Standard and Higher Doses of Olanzapine

in Acutely Ill Patients with Schizophrenia

or Schizoaffective Disorder with
Suboptimal Prior Response:
A Randomized Double-Blind Fixed
Dose Study

BJ Kinon, J Volavka, V Stauffer, SB Edwards, H Liu-Seifert, L

Chen, DH Adams, JP Lindenmayer, JP McEvoy, PF Buckley,
JA Lieberman, HY Meltzer, D Wilson, L Citrome
 Abstract
Objective: The objective of this study was to assess the dose-response relationship of standard and higher
doses of olanzapine in acutely ill, non-treatment-resistant patients with schizophrenia or schizoaffective
disorder with suboptimal response to their current treatment.
Methods: This randomized, double-blind, 8-week, fixed-dose study compared olanzapine 10mg/d (OLZ,
n=199), 20 mg/d (n=200) and 40 mg/d (n=200) for patients with schizophrenia or schizoaffective disorder,
with baseline BPRS score ≥45, scores on at least 2 of the 4 BPRS positive symptom items ≥4 (moderate),
CGI-Severity score ≥4, and less than optimal response to current treatment. Patients with history of
antipsychotic treatment resistance, in particular to atypical antipsychotics, were excluded. The primary
outcome measure was a change in Positive and Negative Syndrome Scale (PANSS) total score. Dose–
response relationship was assessed by linear regression analysis with the log-transformed dose as the
independent variable and PANSS total score as the dependent variable.
Results: The proportion of patients completing the study (67.8%; between group p=.916) and time to
treatment discontinuation (p=.596) did not significantly differ between dose groups. All 3 dose groups
showed statistically significant improvement in PANSS total scores from baseline to endpoint, without
significant dose-response relationship. (p=.295). However, a post-hoc analysis of treatment response
(assessed by PANSS total score) showed a significant interaction between baseline PANSS and dose
(p=.023): patients with higher baseline PANSS scores responded better to higher doses. There was a
significant difference between the 10 and 40 mg dose groups (p=.002), but not between the 20 and 40 mg
(p=.124) or 10 and 20 mg (p=.134) dose groups for mean change in weight (1.9 kg [10 mg/d], 2.3 [20 mg/d],
3.0 [40 mg/d]). There was also a significant difference between the 10 and 40 mg (p<.001), 20 and 40 mg
(p=.004), and 10 and 20 mg (p=.018) dose groups for mean change in prolactin levels (-10.5 ng/ml [10
mg/d], -1.7 [20 mg/d], 4.9 [40 mg/d]).
Conclusions: Over 8 weeks, acutely-ill, non-treatment-resistant patients with schizophrenia or
schizoaffective disorder responded to all 3 doses of olanzapine, without a statistically significant dose-
response relationship. These results suggest that most individuals in the general population of patients with
schizophrenia or schizoaffective disorder may respond to the approved olanzapine dosing range (10-20
mg/d). However, the use of higher doses (up to 40 mg/d) for a more severely ill patient population may be
more effective. Clinicians should consider the relative risks and benefits when optimizing medication dose.
 Background
• While olanzapine (OLZ) doses >20 mg/day have not been extensively studied for the
treatment of schizophrenia in clinical trials to date, available data suggested that olanzapine
at doses of >20 mg/day may provide efficacy benefits for some patients.
– A statistically significant linear trend in dose response for olanzapine 5-15mg over 6
weeks was previously observed in a pooled analysis of 444 patients with schizophrenia
from 2 randomized double-blind trials. 1
– A rapid initial dose escalation (RIDE) study in acutely agitated patients with
schizophrenia or bipolar mania, in which up to 40 mg olanzapine was allowed on Days 1
and 2, found RIDE to be significantly superior to usual clinical practice for improving
symptoms of agitation after 24 hours and 4 days. 2
– In a small, 6-month study of patients with treatment resistant schizophrenia, olanzapine
dosed up to 45 mg/d (mean dose 33.6±11 mg/d) produced statistically significant
symptom improvement compared to baseline that was similar to clozapine treatment. 3
– In a 14-week, double-blind study of 157 inpatients with chronic schizophrenia and who
were treatment resistant, after titration to a fixed 20 mg/d target dose for the first 8 weeks
of the study, olanzapine treatment resulted in further improvement of symptoms when
the dose was increased during Weeks 9 to 14 (dose range: 10 to 40 mg/day; mean
olanzapine dose 30.4±6.6 mg/day).4

• Objective: The objective of this study was to assess the dose-response relationship of
standard and higher doses of olanzapine in acutely ill, non-treatment-resistant patients with
schizophrenia or schizoaffective disorder with suboptimal response to their current
treatment.
 Study Design
Study Period I Study Period II

Screening Double - Blind Therapy Period

Period Down titrate
previous Olanzapine 40 mg/day
antipsychotic
agent
All
Patients Olanzapine 20 mg/day

Up titrate Olanzapine 10 mg/day

study
medication

2-5 days 1 week 1 week 1 week 1 week 2 weeks 2 weeks

titration

V1 V2 V3 V4 V5 V6 V7 V8 Final
Visit
8 weeks
Randomization
 Methods
• Multicenter, randomized, double-blind, parallel, 8-week fixed-dose study of inpatients or outpatients meeting
DSM-IV-TR diagnostic criteria for schizophrenia or schizoaffective disorder.
• Randomization performed 1:1:1 into 3 treatment groups:
– 10 mg/d olanzapine
– 20 mg/d olanzapine
– 40 mg/d olanzapine
• Key inclusion criteria
– Baseline BPRS score (PANSS extracted) ≥45 and scores on at least 2 of the 4 BPRS positive symptom
items ≥4 (moderate)
– Clinical Global Impression Severity (CGI-S) score of ≥4
– Less than optimal response to current treatment in the opinion of the investigator
• Key exclusion criteria
– Patients with history of antipsychotic treatment resistance, in particular to atypical antipsychotics, as
demonstrated by failure to respond to an adequate trial of at least 8 weeks of the following:
• Clozapine, at doses of 300 mg/day or greater; or
• Olanzapine, at doses of 10 mg/day or greater; or
• Risperidone, at doses above 8 mg/day; or
• Quetiapine, at doses above 750 mg/day
– Patients who have a history of an inadequate response, in the opinion of the investigator, to 3 or more
adequate antipsychotic medication trials of at least 8 weeks duration in the past 2 years
 Methods-cont
• Efficacy Assessments:
– Mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score
as assessed at 8 weeks
• Safety Assessments:
– Treatment-emergent adverse events
– Movement disorders assessed by Simpson-Angus Scale, Barnes Akathisia Rating Scale, and
Abnormal Involuntary Movement Scale (AIMS)
– Vital signs, ECG
– Fasting laboratory analyses
– Weight
• Statistical Analyses:
– Primary objective: dose–response relationship was assessed by linear regression analysis
with the log-transformed dose as the independent variable and change in PANSS total score
as the dependent variable
– Analyses were completed on an intent-to-treat basis unless otherwise specified and statistical
significance defined as a two-tailed p value less than .05
– Time to discontinuation and time to response were evaluated with Kaplan-Meier estimator
and dose groups compared with log-rank test
– Change from baseline to endpoint (last observation carried forward (LOCF)) in laboratory
values compared between treatment groups with ANOVA for ranks of changes with treatment
and investigator in the model
 Demographics and Baseline Characteristics
OLZ 10mg OLZ 20mg OLZ 40mg
(n=199) (n=200) (n=200)
Gender (male %) 67.3 67.5 69.5
Age, mean years (SD) 41.16 (10.73) 40.85 (10.78) 41.60 (10.63)
Race (Caucasian %) 44.2 46.5 45
Race (African Descent %) 46.2 42.0 40.5
Diagnosis (%)
Schizophrenia 68.3 68.5 69.5
Schizoaffective 31.7 31.5 30.5
Paranoid Schizophrenia 57.3 56.5 57.0
Onset age of psychosis (mean years ±SD) 23.19 (8.4) 23.75 (9.15) 23.89 (8.86)
Duration of Illness (mean years ±SD) 17.96 (10.88) 17.13 (10.95) 17.63 (10.19)
Previous schizophrenic episodes (# ±SD) 8.56 (7.58) 8.59 (7.85) 8.07 (6.66)
PANSS Total (mean ±SD) 93.57 (12.57) 93.36 (13.15) 93.42 (12.31)
Weight (kg) (mean ±SD) 89.95 (23.82) 88.59 (20.71) 88.63 (21.99)
BMI (mean ±SD) 30.06 (7.54) 29.68 (6.82) 30.18 (7.78)
 Time to Discontinuation for Any Cause
(Survival Curve)
100
Probability of Remaining in Treatment

90
80
70
60
50
OLZ 10mg
40
OLZ 20mg
30 OLZ 40mg
20
Log-rank p value=.596
10
0
0 1 2 3 4 5 6 7 8
Treatment Week

Completed: 10mg 67%; 20mg 69%; 40mg 67%; p=.916

Discontinued due to lack of efficacy: 10mg 3.5%; 20mg 3%; 40mg 2.5%; p=.600
Discontinued due to adverse event: 10mg 8%; 20mg 5%; 40mg 7%; p=.477
Discontinued due to other reason: 10mg 21%; 20mg 24%; 40mg 23.5%; p=.523-1.00
 PANSS Total - Dose Response
0

-5

-10
Baseline to Endpoint at 8 weeks (LOCF)
Mean Change in PANSS Total Score -

-15

-20

-25
-23.51
-26.73 -25.67
-30

-35 OLZ 10
OLZ 20
-40
OLZ 40
-45 Primary analysis of dose response p=.295
-50

p values between group: 10 vs 20, p=.083; 10 vs 40, p=.192; 20 vs 40, p=.661.

 Time to Response
(>20% Reduction in PANSS)
0
10 Log-rank p-value=.899 OLZ 10mg
20 OLZ 20mg
Probability of Responding

30 OLZ 40mg
40
50
60
70
80
90 Median time to response: 3 weeks, Kaplan-Meier
100
0 1 2 3 4 5 6 7 8
Treatment Week

Proportion of responders at 8 weeks based on PANSS total:

OLZ 10 mg 58.2%; OLZ 20 mg 63.9%; OLZ 40 mg 56.6%; p=.321
Interaction of Dose and Baseline Severity

p=.0230 for interaction between baseline PANSS total and log dose
 Dose Response by Baseline Severity
0
-5
Change of PANSS Total
from Baseline (LOCF)

-10
-15
-20 10mg
-25 p=.594 20mg
-30 40mg
-35
p=.179
-40
p=.106
-45 p=.039
-50
<92 (n=293) ≥ 92 (n=298) ≥ 101(n=148) ≥ 111(n=62)

Level of Baseline PANSS Total Scores

p=dose response p-value within each subgroup

 Treatment-Emergent Adverse Events (%)
If Incidence 10% or p<0.1
OLZ 10mg OLZ 20mg OLZ 40mg Fisher’s exact
(n=199) (n=200) (n=200) test p value
Abnormal dreams 2 0.5 0 .052
Fatigue 1.5 2 6.5 .017
Dizziness 2.5 1.5 6.5 .022
Vision blurred 0.5 0 2.5 .036
Hypertension 2 2.5 0 .073
Vomiting 3 3.5 0.5 .096
Dry mouth 8 8 12 .316
Increased appetite 8.5 10 8.5 .889

•There was no significant difference between dose groups in the percentage of

patients who experienced a treatment-emergent serious adverse event (p=.215).
 Mean Change From Baseline to Endpoint in
Weight and Metabolic and Prolactin Lab Values*
Between group p
Mean change to Within group
Item Therapy N
endpoint (SD) p vs. 20mg vs. 40mg

10mg 192 1.9 (3.5) <.001 .134 .002

Weight (kg) 20mg 188 2.3 (4.2) <.001 .124
40mg 195 3.0 (4.0) <.001
10mg 169 9.6 (37.2) .001 .325 .750
Fasting glucose
(mg/dL)
20mg 163 4.3 (24.6) .030 .199
40mg 159 10.3 (39.2) <.001
10mg 162 13.0 (80.5) .035 .819 .117
Fasting Triglycerides
(mg/dL)
20mg 158 13.3 (66.0) .018 .181
40mg 154 27.3 (98.0) <.001
10mg 162 7.0 (32.1) .003 .588 .528
Fasting Cholesterol
(mg/dL)
20mg 158 4.2 (29.6) .047 .923
40mg 154 4.5 (31.1) .047
10mg 156 5.4 (6.19) .006 .380 .572
Fasting LDL (mg/dL) 20mg 155 2.4 (6.19) .114 .768
40mg 147 3.1 (3.87) .036
10mg 162 -0.57 (8.3) .098 0.870 0.068
Fasting HDL (mg/dL) 20mg 157 -0.96 (9.5) .110 0.097
40mg 155 -2.7 (8.0) <.001
10mg 185 -10.5 (32.3) .003 .018 <.001
Prolactin (ng/mL) 20mg 182 -1.7 (25.4) .702 .004
*For patients with at least 40mg 180
1 dose of study drug 4.9 (27.9) .002
Incidence of Treatment-Emergent Abnormally
High Weight Gain and Prolactin Values

% TE Trend exact
Treatment Emergent (TE) Event Therapy n/N*
test p-value
10mg 27/193 14.0
>7% Weight gain at anytime 20mg 40/195 20.5 0.117
40mg 35/190 18.4
10mg 34/109 31.2
Prolactin (males > 18.77 ng/ml, females
20mg 50/117 42.7 <.001
>24.20 ng/ml) at anytime
40mg 69/113 61.1

*For prolactin N reflects patients who were normal at baseline.

 Movement Disorders and QTc Interval

• There were no significant differences between dose groups for

treatment-emergent EPS as assessed with the Modified
Simpson-Angus Scale, akathisia with the Barnes Akathisia
Scale, and symptoms of tardive dyskinesia with the Abnormal
Involuntary Movement Scale.
• There were no significant differences between treatment groups
in the incidence of abnormal increase from baseline in QTc
interval or in the incidence of treatment-emergent abnormally
high QTc interval at anytime post-baseline. No patient
experienced a QTc >500 msec.
 Efficacy Summary
• The proportion of patients completing the study (67.8%; between group p=.916) and time
to treatment discontinuation (p=.596) did not significantly differ between dose groups.
• All 3 dose groups showed statistically significant improvement in PANSS total scores from
baseline to endpoint, without significant dose-response relationship (p=.295).
• There was no significant difference between dose groups in time to response (20%
reduction in PANSS total score; p=.899).
• A post-hoc analysis of treatment response (assessed by PANSS total score) showed a
significant interaction between baseline PANSS and dose. (p=0.023): patients with higher
baseline PANSS scores (≥111) responded better to higher doses.

Safety Summary
• There was a significant difference between the 10 and 40 mg dose groups (p=.002), but
not between the 20 and 40 mg (p=.124) or 10 and 20 mg (p=.134) dose groups for mean
change in weight (1.9 kg [10 mg/d], 2.3 kg [20 mg/d], 3.0 kg [40 mg/d]).
• There was no significant difference between dose groups in the percentage of patients in
each treatment group who experienced clinically significant (≥7%) weight gain (10 mg =
14%, 20 mg=20.5%, 40 mg=18.4%; p=.117).
• There was a significant difference between the 10 and 40 mg (p<.001), 20 and 40 mg
(p=.004), and 10 and 20 mg (p=.018) dose groups for mean change in prolactin levels
(-10.5 ng/ml [10 mg/d], -1.7 [20 mg/d], 4.9 [40 mg/d]); and there was a statistically
significant difference between dose groups in the incidence of treatment-emergent
abnormal prolactin values (p<.001).
• There were no statistically significant pairwise differences between dose groups for mean
change in fasting glucose, triglycerides, or cholesterol.
 Conclusion
• Over 8 weeks, acutely-ill, non-treatment-resistant patients with schizophrenia
responded to all 3 doses of olanzapine, without significant dose-response
relationship.

• These results suggest that most individuals in the general population of patients
with schizophrenia or schizoaffective disorder may respond to the approved
olanzapine dosing range (10-20 mg/d).

• However, the use of higher doses (up to 40 mg/d) for a more severely ill patient
population may be more effective.

• Patients treated with the highest olanzapine dose (40 mg/d) had a significantly
greater increase in mean weight compared with patients who received the 10 mg
dose and had a significantly greater increase in mean prolactin levels compared
with patients who received the 10 or 20 mg dose.

• Clinicians should consider the relative risks and benefits of olanzapine treatment
when optimizing medication dose.
 References
1. Kinon BJ, et al. Presented at: 57th Society of Biological Psychiatry; May 16-
18, 2002; Philadelphia, PA.
2. Baker RW, Kinon BJ, Maguire GA, Liu H, Hill AL. Effectiveness of rapid initial
dose escalation of up to forty Milligrams per day of oral olanzapine in acute
agitation. J Clin Psychopharm 2003;23:342-348.
3. Jayathilake J, Meltzer DO, Small J, Meltzer HY. Comparison of clozapine and
high dose olanzapine in treatment resistant schizophrenia in a double blind,
randomized, 6 month clinical trial. Neuropsychopharmacology 2005;30(suppl
1):202.
4. Volavka J, Czobor P, Sheitman B, Lindenmayer J, et al. Clozapine,
olanzapine, risperidone, and haloperidol in the treatment of patients with
chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 2002;
159:255-262.