antipsychotic. Journal of
Clinical Psychiatry, 60(Suppl 10):20-30, 1999.
Essock, S.M.; Frisman, L.K.; Covell, N.H.; and
Hargreaves, W.A. Cost-effectiveness of clozapine compared with traditional antipsychotic medication for
patients in State hospitals. Archives of General
Psychiatry, 57(10):987-994, 2000.
Geddes, J.; Freemantle, N.; Harrison, P.; and Bebbington,
P. Atypical antipsychotics in the treatment of schizophrenia: Systematic overview and meta-regression analysis.
British Medical Journal, 321:1371-1376, 2000.
Godleski, L.S.; Kerler, R.; Barber, J.W.; Glick, J.L.;
Kellogg, E.; Vieweg, W.V.; and Yank, G.R. Multiple versus single antipsychotic drug treatment in psychosis.
[Letter]. Journal of Nervous and Mental Disease,
177(ll):686-689, 1989.
Goss, J.B. Concomitant use of thioridazine with risperi-
done. [Letter]. American Journal of Health-System
Pharmacy, 52(9): 1012, 1995.
Grimshaw, J.M., and Russell, I.T. Effect of clinical guidelines on medical practice: A systematic review of rigorous
evaluations. Lancet, 342:1317-1322, 1993.
Finally, policy makers should advocate for research
studies that are aimed at evaluating the effectiveness of
commonly used but unproven clinical practices, with a
priority on those that are associated with significant costs.
Randomized clinical trials and innovative approaches to
clinical outcomes research are needed to evaluate the
effectiveness and cost-effectiveness of combination therapy. In the absence of an evidence base supporting the
effectiveness of antipsychotic combination therapy, pressure to contain escalating Medicaid pharmacy costs may
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Dartmouth Medical School and Director of the
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of Psychiatry and Director of the Clinical Trials
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Acknowledgment
Preparation of this paper was supported, in part, by the
New Hampshire Department of Health and Human
Services, Division of Behavioral Health.
The Authors
Robin E. Clark, Ph.D., is Associate Professor of
Community and Family Medicine and Psychiatry at
84