Utilization and dosing of first-line
second-generation antipsychotics: changes
from 1997 to 2004
Citrome L, Jaffe A, Levine J
Nathan S Kline Institute for Psychiatric Research and New York University
School of Medicine, Department of Psychiatry, New York, NY, USA
Abstract
Objectives: To describe the utilization and dosing of first-line
second-generation antipsychotics (risperidone, olanzapine,
quetiapine, ziprasidone, and aripiprazole) among inpatients in
state-operated psychiatric centers in New York State, USA
for the period 1997-2004.
Methods: Information on patients and their antipsychotic
medication treatment was extracted from a database
containing drug prescription information from the inpatient
facilities operated by the New York State Office of Mental
Health. The principal period covered was April 1, 2004
through June 30, 2004 (N=4809). Utilization and dosing
trends over time were calculated by examining the second
quarter of calendar years 1997-2004. Dose distribution for
each antipsychotic was examined by diagnosis, ethnicity,
gender, and length of stay (the latter used as a proxy for
severity of illness). Dosing of antipsychotics when co-
prescribed with each other was calculated using data from
November 15, 2003.
Results: Mean daily dose of certain antipsychotics differs by as
much as 100% from when the product was introduced to the
present time. Among the patients prescribed quetiapine in the
second quarter of 2004 (N=1086), the average daily dose was
620 mg, with 56.1% receiving a daily dose exceeding 500 mg,
and 33.6% exceeding 750 mg. In the equivalent period in
1998, average daily dose of quetiapine (N=267) was 313.7 mg,
with only 10.1% receiving a daily dose exceeding 500 mg.
Likewise for olanzapine, the percentage of patients receiving
doses in excess of 20 mg/day in 2004 was substantial at 44.7%
of 1501 patients, compared with 16.2% of 1151 patients in
1997. Elevations in average daily dose of ziprasidone and
aripiprazole have been more modest. The opposite trend has
occurred for risperidone, where in 2004 patients prescribed
risperidone (N=1287) received an average daily dose of 4.97
mg, substantially lower than the average of 7.0 mg/day received
in 1997 (N=1283). Co-prescription rates are high, and the ratio
of co-prescriptions versus monotherapy prescriptions is 2.6 for
quetiapine, 1.4 for olanzapine, 1.6 for risperidone, 2.0 for
ziprasidone, and 2.0 for aripiprazole. Dose does not change
substantially when antipsychotics are used as monotherapy or
when co-prescribed with other antipsychotics.
Conclusions: Recommended dose ranges obtained during
drug registration trials do not necessarily match what is used
in actual clinical practice settings once sufficient clinical
experience has accumulated. Phase IV clinical trials that
specifically target more difficult-to-treat patients are needed.
1
Introduction
© First-line second-generation antipsychotics (risperidone,
olanzapine, quetiapine, ziprasidone, aripiprazole) are
widely used in the treatment of psychotic disorders.
Advantages over first-generation antipsychotics include a
lower propensity for adverse events, including
extrapyramidal symptoms (EPS), and a possibly broader
spectrum of efficacy that includes reduction in negative
symptoms, mood instability, cognitive dysfunction, and
hostility.1 They may also have an advantage in
treatment-refractory schizophrenia.2
© Recommended doses of these agents, as outlined by the
manufacturers and determined through registration
studies, can differ substantially from doses used
clinically. This may be because registration trials are not
easily generalizable to real-world patients with active
comorbid drug and alcohol abuse and a poor treatment-
response history. Both of these factors are usually
among the exclusion criteria for registration trials, but
both are commonly found among patients hospitalized
within facilities operated by state agencies.
© Prior reports from the USA on dosing have focused on
first-generation antipsychotics,3,4 outpatients,4 or
involved a time period of over 5 years ago (1995-1997)
when second-generation antipsychotics were not as
extensively used as today.5 A review of optimal dosing
can be found elsewhere.6
© This report reviews the US Food and Drug Administration
(FDA)-approved dosing ranges for the first-line second-
generation antipsychotics and the actual dosing ranges
used by patients with severe and persistent mental
illness hospitalized in the inpatient facilities operated by
New York State’s Office of Mental Health. This report
focuses on adult inpatients with schizophrenia.
© Additional details regarding antipsychotic utilization over
time and the use of multiple antipsychotics from within
the New York State Office of Mental Health have been
published elsewhere.7-9

Methods
© Information on recommended oral dosing for physically
healthy adults with schizophrenia was extracted from the
Physicians Desk Reference (PDR),10-14 a widely-
distributed compendium of the product information
sheets produced by the individual pharmaceutical
companies. These descriptions are negotiated with and
approved by the US FDA.
© Data on actual antipsychotic utilization and dosing were
collected using the Integrated Research Database (IRDB)
created by the Information Sciences Division of the
Nathan S Kline Institute for Psychiatric Research.
© Average daily dose is calculated in two ways, average
daily patient dose, and average daily patient dose
weighted by days.
Results
© The percentage of patients receiving first-generation
antipsychotics decreased during the period 1997-2004;
haloperidol use decreased from 22% to 18%,
fluphenazine from 11% to 8%, and chlorpromazine from
8% to 4% (NKI Medication Utilization and Outcome
Research Program 1997-2004).

© During the same period, the utilization of second-

© The IRDB was used to determine the characteristics
(gender, ethnicity, previous admissions, discharges,
length of stay, and diagnosis) of those patients
prescribed antipsychotic medication between 1 April and
30 June 2004 within the 17 adult civil facilities of the New
York State psychiatric hospital system (Table 1). These
psychiatric centers provide intermediate and long-term
care to patients with severe and persistent mental illness.
generation antipsychotics became predominant. The
percentage of patients prescribed olanzapine rose from
20% to 31%, risperidone from 22% to 31%, and
clozapine from 13% to 19%. In addition, use of
quetiapine increased from 5% to 23% between 1998 and
2004; ziprasidone from 2% to 7.6% between 2001 and
2004; and aripiprazole from 10% to 10.2% between
2003 and 2004.

© Table 2 shows that olanzapine, quetiapine and

Table 1. Patient characteristics and drug prescription
information for inpatients within the 17 adult civil facilities of aripiprazole are prescribed at higher doses than the top
the New York State Office of Mental Health (1 April – 30 June end of the ranges recommended in the product labels.
2004)

Number of patients 4809 Table 2. Dose range in product labelling versus actual use in
2004 (NKI Medication Utilization and Outcomes Research
Mean age (SD), years 44.8 (13.4) 10-14
Program 2004)
Gender, %
Male 67 Antipsychotic Target range Actual mean Recommended
Female 33 (mg/day) (mg/day) maximum dose for

Ethnicity, % schizophrenia (mg/day)

Caucasian 46 Risperidone 4-8 4.97 16

African-American 38
Olanzapine 10-15 23.1 20
Hispanic 12
Other 3 Quetiapine 300-500 620.0 800

Previous admission(s), % 67 Ziprasidone 40-160 145.4 200

Discharges, % 17 Aripiprazole 10-15 23.3 30

(34% for those with length
Results shown for the period 1 April – 30 June 2004
of stay ≤360 days)

Length of stay >360 days, % 53

Diagnosis of schizophrenia or 80
schizoaffective disorder, %
All patients hospitalized during reporting period=5,122
Receiving antipsychotic medication=94%
© The IRDB has been successfully used to examine the
extent, pattern of use, and effectiveness, of depot
neuroleptics,15,16 extent of prescribing or co-prescribing
of antipsychotics,7,8 effectiveness of newer atypical
antipsychotics,17 and of the use of valproate18,19 and
other mood stabilizers.20
© Within the facilities of the New York State Office of Mental
Health, high dosing of first-generation antipsychotics
decreased between 1997 and 2004 from 30% to 16%,
33% to 19%, and 18% to 7% in patients prescribed
haloperidol >20 mg/day, fluphenazine >20 mg/day, and
chlorpromazine >1000 mg/day, respectively.
© During the same period, high dosing of the second-
generation antipsychotics olanzapine, quetiapine,
aripiprazole, and ziprasidone increased, with the notable
exception of risperidone (Figure 1a). By 2004, the mean
daily dose of risperidone prescribed to patients had
decreased to 4.97 mg/day (Figure 1b).

2
Figure 1a. Percentage of patients receiving high-dose second- © For quetiapine, in the second quarter of 2004 (n=1086),
generation antipsychotics within the facilities of the New York the average weighted mean daily dose was 620 mg with
State Office of Mental Health between 1997 and 2004 (NKI 56.1% receiving >500 mg/day, and 33.6% receiving
Medication Utilization and Outcome Research Program >750 mg/day. In the equivalent period in 1998, the
1997-2004) average dose of quetiapine (n=267) was 313.7 mg/day,
with only 10.1% receiving >500 mg/day (Figure 3).
Risperidone >8 mg/day
Aripiprazole >30 mg/day Figure 3a. Percentage of patients receiving quetiapine
50 Ziprasidone >160 mg/day
45 >500 mg/day by year
40 Quetiapine >750 mg/day
Patients (%)

35 Olanzapine >20 mg/day

30 60
25 50
20

Patients (%)
15 40
10
5 30
0
1997 1998 1999 2000 2001 2002 2003 2004 20
10
0
1997 1998 1999 2000 2001 2002 2003 2004
Figure 1b. Mean daily dose of risperidone (1 April - 30 June
2004)
Figure 3b. Mean daily dose of quetiapine (1 April – 30 June 2004)
35 Mean 4.67 mg/day Mean 573.5 mg/day
25
30 (Weighted mean 4.97 mg/day) (Weighted mean 620.0 mg/day)
25 20
Patients (%)

Patients (%)
20 15
15
10 10
5 5
0
>0-2 >2-4 >4-6 >6-8 >8-12 >12-16 >16 0
>0- >150- >300- >500- >750- >900- >1200- >1600
Risperidone (mg/day) 150 300 500 750 900 1200 1600
n=1527 Quetiapine (mg/day)
n=1086

© For olanzapine, 75.7% of 1501 patients received doses © Preliminary inspection of patient characteristics reveals
>15 mg/day in 2004 compared with 49.5% of possible effects of gender, ethnicity, and chronicity of
1151 patients in 1997 (Figure 2). illness (as measured by history of prior admission and
length of stay) on dosing levels of quetiapine (Table 3).
Figure 2a. Percentage of patients receiving olanzapine
>15 mg/day by year Table 3. Characterization of patients receiving high-dose
quetiapine (1 April – 30 June 2004)
80
Characteristic n Patients receiving Patients receiving
70 >500 mg/day (%) >750 mg/day (%)
Patients (%)

60 All 1086 56 34
Gender
50 Male 674 57 35
Female 412 54 30
40
1997 1998 1999 2000 2001 2002 2003 2004 Ethnicity
Caucasian 519 52 30
African-American 398 59 38
Hispanic 131 60 35
Figure 2b. Mean daily dose of olanzapine (1 April – 30 June 2004)
Length of stay
Mean 22.2 mg/day Short (30-90 days) 167 54 32
35 (Weighted mean 23.1 mg/day) Long (1-5 years) 284 63 37
30 Prior admission
25
Patients (%)

to state hospital
20 Yes 744 58 36
15
No 342 51 29
10
Diagnosis
5
0 Schizophrenia 448 54 34
>0-5 >5-10 >10-15 >15-20 >20-30 >30-40 >40 Schizoaffective 378 60 36
Olanzapine (mg/day) Bipolar 109 57 36
n=1501

3
 Discussion and Conclusions
© Dosing recommendations provided in the product labeling are the result of carefully designed
registration studies that have a limited number of subjects. They have stringent inclusion and
exclusion criteria, eliminating from consideration many of the patients that will eventually
be treated by the new agent once commercially available.
© Once a medication is FDA-approved and released, it can take several years before sufficient
clinical experience is accumulated and a consensus is reached regarding dosing.
© We have observed changes in the average daily dosing over the past 5 years for risperidone
(lower), olanzapine (higher), and quetiapine (higher).
© Increased dosing of olanzapine and quetiapine reflects the high number of severely and
persistently mentally ill patients within the study population.
© Decreased dosing of risperidone may reflect the increased EPS seen at higher doses of
risperidone.21
© Not described here are the high rates of co-prescription of antipsychotics with both other
antipsychotics (40% of all patients receive more than one antipsychotic) and with anticonvulsants
(50% of all patients also receive either lithium or an anticonvulsant). However, preliminary
inspection of the dosing data does not reveal any major differences in antipsychotic dosing when
these agents are used either as monotherapy or in combination with other antipsychotics.22
© Future research, including Phase IV clinical trials that are done after the introduction of new
agents, need to include patients who have a more refractory course of illness and who are
commonly treated in public psychiatric settings. In addition, for those agents where a high-dose
strategy is commonly used (olanzapine and quetiapine), this treatment option needs to be tested
using appropriately designed controlled clinical trials.

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9. Citrome L et al. J Clin Psychopharmacol (in press, scheduled for August 2005).
10. Risperidone prescribing information, 2003.
11. Olanzapine prescribing information, 2003.
12. Quetiapine prescribing information, 2003.
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The authors acknowledge the production support provided by AstraZeneca in the preparation of this poster.
Partial support for the Integrated Research Database (IRDB) has been provided by unrestricted grants from AstraZeneca,
Abbott Laboratories, Eli Lilly & Company, the Janssen Research Foundation, and Pfizer Inc.

Presented at the 8th World Congress of Biological Psychiatry,

Vienna, Austria, 28 June - 3 July, 2005.