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4
544
A
n enhanced appetite with a
consequent gain in weight is
common among patients with
schizophrenia who are being treated
with antipsychotic drugs. Other obe-
sity-related conditions among these
patients are diabetes mellitus, hyper-
tension, and cardiovascular disease,
all of which may be seriously detri-
mental to good health (1).
Clozapine is a dibenzodiazepine
derivative and a second-generation
antipsychotic drug for treatment of
patients with schizophrenia (2).
Among the second-generation an-
tipsychotics, clozapine appears to
have the greatest potential to induce
weight gain. For example, Allison and
colleagues (3) found that clozapine
and olanzapine led to a mean weight
gain of 4.45 kg and 4.15 kg, respec-
tively, after ten weeks. Lamberti and
coauthors (4) reported a mean weight
gain of 7.7 kg for a group of 36 pa-
tients receiving a mean dosage of 380
mg of clozapine a day for six months.
A retrospective study of 82 patients
who received 500 to 600 mg of cloza-
pine a day for up to 90 months found
that about 50% of them became sub-
stantially overweight (5). Weight gain
induced by antipsychotics is a com-
mon cause of noncompliance, result-
ing in discontinuation of antipsychot-
ic treatment and return of psychotic
symptoms (6).
However, weight gain and metabol-
ic changes, such as higher levels of
glucose, insulin, triglyceride, and
cholesterol and reduced levels of in-
Outcomes of Obese, Clozapine-Treated
Inpatients With Schizophrenia Placed on a
Six-Month Diet and Physical Activity Program
Mei-Kuei Wu, M.S.
Chin-Kun Wang, Ph.D.
Ya-Mei Bai, M.D., Ph.D.
Chih-Yang Huang, Ph.D.
Shin-Da Lee, Ph.D.
Dr. Wu is affiliated with the Section of Nutrition, Yu Li Veterans Hospital, Hualien, Tai-
wan. She and Dr. Wang are with the Graduate Institute of Nutritional Science, Chung
Shan Medical University, Taichung, Taiwan. Dr. Bai is with the Department of Psychi-
atry, Taipei Veterans General Hospital, Taipei, Taiwan. Dr. Huang is with the Gradu-
ate Institute of Chinese Medicine and Dr. Lee is with the Department of Physical Ther-
apy, China Medical University, Taichung, Taiwan. Send correspondence to Dr. Lee at
91 Hsueh-Shih Rd., Taichung, Taiwan 40202 (e-mail: shinda@mail.cmu.edu.tw).
Objective: Patients with schizophrenia treated with clozapine often
gain weight. This study evaluated the effects of dietary control and
physical activity among obese inpatients with schizophrenia being
treated with clozapine. Methods: Fifty-three clozapine-treated obese
patients with schizophrenia in a veterans hospital in eastern Taiwan
who had a body mass index greater than 27 (weight divided by height
in meters squared) and who were taking clozapine were randomly as-
signed to a study group of 28 or a control group of 25. The study group
was placed on a diet that reduced calorie intake by 200 to 300 kcal per
day (to 1,300 to 1,500 kcal per day for women and to 1,600 to 1,800
kcal per day for men) and a six-month regimen of regular physical ac-
tivity in which participants used approximately 600 to 750 kcal per
week (level walking and walking on stairs for 60 minutes three days
per week). Anthropometric, metabolic, and hormonal parameters
were measured after three and six months by using anthropometry, an
enzyme autoanalyzer, immunoassay, and enzyme-linked immunosor-
bent assay. Results: Compared with the control group, the study group
showed a significant decrease in body weight, body mass index (5.4%
reduction), waist circumference (3.3 cm), and hip circumference (3.3
cm) after three months and after six months. Triglyceride and insulin-
like growth factorbinding protein-3 (IGFBP-3) decreased significant-
ly only after six months. Conclusions: A program of dietary control and
regular physical activity can significantly reduce body weight and im-
prove metabolic profiles of insulin, triglyceride, and IGFBP-3 among
obese inpatients taking clozapine for the treatment of schizophrenia.
(Psychiatric Services 58:544550, 2007)
wu.qxd 3/19/2007 11:04 AM Page 544
sulin-like growth factor 1 (IGF-1),
have been reported to be more signif-
icant among patients on long-term
clozapine therapy than among those
being treated with other first- and
second-generation antipsychotics
(79). Therefore, it is important to
manage weight gain among these pa-
tients, especially for those on long-
term treatment with clozapine with-
out alternative medication.
Growth hormone and IGF-1 are
both powerful regulatory agents for
maintaining the effective function-
ing of the cardiovascular system
(10,11). IGF-1 appears to improve
cardiac function because low levels
of this growth factor are associated
with an increased risk of heart dis-
ease (11,12). The insulin-like growth
factorbinding protein-3 (IGFBP-3)
is the most abundant carrying pro-
tein and carries most of the circulat-
ing IGFs (90% in adult serum)
(13,14). In circulation only a minor
fraction of IGF-1 occurs in the free,
unbound form. The free form of
IGF-1 has greater physiological and
clinical relevance than total IGF-1,
and it has anabolic, endocrine, and
autocrine actions (13,14). IGFBP-3
is a key carrying protein for regulat-
ing the distribution and bioavailabil-
ity of IGF-1 to target tissues (14).
The molar ratio of IGF-1 and IGF-
BP-3 (IGF-1/IGFBP-3) was consid-
ered to be a marker of free IGF-1
(14). However, the role of growth
hormone, IGF-1, and IGFBP-3
among patients with schizophrenia
receiving long-term clozapine thera-
py has not yet been investigated.
Weight control has been reported to
be useful for reducing health risks
among overweight or obese patients
with schizophrenia (15,16). In one
study all patients taking second-gener-
ation antipsychotics except those tak-
ing clozapine were able to lose weight
(17). In a randomized study, patients
with schizophrenia were first referred
to a wellness clinic, where a rigorous
evaluation of exercise and dietary
habits was conducted, and they were
then placed on a weight management
program, which led to weight reduc-
tion among outpatients taking olanza-
pine (18). It is known that weight
management by way of caloric restric-
tion and regular physical activity can
prevent morbidity among obese indi-
viduals. However, results of studies of
weight management programs for
clozapine-treated patients with schizo-
phrenia appear to contradict each oth-
er. Wirshing and colleagues (17) re-
ported unsuccessful weight loss in a
six-year study of 20 male outpatients
with schizophrenia taking clozapine.
The therapeutic strategies used in that
study were habit evolution, education,
exercise classes, and group support. In
contrast, Heimberg and associates
(19) reported positive results using di-
etary restriction (1,400 to 2,500 kcal a
day) with ten inpatients for six months,
although no information was provided
about metabolic and hormonal
changes.
The randomized, controlled study
reported here was undertaken to in-
vestigate the effect of six months of
continuous dietary control and regu-
lar physical activity on obese patients
with schizophrenia who were taking
clozapine. The study assessed anthro-
pometric and biochemical parame-
ters (serum glucose, triglyceride, cho-
lesterol, insulin, cortisol, prolactin,
growth hormone, IGF-1, and IGFBP-
3) at three and six months.
Methods
Participants
The sample consisted of participants
selected from 753 hospitalized pa-
tients from September 2003 to Febru-
ary 2004. All patients in the sample
had a DSM-IV diagnosis of schizo-
phrenia and were 18 to 65 years old.
Inclusion criteria consisted of taking
at least 300 mg of clozapine orally per
day for at least a year and having a
body mass index (BMI) greater than
27 kg/m
2
. Asian individuals with a
BMI greater than 27 kg/m
2
are con-
sidered to be obese (20,21). Patients
were excluded if they were taking any
antipsychotic (not clozapine) or lipid-
lowering medications, had any abnor-
mal ambulatory functions or organ
failure, had severe mental illness or
mental retardation, were in an acute
phase of mental illness, were pregnant
or lactating, had a disability that pre-
vented walking, or were not interested
in the program. The 56 patients se-
lected by using the inclusion and ex-
clusion criteria were randomly divid-
ed between the intervention (study)
group and the control group. The
study was performed in accordance
with the Declaration of Helsinki and
was approved by the Yu-Li Veterans
Hospitals Ethics Review Committee.
All patients were completely in-
formed about the study and provided
written consent before participating.
Intervention
Dietary control was implemented by
a registered dietitian, who ensured
that caloric intake was restricted to
1,300 to 1,500 kcal per day for
women and to 1,600 to 1,800 kcal
per day for men. The minimum re-
spective dietary requirements were
1,200 kcal per day for women and
1,500 kcal per day for men (22). We
measured caloric intake and assessed
the types of foods that the patients
ate, including fruit and vegetables
(up to 7.5 servings per day), sugar-
free versions of foods and drinks,
and artificial sweeteners. This intake
of macronutrients ensured that par-
ticipants were compliant with the ex-
pected changes of 20%, 25%, and
55% in energy from protein, fat, and
carbohydrate, respectively (22). The
current average macronutrient com-
position of the Taiwanese diet is 10%
to 14% of calories from protein, 20%
to 30% from fat, and 58% to 68%
from carbohydrate.
The 1996 U.S. Surgeon Generals
Report (23) recommended that per-
sons of all ages obtain a minimum of
30 minutes of physical activity of
moderate intensity (e.g., brisk walk-
ing) on most, if not all, days of the
week. The physical activities in our
study were to be sustained for six
months and performed three days per
week. The program, designed to fit
the hospital environment in which
the patients would be exercising, con-
sisted of level walking for 1.62 km for
about 40 minutes and walking up 231
stairs (14 cm per stair) and down 330
stairs (13.5 cm per stair) for about 20
minutes under supervision. The walk-
ing speed and distances were kept
constant during the six-month inter-
vention, except for warm-up during
the first week, and we encouraged
participants to complete it in about 60
minutes but not to force themselves.
The patients consequently expended
energy at an approximate rate of 600
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to 750 kcal per week, which was esti-
mated by using the formula in the
guidelines of the American College of
Sports Medicine (24). To motivate
participants, different rewards were
offered, such as toilet paper, soap,
and sugar-free drinks.
Anthropometric measurements
Anthropometric and body parame-
ters were assessed after participants
had fasted overnight. Body weight
and body fat percentage were meas-
ured with a body composition analyz-
er by using bioelectrical impedance
analysis (25). Height was measured
using a calibrated stadiometer. Waist
and hip circumference were meas-
ured in centimeters in a standing po-
sition after gentle expiration by using
calibrated plastic tapes midway be-
tween the lowest rib and the iliac
crest and at the greater trochanters,
respectively. BMI was calculated as
weight divided by height squared
(kg/m
2
). The waist-to-hip ratio was
calculated as waist circumference di-
vided by hip circumference.
Blood sampling
Overnight fasting blood samples were
drawn from patients between 7 and 9
a.m. by a trained phlebotomist who
used a venipuncture of an antecubital
vein. Part of each blood sample was
immediately used for the metabolic
analysis and enzyme assay, and the
other part of the sample was cen-
trifuged at 3,000 rpm for 15 minutes at
4 C within one hour of drawing and
subsequently frozen at 80 C until an
enzyme-linked immunosorbent assay
(ELISA) analysis could be performed.
Metabolic analysis and
enzyme immunoassay
The freshly drawn blood was immedi-
ately used to measure serum glucose,
triglyceride, cholesterol, insulin, pro-
lactin, and cortisol. Serum glucose,
triglyceride, and cholesterol were as-
sessed by using an autoanalyzer that
measures glucose oxidase, triglyceride
enzyme, and cholesterol oxidase, re-
spectively (26). Serum cortisol, pro-
lactin, and insulin were measured with
an enzyme immunoassay system (27).
ELISA measurements of growth
hormone, IGF-1, and IGFBP-3 levels
were determined by using commer-
cially available ELISA kits (28) with a
VersaMax Tunable Microplate Read-
er (29). These assays were noncom-
petitive and involved the horseradish
peroxidaselabeled detection anti-
body as previously described (30).
Statistical analysis
The effectiveness of the treatment was
assessed by using variance and covari-
ance analysis (ANCOVA) with SPSS
statistical software (version 10.0) and
was based on a general linear model.
The anthropometric, metabolic, and
hormonal data obtained for the study
group were compared with those ob-
tained for the control group at the be-
ginning of the study and again after
three and six months. The data collect-
ed at the beginning of the assessment
period (baseline) were used as the co-
variate. The comparison was done by
using a repeated-measures ANCOVA
adjusted for all baseline values. A two-
way mixed-design ANCOVA was used
to correct for potentially confounding
variables and to test for correlation be-
tween variables. In all cases, a p value
of .05 was considered to be statistical-
ly significant.
Results
Fifty-three patients completed the
study; three withdrew from the con-
trol group because they were dis-
charged from the hospital in the sec-
ond month of the study. The 53 inpa-
tients, all of whom were clozapine-
treated obese patients with schizo-
phrenia, were randomly assigned to
one of the two groups. Twenty-five
were assigned to the control group,
which included 11 men (44%) and 14
women (56%) with a meanSD age
of 39.06.7 years. Twenty-eight were
assigned to the study group, which in-
cluded 11 men (39%) and 17 women
(61%) with a mean age of 42.27.5
years. No significant differences were
found between the study group and
the control group in gender distribu-
tion or mean age.
Anthropometric measures
BMI, body weight, waist and hip cir-
cumference, waist-to-hip ratio, and
fat percentage of body weight did not
differ significantly between the study
group and the control group at base-
line (Table 1). In the control and
study groups at baseline, the mean
body fat percentages among men
(30.9%4.8% in the study group and
30.0%5.1% in the control group)
and among women (43.6%10.7%
and 41.4%5.7%, respectively) were
similar. At baseline in both the study
and the control groups the body fat
percentage of men was significantly
lower (p<.001) than that of the
women but free fat mass among men
was significantly higher (p<.001).
As shown in Table 1, body fat per-
centages at three and six months were
not significantly lower within the
groups nor was there a difference be-
tween the control and study groups
(Table 1). When data for men and
women were analyzed separately, we
did not observe significant changes in
fat percentage or in free fat mass after
three months or even after six
months. However, BMI, body weight,
and waist and hip circumference
measures in the study group de-
creased significantly (Table 1). BMI,
body weight, and waist circumference
decreased significantly (p<.05) after
both three months and six months for
the study group compared with the
control group, whereas hip circum-
ference decreased only after six
months of the intervention. We ob-
served a significant decrease from
baseline values (p<.05) in BMI, body
weight, and hip circumference in the
study group even after three months,
whereas waist circumference was sig-
nificantly reduced only after six
months (Table 1). Furthermore,
BMI, body weight, and waist-to-hip
ratio values were significantly re-
duced (p<.05) from the third to the
sixth month of the intervention.
Metabolic analysis and
enzyme immunoassay
As Table 2 shows, no significant dif-
ference was found at baseline be-
tween the study and control groups in
serum glucose, triglyceride, choles-
terol, prolactin, cortisol, and insulin
levels. During the intervention,
serum glucose, cholesterol, prolactin,
cortisol, and insulin did not signifi-
cantly differ between the control and
study groups (Table 2). At six months
the triglyceride level of the study
group was significantly lower than
that of the control group (p<.05). No
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significant differences between the
control and study groups were found
in glucose, cholesterol, prolactin, cor-
tisol, and insulin levels after three
months and six months of the inter-
vention (Table 2). In the study group
we observed a significant decrease
(p<.05) from baseline levels for
triglyceride and cortisol concentra-
tion at three and six months, whereas
the insulin level was significantly low-
er (p<.05) only after six months (com-
pared with the three-month level). At
the same time, the triglyceride level
of the control group significantly in-
creased (p<.05) from the third to the
sixth months.
Intervention and growth
hormoneIGF-1 axis
At baseline there were no significant
differences between the control and
the study groups in growth hormone,
IGF-1, IGFBP-3, and the molar ratio
of IGF-1 and IGFBP-3. As Table 3
shows, no significant changes were
observed for either group in the levels
of growth hormone and IGF-1 after
three months or even after six
months. Similarly, no significant
changes in IGFBP-3 level after three
months were observed, although the
IGFBP-3 level of the study group was
significantly lower (p<.05) than that
of the control group after six months
(Table 3). IGFBP-3 concentration in
the study group was significantly low-
er (p<.05) than the baseline level at
three months. The control group, on
the other hand, had a significantly
higher level (p<.05) of this growth
factor at six months compared with
baseline. After six months, the molar
ratio of IGF-1 to IGFBP-3 of the
study group was not only significantly
higher than that of the control group
(Table 3), but it had also increased
significantly (p<.05) at three months
compared with baseline.
Discussion
This study demonstrates the benefits
of a six-month intervention consisting
of integrated dietary control and regu-
lar physical activity for obese patients
with schizophrenia being treated with
clozapine. Our intervention resulted in
significant decreases in BMI, body fat
percentage, and waist and hip circum-
ference. In addition, participating pa-
tients showed improved metabolic
profiles of triglyceride, insulin, IGF-
BP-3 levels, and the IGF-1 to IGFBP-
3 molar ratio. In contrast, the control
group showed no improvement in an-
thropometric measurements and no
amelioration in triglyceride and insulin
levels and had a lower molar ratio of
IGF-1 to IGFBP-3.
Dietary guidelines suggest that
weight loss at the rate of .51.0 kg per
week (diet reduction of 5001,000
kilocalories per day) occurs safely for
up to six months. Our participants di-
ets contained approximately 200 to
300 fewer kilocalories per day than
they normally consumed, and they
were expected to expend approxi-
mately 600 to 750 kcal per week more
energy by increasing their physical
activity. These levels were chosen in
an effort to minimize any possible ad-
verse effects from diet alone, which
we observed in the form of mental
and emotional instability among inpa-
tients who consumed much fewer
calories. The particular physical activ-
ities we selected were suitable for
obese patients with schizophrenia on
clozapine treatment, because they are
mild and uncomplicated and hold no
danger for these patients. Walking
does not require expensive equip-
ment or a designated athletic facility,
and it can be done alone or with an-
other person with minimal or no in-
struction. Patients with severe mental
illness are more likely to walk as their
sole form of physical activity (31).
All 28 patients in the study group
completed the six-month diet control
intervention and at least 90% of the
physical activity program. The level of
compliance and consequently our
success rate may have been lower if
participants had been outpatients
rather than inpatients. However, the
high success rate made it easier to in-
terpret our results at the end of the
program. We are, therefore, able to
assure patients who rigorously follow
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Table 1
Anthropometric data at baseline and changes at three and six months for clozapine-treated inpatients with schizophrenia
assigned to a control group (N=25) or a study group (N=28)
Baseline value Change at 3 months Change at 6 months
Control group Study group Control group Study group Control group Study group
Variable M SD M SD M SD M SD M SD M SD
Body mass index (kg/m
2
)
ae
30.27 3.31 30.43 4.20 .11 .89 1.07 1.25 .35 1.30 1.59 1.66
Body weight (kg)
ae
77.8 112.0 78.4 11.6 .3 2.2 2.8 3.3 1.0 3.4 4.2 4.4
Waist circumference (cm)
b,d,f
97.82 9.67 98.30 7.33 1.24 3.48 .92 3.96 1.02 4.25 3.32 4.18
Hip circumference (cm)
c,d,g
106.1 6.5 108.0 8.5 .2 3.2 2.3 3.7 .3 2.7 3.3 4.5
Waist-to-hip ratio
c,e
.92 .07 .91 .07 .01 .03 .01 .05 .01 .03 <.01 .04
Body fat (%) 38.0 10.6 36.9 7.8 .7 4.3 .6 3.9 1.3 4.2 1.3 6.4
a
Significant difference between the control and study groups at three months (p<.001)
b
Significant difference between the control and study groups at six months (p<.001)
c
In the study group significant difference from baseline at three months (p<.05)
d
In the study group significant difference from baseline at six months (p<.001)
e
In the study group significant difference from three months at six months (p<.05)
f
Significant difference between the control and study groups at three months (p<.05)
g
Significant difference between the control and study groups at six months (p<.05)
wu.qxd 3/19/2007 11:04 AM Page 547
the program that they can reap many
health benefits. Also, within the hos-
pital context, key health care profes-
sionals were on hand to ensure prop-
er implementation of our weight-man-
agement intervention.
The prevention and treatment of
weight gain in psychiatric patients is
difficult but not impossible. Even a
modest 5% to 10% reduction in body
weight has significant health bene-
fits. Our results show that for obese
patients with schizophrenia who are
taking clozapine, the intervention re-
sulted in a significant reduction in
BMI (5.4%), body weight (5.4%),
waist circumference (3.3 cm), and
hip circumference (3.3 cm), suggest-
ing that the program had successful-
ly reduced BMI and improved vari-
ous measures by the end of the six-
month intervention period. Some of
these parameters were reduced after
three months but others only after
six months of intervention. All par-
ticipants anthropometry (including
body weight, BMI, and waist and hip
circumference), physical activity,
and dietary behavior were moni-
tored regularly throughout the study
by investigators and ward staff. The
psychiatric condition of none of the
participants in the control group ap-
peared to have worsened.
In this and previous studies, clozap-
ine-treated patients with schizophre-
nia have been reported to gain weight
and to have increased BMI and fat de-
posits (4,5,32). These patients often
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Table 2
Metabolic and hormonal data at baseline and three and six months for inpatients with schizophrenia assigned to a control
group (N=25) or a study group (N=28)
Baseline 3 months 6 months
Control group Study group Control group Study group Control group Study group
Variable Normal M SD M SD M SD M SD M SD M SD
Glucose (mg/dl) <110 107.16 34.4 103.3 24.9 107.9 19.9 101.4 13.1 99.8 16.9 96.4 16.9
Triglyceride (mg/dl)
ad
<150 237.8 168.7 208.4 121.9 205.5 154.6 165.3 77.7 239.3 188.9 146.8 90.9
Cholesterol (mg/dl) <200 177.2 43.0 179.9 33.0 161.8 37.3 154.8 35.2 166.8 35.2 159.2 36.9
Prolactin (ng/ml) 1.820.3 16.0 24.9 13.3 8.4 17.9 28.9 12.6 8.5 16.5 27.1 11.4 7.4
Cortisol (g/dl)
a,c,e
4.322.4 14.0 3.6 17.5 4.8 15.7 5.9 16.8 6.3 14.5 4.9 13.9 4.8
Insulin (IU/ml)
c,f
015.6 12.3 9.7 9.3 5.2 10.8 8.4 8.0 5.4 9.5 9.2 5.2 3.1
a
In the study group significant difference from baseline at three months (p<.001)
b
In the control group significant difference from three months at six months (p<.05)
c
In the study group significant difference from baseline at six months (p<.001)
d
Significant difference between the control and study groups at six months (p<.05)
e
In the control group significant difference from baseline at three months (p<.05)
f
In the study group significant difference from three months at six months (p<.05)
Table 3
Data on growth hormone, insulin-like growth factor 1 (IGF-1), and insulin-like growth factorbinding protein-3 (IGFBP-3)
at baseline and changes at three and six months for inpatients with schizophrenia assigned to a control group (N=25) or
a study group (N=28)
Baseline value Change at 3 months Change at 6 months
Control group Study group Control group Study group Control group Study group
Variable M SD M SD M SD M SD M SD M SD
Growth hormone
(ng/ml) .19 .39 .22 .38 .05 .60 .01 .46 .10 1.07 .03 .60
IGF-1 (ng/ml)
ad
116.7 67.8 88.2 62.7 24.6 94.4 33.5 48.4 54.8 56.1 71.7 65.6
IGFBP-3 (ng/ml)
c,eh
4,213.6 981.7 4,223.6 779.7 908.0 767.3 611.4 652.6 1,426.0 848.8 960.7 774.3
IGF-1 to IGFBP-3
molar ratio
a,c,h
.100 .058 .077 .049 .025 .078 .037 .045 .010 .048 .038 .049
a
In the study group significant difference from baseline at three months (p<.001)
b
In the control group significant difference from baseline at six months (p<.001)
c
In the study group significant difference from baseline at six months (p<.001)
d
In the study group significant difference from three months at six months (p<.05)
e
In the study group significant difference from baseline at three months (p<.05)
f
In the control group significant difference from three months at six months (p<.001)
g
In the study group significant difference from three months at six months (p<.001)
h
Significant difference between the control and study groups at six months (p<.05)
wu.qxd 3/19/2007 11:04 AM Page 548
exhibit a marked increase in central
adiposity (32,33), although the waist-
to-hip ratio is a better predictor of car-
diovascular disease and death than the
actual amount of adiposity (20,34). In
our current study, the average waist-
to-hip ratio of clozapine-treated pa-
tients with schizophrenia was .88 for
women and .97 for men. Japanese cri-
teria for central obesity are .8 for
women and .9 for men. Therefore, the
women and the men in our study
could be said to have central obesity.
However, on the basis of World Health
Organization criteria of .85 for women
and 1.0 for men, only our female pa-
tients would have been classified as ex-
hibiting central obesity (20). An abrupt
increase in the prevalence of coronary
artery disease was found among Indi-
an patients who had a fat percentage of
more than 25 (35). Among our study
participants, the average body fat per-
centage was as high as 37.4%. Conse-
quently, obese patients with schizo-
phrenia being treated with clozapine
would seem to have a higher risk of
developing cardiovascular diseases,
especially women. Of course, addi-
tional studies are required to address
possible cardiovascular abnormalities
among these patients.
Our weight management program
consisting of dietary control (a reduc-
tion of 200 to 300 kcal a day) and phys-
ical activity (an expenditure of 600 to
750 kcal a week) was successful in re-
ducing clozapine-related weight gain
among patients with schizophrenia.
Only two studies involving weight
management programs for clozapine-
treated patients with schizophrenia
have been published (17,19). Heim-
berg and colleagues (19) observed that
of ten inpatients taking clozapine who
were prescribed a diet of 1,400 to
2,500 kcal a day, the men lost an aver-
age of 7.1 kg, but the women gained
less than .5 kg after six months. In con-
trast, Wirshing and associates (17) ob-
served that 20 outpatients taking
clozapine gained weight even after
therapeutic strategies were used that
included feedback about their weight,
a more rigorous diet and exercise eval-
uation, education, and an exercise
class with group support for six years.
The benefits of reduced levels of
insulin were found in the study
group. Among healthy obese persons
who do not have schizophrenia or glu-
cose intolerance, blood glucose con-
centrations do not usually decrease
after exercise. In addition, it has been
found that an improvement in glu-
cose or insulin concentration ach-
ieved as a consequence of weight loss
may gradually be negated when
weight is regained (36). Our results
show that participants in the study
group had significantly lower concen-
trations of insulin as a consequence of
our intervention, a result similar to
those of previous studies of persons
with no psychiatric illness (3739).
Keeping in mind that obese patients
with elevated insulin and triglyceride
levels face a considerably enhanced
risk of cardiovascular morbidity and
mortality (40), it is clear that our pro-
gram of dietary control and regular
physical activity lowered insulin levels
and may help to lower cardiovascular
risk among obese patients with schiz-
ophrenia who are taking clozapine.
IGFBPs are synthesized by the kid-
ney and may modulate the local au-
tocrine or paracrine actions of IGF-1
(14). IGFBP-3 is the most abundant
IGF-binding protein in human serum
and is now believed to be a critical el-
ement in numerous cellular processes
and a key factor in several disease
states via IGF-dependent or IGF-in-
dependent mechanisms (41). In our
study, we detected lower levels of
IGFBP-3 and consequently a higher
IGF-1 to IGFBP-3 molar ratio after
six months of the intervention. These
results are in agreement with those of
previous studies in which exercise
was also found to reduce IGFBP-3
levels (42,43). These findings imply
that active IGF-1 appears to be en-
hanced by a long-term (longer than
six months) intervention involving di-
etary control and physical activity.
The effect of reduced IGFBP-3 levels
on the availability of IGF-1 is still un-
clear and further studies are needed.
In our study, growth hormone and
IGF-1 levels were not found to be al-
tered by the intervention. However,
growth hormone and IGF-1 levels
have been reported to be elevated by
vigorous exercise among persons with
no mental illness (44), and it may be
that the exercise intensity (fast walk-
ing) we used in our study was insuffi-
cient to induce changes in growth
hormone and IGF-1 concentrations.
There are some difficulties and
weaknesses in the study to address.
The motivation for weight reduction
(dietary restriction and physical ac-
tivity) is very low for psychiatric pa-
tients if these patients are not under
institutional supervision. In addition,
suppression of appetite for long-
term continuance among psychiatric
patients was difficult, so the dietary
reduction was controlled to only
200300 kcal per day in the study.
Therefore, manpower and work-site
support such as dietitians and physi-
cal therapists were very important
for long-term monitoring of risk fac-
tors and for continuously encourag-
ing the patient to continue with
weight reduction.
Conclusions
We found that an intervention involv-
ing dietary control and physical activ-
ity for six months significantly de-
creased the body weight, BMI, waist
and hip circumference, triglyceride,
insulin, and IGFBP-3 levels of obese
inpatients with schizophrenia who
were being treated with clozapine. In
addition, we observed a significantly
increased IGF-1 to IGFBP-3 molar
ratio among these patients. Dietary
control and physical activity seemed
to normalize some metabolic abnor-
malities, minimize hormonal changes,
and attenuate some neuroleptic-re-
lated side effects, such as sedation
and reduced daily activity.
Clozapine appears to present great
risk for weight gain. However, previ-
ous reports have shown that nearly
50% of patients with schizophrenia
have comorbid medical conditions,
and many of these illnesses are misdi-
agnosed or undiagnosed (45). We
propose that it is crucially important
to monitor the health of obese pa-
tients with schizophrenia who are be-
ing treated with clozapine. Because
some other metabolic benefits of the
diet and the exercise program were
not realized until six months of inter-
vention, long-term adherence to such
a program is necessary. We further
propose that lifestyle modification
(continuous dietary control and rou-
tine physical activity) be prescribed
for these patients so that they can
avoid obesity-related abnormalities
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and enjoy long-term benefits.
Acknowledgments and disclosures
The study was supported by grant VHYL-92-10
from Yu Li Veterans Hospital and grant
CMU95-262 from China Medical University,
Taiwan.
The authors report no competing interests.
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