Attenuating effect of reboxetine on appetite and weight gain in olanzapine-treated schizophrenia patients: A double-blind placebo-controlled study


Poyurovsky, M.; Fuchs, C.; Pashinian, A.; Levi, A.; Faragian, S.; Maayan, R.; Gil-Ad, I.

Psychopharmacology 192(3): 441-448

2007


Search for safe and effective strategies to diminish weight gain associated with second generation antipsychotics (SGAs) is imperative. In the present study, we sought to replicate our preliminary findings, which indicated that coadministration of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapineinduced weight gain. Materials and method Fifty-nine patients hospitalized for first-episode DSM-V schizophrenic disorder participated in this randomized double-blind study. Reboxetine (4 mg/day; 31 patients) or placebo (29 patients) was coadministered with olanzapine (10 mg/ day) for 6 weeks. Analysis was by intention-to-treat. Results Nine patients in each group prematurely discontinued the trial. Olanzapine/reboxetine-treated patients showed a significantly lower increase in body weight (mean=3.31 kg, SD=2.73) than their olanzapine/ placebo- treated counterparts (mean=4.91 kg, SD=2.45). Significantly fewer olanzapine/ reboxetine- treated patients gained at least 7% of their initial weight, the cutoff for clinically significant weight gain (6 [19.4%] of 31 patients vs 13 [46.4%] of 28 patients). Seven (22.6%) olanzapine/ reboxetine- treated patients compared to only one patient (3.6%) in the olanzapine/ placebo group revealed no weight change or even modest weight loss. Appetite increase was significantly lower in the olanzapine/ reboxetine than olanzapine/ placebo group and was correlated with attenuation of weight gain. Reboxetine addition was safe and well tolerated. Conclusions The results confirm that coadministration of reboxetine promotes a clinically meaningful attenuation of olanzapine-induced weight gain in schizophrenia patients. If substantiated in long-term studies, along with behavioral management and diet counseling, reboxetine may have a clinical utility in controlling SGA-induced weight gain.

Psychopharmacology
(2007)
192:441-448
DOI
10.1007/s00213-007-0731-1
ORIGINAL
INVESTIGATION
Attenuating
effect
of
reboxetine
on
appetite
and
weight
gain
in
olanzapine-treated
schizophrenia
patients:
a
double-blind
placebo
-controlled
study
Michael
Poyurovsky
Camil
Fuchs
Artashez
Pashinian
Aya
Levi
Sarit
Faragian
Rachel
Maayan
Irit
Gil
-Ad
Received:
12
December
2006
/Accepted:
26
January
2007
/
Published
online: 20
February
2007
©
Springer-Verlag
2007
Abstract
Rationale
Search
for
safe
and
effective
strategies
to
diminish
weight
gain
associated
with
second
generation
antipsychotics
(SGAs)
is
imperative.
In
the
present
study,
we
sought
to
replicate
our
preliminary
fi
ndings,
which
indicated
that
coadministration
of
the
selective
norepineph-
rine
reuptake
inhibitor
reboxetine
attenuates
olanzapine-
induced
weight
gain.
Materials
and
method
Fifty-nine
patients
hospitalized
for
first
-episode
DSM-IV
schizophrenic
disorder
participated
in
this
randomized
double-blind
study.
Reboxetine
(4
mg/day;
M.
Poyurovsky
A.
Pashinian
A.
Levi
S.
Faragian
Research
Unit,
Tirat
Carmel
Mental
Health
Center,
P.O.
Box
9,
Tirat
Carmel
30200,
Israel
M.
Poyurovsky
(E)
Rappaport
Faculty
of
Medicine,
Israel
Institute
of
Technology—Technion,
Haifa,
Israel
e-mail:
poyurovs@tx.technion.ac.il
C.
Fuchs
Department
of
Statistics
and
Operations
Research,
Tel
-Aviv
University,
Tel
-Aviv,
Israel
R.
Maayan
I.
Gil
-Ad
Laboratory
of
Biological
Psychiatry,
Felsenstein
Medical
Research
Center,
Geha
Psychiatric
Hospital,
Petah
Tiqva,
Israel
Present
address:
C.
Fuchs
Department
of
Statistics,
University
of
Pittsburgh,
Pittsburgh,
PA,
USA
31
patients)
or
placebo
(29
patients)
was
coadministered
with
olanzapine
(10
mg/day)
for
6
weeks.
Analysis
was
by
intention
-to
-treat.
Results
Nine
patients
in
each
group
prematurely
discontin-
ued
the
trial.
Olanzapine/reboxetine-treated
patients
showed
a
significantly
lower
increase
in
body
weight
(mean=3.31
kg,
SD
=2.73)
than
their
olanzapine/placebo-treated
counterparts
(mean=4.91
kg,
SD
=2.45).
Significantly
fewer
olanzapine/
reboxetine-treated
patients
gained
at
least
7%
of
their
initial
weight,
the
cutoff
for
clinically
significant
weight
gain
(6
[19.4%]
of
31
patients
vs
13
[46.4%]
of
28
patients).
Seven
(22.6%)
olanzapine/reboxetine-treated
patients
com-
pared
to
only
one
patient
(3.6%)
in
the
olanzapine/placebo
group
revealed
no
weight
change
or
even
modest
weight
loss.
Appetite
increase
was
significantly
lower
in
the
olanzapine/
reboxetine
than
olanzapine/placebo
group
and
was
correlated
with
attenuation
of
weight
gain.
Reboxetine
addition
was
safe
and
well
tolerated.
Conclusions
The
results
confirm
that
coadministration
of
reboxetine
promotes
a
clinically
meaningful
attenuation
of
olanzapine-induced
weight
gain
in
schizophrenia
patients.
If
substantiated
in
long-term
studies,
along
with
behavioral
management
and
diet
counseling,
reboxetine
may
have
a
clinical
utility
in
controlling
SGA-induced
weight
gain.
Keywords
Second
generation
antipsychotics
Olanzapine
Reboxetine
Weight
gain
Introduction
Weight
gain
is
one
of
the
major
drawbacks
of
treatment
with
second
generation
antipsychotic
agents
(SGAs).
SGA-
4
kl
Springer
442
Psychopharmacology
(2007)
192:441-448
induced
weight
gain
is
associated
with
patient
nonadher-
ence
to
medication,
reduced
quality
of
life,
increased
morbidity
(e.g.,
cardiovascular
disease,
type
2
diabetes),
and
mortality
(Newcomer
and
Haupt
2006).
Olanzapine,
along
with
clozapine,
has
the
greatest
propensity
of
all
available
SGAs
to
induce
weight
gain.
Despite
extensive
research
during
the
last
decade,
a
pathophysiological
mechanism
underlying
olanzapine-
induced
weight
gain
remains
unclear.
Neurotransmitter
systems,
primarily
serotonergic
(5
-HT),
noradrenergic
(NE),
and
histaminergic
(H),
apparently
play
a
role
(Elman
et
al.
2006).
It
was
suggested
that
the
antagonistic
effect
of
olanzapine
on
NE
neurotransmission
contributes,
along
with
its
5-HT
2c
and
H
1
receptor
blockade,
to
its
high
propensity
to
cause
weight
gain
(Kroeze
et
al.
2003;
Poyurovsky
et
al.
2003).
In
contrast,
phentermine
and
sibutramine,
both
potent
appetite
suppressants
and
antiobe-
sity
agents,
facilitate
adrenergic
tone
by
stimulating
NE
release
and
NE
and
5
-HT
reuptake
inhibition
(Henderson
et
al.
2005).
Increased
NE
neurotransmission
has
consistently
been
implicated
in
regulation
of
food
intake,
body
weight,
and
energy
expenditure
in
preclinical
models
of
obesity
(Ste
Marie
et
al.
2005).
Reboxetine,
a
selective
norepinephrine reuptake
inhibitor
(NRI),
is
broadly
used
as
an
antidepressant
and
antianxiety
agent.
Overall,
in
these
patient
populations,
reboxetine
produced
a
neutral
effect
on
body
weight,
but
weight
loss
has
also
been
reported
(Schatzberg
2000;
Bertani
et
al.
2004).
Based
on
the
assumption
that
stimulation
of
NE
activity
by
the
selective
NRI
reboxetine
may
diminish
olanzapine-
induced
weight
gain,
we
conducted
a
pilot
study
in
which
reboxetine
was
coadministered
with
olanzapine
in
schizophre-
nia
patients
(Poyurovsky
et
al.
2003).
In
accordance
with
our
assumption,
patients
given
olanzapine
and
reboxetine
demon-
strated
a
significantly
lower
increase
in
body
weight
than
those
given
olanzapine
with
placebo.
The
addition
of
reboxetine
to
olanzapine
treatment
was
safe
and
well
tolerated
by
the
patients.
Noteworthy,
the
participants
were
young
first
-
episode
schizophrenia
patients
previously
unexposed
to
antipsychotic
medication
who
seem
to
be
particularly
vulner-
able
to
olanzapine-induced
weight
gain
(Kinon
et
al.
2001).
In
the
present
double-blind
placebo
-controlled
study,
we
sought
to
replicate,
in
a
larger
sample,
our
preliminary
findings
indicating
that
reboxetine
coadministration
attenuates
olanza-
pine-induced
weight
gain.
In
addition,
as
increased
appetite
and
food
intake
seem
to
be
a
major
behavioral
pathway
by
which
olanzapine
produces
weight
gain
(Gothelf
et
al.
2002;
Kinon
et
al.
2005;
Cope
et
al.
2005),
we
also
assessed
the
effect
of
reboxetine
on
appetite
and
its
relationship
to
weight
gain.
To
increase
comparability
of
the
results,
similar
to
the
previous
study,
we
recruited
first
-episode
predominantly
drug
-naïve
schizophrenia
patients
for
whom
olanzapine
treatment
was
indicated.
Subjects
and
methods
Subjects
and
study
design
This
study
was
conducted
in
Tirat
Carmel
Mental
Health
Center
(Tirat
Carmel,
Israel)
between
October,
2003
and
October,
2006.
The
study
protocol
was
approved
by
the
local
ethics
committee
and
was
undertaken
in
accordance
with
Good
Clinical
Practice
and
the
provisions
of
the
International
Conference
on
Harmonization,
with
all
patients
providing
written
informed
consent
after
they
received
a
full
explanation
of
the
study
procedures.
Patients
hospitalized
for
a
first
psychotic
episode
were
enrolled
in
the
study.
All
met
the
DSM-IV
criteria
for
schizophrenia
or
schizophreniform
disorder.
The
diagnosis
was
based
on
information
obtained
from
the
Structured
Clinical
Interview
for
DSM-IV
Axis
-I
Disorders,
Patient
Edition
(First
et
al.
1995).
Similar
to
the
previous
pilot
study,
inclusion
criteria
in
the
present
study
were
none
or
less
than
4
weeks
of
antipsychotic
drug
exposure
and
a
recommendation
for
olanzapine
treatment
by
the
treating
physician.
Exclusion
criteria
included
major
mood
disorders,
aggressive
or
suicidal
behavior,
medical
illnesses
that
could
affect
body
weight
(e.g.,
diabetes
mellitus
and
hypothyroidism),
and
obesity
(body
mass
index
[BMI]>30
kg/m
2
).
Of
the
85
patients
who
were
screened
for
participation
in
the
study,
69
met
entry
criteria,
59
patients
(38
men,
21
women)
were
randomized,
whereas
ten
patients
refused
to
participate
(Fig.
1).
There
were
no
differences
in
socio-demographic
or
clinical
variables
between
participants
(N=59)
and
those
who
refused
to
participate
(N=10).
The
olanzapine/reboxetine
group
consisted
of
31
patients
(23
men,
8
women;
age
30.3+8.5
years,
range
19-48
years),
and
the
olanzapine/placebo
group
consisted
of
28
patients
(15
men,
13
women;
age
29.5+7.2
years,
range
19-
46
years).
Before
the
beginning
of
the
study,
13
patients
in
the
olanzapine/reboxetine
group
were
drug
-naïve,
eight
patients
received
risperidone
(2-4
mg/day),
fi
ve
patients
received
haloperidol
(5-10
mg/day),
and
fi
ve
patients
received
perphenazine
(8-24
mg/day).
In
the
olanzapine/
placebo
group,
12
patients
were
drug
-naïve,
five
patients
received
risperidone
(2-6
mg/day),
fi
ve
patients
received
haloperidol
(10
mg/day),
fi
ve
patients
received
perphena-
zine
(8-16
mg/day),
and
one
patient
received
quetiapine
(600
mg/day).
None
of
the participants
received
medica-
tions
other
than
psychotropic
agents
during
the
study.
None
of
them
had
abnormal
findings
on
routine
physical
examination
and
laboratory
tests,
including
electrocardiog-
raphy
and
drug
screening,
when
appropriate.
A
double-blind
placebo
-controlled
randomized
design
was
used
in
the
present
study.
The
participants
were
allocated
according
to
entries
on
a
table
of
random
numbers
to
receive
olanzapine
(fixed
dose
of
10
mg
at
8:00
P.M.)
4i
Springer
Psychopharmacology
(2007)
192:441-448
443
85
patients
screened
69
patients
met
entry
criteria
59
patients
randomized
16
did
not
meet
entry
criteria
6
refused
to
sign
informed
consent
4
for
other
reasons
31
patients
olanzapine/reboxetine
group
9
drop
-outs
22
completed
trial
31
evaluated
for
primary
outcome
28
patients
olanzapine/placebo
group
9
drop
-outs
9
completed
trial
28
evaluated
for
primary
outcome
Fig.
1
Trial
profile.
Primary
analysis
was
done
on
the
intention
-to
-
treat
population
with
either
reboxetine
(4
mg/day,
administered
in
2
-mg
doses
twice
daily)
or
placebo
(twice
daily)
for
6
weeks.
All
study
medications
were
dispensed
in
identical
capsules,
and
patients
received
two
capsules
per
day.
Clinical
and
research
staff
and
patients
were
unaware
of
and
could
not
determine
the
study
drug
assignment
by
appearance
or
otherwise.
The
reboxetine
dose
was
determined
based
on
our
previous
report
(Poyurovsky
et
al.
2003).
Administra-
tion
of
an
anticholinergic
agent
(trihexyphenidyl
5
mg/day;
biperiden
2-4
mg/day)
for
extrapyramidal
side
effects
(extrapyramidal
symptoms,
EPS)
and
benzodiazepines
(lorazepam
1-3
mg/day;
diazepam
5
mg/day)
for
insomnia
or
agitation
were
allowed
on
an
as
-needed
basis;
no
other
antipsychotics,
antidepressants,
or
mood
stabilizers
were
permitted.
The
doses
of
all
medications
remained
un-
changed
during
the
entire
study
period.
Meals
were
served
three
times
a
day,
and
patients
were
not
placed
on
a
special
diet
or
physical
exercise
program
for
weight
reduction.
Assessments
Body weight
and
BMI
were
measured
before
breakfast
at
baseline
and
then
weekly.
All
weight
measurements
were
performed
by
a
research
assistant
blinded
to
the
patients'
treatment
assignment.
To
assess
a
change
of
appetite,
we
used
a
visual
analog
scale
with
the
following
scores:
0,
no
change;
1,
minimal
increase;
2,
moderate
increase;
3,
substantial
increase;
—1,
minimal
decrease;
—2,
moderate
decrease;
—3,
substantial
decrease.
Appetite
ratings
were
completed
at
the
end
of
the
trial.
Clinical
assessment
instruments
included
the
Scale
for
the
Assessment
of
Positive
Symptoms
(SAPS;
Andreasen
1984),
Scale
for
the
Assessment
of
Negative
Symptoms
(SANS;
Andreasen
1983),
Clinical
Global
Impression
scale
for
psychosis
(CGI;
Guy
1976),
and
the
Hamilton
Rating
Scale
for
Depression
(HAM
-D;
Hamilton
1960).
EPS
were
assessed
using
the
Barnes
Akathisia
Scale
(BAS;
Barnes
1989)
and
Simpson
—Angus
Scale
(SAS;
Simpson
and
Angus
1970).
Emergent
non-EPS
drug
-
induced
side
effects
were
closely
monitored.
Clinical
ratings
were
completed
at
baseline
and
at
week
6
by
the
same
trained
psychiatrist
(A.
Pashinian)
who
was
blinded
to
the
patients'
treatment
assignments.
Statistical
analysis
Statistical
analysis
was
carried
out
using
SPSS
for
Windows
13
(SPSS,
Chicago,
III).
The
sample
size
of
approximately
30
in
each
group
was
determined
to
provide
80%
power
in
detecting
a
between
-group
difference
of
at
least
2
kg,
when
the
significance
level
of
the
two-sided
test
is
a=0.05,
and
the pooled
SD
is
2.9,
as
obtained
in
our
previous
pilot
study
(Poyurovsky
et
al.
2003),
and
allowing
for
a
25%
attrition
rate.
The
primary
statistical
analysis
was
by
intention
to
treat
and
included
all
randomized
partic-
ipants.
A
complementary
analysis
of
weight/BMI
changes
in
completers
was
also
performed.
We
used
analysis
of
variance
with
repeated
measurements
(ANOVA-RM)
to
evaluate
between
-group
differences
in
weight
and
BMI
during
the
6
-week
trial
with
time
as
a
within
-subject
factor
and
group
as
a
between
-subject
factor.
In
addition,
similar
to
the
previous
study,
the
mean
changes
in
weight/BMI
during
the
trial
period
(difference
between
baseline
and
each
time
point)
were
analyzed
for
each
group.
We
used
the
regression
method
to
treat
missing
data.
In
this
method,
for
each
week
with
missing
weight/BMI,
the
values
were
substituted
by
those
obtained
from
the
fi
tted
values
based
on
the
regression
of
the
values
of
the
participants
with
complete data
for
the
given
week
on
the
data
for
the
previous
week.
This
imputation
method
takes
into
account
the
direction
and
the
effect
size
of
weight/BMI
changes
in
the
group
to
which
the
patients
with
missing
data
were
ascribed.
We
also
carried
out
an
alternative
method
of
imputation
based
on
the
last
observation
carried
forward
(LOCF).
We
used
the
changes
in
weight
and
BMI
as
the
primary
continuous
outcome
variable
and
the
proportion
of
patients
who
gained
7%
of
their
initial
body
weight,
the
established
cut-off
for
clinically
significant
weight
gain
(Kanders
et
al.
1991),
as
a
primary
categorical
outcome
variable.
Between
-
Springer
444
Psychopharmacology
(2007)
192:441-448
group
differences
in
the
proportion
of
patients
who
gained
7%
of
their
initial
body
weight
were
tested
by
x2
test
and
odd
ratios.
Between
-group
differences
in
demographic
and
clinical
variables
and
in
changes
fr
om
baseline
to
endpoint
in
the
appetite
visual
analog
scale,
SAPS,
SANS,
CGI,
HAM
-D,
SAS,
and
BAS
scores
were
analyzed
using
t
test
or
x
2
test,
as
appropriate.
Pearson's
correlation
analysis
was
used
to
assess
the
relationship
between
appetite
and
weight
changes
at
the
end
of
the
trial
and
the
relationship
between
baseline
weight
and
weight
change
at
the
end
of
the
trial.
All
tests
were
two
-tailed
with
a
significance
level
of
a
=0.05.
Measures
are
given
as
mean+SD.
Role
of
the
funding
source
The
study
was
funded
by
the
Stanley
Medical
Research
Institute.
The
funding
source
had
no
role
in
gathering,
analyzing,
or
interpreting
the
data
or
in
deciding
to
submit
the
paper
for
publication
in
Psychopharmacology.
Results
Figure
1
depicts
the
fl
ow
of
patients
through
the
study.
There
were
no
significant
between
-group
differences
in
demographics,
baseline
clinical
characteristics,
body
weight,
and
BMI
(Table
1).
Nine
patients
in
each
group
discontinued
the
study
medication
because
of
a
lack
of
efficacy
of
olanzapine
(seven
patients
in
each
group),
withdrew
consent
(olanzapine/reboxetine:
one
patient;
olan-
zapine/placebo:
two
patients),
and
discharge
from
the
hospital
(olanzapine/reboxetine:
one
patient).
The
missing
data
patterns
for
weight/BMI
values
were
similar
between
the
two
groups.
None
of
the
patients
discontinued
the
study
because
of
weight
gain,
and
the
majority
(olanzapine/
reboxetine:
eight
of
nine
patients;
olanzapine/placebo:
six
of
nine
patients)
dropped
out
before
the
fourth
assessment
(third
week).
There
were
no
differences
in
demographic
or
clinical
characteristics
or
weight/BMI
values
between
the
patients
who
dropped
out
of
the
study
and
those
who
did
not.
Body
weight/BMI
changes
fr
om
baseline
in
both
groups
are
presented
in
Table
2.
ANOVA-RM
revealed
a
highly
significant
effect
of
time
(weight:
F=88.89;
df=
5,287,
p<0.01;
BMI:
F=84.35;
df=5,
287,
p<0.01)
and
effect
of
group
(weight:
F=6.46,
df=1,
p=0.014;
BMI:
F=6.37;
df=1,
57,
p=0.014)
but
not
the
interaction
between
time
and
group
(weight:
F=1.77,
df=5,
287,
p=0.12;
BMI:
F=1.83;
df=5,287,
p=0.11).
Analysis
of
the
changes
in
weight
gain
in
the
two
groups
(Table
2)
revealed
a
gradual
cumulative
effect
in
weight
gain
fr
om
the
baseline
in
favor
of
reboxetine,
resulting
in
statistically
significant
between
-
group
differences
in
each
of
the
weeks
starting
from
week
2
through
the
end
of
the
6
-week
trial.
Although
the
cumulative
effect
from
baseline
was
significant,
the
between
-group
week
-to
-week
differences
in
weight
were
relatively
small
and
not
statistically
significant,
accounting
for
the
failure
of
ANOVA-RM
to
detect
significant
group
x
time
interaction
for
the
sample
sizes.
Overall,
at
the
end
of
the
trial,
patients
in
the
olanzapine/reboxetine
group
gained
significantly
less
weight
than
their
counterparts
in
the
olanzapine/placebo
group
(3.31+2.73
and
4.91+2.45
kg,
respectively;
t
=
2.
55;
df=
57
;
p=0.013),
namely,
a
between
-
group
difference
in
mean
weight
gain
of
1.61+0.62
kg.
The
corresponding
increase
in
BMI
was
1.12+0.87
kg/m
2
in
the
olanzapine/reboxetine
group
and
1.71+0.91
kg/m
2
in
the
olanzapine/placebo
group
(t=2.56,
df=
57
,
p=0.013),
with
a
between
-group
mean
difference
of
0.59+0.23
kg/m
2
.
Table
2
highlights
the
statistically
significant
between
-
group
difference
in
body
weight
and
BMI
in
favor
of
reboxetine,
which
was
evident
in
the
first
week,
strength-
ened
by
the
third
week
and
which
remained
significant
until
the
end
of
the
trial.
The
LOCF
analysis
also
yielded
a
Table
1
Demographics
and
baseline
clinical
characteristics
of
the
study
participants
Variables
Olanzapine/reboxetine
(n=31)
Olanzapine/placebo
(n
=
28)
Statistic
Age
(years)
Gender
(male/female)
Education
(years)
30.3
(8.5)
23/8
11.7
(1.8)
29.5
(7.2)
15/13
11.6
(1.7)
4
57)
-0.40
X
2
=2.73
t(57)-0.08
0.69
0.10
0.94
Duration
of
illness
(years)
4.0
(5.6)
3.0
(4.0)
4
57)
-0.75
0.46
No.
of
hospitalizations
1.7
(1.3)
1.3
(0.5)
4
57)
-1.78
0.08
Weight
(kg)
67.1
(12.0)
68.4
(13.2)
457)-
0.38
0.71
BMI
Body
Mass
Index;
SAPS
Scale
for
the
Assessment
of
BMI
(kg/m
2
)
Rating
scales
22.6
(3.21)
23.3
(3.36)
4
57)
-0.82
0.42
Positive
Symptoms;
SANS
Scale
for
the
Assessment
of
SAPS
6.4
(3.2)
5.8
(2.4)
4
57)
-0.82
0.42
Negative
Symptoms;
CGI
SANS
12.9
(3.6)
12.9
(3.0)
4
57)
=-0.06
0.96
Clinical
Global
Impression
for
CGI
4.2
(0.5)
4.1
(0.6)
4
57)
-0.13
0.90
psychosis;
HAM
-D
Hamilton
HAM
-D
10.0
(3.5) (4.3)
4
57)
-0.67
0.50
Rating
Scale
for
Depression;
SAS
11.3
(2.7)
11.5
(2.6)
457)-
0.31
0.76
SAS
Simpson
-Angus
Scale;
BAS
0.7
(1.0)
0.6
(1.0)
t
(57)
-0.55
0.59
BAS
Barnes
Akathisia
Scale
4i
Springer
Psychopharmacology
(2007)
192:441-448
445
Weight/BMI
values
(mean±SD);
changes
from
baseline
in
olanzapine/reboxetine
and
olanzapine/placebo
groups
Body
Mass
Index
(BMI):
difference
from
baseline
Weight:
difference
from
baseline
••.
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'Between
group
differences
in
weight/BMI
significant
between
-group
to
difference
in
weight
gain
(olanzapine/reboxetine:
2.68+2.62
kg;
olanzapine/placebo:
4.14+2.85
kg;
Aweight=1.46+0.61,
t=2.05,
df=57,
p=0.045)
and
BMI
(olanzapine/reboxetine:
0.92+0.96
kg/
m
2
;
olanzapine/placebo:
1.45+1.04
kg/m
2
;
ABMI=0.53+
0.26
kg/m
2
,
t=2.03,
df=57,
p=0.047).
Complementary
analysis
in
completers
revealed
a
similar
to
intent
-to
-treat
population
trajectory
and
effect
size
of
weight/BMI
changes
in
the
olanzapine/reboxetine
(N=22)
and
olanzapine/place-
bo
(N=19)
group
(Aweight=1.78+0.80
kg;
t=2.22,
df=37,
p=0.032;
ABMI=0.65+0.30
kg/m
2
;
t=2.17,
df=37,
p-0.036).
The
two
groups
were
unbalanced
with
respect
to
gender,
with
less
women
in
the
olanzapine/reboxetine
group
than
in
the
olanzapine/placebo
group
(8
and
13,
respectively).
Using
gender
as
a
fixed
factor
in
a
two-way
analysis
of
variance,
there
was
no
effect
of
gender
(p=0.96)
on
the
between
-group
difference
in
weight
gain
(Aweight:
olan-
zapine/reboxetine,
men=3.38+2.12
kg,
women=3.09+
3.16
kg;
olanzapine/placebo,
men=4.81+2.68
kg,
women=
5.04+2.26
kg).
The
weight
-attenuating
effect
of
reboxetine
is
further
supported
by
the
fact
that
significantly
less
patients
in
the
olanzapine/reboxetine
group
than
in
olanzapine/placebo
group
increased
their
initial
weight
by
at
least
7%,
the
cut-off
for
clinically
significant
weight
gain
(Kanders
et
al.
1991;
6/31
[19.4%]
and
13/28
[46.4%],
respectively;
x
2
=
4.94,
df=1,
p=0.026;
odds
ratio
-3.61
[95%CI
1.13-
11.52]).
These
patients
did
not
differ
significantly
from
their
counterparts
who
gained
weight
in
any
of
demograph-
ic
or
clinical
characteristics
and
baseline
weight/BMI
indices.
Noteworthy,
7
(22.6%)
of
the
31
olanzapine/
reboxetine-treated
patients
compared
to
only
one
patient
(3.6%)
in
the
olanzapine/placebo
group
revealed
no
weight
change
from
baseline
or
even
minor
weight
loss
(x
2
4.54,
df=1,
p=0.033).
No
significant
correlation
between
initial
BMI
and
change
in
body
weight
at
6
weeks
in
either
group
(r=0.02,
df=29,
p=0.92
for
the
olanzapine/reboxetine
group;
r=0.01,
df=26,
p=0.97
for
the
olanzapine/placebo
group)
was
found.
Regarding
reboxetine's
effect
on
appetite,
there
was
a
significantly
lower
increase
in
appetite
in
the
olanzapine/
reboxetine
than
in
the
olanzapine/placebo
group
(0.82+1.13
and
1.50+0.88,
respectively;
t=-2.49;
df=57,
p=0.016).
Specifically,
less
patients
in
the
olanzapine/reboxetine
group
reported
moderate
to
substantial
increase
in
appetite
at
the
end
of
the
trial,
as
reflected
by
the
scores
"2"
and
"3"
on
the
appetite
scale
(olanzapine/reboxetine=8/31
(25.8%);
olanzapine/placebo=15/28
(53.5%);
x
2
=4.77,
df=1,
p=0.02;
odds
ratio
-3.32
[95%CI
1.11-9.92]).
Notably,
there
was
a
strong
positive
correlation
between
increase
in
appetite
and
weight
gain
in
each
group
(olanzapine/
4
kl
Springer
446
Psychopharmacology
(2007)
192:441-448
Table
3
Changes
from
baseline
in
psychometric
rating
scale
scores
(mean±SD)
for
olanzapine/reboxetine
and
olanzapine/placebo
groups
Rating
scales
Olanzapine/reboxetine
(n
=
31)
Olanzapine/placebo
(n
=
2
8
)
Between
-group
mean
differences
t
Statistics
SAPS
—3.19
(3.74)
—3.14
(3.88)
t
05
(57)
-
0.96
SANS
—4.52
(3.82)
—4.04
(4.47)
t(57)
=
—0-
43
0.67
CGI
—0.82
(0.90)
—0.96
(0.84))
t =
0
56
(57)
-
0.58
HAM
-D
—4.65
(3.73)
—1.5
(5.07)
t(57)
= -
2-
69
0.01
SAS
—2.10
(2.49)
—2.36
(2.45)
t =
0
40
(57)
-
0.69
BAS
—0.68
(0.94)
—0.50
(0.92)
t(57)
=
—0
73
0.47
SAPS
Scale
for
the
Assessment
of
Positive
Symptoms;
SANS
Scale
for
the
Assessment
of
Negative
Symptoms;
CGI
Clinical
Global
Impression
for
psychosis;
HAM
-D
Hamilton
Rating
Scale
for
depression;
SAS
Simpson
—Angus
Scale;
BAS
Barnes
Akathisia
Scale
reboxetine:
r=0.77,
df=29,
p<0.01;
olanzapine/placebo:
r=0.71,
df=26,
p<0.01,
respectively).
Patients
from
both
groups
demonstrated
a
comparable
reduction
in
scores
of
SAPS,
SANS,
and
CGI
rating
scales,
and
no
between
-group
differences
in
change
from
baseline
scores
were
revealed
(Table
3).
In
contrast,
the
improve-
ment
in
the
HAM
-D
scores
was
significantly
greater
in
the
olanzapine/reboxetine
group
than
in
the
olanzapine/
placebo
group
(Table
3).
Noteworthy,
no
correlation
between
changes
in
HAM
-D
scores
and
body
weight
in
the
olanzapine/reboxetine-treated
patients
was
revealed
(r=0.14,
p
=0.46).
The
coadministration
of
olanzapine
with
reboxetine
or
placebo
was
safe
and
well
tolerated.
There
was
a
significant
reduction
in
scores
in
BAS
and
SAS
rating
scales
in
both
groups
without
between
-group
difference
(Table
3).
Anticholinergic
medication
for
EPS
was
required
by
two
patients
in
the
olanzapine/reboxetine
group
and
three
patients
in
the
olanzapine/placebo
group.
Lorazepam
(1-2
mg/day)
or
diazepam
(5
mg/day)
for
insomnia
was
required
by
12
patients
fr
om
the
olanzapine/reboxetine
group
and
nine
fr
om
the
olanzapine/placebo
group.
No
abnormal
changes
were
found
in
routine
laboratory
tests.
Discussion
Weight
gain
associated
with
SGAs,
primarily
clozapine
and
olanzapine,
is
a
frequent
adverse
effect
and
a
major
contributor
to
patient
morbidity
and
noncompliance
with
medication.
Effective
and
safe
approaches
to
control
SGA-
induced
weight
gain
remain
major
unmet
needs
in
SGA
treatment.
The
major
fi
nding
of
the
present
study
is
that
the
selective
NRI
reboxetine
(4
mg/day)
given
for
6
weeks
attenuates
olanzapine-induced
weight
gain
in
first
-episode
schizophrenia
patients.
Reboxetine
coadministration
with
olanzapine
resulted
in
significantly
less
weight
gain
compared
to
olanzapine/placebo
treatment
as
reflected
in
mean
between
-group
difference
of
1.6
kg
by
the
end
of
the
trial.
Twice
as
many
of
the
olanzapine/placebo
than
olanzapine/reboxetine-treated
patients (46.4
vs
19.4%)
increased
weight
by
more
than
7%,
a
cut-off
for
clinically
significant
weight
gain.
Importantly,
reboxetine
prevented
weight
increase
or
led
to
a
minor
weight
loss
in
a
clinically
meaningful
proportion
(22.6%)
of
olanzapine/reboxetine-
treated
patients.
Finally,
we
corroborated
our
preliminary
findings
indicating
that
reboxetine
coadministration
with
olanzapine
is
safe
and
well
-tolerated
by
schizophrenia
patients
and
does
not
interfere
with
olanzapine's
effect
on
core
schizophrenia
symptoms.
The
beneficial
effect
of
reboxetine
on
depressive
symptoms
revealed
in
our
schizophrenia
patients,
as
reflected
by
a
significant
reduc-
tion
in
HAM
-D
scores,
is
also
of
clinical
value.
The
short
duration
of
the
trial
and
a
relatively
high
attrition
rate
are
major
limitations
of
the
present
study.
Roughly
30%
of
the participants
prematurely
discontinued
the
trial.
To
substitute
for
missing
data,
we
used
two
imputation
strategies,
regression
model
and
LOCF,
and
in
addition,
we
compared
the
results
in
the
intention
-to
-treat
population
and
the
completers.
Overall,
regardless
of
the
statistical
strategy
employed,
the
revealed
between
-group
difference
in
weight
gain
was
remarkably
similar.
This
may
be accounted
for
by
the
fact
that
reasons
for
discontinuation
were
unrelated
to
weight
gain
in
this
short-term
study.
It
remains
to
be
evaluated
whether
reboxetine
maintains
its
weight
-attenuating
effect
throughout
a
longer
period
of
administration.
If
substantiated,
rapid
weight
attenuation
achieved
by
reboxetine
may
be
of
particular
clinical
utility,
as
olanzapine-induced
weight
gain
seems
to
manifest
during
the
initial
period
of
treatment
(Kinon
et
al.
2005).
Whether
weight
gain
induced
by
other
SGAs
would
be
attenuated
by
reboxetine
and
whether
administration
of
a
different
NRI
(e.g.,
atamoxetine)
would
also
be
associated
with
the
weight
-attenuating
effect
merit
further
investiga-
tion.
As
female
patients
seem
to
be
more
vulnerable
to
antipsychotic-induced
weight
gain
(Ascher-Svanum
et
al.
2005),
explicit
comparative
evaluation
of
reboxetine's
4i
Springer
Psychopharmacology
(2007)
192:441-448
447
attenuating
effect
on
body
weight
in
male
and
female
schizophrenia
patients
is
warranted.
The
magnitude
of
reboxetine's
weight
-attenuating
effect
was
less,
although
not
statistically
significant,
than
in
our
previous
study
(1.6
vs
3.0
kg).
Visual
analysis
of
the
group
behavior
revealed
a
similar
monotonic
increase
in
mean
weight
difference
in
favor
of
reboxetine
during
both
trials.
In
our
previous
study,
unexpected
mean
weight
decrease
in
the
olanzapine/reboxetine
group
between
weeks
4
and
5
resulted
in
a
larger
magnitude
of
the
between
-group
difference
in
weight
gain
by
the
end
of
the
trial.
Considering
this
fact
and
a
threefold
larger
power
of
the
present
study,
the
effect
size
of
1.6
kg
seems
to
approxi-
mate
the
true
weight
-attenuating
effect
of
reboxetine.
Such
magnitude
of
effect
is
apparently
modest;
however,
even
a
modest
weight
attenuation
may
potentially
be
beneficial
for
olanzapine-treated
patients.
The
impact
of
reboxetine
coadministration
on
biochemical
indices
relevant
to
weight
gain
(e.g.,
lipid
profile,
insulin
resistance,
and
leptin)
is
essential
and
is
currently
under
investigation
by
our
group.
The
mechanism
of
reboxetine's
weight
-attenuating
effect
is
unknown.
Appetite
increase
was
substantially
less
pronounced
in
the
olanzapine/reboxetine
than
olanzapine/
placebo
group
and
was
strongly
correlated
with
the
attenuation
of
weight
gain.
These
findings
support
the
assumption
that
one
of
the
possible
pathways
by
which
olanzapine
produces
weight
gain
is
by
increased
appetite
(Gothelf
et
al.
2002;
Kinon
et
al.
2005;
Cope
et
al.
2005).
It
is
conceivable
that
reboxetine
like
other
norephinephrine
enhancers
(e.g.,
phentermine)
acts
as
an
appetite
suppressant
by
facilitating
NE
neurotransmission
by
a
selective
blockade
of
the
NE
transporter.
In
addition,
reboxetine
may
counteract
olanzapine's
antagonistic
effect
at
the
alpha
-1
and
beta
-3
adrenoreceptors,
which
may
disrupt
peripheral
and/or
central
energy
homeostasis
resulting
in
weight
gain
(Bymaster
et
al.
1999).
The
evaluation
of
energy
expenditure
and
energy
intake
during
reboxetine
treatment
may
clarify
its
effect
on
energy
homeostasis.
Pharmacogenetic
aspects
of
NE
neuro-
transmission
in
weight regulation
apparently
play
a
role,
based
on
the
revealed
contribution
of
beta
3
subunit
gene
(C825T)
polymorphism
and
alpha
2a-adrenergic
receptor
1,291
C/G
polymorphism
to
olanzapine-induced
weight
gain
(Bishop
et
al.
2006;
Park
et
al.
2006).
Finally,
the
possibility
of
pharmacokinetic
interactions
between
olanzapine
and
reboxetine
should
be
considered.
However,
reboxetine
appears
to
have
low
propensity
for
clinically
meaningful
pharmacokinetic
interactions
with
atypical
antipsychotics,
particularly
olanzapine
(Spina
et
al.
2003).
In
conclusion,
the
results
of
the
present
study
confirm
that
the
addition
of
the
selective
NRI
reboxetine
is
safe
and
well
-tolerated
and
result
in
clinically
meaningful
attenua-
tion
of
olanzapine-induced
weight
gain
in
schizophrenia
patients.
As
weight
management
programs
including
physical
exercises
and
diet
counseling
proved
effective
in
olanzapine-treated
patients
(Kwon
et
al.
2006),
their
combination
with
pharmacological
approaches
such
as
add-on
reboxetine
merit
further
evaluation.
Acknowledgments
The
study
was
supported
in
part
by
grant
no.
03T-294
from
the
Stanley
Medical
Research
Institute.
The
authors
thank
Rena
Kurs
for
assistance
in
preparation
of
the
manuscript.
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