Obesity and Clozapine use in Schizophrenia

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OBESITY RESEARCH
Open Journal http://dx.doi.org/10.17140/OROJ-3-124
Obes Res Open J
ISSN 2377-8385
Obesity and Clozapine use in Schizophrenia
Viviane Carvalho Franco, MSc1,2; Karine Zortéa, PhD1,2*; Paulo Silva Belmonte de
Abreu, PhD1,2,3
1Department of Schizophrenia Program, Hospital de Clínicas de Porto Alegre, Porto Alegre
90035-903, RS, Brazil
2Postgraduate Program in Medicine: Psychiatry, Universidade Federal do Rio Grande do Sul,
Porto Alegre 90035-903, RS, Brazil
3Hospital de Clínicas de Porto Alegre, Serviço de Psiquiatria, Laboratório de Psiquiatria
Molecular, Porto Alegre 90035-903, RS, Brazil
*Corresponding author
Karine Zortea, PhD
Department of Schizophrenia Program
Hospital de Clínicas de Porto Alegre;
Postgraduate Program in Medicine:
Psychiatry, Universidade Federal do Rio
Grande do Sul, Porto Alegre 90035-903
RS, Brazil
Tel. +55 51 82433554
E-mail: karine.personaldiet@gmail.com
Article History
Received: May 23rd, 2016
Accepted: July 12th, 2016
Published: July 13th, 2016
Citation
Franco VC, Zortéa K, de Abreu PSB.
Obesity and clozapine use in schizo-
phrenia. Obes Res Open J. 2016;
3(2): 24-29. doi: 10.17140/OROJ-3-
124
Copyright
©2016 Zortéa K. This is an open
access article distributed under the
Creative Commons Attribution 4.0
International License (CC BY 4.0),
which permits unrestricted use, dis-
tribution, and reproduction in any
medium, provided the original work
is properly cited.
Volume 3 : Issue 2
Article Ref. #: 1000OROJ3124
Systematic
Review
Page 24
ABSTRACT
Introduction: Schizophrenia is a chronic mental disorder, and treatment is based on the use of
antipsychotics, such as clozapine. These drugs have been associated with obesity and metabolic
changes.
Objective: A systematic review to assess the association of obesity with the use of clozapine in
schizophrenic patients.
Method: It was made a search for articles in PUBMED and Capes of the regular databases with
the keywords “Schizophrenia” “obesity” “clozapine” “weight gain”. The search included arti-
cles in English that were published between 2004 and 2015. We included only articles with re-
trospective studies and the following inclusion criteria: both sexes, patients older than 20 years,
use of time of clozapine minimum of three months and sample size less than 50 individuals.
Results: They were selected 4 articles contemplated the inclusion criteria. In all items selected
for this study, obesity was associated with clozapine.
Conclusions: There is a higher prevalence of overweight and obesity in patients with schi-
zophrenia compared with the general population, this is due to some factors such as the use of
atypical antipsychotics, such as clozapine.
KEYWORDS: Schizophrenia; Clozapine; Obesity.
ABBREVIATIONS: SZ: Schizophrenia; WHO: World Health Organization; BMI: Body Mass
Index; IBGE: Brazilian Institute of Geography and Statistics; IMCI: Integrated Management
of Childhood Illness; QoL: Quality of Life; WHR: Waist/hip ratio; WC: Waist Circumference.
INTRODUCTION
Schizophrenia (SZ) is a chronic mental disorder that affects about 1% of the world population,
and mainly happens in the end of adolescence and the beginning of adulthood, regardless of
gender or social groups.1 It is a disease characterized by distortions in thoughts, bizarre delu-
sions and changes in sensory perception and inappropriate emotional responses that lead pa-
tients to some degree of deterioration.2
 Itssymptomsdifferamongindividualsandmayafictthemgraduallyorexplosively.
These symptoms are still divided into negative or positive. Negative symptoms of SZ, facing
decreased brain function, were described by Kaiser et al3 asdeningthiscondition,asitoften
manifests itself together, and differs from other psychopathological conditions.
Negative symptoms described were: apathy, loss of pleasures in activities once the
provided, unwillingness to start a behavior directed at a goal and poverty of speech. As the
positives symptoms are the level of mental disorders such as delusions, distortion of thoughts,
unreal perceptions, such as audio-visual hallucinations, excessive anxiety, impulses and ag-
gression.

OBESITY RESEARCH
Open Journal http://dx.doi.org/10.17140/OROJ-3-124
Obes Res Open J
ISSN 2377-8385
Page 25
The treatment of SZ, focused on minimizing the symp-
toms, is based on the use of antipsychotics. These drugs are
inhibitors of psychomotor functions (in excitation and stirring
conditions) and minimize psychotic symptoms, such as delu-
sionsandhallucinations.Thesedrugscanbeclassiedastypical
or atypical.
The major typical antipsychotic drugs block only D2
receptors. The atypical antipsychotic drugs are associated to
lower risks of extrapyramidal effects, not block D2 receptors
only, but also other monoamines, such as the 5HT-2. These in-
clude: Clozapine, Olanzapine, Quetiapine and Respiridona.4
Clozapine is a reference atypical antipsychotic, hav-
ing distinct characteristics of the medications available before
its release, which showed effective in 30% to 60% of psycho-
ses that do not respond to traditional drugs, and low incidence
of adverse effects, becoming the main indication for refractory
schizophrenia. Atypical offer several important advantages over
typical, including its characteristics of low risk of extrapyrami-
dal symptoms such as akathisia, dystonia, parkinsonism and tar-
dive dyskinesia, improved cognition, reduced suicide and minor
depression compared with typical antipsychotics at clinically
relevant doses.5
The use of antipsychotics is an important component
in the clinical treatment of patients with schizophrenia, but has
been associated with metabolic abnormalities5 and also obesity,
diabetes, dyslipidemia, metabolic syndrome and high mortality.6
Associated with pharmacological treatment, nutrition-
al and psychological treatments are very important in the im-
provement of the condition of these patients.7 Obesity is a non-
transmissible chronic disease, which presents itself not only as
a scientic problem, but also as a public health problem. The
modern lifestyle with a more westernized diet, associated with a
decrease in physical activity, converges to the increase in world-
wide obesity.8
According to World Health Organization (WHO), obe-
sity is dened as an abnormal fat accumulation that may im-
pair health.9 Body mass index (BMI) is an index which corre-
lates weight and height (kg/m2),therebyobesityisclassiedas
BMI≥30kg/m2.
The World Health Organization (WHO) projected that
in 2005 the world would have 1.6 billion people over the age
of 15 overweight (Integrated Management of Childhood Illness
(IMCI)≥25kg/m2)and400millionobese(BMI≥30kg/m2). The
projection for 2015 is even more pessimistic: 2.3 billion people
overweight and 700 million obese. These data indicate a 75%
increase in obesity cases in 10 years.9
In 2010, the Brazilian Ministry of Health and the Bra-
zilian Institute of Geography and Statistics (IBGE) released two
large surveys of the numbers of overweight and obesity in Bra-
zil, called “VIGITEL Brazil 2009: Risk and Protective Factors
Surveillance for Chronic Diseases using Telephone Survey and
Household Budget Survey 2008-2009 (POF)”.10
Studies showed an excess weight in 46.6% of the
population, was higher among men (51.0%) than among women
(42.3%). Already the POF (2008-2009) shows a steady increase
of overweight and obesity in the population over 20 years of age
over 35 years. Overweight nearly tripled among men, 18.5% in
1974-1975 to 50.1% in 2008-2009. In women, the increase was
smaller: from 28.7% to 48%.9
Obesity is associated with a lower quality of life both
in schizophrenic patients and the general population. This is due
to eating disorders and metabolic disorders such as oxidative
stress. These patients deserve greater attention in the manage-
ment and intervention in weight.5
The objective of this study is to evaluate the association
of obesity with the use of clozapine in schizophrenic patients, as
explained above, there is an increasing prevalence of obesity in
recent decades, which compromises the expectation and quality
of life (QoL) of these patients.
MATERIALS AND METHODS
A review of the literature was conducted between 2004-2015 on
obesity in schizophrenic patients with clozapine, and the asso-
ciation of this atypical antipsychotic with these conditions was
the main target of this study.
This research used two databases: PubMed (MED-
LINE) and Journal of Capes. The terms used in the search were:
“Schizophrenia”, “Obesity”, “Clozapine” and “Weight gain”.
The selection of items was conducted by a researcher,
taking into account the following inclusion criteria: English
language, both sexes, retrospective study, patients aged over
20 years, the minimum clozapine use time of three months and
sample size equal or higher than 50 individuals.
For the extraction of data from the articles was pre-
pared a card (Table 1).
Table 1: Data extraction form.
Data extraction form
Article Title: ________________________________________________
Design: ______________________________________________
Medication And Use Time: _______________________________________
Tracking Time: ___________________________________
Sex: ________________________________
Patient Age: ______________________
Parameters Used to Evaluate Obesity: ______________________
Sample Size: _______________________
Study Outcome: ________________________

OBESITY RESEARCH
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ISSN 2377-8385
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RESULTS
They were found 323 articles, of which 306 in English in the
initial search. After careful selection, 57 were excluded because
they did not conform to the proposed theme (different diseases
or medications), 94 were excluded after reading the title because
they are from different areas, 32 to be another type of resource,
such as reviews or Congress act, 57 repeated, 54 previously pub-
lished for 2004, the remaining 12 articles, which were read and
examined again taking into account the inclusion criteria, with
only 4 items selected and included in this review (Figure 1).
Thus, the individual description of each study was
made, following the reverse chronological order of publication
as shown in Table 1 and their outcomes in Table 2.
The study Villanueva et al11 measured the change in
BMI induced by clozapine, in both sexes, in two stages, 18 and
56 weeks follow-up. They analyzed 76 patients at 18 weeks and
57 in 56 weeks.
 Atrst itwasdeterminedbaseline BMIandthen was
made periodic reviews weight, height, BMI and clozapine dos-
98 Pubmed Articles 225 Cappes Periodic
Articles
323 Articles
EXCLUDED
57 articles: Not suitable for the proposed theme (different conditions or different medications);
94 articles: Because they are from different areas (not address obesity and focus on other
areas of research, such as genetics, cognitive therapy, etc.).
17 articles: Because they are from another language other than English
32 articles: For being review, Congress act or textual resources.
54 articles: Previous publication date to 2004.
57 articles: Repited.
12 Articles
4 Articles
INCLUSION CRITERIA
- Retrospective study;
-Patients of both sexes over the age
of 20 years;
- Operating time of clozapine mini-
mum of three months;
- Sample size less than 50 individuals.
EXCLUDED
3 for not being retrospective studies;
1 by not using clozapine for at least
3 months;
1 to have smaller sample size than
50 individuals;
Figure 1: Organization chart of items excluded.
Analysis of the articles included
Authors in studies
year Outline Population
sample size Medication and time use Parameters used to
evaluate obesity
Villanueva et al11 Coorte
retrospective study
Men and women
76 patients
Clozapine
18 to 56 weeks
BMI*
and
body weight
Choong E et al12 Cross retrospective
study
Men and women
196 patients
Clozapine, olanzapine, quetiapine,
risperidone, lithium and valproate.
>3 months of use
BMI*
and
body weight
Ya Mei Bai et al13
Retrospective study
Men and women
96 patients, 55 being
accompanied.
Clozapine
8 years
BMI*
and
body weight
Covell NH et al14 Retrospective study Men and women
38 patients
Clozapine
2 years
BMI*
and
body weight
*BMI: Body Mass Index
Table 2: Analysis of the articles included.

OBESITY RESEARCH
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ISSN 2377-8385
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age. As a result at 18 weeks of follow-up there was a variation
in BMI of 1.83 kg/m2, and of these 18 patients (19.7%) had a
decrease in BMI. There was no difference between sexes in BMI
changes. At 56 weeks of follow-up there was a BMI range of
2.67 kg/m2, and of these 10 patients (17.5%) had a decrease in
BMI. There was no difference between sexes in BMI changes,
alsothistime.Therewasastatisticallysignicantinverserela-
tionship between BMI and baseline BMI in both times. In this
study, the authors concluded that despite the increase in weight
with the use of clozapine, physicians should not discourage the
use for refractory patients.
Choong et al’s12 study evaluated the importance of
side effects associated with weight gain psychotropic drugs and
their metabolic consequences. Patients received for more than
three months drugs: Clozapine, olanzapine, quetiapine, risperi-
done, lithium and/or valproate. 196 patients were analyzed. The
weightgain (≥10%ofinitialbodyweight)aftertreatment with
clozapine was reported in 47% of patients.
 The prevalence of obesity (BMI≥30) was present in
38% of patients. The highest dose, an increase in appetite after
the introduction of medication, type of medication (clozapine
or olanzapine>quetiapine, or risperidone>lithium or valproate),
and sex was signicantly associated with the development of
BMI.
Yamei Bai13 study tested whether the initial clozapine
response is related to weight gain. This study was a retrospec-
tive study of 8 years of 96 hospitalized patients with schizophre-
nia. There was a loss of 41 patients (death, incomplete weights,
unavailable medical records, change of antipsychotic). The
monthly weight change data were analyzed, the initial clinical
response, age, sex, clozapine, and concomitant use of mood
stabilizers and other antipsychotics. To analyze the weight gain
BMI was used.
The patients receiving clozapine (55 patients, 57.3%)
throughout the study period, achieved an average weight gain
of 11.7 kg (SD=1.6). The multiple linear regression analysis
showed signicant initial clinical response and lower initial
body mass index was associated with higher weight gain. The re-
sults show that the initial response to the antipsychotic clozapine
is associated with higher weight gain in the long term, measured
over 8 years.
Covell NH14 study analyzed the percentage weight gain
of 138 randomized patients taking clozapine for 2 years and 89
whocontinuedtoreceiverst-generationantipsychotics.
In each group, 39% of participants were women. Two
patients who were randomized to clozapine, did not start its use
and were excluded and 3 patients had their weight measured
outside the patterns and were also excluded from the analysis
Table 2.
Demographic data were collected, the daily log of med-
ications and weight from information available through chart re-
view. When more than one weight measurement was available
in a given month, we used the latest weight for analysis. It also
calculated body mass index.
 The groups did not differ signicantly from the ini-
tial weight and average BMI. The random regression analysis
showed that patients who switched to clozapine gained more
weightthanpatientswhoremainedintherstgenerationofanti-
psychotic agents.
DISCUSSION
In the four studies selected in this systematic review, BMI was
used as a parameter to assess weight gain. However, this param-
eter measures the weight as a whole, and does not assess body
composition. Thus, the weight increase may be associated with
increased lean body mass or fat mass, and only the latter being
associated with obesity.
According Garn and colleagues15 there are three limita-
tions to the use of BMI: The correlation with height, the correla-
tionwiththefat-freemassandtheinuenceofbodyproportion-
ality (size ratio of the legs/trunk), such that individual less leg
length have a higher BMI. These limitations could jeopardize
the use of BMI as body fat indicator.
To get a real idea of the incidence of obesity in these
studies, the authors should associate with BMI, bioimpedance
test or skin folds (done with skinfold), and then perform the
comparison of these parameters before and after the use of clo-
zapine Table 3.
To Cerve,16 although BMI has high correlation with
body mass, it has low with height, so it is important to correlate
with other independent measures of body composition, which
determine the composition in terms of body fat and muscle mass
to have greater reliability as anthropometric parameters, such
as bioelectrical impedance, skinfold thickness, waist/hip ratio
(WHR) and waist circumference (WC).
And the study of Choong,12 comparison was made with
other antipsychotic drugs, and the results showed that clozapine
and olanzapine are those with largest increase of appetite and
consequent increased weight gain.
Studies show a high prevalence of obesity, hypergly-
cemia, dyslipidemia and metabolic syndrome in patients treated
with atypical antipsychotics, with evidence of greater effect for
those using clozapine and olanzapine.6
Like clozapine, olanzapine is also associated with
weight gain, an increase from baseline of 6.12 kg in 6 to 12
months of treatment.17
In the study Covell14 signicant difference in weight
gain after Clozapine especially in women, unlike other studies.

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ISSN 2377-8385
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This may have been because it was a study with the smaller sam-
ple size of the four selected. In the other there was no difference
between the sexes in both studied moments.
The databases used periodicals and CAPES, PUBMED
is quite academic relevance, encompassing medical articles
fromvariouselds,whichincreasesthecredibilityofthereview
further.
CONCLUSION
In all items selected for this study, obesity was associated with
clozapine. However, this fact is directly related to lack of infor-
mation on healthy eating and physical inactivity.
It has been noted the growing interest of researchers
in exploring non-pharmacological treatments for psychiatric pa-
tients,sincewehaveseensignicantimprovementsinthequal-
ity of life of these patients, when reduced dosage or deleted the
indication of these drugs. Thus, it is necessary greater awareness
of physicians indicate these multidisciplinary treatments to their
patients, such as nutritional care, exercise, behavioral and oc-
cupational therapy (art and music).
CONFLICTS OF INTEREST
Theauthorsdeclarethattheyhavenoconictsofinterest.
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Villanueva et al11
There was a change in BMI in both periods. In the 18th week
this change was 1.83 kg/m2 and in the 56th week of 2.67 kg/
m2. Only 18 patients (19.7%) had decreased BMI at 1 time
and 10 patients (17.5%) had decreased this index in the 2nd
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Choong E et al12
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in appetite.
Ya Mei Bai et al13
The patients (55 patients - 57.3% of the sample) received clo-
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average 11.7 kg body weight.
Covell NH et al14
Patients who used clozapine had higher weight gain (13.7%)
of those taking medications 1st generation (5.4%). Patients
with normal weight were more likely to become obese
(BMI≥30 kg/m2), especially among women.
*BMI: Body Mass Index
Table 3: Analysis of outcomes.

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