Intramuscular Olanzapine Versus

Intramuscular Haloperidol Plus

Lorazepam For The Treatment of
Acute Schizophrenia with
Agitation : An Open-Label,
Randomized Controlled Trial
Dibacakan Oleh :
Zulvikar Umasangadji
Pembimbing :
dr. Widodo Sarjana AS, MKM, Sp.KJ
1

AGENDA

Abstract

Introduction

Methods

Result

Discussion

Conclusion

ABSTRACT

BACKGROUND

To compare the efcacy and safety prole

between intramuscular (IM) olanzapine and
IM haloperidol plus IM lorazepam in acute
schizophrenic patients with moderate to
severe agitation.

METHODS

This was a prospective, randomized, open-label study. Acutely

agitated patients with schizophrenia or schizoaffective disorder
(n = 67) were randomized to receive 10 mg IM olanzapine (n =
37) or 5 mg IM haloperidol plus 2 mg IM lorazepam (n = 30).

Agitation was measured with Positive and Negative Syndrome

Scale Excited Component (PANSS-EC) and Agitatione Calmness
Evaluation Scale (ACES) during the rst 2 hours and at 24 hours
after the rst injection.

Safety was assessed using the Simpsone-Angus Scale and

Barnes Akathisia Rating Scale and by recording adverse events
at 24 hours following the rst injection. The Clinical Global
Impression-Severity scale was also rated.
5

RESULT

The PANSS-EC scores decreased signicantly at 2

hours after the rst injection in both groups
(olanzapine: -10.2, p < 0.001; haloperidol +
lorazepam: -9.9, p < 0.001). Haloperidol plus
lorazepam was not inferior to olanzapine in reducing
agitation at 2 hours.

There were no signicant differences in PANSS-EC or

ACES scores between the two groups within 2 hours
following the rst injection.

The frequencies of adverse events and changes in

Clinical Global Impression-Severity, SimpsoneAngus6
Scale, and Barnes Akathisia Rating Scale scores from

CONCLUSION

The ndings suggest that IM haloperidol (5 mg) plus

lorazepam (2 mg) is not inferior to IM olanzapine (10
mg) in the treatment of acute schizophrenic patients
with moderate to severe agitation.

INTRODUCTION

Schizophrenia is a disorder with a complex course. Acute agitation

is common in the course of schizophrenia and may be accompanied
by destructive and/or violent behaviors.

Rapid tranquilization with preferred intramuscular (IM)

formulations of psychotropic medications is usually warranted.

The most common approach of rapid tranquilization is concomitant

administration of haloperidol and lorazepam.

However, there have been concerns over the potential adverse effects
of acute dystonia and extrapyramidal symptoms with
antipsychotics, and sedation, confusion, and respiratory depression
9
with benzodiazepines.

Data from randomized clinical trials have shown that IM

olanzapine is safe and effective in reducing acute agitation in
patients with schizophrenia, bipolar mania, and dementia.

In the management of agitation, IM olanzapine has been

reported to be comparable to IM haloperidol monotherapy in
schizophrenia, superior to IM lorazepam monotherapy in
bipolar mania, and comparable to IM lorazepam
monotherapy in dementia.

10

Preliminary evidence has demonstrated that IM olanzapine

is associated with fewer adverse movement disorders than
monotherapy with IM haloperidol.

An expert consensus panel has endorsed second generation

antipsychotic monotherapy (e.g., olanzapine) or the
combination of a benzodiazepine and a rst-generation
antipsychotic (e.g., haloperidol) for the treatment of
behavioral emergencies in patients with schizophrenia.

11

Most of the previous randomized controlled studies of IM

olanzapine in schizophrenia were sponsored by a pharmaceutical
company, and only compared IM olanzapine with IM haloperidol,
although such patients are frequently treated with a combination of
IM haloperidol and lorazepam injection in clinical practice.

To determine the most appropriate use of this expensive agent,

additional studies comparing IM olanzapine and combination
therapy with an antipsychotic plus benzodiazepine injection in
more severely agitated patients are needed.
12

The aim of this study to compare the efcacy and safety

prole between IM olanzapine and IM haloperidol plus IM
lorazepam in acute schizophrenic patients with moderate to
severe agitation.

We hypothesized that IM haloperidol plus lorazepam would

be non inferior to IM olanzapine in terms of the PANSS-EC
change at 2 hours.

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METHODS

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This study was a prospective, randomized, parallel trial comparing

IM olanzapine and IM haloperidol plus IM lorazepam in three
acute psychiatric inpatient units [National Taiwan University
Hospital (NTUH) and its Yun-Lin branch hospital, Yu-Li Psychiatric
Hospital] in a 24-hour treatment period.

It was conducted from September 2006 to February 2009, and was

performed in accordance with the principles of the Declaration of
Helsinki and Good Clinical Practice.

The study protocol was approved by the institutional review board

of each participating center, and all participants provided informed
consent.
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PATIENTS

Recently hospitalized patients who were 18 -65 years old and

who had been clinically diagnosed by the study investigators
as having schizophrenia or schizoaffective disorder were
recruited.

In order to enroll patients with different degrees of agitation,

the patients signed informed consent forms for this trial and
for admission on the day of admission after the study
procedure had been fully explained to them.

16

The Inclusion crieteria :

1.

Having a total score of 14 (of a maximum of 35) on the

PANSS-EC, which comprises ve items: tension,
uncooperativeness, hostility, poor impulse control, and
excitement.

2.

Having a score of 4 (of a maximum of 7) on at least

one of these ve items.

3.

Being acutely agitated to the extent that parenteral

antipsychotic therapy was indicated.
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The Exculsion crieteria :

1.

Women who were pregnant or lactating.

2.

Patients with severe medical illnesses.

3.

Patients who had received injectable depot antipsychotics within 1 month.

4.

Patients who had used psychostimulants or reserpine within 1 week.

5.

Patients who had received newly added oral or IM benzodiazepines within 4

hours.

6.

Patients who had received newly added oral or rapid-acting IM

antipsychotics within 2 hours

7.

Patients with a history of allergic reaction or intolerance to the study

medication(s).
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Randomization and Allocation

Concealment

Treatment assignments were based on a computer generated random

number list created by the central ofce prior to the start of the study.
The central ofce prepared consecutively numbered, sealed, identical
opaque envelopes with a randomization code inside according to the
random number list. The envelope and relevant questionnaires and
rating scales for each participant were placed together in a folder.

These folders were then sent to the three study sites where the clinical
staff performed the study according to the order found inside the sealed
envelopes. By concealment of allocation, selection bias could be avoided.
The random number list and randomization codes were kept from the
clinical staff until the end of the data analysis of the study.

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PROCEDURES

This study consisted of a screening phase and a 24-hour treatment phase.

Following screening, the patients who fullled the inclusion and
exclusion criteria were randomly allocated to treatment with IM
olanzapine or IM haloperidol plus lorazepam.

The patients could receive a maximum of three injections within the 24hour period. Second and third injections were prescribed at the
discretion of the clinical investigators. A second injection was allowed
after 2 hours had elapsed since the rst injection. A third injection was
allowed after 4 hours had passed since the second injection.

20

Experienced clinical staff were trained to handle and administer

injections according to the randomization code.

To ensure adequate reliability among raters, joint evaluations of six

agitated patients (2 with mild agitation and 4 moderate to severe
agitation) between the principal investigator (T.-J.H.) and other raters
were conducted before the study commenced.

All raters were not blinded to the medications.

Each unblinded psychiatrist completed the ratings together with the
respective attending nurse who observed the patients condition most
closely.
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EFFICACY ASSESSMENTS

Patients were assessed by the study investigators at the screening visit

and at 15 minutes, 30 minutes, 60 minutes, and 120 minutes after the rst
injection.

The primary efcacy measure was PANSS-EC, which was derived from
the PANSS by its originators using a principal components factor
analysis, and includes the items of tension, uncooperativeness, hostility,
poor impulse control, and excitement.

Agitation was further assessed by the Agitatione-Calmness Evaluation

Scale (ACES)

The Clinical Global Impression Severity (CGI-S) scale was used to assess
the general psychiatric condition.
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STATISTICAL ANALYSIS

The efcacy analyses were based on the intent to treat population

dened as all of the randomized patients.

Demographic characteristics and clinical parameters at baseline were

compared by the treatment group using the t test for continuous
variables and Chi-square test for categorical variables.

The primary endpoint was the change in PANSS-EC score 2 hours after
the rst injection, and the secondary endpoints included change in ACES
score 2 hours after the rst injection, and change in PANSS-EC, ACES,
and CGI-S scores 24 hours after the rst injection.

23

Within-group comparison was performed using paired t test.

Responder was dened as those with at least 40% reduction

from baseline on the PANSS-EC at 2 hours.

To compare the number of differences in adverse events and

response rate between the two treatment groups, Fishers
exact test was used.

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RESULTS

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DEMOGRAPHIC CHARACTERISTICS AND

CLINICAL PARAMETERS AT BASELINE

A total of 294 patients received an initial assessment after

acute admission. After exclusion, 67 patients (NTUH, 6;
NTUH Yun-Lin branch, 21; Yu-Li Psychiatric Hospital, 40)
were entered into the randomization phase. The patient ow
is shown in Fig. 1.

The main reasons for exclusion were did not sign informed
consent and having received recent depot injections or
newly added benzodiazepines or antipsychotics.

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Figure 1.

27

Another 180 patients did not enter the randomization phase

because of inadequate severity of agitation as judged by the raters.
The 67 patients, including 58 individuals with schizophrenia and
nine with schizoaffective disorder, were randomized to the two
treatment groups (37 in the olanzapine group, 30 in the haloperidol
plus lorazepam group), and they all completed the trial.

There were no signicant between-group differences in sex, age,

age of onset, length of current psychotic episode, or baseline
PANSS-EC score (Table 1).
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EFFICACY

In terms of primary endpoint, the PANSS-EC scores decreased

signicantly at 2 hours following the rst injection in both groups
(olanzapine: -10.2 6.5, t = 9.750, p < 0.001; haloperidol +
lorazepam: -9.9 5.6, t = 9.900, p < 0.001).

The difference between haloperidol plus lorazepam and

olanzapinewas 0.3 units favoring olanzapine (with one-sided lower
97.5% condence limit = -3); therefore non-inferiority (-3 vs. -10.2 x
0.4 = -4.1) could be concluded.

30

Regarding sedative effect, the ACES scores increased signicantly

at 2 hours in both groups (olanzapine: 2.1 1.7, t = 7.225, p <
0.001; haloperidol + lorazepam: 2.2 1.7, p < 0.001).

There were no signicant differences in PANSS-EC or ACES scores

between the two groups at 15 minutes, 30 minutes, 60 minutes,
and 120 minutes following the rst injection (Figs. 2 and 3),
although the olanzapine group tended to have faster action in the
1st hour after the rst injection.

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32

The changes in CGI-S and PANSS-EC from baseline to 24 hours after the
rst injection showed no signicant difference between the two groups
(Table 2).

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ADVERSE EFFECTS

The changes in SAS and Barnes Akathisia Rating Scale scores from
baseline to 24 hours after the rst injection showed no signicant
differences between the two groups (Table 2).

The incidences of adverse reactions were also not signicantly different

between the two groups (Table 3). However, acute dystonia only
occurred in the haloperidol plus lorazepam group.

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DISCUSSION

36

This study is the rst randomized controlled trial in a Chinese

population comparing IM olanzapine with a frequently used
combination of IM haloperidol plus IM lorazepam in the treatment of
acute schizophrenia with moderate to severe agitation.

The results showed that 5 mg IM haloperidol plus 2 mg IM lorazepam

were not inferior to 10 mg IM olanzapine for the treatment of acute
agitation, as revealed by the changes in the PANSS-EC scores within and
at 2 hours after the rst injection. Furthermore, the treatment regimens
demonstrated similar efcacy as measured by injection frequency and
the changes in CGI-S score from baseline to 24 hours after the rst
injection.

37

There was still a trend of a slightly faster action of IM olanzapine

treatment as observed by the changes in the PANSS-EC scores within 1
hour after the rst injection.

However, the differences did not reach statistical signicance and became
nearly zero at 2 hours after the rst injection, suggesting that IM
olanzapine may have faster action, but IM haloperidol plus lorazepam
are not inferior at 2 hours following the rst injection (Fig. 2).

The study showed these two treatments both demonstrated an acceptable

calming effect without too much sedation in the rst 2 hours after
injection.

38

This study found no signicant differences in adverse events between the

two groups at the end of 24 hours (Table 3), their proles were slightly
different. For example, acute dystonia only occurred in the haloperidol
plus lorazepam group (1 of 30 patients, 3.3%), and the gure was lower
than 4.0-7.1% reported in association with IM 7.5 mg haloperidol in
previous studies.

There seemed to be a higher incidence of dizziness/drowsiness in the

haloperidol plus lorazepam group.

Compared with IM lorazepam, olanzapine has been reported to cause a

similar incidence of somnolence and dizziness.

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LIMITATIONS
1.

This is an open-label trial, so some bias may have been introduced into
the evaluation process.

2.

There was no placebo group, although the efcacy of these drugs has
already been proven, which cannot be explained by a placebo effect.

3.

Our sample size may not be large enough to have adequate power to
detect differences between the two treatment regimens.

4.

The severity of agitation of the 180 excluded patients was based on the
raters clinical judgment rather than formal rating using the PANSS-EC
scale; thus, some of them might have been qualied for enrollment if
they had received formal ratings.
40

CONCLUSION

41

The ndings suggest that IM haloperidol (5 mg) plus

lorazepam (2 mg) is not inferior to IM olanzapine (10
mg) in the treatment of acute schizophrenic patients
with moderate to severe agitation.

42

THANK YOU

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