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A Double-blind, Placebo-Controlled Dose-Response Comparison of Intramuscular Olanzapine and Haloperidol in the Treatment of Acute Agitation in Schizophrenia
Alan Breier, MD;
Karena Meehan, MB, MRCP, MRCPsych;
Martin Birkett, BSc;
Stacy David, PhD;
Iris Ferchland, MSc;
Virginia Sutton, PhD;
Cindy C. Taylor, PhD;
Rebecca Palmer, MS;
Martin Dossenbach, MD;
Geri Kiesler, RPh;
Shlomo Brook, MD;
Padraig Wright, MRCPsych, MD
Arch Gen Psychiatry. 2002;59:441-448.
ABSTRACT
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Background An intramuscular (IM) formulation of olanzapine has been developed because
there are no rapid-acting IM atypical antipsychotic drugs currently available
in the United States for treating acute agitation in patients with schizophrenia.
Methods Recently hospitalized acutely agitated patients with schizophrenia (N
= 270) were randomized to receive 1 to 3 IM injections of olanzapine (2.5,
5.0, 7.5, or 10.0 mg), haloperidol (7.5 mg), or placebo within 24 hours. A
dose-response relationship for IM olanzapine in the reduction of agitation
was assessed by measuring the reduction in Positive and Negative Syndrome
Scale Excited Component (PANSS-EC) scores 2 hours after the first injection.
Safety was assessed by recording adverse events and with extrapyramidal symptom
scales and electrocardiograms at 24 hours after the first injection.
Results Olanzapine exhibited a dose-response relationship for reduction in agitation
(F1,179= 14.4; P<.001). Mean PANSS-EC
reductions 2 hours after the first injection of olanzapine (2.5 mg = -5.5;
5.0 mg = -8.1; 7.5 mg = -8.7; 10.0 mg = -9.4) were superior
to those with placebo (-2.9; P = .01 vs olanzapine
at 2.5 mg; P<.001 for each other olanzapine dose)
but not with haloperidol (-7.5). A dose of 5.0, 7.5, or 10.0 mg of olanzapine
caused a greater reduction in agitation than placebo 30 minutes after the
first injection. There were no differences between treatment groups for hypotension,
the most frequently reported adverse event, or for clinically relevant changes
in the QTc interval. There was a greater incidence of treatment-emergent parkinsonism
during treatment with IM haloperidol (16.7%) than with 2.5 (P = .03), 5.0 (P = .03), or 7.5 mg (P = .01) of IM olanzapine (0%) or with placebo (0%) (P = .01).
Conclusions Intramuscular olanzapine at a dose of 2.5 to 10.0 mg per injection exhibits
a dose-response relationship in the rapid treatment of acute agitation in
patients with schizophrenia and demonstrates a favorable safety profile.
INTRODUCTION
ACUTE AGITATION is common in patients with schizophrenia and may be
accompanied by destructive and/or violent behavior.1-3
Rapid treatment with intramuscular (IM) typical antipsychotic and/or benzodiazepine
agents may be essential to prevent injury to the patient or others.4-5 However, IM typical antipsychotics
are associated with acute dystonia,6-7
akathisia,8 neuroleptic malignant syndrome,9 and electrocardiographic (ECG) abnormalities including
prolongation of the QTc interval.10-11
Intramuscular benzodiazepines may cause excessive sedation leading to respiratory
depression,12-15
ataxia, and confusion.16 These adverse events
present a greater risk when typical antipsychotic agents and benzodiazepines
are administered together and/or intravenously.17-20
An IM formulation of an atypical antipsychotic agent may present several
treatment advantages when rapid treatment of acute agitation is essential
in patients with schizophrenia. Atypical antipsychotic agents are significantly
less likely to cause extrapyramidal symptoms than typical antipsychotic agents.21-23 In addition, some
atypical agents (eg, olanzapine and risperidone), but not all (sertindole
or ziprasidone [Pfizer Pharmaceuticals, New York, NY, unpublished data, 2000]),
have a more favorable ECG safety profile than specific (eg, thioridazine or
droperidol), but not all (haloperidol), typical antipsychotic agents .10, 22-24 Furthermore,
oral atypical antipsychotic agents are widely used for long-term maintenance
therapy, and an IM atypical antipsychotic agent may therefore facilitate the
transition to oral atypical maintenance therapy.25
This study tested the a priori primary hypothesis that 2.5, 5.0, 7.5,
and 10.0 mg per injection of IM olanzapine would exhibit a dose-response relationship
in reducing agitation in patients with schizophrenia, as measured by the mean
change on the Positive and Negative Syndrome Scale Excited Component (PANSS-EC)26 from the time of first injection until 2 hours later.
This study also tested the following secondary hypotheses: (1) IM olanzapine
would be superior to IM placebo in reducing acute agitation and no different
from 7.5 mg of IM haloperidol at 2 hours after the first injection; (2) the
efficacy of IM olanzapine in reducing agitation would be confirmed by measuring
response rates, benzodiazepine use, and injection frequency and by the use
of additional rating scales for agitation and general psychiatric status;
(3) the efficacy of IM olanzapine would be sustained for a clinically useful
period (24 hours); and (4) IM olanzapine would have a better overall safety
profile than IM haloperidol. The dose of 7.5 mg of IM haloperidol was chosen
based on the literature20, 27-29
and clinical experience indicating that both 5.0-mg and 10.0-mg doses are
commonly used to treat acute agitation; thus, 7.5 mg represents a compromise
between these doses. In addition, a dose-response analysis suggests that escalating
doses up to 7.5 mg results in an incremental enhancement of efficacy, but
doses that exceed 7.5 mg to 10.0 mg do not appreciably increase immediate
efficacy for most patients and may cause additional adverse effects.30
SUBJECTS AND METHODS
Recently hospitalized patients 18 years or older who had been clinically
diagnosed by the study investigators as having schizophrenia, schizophreniform
disorder, or schizoaffective disorder (according to the DSM-IV31) were recruited by the site
investigators based on their suitability as defined by inclusion and exclusion
criteria. All patients had a total score of 14 or higher (of a maximum of
35) on the PANSS-EC with a score of 4 or higher (of a maximum of 7) on at
least 1 item and were acutely agitated to the extent that parenteral antipsychotic
therapy was warranted. However, patients were not so agitated that they were
unable to provide informed consent or cooperate with the requirements of the
study. Thus, patients were physically and verbally overactive and were occasionally
hostile, destructive to property, or threatening, but no patient required
physical restraint or was violent toward other individuals. Patients with
significant medical disorders, including alcohol and/or drug dependency, were
excluded from this trial.
The study was conducted at 4 sites in Croatia (69 patients), 1 in Italy
(3 patients), 3 in Romania (82 patients), and 6 in South Africa (116 patients).
The study protocol was approved by local ethical review boards. The review
boards approved the use of placebo given the hospitalized status of all participating
patients, the 5:1 randomization ratio for active treatment vs placebo, the
brief duration of the study (24 hours), and the use of active medication based
on the clinical judgment of the investigator at the time of randomization.
Written informed consent was obtained from all patients and from a relative
or legal representative when required by local law or custom.
PROCEDURE
The study consisted of a screening period and a 24-hour IM treatment
period. Patients were not allowed to receive any antipsychotic treatment during
the screening period, which lasted for a minimum of 2 hours. On entering the
treatment period, patients were randomly allocated to treatment with 2.5,
5.0, 7.5, or 10.0 mg per injection of IM olanzapine, 7.5 mg per injection
of IM haloperidol, or IM placebo by the assignment of treatment kits. The
doses of IM olanzapine were based on data from 2 previous open-label pilot
clinical trials (N = 118) in which doses from 2.5 to 10.0 mg were found to
be safe and effective.32-33 Intramuscular
haloperidol was chosen for comparison because it is the most frequently used
IM antipsychotic worldwide for treating acute agitation in patients with schizophrenia.34
Patients could receive a maximum of 3 injections within the 24-hour
treatment period. Second and third injections were administered at the discretion
of the investigator, as clinically indicated. The second injection was allowed
after 2 hours had passed since the first injection, and a third injection
was allowed after 4 hours had elapsed since the second injection, with both
to have been administered within 20 hours after the first injection. All investigators,
raters, clinical staff involved with patient care, and patients were kept
blind to treatment assignment throughout the study. To ensure blinding, unblinded
third-party personnel, who played no role in evaluating patients, were trained
to handle and administer injections in identical, unmarked syringes.
Concomitant treatment with alpidem, anorectics, antiemetics, antiarrythmics,
carbamazepine, methyldopa, neuroleptics, phenobarbital, reserpine, or zolpidem
tartrate was prohibited during the study. Concomitant treatment with benzodiazepines
was prohibited from 4 or more hours before until 3 or more hours after administration
of the first injection. Thereafter, patients who received 1, 2, or 3 injections
of the study drug were permitted to receive 0, 1, or 2 benzodiazepine doses,
respectively (2-4 mg of lorazepam [IM or oral], 10-20 mg of diazepam [IM,
intravenous, or oral], 10-30 mg of oxazepam [oral], or 5-50 mg of clorazepate
[IM or oral]), each dose being administered 1 or more hours after the previous
injection of the study drug. Anticholinergic medication was permitted for
the treatment of newly emergent extrapyramidal symptoms, but prophylactic
use was prohibited.
ASSESSMENTS
Efficacy
Patients were assessed by the study investigators (14 investigators,
all of whom underwent training and interrater reliability testing) at the
screening visit, immediately prior to and at 30, 60, and 90 minutes and 2,
4, 6, 12, and 24 hours after the first injection. The primary efficacy measure
was the PANSS-EC, which includes the items tension, uncooperativeness, hostility,
poor impulse control, and excitement and was derived from the PANSS by its
originators using a principal-components factor analysis.26
The PANSS-EC was chosen as the primary efficacy measure because (1) it has
high face validity in the measurement of agitation; (2) data from agitated
and nonagitated patients who had participated in a registration trial of oral
olanzapine (n = 1996) provided confirmatory validation of the PANSS-EC (Eli
Lilly and Company, Indianapolis, Ind, unpublished data, 1997); and (3) it
is rated by physician observation as opposed to patient participation and
thus is well suited for the assessment of agitation because it avoids the
need for interaction that could exacerbate agitation. The validity of each
PANSS-EC recording was ensured by requiring investigators to read PANSS-EC
item descriptors and complete separate record pages at each evaluation.
Agitation was further assessed with the Agitated Behavior Scale (ABS)35 and the Agitation Calmness Evaluation Scale (ACES)
(Copyright 1998, Eli Lilly and Company; all rights reserved), a single-item
scale developed by Eli Lilly and Company on which 1 indicates marked agitation;
2, moderate agitation; 3, mild agitation; 4, normal; 5, mild calmness; 6,
moderate calmness; 7, marked calmness; 8, deep sleep; and 9, unable to be
aroused. The PANSS-derived Brief Psychiatric Rating Scale (BPRS) and Clinical
Global Impressions–Severity (CGI-S) scale36
were used to assess general psychiatric status.
Safety
During the 24-hour treatment period, safety was assessed by clinical
examination and laboratory investigations, recording spontaneously reported
adverse events, completing the Simpson-Angus37
and Barnes Akathisia Scales,38 and recording
ECGs during screening or immediately prior to the first IM injection and at
2 and 24 hours after the first IM injection. The ECG QT interval correction
formula was QTc = QT/RR1/2.
STATISTICAL METHODS
A dose-response relationship on the PANSS-EC at 2 hours after the first
IM injection was investigated across IM olanzapine treatment groups using
a linear trend test with contrast coefficients of -3, -1, 1, and
3 for IM olanzapine at 2.5 mg, 5.0 mg, 7.5 mg, and 10.0 mg, respectively.
Comparisons among IM olanzapine treatment groups, between IM olanzapine
and IM placebo groups, and between IM olanzapine and IM haloperidol groups
were performed using analysis of variance models (raw data) that took into
account treatment and country. The analysis was not planned a priori to assess
investigator site effects, although these were performed post hoc. Adjustments
for multiple comparisons were not performed for the pairwise comparisons.
Comparisons between treatment groups at each of the 30-, 60-, and 90-minute
assessment times were also performed.
Response was defined a priori as a 40% reduction or more in PANSS-EC
score from baseline to 2 hours after the first IM injection because open-label
studies showed that a 40% PANSS-EC score reduction reasonably represented
the rapid, substantial, and sustained reduction in agitation desired when
an IM antipsychotic is administered.32-33
Response rates were compared across all treatment groups using the stratum-adjusted
Pearson  2 test (Cochran-Mantel-Haenszel option; SAS statistical
software version 6.08 [SAS Institute Inc, Cary, NC]) controlling for country.
Pairwise comparisons were also performed using the Cochran-Mantel-Haenszel
statistic,39 stratifying by country, and the
Breslow-Day test40 to investigate the homogeneity
of odds ratios across countries. A dose-response relationship for response
rates was investigated using the extended Mantel-Haenszel correlation statistic,41 stratifying by country.
Categorical data (demographic variables, reasons for study discontinuation,
treatment-emergent adverse events, incidence of benzodiazepine and anticholinergic
use, and potentially clinically significant ECGs) were evaluated in a pairwise
fashion using the Fisher exact test. The incidence of treatment-emergent parkinsonism
(the proportion of patients with a Simpson-Angus Scale total score >3 during
the 24-hour IM period among those with a total score  3 at baseline) and
treatment-emergent akathisia (the proportion of patients with a Barnes Akathisia
Scale global score [item 4]  2 during the 24-hour IM period among those
with a score <2 at baseline) were evaluated in a pairwise fashion using
the Fisher exact test. To determine whether there was an association between
treatment and number of IM injections received (1, 2, or 3), a Cochran-Mantel-Haenszel
test was performed stratifying by country. All hypothesis tests were performed
using 2-tailed tests.
RESULTS
PATIENT CHARACTERISTICS AND DISPOSITION
Most of the 270 patients (IM olanzapine: n = 48 for 2.5 mg, n = 45 for
5.0 mg, n = 46 for 7.5 mg, and n = 46 for 10.0 mg; IM haloperidol: n = 40;
IM placebo: n = 45) who participated in this study were white (65.9%) men
(57.4%), with ages ranging from 18 to 73 years (mean ± SD age, 36.3
± 10.7 years) and a mean ± SD age at onset of illness of 25.1
± 7.3 years. There were no treatment group differences at baseline
for any patient characteristics (Table 1).
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Table 1. Patient Characteristics at Baseline*
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Almost all patients (268 or 99.3%) completed the 24-hour IM treatment
period. Two patients (0.7%) receiving 5.0 mg of IM olanzapine discontinued
treatment (lack of efficacy; physician decision), but both were included in
efficacy and safety analyses because postbaseline data were collected on these
individuals.
EFFICACY
PANSS-EC Change From Time of First Injection Until 2 Hours Later
A monotonic dose-response relationship existed across the IM olanzapine
dose range (F1,179 = 14.4; P<.001).
All IM olanzapine doses and 7.5 mg of IM haloperidol were superior to IM placebo
in reducing agitation, but IM olanzapine at 2.5 mg was less effective than
any of the other IM olanzapine doses or IM haloperidol (Table 2). Patients treated with 5.0, 7.5, or 10.0 mg of IM olanzapine
had greater mean improvement than those given IM placebo at all time points
(Figure 1). The groups given 2.5
mg of IM olanzapine or IM haloperidol did not show greater mean improvement
compared with those given IM placebo until 60 minutes after the first injection.
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Table 2. Mean PANSS-EC Score Change From Baseline to 2 Hours After
the First IM Injection (LOCF)*
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Mean change in Positive and Negative Syndrome Scale Excited Component
score from baseline to each time point within 2 hours after the first intramuscular
(IM) injection. For IM olanzapine at 2.5 mg vs IM placebo, P = .65 at 30 minutes, P = .05 at 60 minutes, P = .02 at 90 minutes, and P =
.01 at 120 minutes. For IM olanzapine at 5.0 mg vs IM placebo, P = .03 at 30 minutes and P<.001 at 60,
90, and 120 minutes. For IM olanzapine at 7.5 mg vs IM placebo, P = .007 at 30 minutes and P<.001 at 60,
90, and 120 minutes. For IM olanzapine at 10.0 mg vs IM placebo, P = .05 at 30 minutes and P<.001 at 60,
90, and 120 minutes. For IM haloperidol at 7.5 mg vs IM placebo, P = .34 at 30 minutes and P<.001 at 60,
90, and 120 minutes.
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There was a monotonic dose-response relationship across the IM olanzapine
dose groups (21 = 12.0; P<.001)
for PANSS-EC response rates 2 hours after the first IM injection. Greater
response rates were observed with IM olanzapine at 2.5 mg (50.0%; 21 = 9.1; P = .003), 5.0 mg (62.6%; 21 = 16.7; P<.001), 7.5 mg (73.9%; 21 = 26.5; P<.001), and 10.0
mg (80.4%; 21 = 34.4; P<.001)
and with IM halo-peridol (60.0%; 21 = 15.0; P<.001) than with IM placebo (20.0%). Greater response
rates were observed with IM olanzapine at 7.5 mg (21= 5.7; P = .02) and 10.0 mg (21 = 10.2; P<.001) than at 2.5 mg, whereas
there were no differences between any IM olanzapine dose (including 2.5 mg)
and IM haloperidol.
Additional Efficacy Measures
On the ABS, ACES, and BPRS Total and Positive scales, all IM olanzapine
and IM haloperidol groups showed greater mean improvement at 2 hours after
the first IM injection than the IM placebo group, except IM olanzapine at
2.5 mg on the ACES and IM haloperidol on the BPRS Positive (Table 3). Compared with IM haloperidol, greater improvement was
observed on the ABS with IM olanzapine at 7.5 mg (t261 = 2.4; P = .02) and 10.0 mg (t261 = 2.3; P = .02) and on the
ACES with IM olanzapine at 10.0 mg (t261
= 2.3; P = .02).
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Table 3. Mean Change From Baseline to 2 Hours After the First IM Injection
(LOCF) in Additional Efficacy Measures*
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At 24 hours after the first IM injection, on the PANSS-EC, ABS, ACES,
BPRS Total, and BPRS Positive scales, all IM olanzapine treatment groups showed
greater mean improvement than the IM placebo group except IM olanzapine at
2.5 mg on the BPRS Positive (t262= 1.8; P = .07) (Table 4).
On the CGI-S at 24 hours, patients receiving 5.0 mg (t261 = 2.2; P = .03) and 7.5 mg (t261 = 3.1; P = .003) of IM olanzapine
showed greater improvement than those receiving IM placebo. Intramuscular
haloperidol was different from IM placebo at 24 hours on the BPRS Positive
(t262 = 2.3; P
= .02) and ABS (t262 = 2.0; P = .05). At 24 hours, patients given the 7.5-mg (t262 = 2.5; P = .02) and 10.0-mg
(t262 = 2.2; P
= .03) doses of IM olanzapine showed greater mean improvement on the ABS than
those receiving IM haloperidol.
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Table 4. Mean Change From Baseline to 24 Hours After the First IM Injection
(LOCF) in Efficacy Measures*
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Benzodiazepine Use
During the 24-hour IM treatment period, the incidence of benzodiazepine
use was greater during treatment with IM placebo than with any dose of IM
olanzapine or IM haloperidol. There were no differences between any of the
IM olanzapine dose groups and the IM haloperidol group (Table 5).
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Table 5. Dosage Administered, Injection Frequency, and Benzodiazepine
Use During the 24-Hour IM Treatment Period*
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Dosage Administered and Injection Frequency During the 24-Hour IM Treatment
Period
The mean total study medication dosages administered to patients in
each group during the 24-hour IM treatment period are shown in Table 5. There was an overall treatment group difference in the
proportion of patients receiving 1 to 3 IM injections (25 = 54.8; P<.001), with the number of injections
different between each active treatment group and the IM placebo group.
SAFETY
Spontaneously Reported Treatment-Emergent Adverse Events During the
24-Hour IM Treatment Period
Overall, the most frequently reported adverse event was hypotension
(IM olanzapine at 2.5 mg, 4.2% [2/48 patients]; IM olanzapine at 5.0 mg, 4.4%
[2/45 patients]; IM olanzapine at 7.5 mg, 2.2% [1/46 patients]; IM olanzapine
at 10.0 mg, 4.3% [2/46 patients]; IM haloperidol, 0% [0/40 patients]; IM placebo,
0% [0/45 patients]), although no between-group differences were observed.
Acute dystonia occurred in 0% (0/185 patients) of patients treated with IM
olanzapine, 0% (0/45 patients) of those receiving IM placebo, and 5.0% (2/40
patients) of those treated with IM haloperidol, with no between-group differences.
Treatment-Emergent Extrapyramidal Symptoms and Anticholinergic Use
During the 24-Hour IM Treatment Period
Treatment-emergent parkinsonism was less common in patients treated
with IM olanzapine (2.5-7.5 mg, 0% [0/107 patients]; 10.0 mg, 2.9% [1/35 patients])
and IM placebo (0% [0/37 patients]) than with IM haloperidol (16.7% [6/36
patients]), with differences (Fisher exact test) noted between IM haloperidol
and IM olanzapine at 2.5 mg (P = .03), 5.0 mg (P = .03), and 7.5 mg (P = .01)
and vs IM placebo (P = .01). Treatment-emergent akathisia
was less common in patients treated with IM olanzapine (2.5 mg, 7.5 mg, and
10.0 mg, 0% [0/129 patients]; 5.0 mg, 4.8% [2/42 patients]) and IM placebo
(0% [0/42 patients]) than with IM haloperidol (7.9% [3/38 patients]), although
no between-group differences were observed.
Anticholinergic medication was received by 3 patients (7.5%) treated
with IM haloperidol and 1 patient (2.1%) treated with 2.5 mg of IM olanzapine,
with no between-group differences.
Changes in ECG QTc Intervals During the 24-Hour IM Treatment Period
No patient had an increase in the QTc interval of 500 milliseconds or
greater, and there were only small baseline-to-24-hour end point changes in
mean ± SD QTc intervals, with none being clinically relevant (IM olanzapine
at 2.5 mg, -4.3 ± 22.3; IM olanzapine at 5.0 mg, -3.1 ±
23.2; IM olanzapine at 7.5 mg, -2.8 ± 19.6; IM olanzapine at
10.0 mg, -1.9 ± 31.0; IM haloperidol at 7.5 mg, 6.5 ±
24.7; IM placebo, 1.2 ± 21.5). The incidence of potentially clinically
significant QTc interval values, based on the sex-specific criteria of a QTc
interval of 430 milliseconds or more for men and 450 milliseconds or more
for women (IM olanzapine at 2.5 mg, 0% [0/45 patients]; IM olanzapine at 5.0
mg, 9.8% [4/41 patients]; IM olanzapine at 7.5 mg, 4.4% [2/45 patients]; IM
olanzapine at 10.0 mg, 7.9% [3/38 patients]; IM haloperidol, 14.3% [5/35 patients];
IM placebo, 19.0% [8/42 patients]), was greater during treatment with IM olanzapine
at 5.0 mg (P = .05), IM haloperidol (P = .01), and IM placebo (P = .002) than with
IM olanzapine at 2.5 mg and with IM placebo vs IM olanzapine at 7.5 mg (P = .05).
COMMENT
This study demonstrated a dose-response relationship for IM olanzapine
across the dose range of 2.5, 5.0, 7.5, and 10.0 mg per injection for a reduction
in agitation, as measured by changes on the PANSS-EC from the time of first
injection until 2 hours afterward. Intramuscular olanzapine at doses of 2.5,
5.0, 7.5, and 10.0 mg and IM haloperidol at 7.5 mg were superior in efficacy
on the PANSS-EC compared with IM placebo 2 hours after the first IM injection,
and this effect was sustained with IM olanzapine for up to 24 hours. Although
hypotension was the most frequently reported treatment-emergent adverse event
overall, there were no between-group differences or clinically relevant changes
in the QTc interval. Spontaneously reported acute dystonia did not occur in
any of the 185 IM olanzapine-treated patients but did occur in 2 of the 40
IM haloperidol-treated patients. Treatment-emergent parkinsonism was more
common during treatment with IM haloperidol than with either IM olanzapine
or IM placebo.
This study has several limitations. First, it was designed to have sufficient
power to detect differences between each dose of active medication and placebo
rather than between individual doses of active medication. Second, the study
was not designed to recruit adequate numbers of patients at all investigator
sites to investigate potential differential treatment effects between sites;
however, results from the 6 largest recruiting sites (accounting for 193/270
patients [71.5%]) were consistent with the overall findings comparing each
active treatment group with IM placebo. Third, the initial injection of active
medication was so efficacious in most patients that a second or third injection
was rarely required; thus, there is limited data on repeated dosing, particularly
for IM olanzapine at 10.0 mg. Fourth, benzodiazepines were used in this study
as described previously, and these may confound the efficacy outcomes. However,
benzodiazepine use was limited, and it is likely that any potential bias would
favor IM placebo because IM placebo-treated patients received significantly
more benzodiazepines than IM olanzapine-treated patients. Fifth, a medication
history was not collected. Nevertheless, because of the chronic nature of
schizophrenia and related disorders, most patients were probably receiving
antipsychotic medication. Sixth, DSM-IV diagnoses
of schizophrenia, schizophreniform disorder, or schizoaffective disorder were
determined by the site investigators using all available information; however,
structured diagnostic interviews were not obtained. Finally, although the
study patients had schizophrenia and were sufficiently agitated to be appropriate
candidates for parenteral antipsychotic therapy, they were not so agitated
that they were unable to provide informed consent or participate in the clinical
trial. Therefore, it will be important to determine if our data generalize
to patients who are more agitated than those studied. The moderate level of
agitation, the 24-hour duration of the study, and the use of second and third
injections and concomitant benzodiazepines probably account for the high completion
rates (99.3%).
Doses of 5.0, 7.5, and 10.0 mg of IM olanzapine were superior to IM
placebo on the PANSS-EC by 30 minutes after the first IM injection, indicating
a rapid onset of effect with these doses. Intramuscular olanzapine also resulted
in greater improvement than IM haloperidol on the ABS (7.5 mg and 10.0 mg)
and ACES (10.0 mg). In addition, 7.5 mg of IM haloperidol was not different
from IM placebo on the PANSS-EC at 24 hours after the first injection, whereas
all doses of IM olanzapine were. The response rates for IM olanzapine at 5.0
to 10 mg and IM haloperidol at 7.5 mg were more than double those of IM placebo
and superior at 2 hours after the first IM injection. Overall, these efficacy
results provide evidence of the superiority of IM olanzapine at 5.0, 7.5,
and 10.0 mg and haloperidol at 7.5 mg compared with IM placebo in the treatment
of acute agitation in schizophrenia. Furthermore, these data suggest that
10.0 mg of IM olanzapine may have efficacy advantages in comparison with 7.5
mg of IM haloperidol, as reflected by its more rapid onset of effect, the
ABS and ACES results, and the persistence of effect at 24 hours.
Acute dystonia is frightening and distressing to patients and has been
associated with noncompliance with medication.42-43
Acute dystonia was spontaneously reported in 5.0% (2/40) of IM haloperidol-treated
patients but in none of those treated with IM olanzapine or IM placebo. Furthermore,
there was a lower incidence of treatment-emergent parkinsonism among IM olanzapine-treated
patients than IM haloperidol-treated patients; in addition, numerically more
patients treated with IM haloperidol than with IM olanzapine received anticholinergic
medication. These findings are in keeping with previous comparisons of oral
olanzapine vs oral haloperidol44 and suggest
that IM olanzapine may have safety advantages compared with IM haloperidol
regarding extrapyramidal symptoms.
The incidence of the most frequently reported adverse event in patients
treated with IM olanzapine (hypotension) was no different from that with IM
placebo. Furthermore, there were no differences in the ECG QTc interval from
the time of first injection until 2 or 24 hours later for any of the IM olanzapine
treatment groups compared with IM haloperidol or IM placebo. This result is
in accordance with findings from previous oral olanzapine studies45-47 and suggests that
the ECG safety of IM olanzapine is comparable with that of IM placebo. The
ECG safety of IM haloperidol was further confirmed by this study.
Overall, these results suggest that IM olanzapine has a safety profile
similar to that of oral olanzapine and may be superior in this regard to IM
haloperidol. To address potential safety concerns regarding repeated IM olanzapine
dosing, we conducted an open-label pharmacokinetics study of 3 consecutive
doses of IM olanzapine at 10.0 mg given 4 hours apart within 24 hours.32 These data demonstrated that olanzapine plasma concentrations
were all within the range of steady-state plasma concentrations observed with
a daily oral dose of olanzapine. Thus, if doses of 10 mg per injection of
IM olanzapine are used, it seems prudent to recommend that the cumulative
daily dose of olanzapine (including orally administered olanzapine) should
not exceed 30 mg until further experience is gained with this formulation
in the clinical setting.
In summary, this study provides evidence that 2.5, 5.0, 7.5, and 10.0
mg per injection of IM olanzapine exhibit a dose-response relationship in
the treatment of acute agitation in patients with schizophrenia and demonstrate
a favorable safety profile. A dose of 10.0 mg per injection of IM olanzapine
is probably most effective for the majority of patients.
AUTHOR INFORMATION
Submitted for publication September 7, 2000; final revision received
February 8, 2001; accepted August 13, 2001.
This study was sponsored by Eli Lilly and Company, Indianapolis, Ind.
Corresponding author and reprints: Alan Breier, MD, Lilly Research
Laboratories, Eli Lilly and Company, Lilly Corporate Center, DC 1748, Indianapolis,
IN 46285 (e-mail: Breier_Alan{at}lilly.com).
From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis,
Ind (Drs Breier, David, Sutton, and Taylor, Mr Birkett, and Mss Palmer and
Kiesler); Maudsley Hospital, London, England (Dr Meehan); Lilly Research Centre,
Eli Lilly and Company Limited, Surrey, England (Dr Wright and Ms Ferchland);
Eli Lilly and Company, Vienna, Austria (Dr Dossenbach); Sterkfontein Hospital,
Krugersdorp, South Africa (Dr Brook); and the Institute of Psychiatry, University
of London, London, England (Drs Wright and Meehan).
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