Real-World Antipsychotic Treatment
Troy A. Moore, PharmD, MSa, Nancy H. Covell, PhDb,c,
Susan M. Essock, PhDd,e, Alexander L. Miller, MDa,*
aDivision of Schizophrenia and Related Disorders, Department of Psychiatry, The University
of Texas Health Science Center at San Antonio, Related Disorders—MSC 7792,
7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
bDivision of Health Services Research, Department of Psychiatry, Mount Sinai School of Medicine,
One Gustave L. Levy Place, New York, NY 10029-6574, USA
cResearch Division, Department of Mental Health and Addiction Services, 410 Capitol Ave.,
MS 14RSD, Hartford, CT 06134, USA
dDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University,
Room 2702, Box 100, 1051 Riverside Drive, New York, NY 10032, USA
eDepartment of Mental Health Services and Policy Research, New York State Psychiatric Institute,
Room 2702, Box 100, 1051 Riverside Drive, New York, NY 10032, USA
mendations and guidelines, and by examining the roles of side effects and
medication adherence in real-world prescribing decisions. The authors first ex-
amine patterns of use of antipsychotic agents and of frequently coprescribed
psychotropic agents and compare actual use with recommendations found in
widely cited medication algorithms and guidelines. They then evaluate the
strength of the evidence underlying common recommendations. Next they re-
view recent evidence pertaining to side effects from the Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) trial  that may help inform the
selection of antipsychotic for individual patients. Finally, they address the pos-
sible impact of adherence to medication on prescribing decisions and review
evidence concerning treatments to improve medication adherence.
his article examines real-world antipsychotic use in the treatment of
schizophrenia by comparing real-world prescribing with medication
algorithms and guidelines, by evaluating the evidence underlying recom-
GUIDELINES AND ALGORITHMS FOR ANTIPSYCHOTIC
One way to evaluate real-world prescribing of antipsychotic medications is
to compare actual practice with the recommendations of guidelines and
This work was supported by grants R01 MH59312 (SME), R03 MH 071663 (NHC), and R24 MH072830
(ALM)) from the National Institutes of Mental Health.
*Corresponding author. E-mail address: firstname.lastname@example.org (A.L. Miller).
0193-953X/07/$ – see front matter
ª 2007 Elsevier Inc. All rights reserved.
Psychiatr Clin N Am 30 (2007) 401–416
OF NORTH AMERICA
algorithms for medication treatment of schizophrenia, which reflect a combina-
tion of evidence and expert consensus. Some of the widely cited treatment
guidelines for schizophrenia include the American Psychiatric Association
(APA) Schizophrenia Treatment Guideline [2,3], the Expert Consensus Guide-
line on Treatment of Schizophrenia , the Texas Medication Algorithm Pro-
ject (TMAP) Schizophrenia Algorithm , the Schizophrenia Patient Outcomes
Research Team (PORT) recommendations , and the International Psycho-
pharmacology Algorithm Project Schizophrenia Algorithm .
Guideline and algorithm recommendations for the use of antipsychotic
agents at various points of treatment for schizophrenia are shown in Table 1.
Although these algorithms and guidelines differ in some details, the following
three recommendations stand out as common to many or all: (1) preferential
use of second-generation antipsychotics (SGAs) for first-episode schizophrenia,
(2) use of clozapine after one or two failed trials of other antipsychotics, and (3)
no or last-resort use of combination antipsychotic medications. Given the
considerable consensus around each of these recommendations, one might
expect that real-world practices using antipsychotic agents would mirror these
recommendations closely. In the following sections the authors review the real-
world prescribing practices in each area and the evidence underlying each of
these recommendations. When recommendation and practice differ, they
explore possible reasons for the discrepancies.
Guideline and algorithm recommendations for treatment with antipsychotic agents
SGA SGASGA SGA,
SGA SGA SGA, FGA,
Abbreviations: FGA, first -generation antipsychotic; SGA, second-generation antipsychotic.
aAmerican Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia.
402MOORE, COVELL, ESSOCK, ET AL
RECOMMENDATION 1: SECOND-GENERATION
ANTIPSYCHOTICS ARE PREFERRED FOR TREATMENT
OF PATIENTS PRESENTING WITH FIRST-EPISODE
Algorithms and Guidelines
With the exception of the PORT recommendations, each of these expert panels
concluded that a second-generation antipsychotic agent should be used to treat
a person’s first episode of schizophrenia [2–5,7]. PORT lists both first-
generation antipsychotics (FGAs) and SGAs as options .
Statistics on prescribing antipsychotic agents for schizophrenia in North America
of schizophrenia-spectrum disorders . Data from IMS Health show the use of
SGAs in the United States in 2002 was over 70% . It seems likely, based on
clinician reports, that theuse of SGAs in first-episodepatientsis even higher, sup-
porting the conclusion that most first-episode patients are treated with SGAs.
ies indicate that these agents are effective but also find that first-episode patients
are particularly prone to weight gain. In the Comparison of Atypicals in First
Episode (CAFE´) study, all groups had substantial weight gains, but patients
taking olanzapine had almost twice the increases as patients taking quetiapine
or risperidone . The Preventing Morbidity trial comparing risperidone and
olanzapine showed no difference in cumulative response rates after 16 weeks
of treatment and significantly more weight gain in patients taking olanzapine
. Ziprasidone and aripiprazole have lower tendencies to cause weight gain,
but studies of these agents in first-episode schizophrenia are lacking .
In examining the evidence comparing SGAs and FGAs for first-episode
schizophrenia, no differences in symptom response rates were found in studies
comparing risperidone with haloperidol [12,13], olanzapine with haloperidol
[16,17], and clozapine with chlorpromazine . More subjects were adherent
to olanzapine than to haloperidol during the 12-week acute phase of a 104-week
study (67% versus 54%, respectively) . The 2-year data from the study
found patients taking olanzapine had a longer time to discontinuation of med-
ication than patients taking haloperidol (322 days versus 230 days) and had
greater rates of remission (57% versus 44%) . The median time to relapse
was substantially better with risperidone than with haloperidol (466 days ver-
sus 205 days) . At 52 weeks, 85% of patients taking clozapine remained in
the study, versus 77.5% in the chlorpromazine group .
The risk of tardive dyskinesia (TD) with antipsychotic agents increases with
age . A study examining TD in patients who had first-episode schizophrenia
403 REAL-WORLD ANTIPSYCHOTIC TREATMENT PRACTICES
TD was 2.1% with SGAs, versus 5.4% in patients receiving haloperidol .
Thus, although guideline recommendations favor the use of SGAs for first-
episode schizophrenia, the evidence from randomized, controlled trials does
not indicate efficacy advantages for SGAs in short-term studies. The advantage
of risperidone over haloperidol in time to relapse during maintenance treat-
ment is an important finding that needs replication in comparisons with other
SGAs and other FGAs. The same is true of the finding that patients discontinue
haloperidol sooner than olanzapine. Although agents clearly differ in side
effects, it is not so clear which side effects should take precedence when select-
ing an antipsychotic agent for this population of patients. A number of key gaps
in the evidence remain:
1. Is the course of illness different with SGAs versus FGAs over the long term
(eg, 5 years or longer)?
2. Do the relative risks of TD in this population differ with SGAs versus FGAs,
and do the SGAs differ from one another in the risk of TD?
3. Are side-effects profiles the only basis for choosing among antipsychotics for
first episode schizophrenia?
In summary, expert recommendations and real-world prescribing practices
for antipsychotic agents are quite congruent in the preferential use of SGAs
for first-episode schizophrenia. The evidence supporting this practice is not de-
finitive, however, and further studies are needed.
RECOMMENDATION 2: CLOZAPINE SHOULD BE USED
FOR TREATMENT-RESISTANT SCHIZOPHRENIA
Algorithms and Guidelines
The various algorithms and guidelines differ somewhat in the number of failed
trials suggested before a trial of clozapine is undertaken, but the range is not
great. The APA guideline indicates clozapine as an option after failure of
only one SGA or FGA. The others suggest that two failed trials are sufficient
to warrant a clozapine trial, although the TMAP does present the option of
a third trial before clozapine. None of the algorithms or guidelines specifies
the duration of nonresponse that should warrant a clozapine trial.
Data obtained in 1999 from Novartis estimated that treatment with clozapine
had been used in 160,000 patients who had schizophrenia-spectrum disorder
in the United States . If one assumes that 20% to 30% of the 2.6 million pa-
tients who had schizophrenia in the United States at that time were treatment
resistant (25% ¼ 650,000), only 25% of the patients who had treatment-resis-
tant schizophrenia had been treated with clozapine .
It is estimated that 20% to 30% of patients who have schizophrenia are treat-
ment resistant, and only a modest fraction of these patients are being treated
404 MOORE, COVELL, ESSOCK, ET AL
with clozapine . Clozapine has been shown to be more effective than FGAs
in treating patients who have not responded to trials with FGAs [22–27].
Clozapine also has been shown to be more effective than other SGAs in treat-
ing patients who have had an inadequate response to FGAs [28–30]. Recent
data from the CATIE trial show that patients for whom an initial SGA was in-
effective have a longer median time to discontinuation of clozapine than with
quetiapine, risperidone, or olanzapine (10.5 months versus 2.7–3.3 months)
Many factors may play a role in the diminished used of clozapine; among
them are the required laboratory monitoring, increased frequency of physician
and clinic visits, and medication side effects (agranulocytosis, weight gain, hy-
perlipidemia, and increased risk of diabetes). In many clinical settings clinicians
refer treatment-resistant patients to a separate team for clozapine management.
Although this practice may improve efficiency, it also means that, to receive
clozapine, patients often must change prescribers and sometimes even the treat-
ment location. The need to make such changes probably acts as an additional
disincentive for patients to try clozapine. An unintended consequence of the
use of specialized clozapine clinics also may be that many psychiatry trainees
have little, if any, practice in initiating treatment with clozapine, and this lack
of familiarity may contribute to their later hesitancy to initiate use of this
In summary, the guidelines and algorithms and the evidence support the use
of clozapine after one or two failed trials of an antipsychotic agent. Conversely,
data from real-world prescribing practices indicate that the rate of clozapine use
is much lower than the incidence of treatment-resistant schizophrenia.
RECOMMENDATION 3: ANTIPSYCHOTIC POLYPHARMACY
SHOULD BE A LAST OPTION
Algorithms and Guidelines
Prescribing more than one antipsychotic medication (hereafter, ‘‘polyphar-
macy’’) other than in combination with clozapine is omitted from consideration
in all but one guideline, TMAP, in which polypharmacy is listed as a last resort
Increasingly, patients who have schizophrenia are being treated with antipsy-
chotic polypharmacy [32–40], with recent studies reporting an FGA plus
SGAs as the most common combinations [41–43]. Reports of the prevalence
of antipsychotic polypharmacy among people who have schizophrenia-
spectrum disorders vary, with most reporting rates of 10% to 30% [42–53]. Ad-
ditionally, studies examining prescribing practices through time have shown
a trend toward the increasing use of antipsychotic polypharmacy [42,54–56].
For example, a recent report examining antipsychotic polypharmacy in more
than 30,000 Medicaid recipients who had schizophrenia found an increase
from 32% in 1998 to 41% in 2000 .
405 REAL-WORLD ANTIPSYCHOTIC TREATMENT PRACTICES
A recent review examining 52 published studies of antipsychotic polypharmacy
from 1976 to 2002 concluded that definitive evidence to support this practice
was lacking . In one small (n ¼ 40) randomized, double-blind, controlled
trial comparing risperidone augmentation with placebo for individuals who
continued to experience significant psychotic symptoms despite adequate treat-
ment with clozapine, risperidone augmentation was associated with significant
improvements in psychiatric symptoms and was as well tolerated as placebo
. Several small, uncontrolled studies also have reported improvement in
psychotic symptoms when clozapine has been augmented with risperidone,
olanzapine, pimozide, or loxapine [59–64]. Several additional studies report
symptomatic improvements after combining FGAs and SGAs [65–67]. On
the other hand, one pre-/post study suggests that switching from combined
antipsychotic therapy to a single antipsychotic agent does not necessarily desta-
bilize individuals and may even lead to improvement .
In the small literature of rigorous studies assessing antipsychotic polyphar-
macy, most studies have examined clozapine augmented with another agent
. Although two studies reported superior results when clozapine was
combined with sulpiride  or with risperidone , two others did not
find any benefit of augmenting clozapine with risperidone [70,71]. To date,
in the only controlled study evaluating the efficacy and safety of antipsychotic
combinations that did not include clozapine, the authors found no significant
differences between polypharmacy combining two FGAs and monotherapy
with a third FGA . Rigorous trials examining the combination of an
FGA and a SGA are completely lacking, even though these combinations are
most common forms of antipsychotic polypharmacy.
Although there is no definitive evidence to support the practice of prescribing
more than one antipsychotic medication, some studies have documented an in-
crease in adverse events with this practice. For example, an elevated risk for
treatment-emergent diabetes mellitus was associated with the use of two
SGAs , and significantly greater increases in fasting glucose levels were
seen in individuals taking clozapine and risperidone than in those taking
placebo . Moreover, higher rates of sedation , hyperprolactinemia
, and other adverse effects (mostly movement disorders)  have been
observed more often in individuals treated with antipsychotic polypharmacy
than in those receiving monotherapy.
RECOMMENDATION 4: ADJUNCTIVE PSYCHOTROPIC
MEDICATIONS, SUCH AS ANTIDEPRESSANTS AND MOOD
STABILIZERS, SHOULD BE USED WHEN INDICATED
Algorithms and Guidelines
These algorithms and guidelines do not provide a great deal of direction on the
use of adjunctive psychotropic agents other than antipsychotics to treat schizo-
phrenia. Each, however, encourages treatment of comorbid conditions and/or
symptoms as clinically indicated. The APA guideline goes into the greatest
406 MOORE, COVELL, ESSOCK, ET AL
detail in reviewing the evidence on the use of antidepressants, mood stabilizers,
beta-blockers, and other psychotropic medications.
The adjunctive medications most commonly used in schizophrenia are antide-
pressants, mood stabilizers, anxiolytics, and sedative hypnotics. Baseline data
on patients entering the CATIE study found that patients taking antipsychotic
agents frequently used adjunctive medication: 38% of the patients were taking
antidepressants, 22% were taking anxiolytics, 19% were taking sedative hyp-
notics, 4% were taking lithium, and 15% were taking other mood stabilizers
. Patients participating in the CATIE study had a number of adjunctive
medications added to their antipsychotic regimen during the initial treatment
period (mean duration of 6 months), including anticonvulsants (3.5%), antide-
pressants (12%), anxiolytics (12%), and sedative hypnotics (7%) .
A retrospective cohort study that lasted 1 year (1995) evaluating patients
who had schizophrenia showed that nearly 90% of the patients received a con-
comitant medication during the year . A variety of studies have shown that
a number of patients who have schizophrenia are treated with adjunctive
medications such as antidepressants, anxiolytics, and mood stabilizers
[75–78]. The use of these agents seems to be increasing since the introduction
of the SGAs [77,78].
Most of these adjunctive medications have not been studied specifically in
schizophrenia. The evidence for the efficacy of antidepressants for comorbid
depressive symptoms is not as robust as one might expect [79–83].
Because the use of concomitant psychotropic medications is so common in
persons who have schizophrenia, there have been recent efforts to assess the
effects of reducing concomitant psychotropic medication burden. In 37 patients
who had schizophrenia, gradual tapering of concomitant psychotropic medica-
tions (antidepressants, mood stabilizers, and miscellaneous agents) from an
average of one to zero over a 3- to 6-month period did not affect the Clinical
Global Impression outcome in most patients, and the number of patients wors-
ening during the taper was equivalent to the number improving .
The paucity of studies highlights the need for further examination of the ef-
ficacy of adjunctive medications in schizophrenia, as well as the need to con-
sider discontinuing these agents once target symptoms or conditions have
RECOMMENDATION 5: MOST PATIENTS WHO HAVE
SCHIZOPHRENIA WILL RESPOND TO, AND SHOULD BE
TREATED WITH, DOSAGES OF ANTIPSYCHOTIC MEDICATIONS
WITHIN A THERAPEUTIC RANGE
Algorithms and Guidelines
With the exception of the International Psychopharmacology Algorithm
Project, the guidelines and algorithms reviewed here contain specific
407 REAL-WORLD ANTIPSYCHOTIC TREATMENT PRACTICES
recommended ranges of dosages for antipsychotic agents. As discussed later,
the dosing recommendations are not uniform across guidelines, reflecting the
dynamic nature of knowledge about optimal dosing.
The PORT study showed that real-world treatments for schizophrenia often
did not follow dosing recommendations, especially in outpatients . Antipsy-
chotic medications were prescribed for 89.2% of inpatients and for 92.3% of
outpatients. Only 62% of inpatients and 29% of outpatients were receiving
antipsychotic medications at dosages that were in the therapeutic range defined
by an expert panel. A recent survey of physicians in the APA practice network,
however, found that dosages of antipsychotics were within recommended
ranges 83% of the time .
A study examining national Department of Veterans Affairs data in fiscal
year 2000 found 27.8% (14,932 patients) of patients who had schizophrenia
were dosed below PORT dosing recommendations, and 10.1% (5425 patients)
were dosed above PORT dosing recommendations. Patients who were black,
who had a greater than 50% service connection, who were prescribed SGAs,
and who were treated in facilities with higher proportions of total cost spent
on mental health or research and education were more likely to be dosed above
PORT recommendations. Patients who were elderly (age 65 years or over),
who were female, who had a less than 50% service connection, or who had co-
morbid psychiatric disorders were more likely to be dosed below recommen-
ded PORT dosing ranges .
In a Medicaid beneficiary sample of patients who had schizophrenia and
were at high-risk for hospitalization, 144 patients (40.7%) were receiving anti-
psychotic agents at dosages above 1000 chlorpromazine (CPZ) equivalents
. A trend toward increased side effects (P ¼ .07) was seen in patients treated
with higher dosages of antipsychotic agents.
Antipsychotic dosing outside the recommended dosage range occurs 17% to
36% of the time during inpatient treatment [85,86]. Although based on a small
number of studies, this percentage range is what one might expect, given that
treatment-resistant patients and outliers may need higher dosages to obtain a re-
sponse. Out-of-range antipsychotic dosing in outpatient settings is harder to
decipher because of the lack of easily obtainable pharmacy and diagnostic
data in the United States.
Because dosage ranges are determined on the basis of large-scale studies
designed to enroll typical, physically healthy patients, it is inevitable that in
real-world practice prescribers will encounter patients who require dosages
above or below the recommended range. What is lacking, in terms of evidence,
are studies that systematically examine the effects of changing the dosage of
patients who are stable on dosages outside the recommended range so that
the dosage is within the recommended range.
408MOORE, COVELL, ESSOCK, ET AL
After the US Food and Drug Administration (FDA) has approved a drug,
clinical practice and postmarketing studies may indicate the need to change
the recommended dosage range of a medication. Risperidone is a good exam-
ple. The dosage range in clinical trials ranged from 4 to 16 mg/d, and the FDA
approved dosage within this range . Postmarketing studies, however, found
the maximal benefits of risperidone to be achieved with dosages between 4 and
8 mg/d. Higher doses were not associated with additional benefits but did result
in increased extrapyramidal side effects. The experience was similar with
haloperidol, an extensively studied FGA [90,91]. Postmarketing studies also
can lead to the use antipsychotic dosages higher than those approved by the
FDA. In the CATIE study, for instance, the dosing range of olanzapine was
extended to 30 mg/d, although the FDA-approved maximum dose is 20 mg/d
. Additionally, positron emission tomography and single-photon emission
CT allow in vivo measurement of the central effects of antipsychotic agents
on neurotransmitter receptors to determine the optimal doses required to
provide benefit while not inducing extrapyramidal side effects .
Dosing of antipsychotics outside the recommended dosage ranges should be
performed judiciously. Practitioners need to monitor symptoms and effects of
subsequent dose changes objectively to justify dosages of antipsychotic agents
outside the recommended range. One also must be aware that outliers and
treatment-resistant patients may benefit from higher or lower dosages.
RECOMMENDATION 6: SIDE EFFECTS SHOULD GUIDE
MEDICATION SELECTION AND SHOULD BE MONITORED AFTER
INITIATION OF ANTIPSYCHOTIC TREATMENT
Algorithms and Guidelines
The Expert Consensus Guidelines for the treatment of schizophrenia provide
the best-detailed recommendations for selecting medications to avoid side
effects . Depending on patient presentation, the practitioner can use pa-
tient-specific information to guide the choice of an appropriate antipsychotic
agent to avoid or help alleviate side effects.
Medication selection in psychiatry is individualized to the specific needs of each
patient. The type of antipsychotic chosen depends on the patient’s medication
history, risk factors for side effects (TD, metabolic side effects, and others), and
likelihood of adherence. The antipsychotic agent with the greatest likelihood of
benefit and least likelihood of risk should be chosen. Unfortunately, these de-
cisions are complex because of conflicting evidence about the degree and
severity of the side effects caused by the antipsychotic medications.
The CATIE and Cost Utility of the Latest Antipsychotic Drugs in Schizo-
phrenia Study (CUtLASS) studies provide data on the frequency of switching
antipsychotic agents because of adverse medication effects. In phase I of the
CATIE study, 15% of patients discontinued because of side effects . In the
CUtLASS study, 51% of those enrolling did so because of medication-induced
409 REAL-WORLD ANTIPSYCHOTIC TREATMENT PRACTICES
adverse events . These studies made every effort to enroll typical patients
who had schizophrenia, and these numbers illustrate the range of frequencies of
side effects as a basis for changing antipsychotics.
The CATIE study is particularly helpful in evaluating the comparative
likelihood of side effects when various antipsychotics are used. These data
can help guide drug selection and information given to patients. Two major
domains of side effects well addressed by CATIE data are extrapyramidal
side effects and metabolic syndrome.
With regard to extrapyramidal side effects, there were no significant differ-
Scale mean score of 1 or higher among the medications, including perphenazine,
in the dosage ranges used in the CATIE study . The perphenazine group had
the largest percentage of patients taking anticholinergic agents, and there was
a significant difference across treatment groups in the percentage of patients hav-
ing an anticholinergic agent added to their regimen. There also was a significant
difference across the treatment groups in the percentage of patients discontinu-
ing treatment because of extrapyramidal side effects, with the perphenazine
group being highest but not by a large margin. There was no difference in
Abnormal Involuntary Movement Scale (AIMS) global severity score of 2 or
higher in the medication groups, but CATIE was too brief a study to allow
conclusions about relative likelihood of new-onset TD .
There were significant differences across treatment groups in metabolic
measures. Of the antipsychotic medications tested, the largest increases in
weight and in glycosylated hemoglobin, total cholesterol, and triglycerides
levels were seen with olanzapine . Reductions in weight and in glycosylated
hemoglobin, total cholesterol, and triglycerides levels were seen with ziprasi-
done . Similar results were found in phase II of CATIE, with patients tak-
ing olanzapine having greater weight gain, total cholesterol level, and
triglycerides level, and patients taking ziprasidone having a reduction in these
A follow-up analysis of CATIE data examining the effectiveness of switching
antipsychotic medications found that patients randomly assigned to olanzapine
or risperidone at baseline and then re-randomized to stay on the same medica-
tion had significantly longer times to discontinuation than patients randomly
assigned to switch medications (>11.6 and 8.4 weeks, respectively, versus 7.7
and 4.7 weeks, respectively; P ¼ .007) . Therefore, for patients who have
problems with side effect, an argument can be made for trying to ameliorate
the side effects rather than changing antipsychotic agents, if adequate symptom
relief has been achieved.
THE ROLE OF ADHERENCE IN REAL-WORLD PRESCRIBING
In real-world prescribing, the importance of evaluating adherence to antipsy-
chotic medication cannot be overestimated. High rates of partial adherence
410 MOORE, COVELL, ESSOCK, ET AL
and nonadherence to antipsychotic medications are well documented, with
mean rates across studies of 40% to 50% . Nonadherence to antipsychotic
medications may be second only to poor adherence to weight loss treatments
. Consequences of nonadherence or partial adherence with antipsychotic
medication include increased rates of relapse and hospitalization and increased
Providers in real-world settings probably factor into their prescribing
decisions their sense of whether individuals will take medications as prescribed,
and the published literature can inform this assessment. In a review of 39 stud-
ies published from 1980 through 2002 examining predictors of adherence to
antipsychotic medications, poor insight, negative attitude or subjective re-
sponse to medication, prior nonadherence, shorter illness duration, poor ther-
apeutic alliance, and poor environment following discharge from hospital were
all associated with lower adherence to antipsychotic medication . Use of
injectable antipsychotic medications and the presence of and/or severity of
side effects were not consistently related to medication adherence, although
the authors note that systematic assessments of side effects, particularly subjec-
tive side effects, were rarely obtained .
Even with awareness of predictors of nonadherence, given the magnitude of
the problem overall, providers in real-world settings probably will find
themselves intervening with about half of the individuals in their caseload in
the hopes of improving adherence. A review of 21 studies published between
1980 and 2001 examining treatments to improve adherence to antipsychotic
medications concluded that interventions using a combination of educational,
behavioral, and affective (including appeals to feeling and emotion or social
relationships and supports) strategies were more effective in increasing adher-
ence to medication than those offering a purely educational approach .
Further, when adherence improved, individuals also experienced secondary
gains including reduced relapse and hospitalization, decreased psychopathol-
ogy, improvements in social functioning, and increased insight , suggesting
that the time invested in such strategies may provide long-lasting benefits for
Before leaving the discussion of adherence, it is important to mention a grow-
ing concern regarding how adherence is measured and categorized. In a recent
review examining 161 articles published between 1970 and February 2006
reporting studies examining adherence to oral antipsychotic medications, the
method most commonly used to assess adherence was self-report; in only
23% of the studies were direct or objective measures (eg, pill counts, blood
or urine analyses, electronic monitoring, or electronic refill records) used to as-
sess adherence . Additionally, because definitions of adherence varied
broadly across studies, an individual could be categorized as adherent in one
study and nonadherent in another . Given these inconsistencies, and given
that those who decline to take all medication probably differ from those who
are partially adherent, Velligan and colleagues  suggest distinguishing
these groups in both research and targeted interventions. Further, the authors
411 REAL-WORLD ANTIPSYCHOTIC TREATMENT PRACTICES
suggest that future studies should include at least two measures of adherence,
with at least one direct or objective measure .
 Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients
with chronic schizophrenia. N Engl J Med 2005;353(12):1209–23.
 Lehman AF, Lieberman JA, Dixon LB, et al. Work Group on Schizophrenia. American
Psychiatric Association practice guideline for the treatment of patients with schizophrenia.
2nd edition. 2004. Available at: http://www.psych.org/psych_pract/treatg/pg/
Schizophrenia2ePG_05-15-06.pdf. Accessed October 13, 2006.
 McIntyre JS, Charles SC, Anzia DJ, et al. American Psychiatric Association. Treating
schizophrenia: a quick reference guide. Available at: http://www.psych.org/psych_
pract/treatg/quick_ref_guide/Schizophrenia_QRG.pdf. Accessed October 13, 2006.
 McEvoy JP, Scheifler PL, Frances A. The Expert Consensus Guideline Series: treatment of
schizophrenia 1999. J Clin Psychiatry 1999;60(Suppl 11):1–81.
 Miller AL, Hall CS, Buchanan RW, et al. The Texas Medication Algorithm Project
antipsychotic algorithm for schizophrenia: 2003 update. J Clin Psychiatry 2004;65:
 Lehman AF, Kreyenbuhl J, Buchanan RW, et al. The Schizophrenia Patient Outcomes
Research Team (PORT): updated treatment recommendations 2003. Schizophr Bull
 The International Psychopharmacology Algorithm Project. IPAP schizophrenia algorithm.
Available at: www.ipap.org/schiz. Accessed October 13, 2006.
 Duggan M. Do new prescription drugs pay for themselves? The case of second-generation
antipsychotics. J Health Econ 2005;24:1–31.
 IMS Health. Atypical antipsychotics: generating evidence to inform policy and practice.
Available at: http://research.imshealth.com/research_schizophrenia.htm. Accessed
December 18, 2006.
 Lieberman JA, Phillips M, Gu H, et al. Atypical and conventional antipsychotic drugs in
treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs
chlorpromazine. Neuropsychopharmacology 2003;28(5):995–1003.
 Woerner MG, Robinson DG, Alvir JMJ, et al. Clozapine as a first treatment of schizophre-
nia. Am J Psychiatry 2003;160(8):1514–6.
 Emsley RA. Risperidone in the treatment of first-episode psychotic patients: a double-blind
multicenter study. Risperidone Working Group. Schizophr Bull 1999;25(4):721–9.
 Schooler N, Rabinowitz J, Davidson M, et al. Risperidone and haloperidol in first-episode
psychosis: a long-term randomised trial. Am J Psychiatry 2005;162:947–53.
 Robinson DG, Woerner MG, Napolitano B, et al. Randomized comparison of olanzapine
versus risperidone for the treatment of first-episode schizophrenia: 4-month outcomes.
Am J Psychiatry 2006;163:2096–102.
 McEvoy JP, Lieberman JA, Perkins D, et al. Efficacy and tolerability of olanzapine, quetia-
pine, and risperidone in the treatment of early psychosis: a randomized, double-blind,
52-week comparison. Am J Psychiatry, in press.
 LiebermanJA,TollefsonG, TohenM, et al,HGDHStudyGroup.Comparative efficacyand
safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a ran-
domized, double-blind trial of olanzapine versus haloperidol. Am J Psychiatry 2003;
 Green AI, Lieberman JA, Hamer RM, et al, HGDH Study Group. Olanzapine and haloper-
idol in first episode psychosis: two-year data. Schizophr Res 2006;86:234–43.
 Lublin H, Eberhard J, Levander S. Current therapy issues and unmet clinical needs in the
treatmentofschizophrenia:areviewofthenewgenerationantipsychotics. Int ClinPsycho-
412MOORE, COVELL, ESSOCK, ET AL
 Corell CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-
generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry
 Oosthuizen PP, Emsley RA, Maritz JS, et al. Incidence of tardive dyskinesia in first-episode
psychosis patients treated with low-dose haloperidol. J Clin Psychiatry 2003;64:
 Buckley P, Miller AL, Olsen J, et al. When symptoms persist: clozapine augmentation strat-
egies. Schizophr Bull 2001;27:615–28.
 Claghorn J, Honigfeld G, Abuzzahab FS, et al. The risks and benefits of clozapine versus
chlorpromazine. J Clin Psychopharmacol 1987;7:377–84.
 Pickar D, Owen RR, Litman RE, et al. Clinical and biological response to clozapine in pa-
tients with schizophrenia: crossover comparison with fluphenazine. Arch Gen Psychiatry
 Breier A, Buchanan RW, Kirkpatrick B, et al. Clozapine in schizophrenic outpatients:
effects on positive and negative symptoms. Arch Gen Psychiatry 1994;151:20–6.
 Carpenter WT Jr, Conley RR, Buchanan RW, et al. Patient response and resource manage-
ment: another view of clozapine treatment of schizophrenia. Am J Psychiatry 1995;152:
 Essock SM, Hargreaves WA, Covell NH, et al. Clozapine’s effectiveness for patients
in state hospitals: results from a randomized trial. Psychopharmacol Bull 1996;32:
 Volavka J, Czobor P, Sheitman B, et al. Clozapine, olanzapine, risperidone, and haloper-
idol in the treatment of patients with chronic schizophrenia and schizoaffective disorder.
Am J Psychiatry 2002;159:255–62 [erratum: 159: 2132].
 Chakos M, Lieberman J, Hoffman E, et al. Effectiveness of second-generation antipsy-
chotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of
randomized trials. Am J Psychiatry 2001;158:518–26.
 Conley RR, Kelly DL, Richardson CM, et al. The efficacy of high-dose olanzapine in
 McEvoy JP, Lieberman JA, Stroup TS, et al. Effectivness of clozapine versus olanzapine,
quetiapine, and risperidone in patients with chronic schizophrenia who did not respond
to prior atypical antipsychotic treatment. Am J Psychiatry 2006;163:600–10.
 Ereshefsky L. Pharmacologic and pharmacokinetic considerations in choosing an antipsy-
chotic. J Clin Psychiatry 1999;60(Suppl 10):20–30.
cross-sectional survey of a random sample of French psychiatrists. Br J Clin Pharmacol
 ItoC,KubotaY, SatoM.Aprospectivesurveyondrugchoicefor prescriptionsforadmitted
patients with schizophrenia. Psychiatry Clin Neurosci 1999;53(Suppl):S35–40.
 Keks NA, Altson K, Hope J, et al. Use of antipsychosis and adjunctive medications by an
inner urban community psychiatric service. Aust N Z J Psychiatry 1999;33(6):896–901.
 Meltzer HY, Kostaoglu AE. Combining antipsychotics: is there evidence for efficacy?
Psychiatric Times 2000;17(9):25–34.
 RittmannsbergerH, Meise U, Schauflinger K, et al. Polypharmacy in psychiatric treatment.
Patterns of psychotropic drug use in Austrian psychiatric clinics. Eur Psychiatry
 Stahl SM. Antipsychotic polypharmacy, part 2: tips on use and misuse. J Clin Psychiatry
 Stahl SM. Antipsychotic polypharmacy, part 1: therapeutic option or dirty little secret?
J Clin Psychiatry 1999;60(7):425–6.
413REAL-WORLD ANTIPSYCHOTIC TREATMENT PRACTICES
 Tapp A, Wood AE, Secrest L, et al. Combination antipsychotic therapy in clinical practice.
Psychiatr Serv 2003;54(1):55–9.
 Centorrino F, Fogarty KV, Sani G, et al. Use of combinations of antipsychotics: McLean
Hospital inpatients, 2002. Hum Psychopharmacol 2005;20:482–92.
 Ganguly R, Kotzan JA, Miller LS, et al. Prevalence, trends, and factors associated
with antipsychotic polypharmacy among Medicaid-eligible schizophrenia patients,
1998–2000. J Clin Psychiatry 2004;65:1377–88.
 Ito H, Koyama A, Higuchi T. Polypharmacy and excessive dosing: psychiatrists’ percep-
tions of antipsychotic drug prescription. Br J Psychiatry 2005;187:243–7.
 Biancosino B, Barbui C, Marmai L, et al. Determinants of antipsychotic polypharmacy in
psychiatric inpatients: a prospective study. Int Clin Psychopharmacol 2005;20:305–9.
 Brunot A, Lachaux B, Sontag H, et al [Pharmaco-epidemiological study on antipsychotic
drug prescription in French Psychiatry: patient characteristics, antipsychotic treatment,
and care management for schizophrenia]. Encephale 2002;28(2):129–38 [French].
 Centorrino F, Eakin M, Bahk WM, et al. Inpatient antipsychotic drug use in 1998, 1993,
and 1989. Am J Psychiatry 2002;159:1932–5.
 Chee YK,Ungvari GS,KinCH,etal.Asurveyofantipsychotictreatmentfor schizophrenia
in Hong Kong. Chin Med J (Engl) 1997;110:792–6.
 Covell NH, Jackson CT, Evans AC, et al. Antipsychotic prescribing practices in Connecti-
cut’s public mental health system: rates of changing medications and prescribing styles.
Schizophr Bull 2002;28:17–29.
 Frangou S, Lewis M. Atypical antipsychotics in ordinary clinical practice: a pharma-
co-epidemiologic survey in a south London service. Eur Psychiatry 2000;15(3):
 Leslie DL, Rosenheck RA. Use of pharmacy data to assess quality of pharmacotherapy for
schizophrenia in a national health care system: individual and facility predictors. Med
 Procyshyn RM, Kennedy NB, Tse G, et al. Antipsychotic polypharmacy: a survey of
discharge prescriptions from a tertiary care psychiatric institution. Can J Psychiatry
 Wang PS, West JC, Tanielian T, et al. Recent patterns and predictors of antipsychotic med-
icationregimensused to treatschizophrenia andotherpsychoticdisorders. SchizophrBull
 Weissman EM. Antipsychotic prescribing practices in the Veterans Healthcare Administra-
tion–New York metropolitan region. Schizophr Bull 2002;28(1):31–42.
 ClarkRE,Bartels SJ,MellmanTA, et al.Recenttrendsinantipsychoticcombinationtherapy
of schizophrenia and schizoaffective disorder: implications for state mental health policy.
Schizophr Bull 2002;28(1):75–84.
 Johnson DAW, Wright NF. Drug prescribing for schizophrenic outpatients on depot injec-
tions: repeat surveys over 18 years. Br J Psychiatry 1990;156:827–34.
 Taylor D, Holmes R, Hilton T, et al. Evaluating and improving the quality of risperidonepre-
scribing. Psychiatr Bull R Coll Psychiatr 1997;22:680–3.
 Patrick V, Levin E, Schleifer S. Antipsychotic polypharmacy: is there evidence for its use?
J Psychiatr Pract 2005;11:248–57.
 Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the
treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J
 Friedman J, Ault K, Powchik P. Pimozide augmentation for the treatment of schizophrenic
patients who are partial responders to clozapine. Biol Psychiatry 1997;42(6):522–3.
 Gupta S, Sonnenberg SJ, Frank B. Olanzapine augmentation of clozapine. Ann Clin
phrenics. J Clin Psychiatry 1996;57(9):395–7.
414MOORE, COVELL, ESSOCK, ET AL
 Morera AL, Barreiro P, Cano-Munoz JL. Risperidone and clozapine combination for the
treatment of refractory schizophrenia. Acta Psychiatr Scand 1999;99(4):305–6 [discus-
 Mowerman S, Siris SG. Adjunctive loxapine in a clozapine-resistant cohort of schizo-
phrenic patients. Ann Clin Psychiatry 1996;8(4):193–7.
 Raskin S, Katz G, Zislin Z, et al. Clozapine and risperidone: combination/augmentation
treatment of refractory schizophrenia: a preliminary observation. Acta Psychiatr Scand
 Bacher NM, Kaup BA. Combining risperidone with standard neuroleptics for refractory
schizophrenic patients. Am J Psychiatry 1996;153(1):137.
 Goss JB. Concomitant use of thioridazine with risperidone. Am J Health Syst Pharm
 Waring EW, Devin PG, Dewan V. Treatment of schizophrenia with antipsychotics in com-
bination. Can J Psychiatry 1999;44(2):189–90.
 Suzuki T, Uchida H, Tanaka KF, et al. Revising polypharmacy to a single antipsychotic reg-
imen for patients with chronic schizophrenia. Int J Neuropsychopharmacol 2004;7:
 Shiloh R, Zemishlany Z, Aizenberg D, et al. Sulpiride augmentation in people with schizo-
phrenia partially responsive to clozapine. A double-blind, placebo-controlled study. Br J
 Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of
adjunctive treatment with risperidone in schizophrenic patients partially responsive to clo-
zapine: efficacy and safety. J Clin Psychiatry 2005;66(1):63–72.
 Honer WG, Thornton AE, Chen EY, et al. Clozapine alone versus clozapine and risperi-
done with refractory schizophrenia. N Engl J Med 2006;354(5):472–82.
 Knight RG, Harrison A. A double-blind comparison of thiothixene and trifluoperazine/
 CitromeL,JaffeA, LevineJ,et al.Relationshipbetweenantipsychoticmedication treatment
and new cases of diabetes among psychiatric inpatients. Psychiatr Serv 2004;55(9):
 Centorrino F, Goren JL, Hennen J, et al. Multiple versus single antipsychotic agents for hos-
pitalized psychiatric patients: case-control study of risks versus benefits. Am J Psychiatry
 Chakos MH, Glick ID, Miller AL, et al. Baseline use of concomitant psychotropic medica-
tions to treat schizophrenia in the CATIE trial. Psychiatr Serv 2006;57(8):1094–101.
 Williams CL, Johnstone BM, Keterson JG, et al. Evaluation of antipsychotic and concomi-
tant medication use patterns in patients with schizophrenia. Med Care 1999;37(4):
 McCue RE, Waheed R, Urcuyo L. Polypharmacy in patients with schizophrenia. J Clin Psy-
 Edlinger M, Hausmann A, Kemmler G, et al. Trends in the pharmacological treatment of
patients with schizophrenia over a 12 year observation period. Schizophr Res
 Siris SG. Akinesia and postpsychotic depression: a difficult differential diagnosis. J Clin
 Siris SG, Bermanzohn PC, Mason SE, et al. Maintenance imipramine therapy for second-
ary depression in schizophrenia: a controlled trial. Arch Gen Psychiatry 1994;51:
 Kirli S, Caliskan M. A comparative study of sertraline versus imipramine in postpsychotic
depressive disorder of schizophrenia. Schizophr Res 1998;33:103–11.
 AddingtonD,AddingtonJ, PattenS,etal.Double-blind,placebo-controlledcomparisonof
the efficacy of sertraline as treatment for a major depressive episode in patients with remit-
ted schizophrenia. J Clin Psychopharmacol 2002;22:20–5.
415REAL-WORLD ANTIPSYCHOTIC TREATMENT PRACTICES