ARTICLE IN PRESS

SCHRES-03361; No of Pages 10

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Schizophrenia Research xx (2007) xxx – xxx

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Weight gain induced by haloperidol, risperidone and olanzapine after

1 year: Findings of a randomized clinical trial in a
drug-naïve population ☆
Rocio Perez-Iglesias a , Benedicto Crespo-Facorro a,⁎, Obdulia Martinez-Garcia a ,
Maria L. Ramirez-Bonilla a , Mario Alvarez-Jimenez a , Jose M. Pelayo-Teran a ,
Maria T. Garcia-Unzueta b , Jose A. Amado b , Jose L. Vazquez-Barquero a
a
Department of Psychiatry, Marques de Valdecilla University Hospital, Avda. Valdecilla s/n, 39008, University of Cantabria, Spain
b
Department of Endocrinology, Marqués de Valdecilla University Hospital, Avda. Valdecilla s/n, 39008, University of Cantabria, Spain
Received 24 July 2007; received in revised form 17 September 2007; accepted 18 October 2007

Abstract

Background: There is little information about weight gain induced by antipsychotics at long-term.
Objective: To quantify the weight gain induced by first (haloperidol) and second generation antipsychotics (olanzapine and
risperidone) in a cohort of drug-naïve subjects after 1 year of treatment.
Methods: This is a prospective, randomized clinical trial, including a representative sample of first episode psychotic incident cases
from a population area of 555.000 people. The main outcome measures were changes in body weight and body mass index at
3 months and at 12 months. Both a per protocol analysis and an intention to treat analysis were conducted.
Results: A total of 164 drug-naïve patients were included. At 12 months 144 patients were evaluated. Of them, 66% completed the
protocol and 34% needed treatment switch. We found statistically significant differences in weight gain at 3 months: 3.8 kg (±4.1)
for haloperidol, 5.9 kg (± 5.1) for risperidone and 8.4 kg (±5.0) for olanzapine (F = 7.045; p = 0.002). After 1 year the difference in
weight gain had disappeared: 9.7 kg (± 5.7) for haloperidol, 8.9 kg (± 8.8) for risperidone and 10.9 kg (± 7.2) for olanzapine
(F = 0.817; p = 0.445).
Conclusions: Drug-naïve patients experience an extraordinary weight gain after 1 year of treatment with haloperidol, olanzapine or
risperidone. The main difference among these treatments is the pattern of weight gain but not the final amount of weight gain.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Weight gain; Long-term; Antipsychotics; First episode psychosis; Olanzapine; Risperidone; Haloperidol

1. Introduction
☆
Previous presentation: presented at the “International Congress on
Schizophrenia Research (ICOSR)” April, 2007, Colorado, USA. Since atypicals or second generation antipsychotics
⁎ Corresponding author. Hospital Universitario Marqués de Valde-
(SGA) were introduced, the antipsychotic-induced
cilla. Department of Psychiatry. Planta 2a, Edificio 2 de Noviembre.
Avda. Valdecilla s/n, 39008, Santander. Spain. Tel.: +34 942 202537; weight gain has become one of the main foci of interest
fax: +34 942 203447. of psychopharmacology. Second generation antipsycho-
E-mail address: bcfacorro@humv.es (B. Crespo-Facorro). tics represented an advance in schizophrenia treatment
0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2007.10.022

Please cite this article as: Perez-Iglesias, R., et al., Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a
randomized clinical trial in a drug-naïve population, Schizophr. Res. (2007), doi:10.1016/j.schres.2007.10.022
 ARTICLE IN PRESS
2 R. Perez-Iglesias et al. / Schizophrenia Research xx (2007) xxx–xxx
compared with first generation antipsychotics (FGA),
not clear in terms of efficacy (Geddes et al., 2000;
Rosenheck et al., 2003) but obvious from looking at the
extrapyramidal side effects profile (Correll et al., 2004;
Crespo-Facorro et al., 2006). This advantage has led
to an enormous increase in prescription rates of SGA in
the last years despite their high economic cost. How-
ever SGA have been associated more frequently than
FGA with weight gain and metabolic disturbances
(Haupt, 2006; Newcomer, 2005).
Regardless of weight gain being one of the most
frequent and unwanted side effects, an accurate estima-
tion of the independent effect of antispychotics does not
yet exist. Numerous short-term studies have estimated
the amount of weight gain induced by SGA and FGA
treatments. Notable differences in magnitude have been
found related to methodological problems, but most
studies have reported that olanzapine has the highest
liability among new SGAs, with mean weight gain
ranges from 4.1 kg to 9.2 kg over 12 weeks.(Lieberman
et al., 2005; Perez-Iglesias et al., 2007; Simpson et al.,
2005; Zipursky et al., 2005) Other SGAs like risper-
idone have been associated to a moderate effect with a
mean weight gain of around 2 kg.(Allison et al., 1999;
Newcomer, 2005) A zero or very modest effect has been
reported for haloperidol(Allison et al., 1999; Tollefson
et al., 1997), the most frequently used FGA in trials and
in clinical practice. Long-term studies are more scarce,
methodologically weaker and the results are inconclu-
sive but it seems that the differences found in short-term
evaluations become less pronounced.(Gentile, 2006)
Considering these treatments are mainly prescribed
for patients with chronic disorders who have to take these
drugs for years or a lifetime, the most interesting
questions are: 1) how antipsychotic treatment affects
the BMI at medium-long term? 2) Do differences
between FGA and SGA persist long-term? And 3) is
there a significant difference between SGAs (olanzapine
and risperidone) at long-term? In order to answer these
questions we propose a prospective randomized study
comparing FGA (haloperidol) and SGA (olanzapine and
risperidone) in a drug naïve population. Patients
included in this study were a representative sample of
incident cases of first episode psychosis in our province
from February 2001 to February 2005. They were treated
in the context of real-world clinical practice with the
lowest effective doses and they were followed for 1 year.
2. Method
This study was conducted in the outpatient and in-
patient psychiatric units of Marques de Valdecilla Uni-
Please cite this article as: Perez-Iglesias, R., et al., Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a
randomized clinical trial in a drug-naïve population, Schizophr. Res. (2007), doi:10.1016/j.schres.2007.10.022
versity Hospital, located in the province of Cantabria, in
the north of Spain. The Hospital is a reference centre of a
catchment area population of 555,000 people and pro-
vides the only psychiatric acute inpatient unit and 24 h
emergency care service for the whole province. To
guarantee the inclusion of all first episodes of psychosis
regular meetings with all Mental Health Care services of
Cantabria were maintained. The study protocol was
approved by the ethics committee of our hospital.
2.1. Subjects
Patients recruited into this study were drawn from a
consecutive sample of psychotic patients referred to our
psychiatric units from February 2001 to February 2005
who met the following criteria: 1) age 15–60 years, 2)
living in the catchment area, 3) experiencing their first
episode of psychosis 4) never treated with antipsychotic
medication, 5) meeting DSM-IV criteria for brief
psychotic disorder, schizophreniform disorder, schizo-
phrenia, or schizoaffective disorder, 6) they understood
the nature of the study and signed an informed consent
document (required from each patient or the patient's
authorized legal representative). Patients were excluded
for any of the following reasons: 1) meeting DSM-IV
criteria for drug dependence, 2) meeting DSM-IV criteria
for mental retardation, 3) having a serious medical illness.
The diagnosis were confirmed according to the
DSM-IV criteria, using the Structured Clinical Interview
for DSM-IV (SCID-I) by an expertise psychiatrist after
6 months of the initial contact.
All participants were in good general health and none
of them were receiving drugs that can possibly affect
their weight. Advice on diet, exercise and lifestyle was
given to all patients.
2.2. Study design
Patients were randomly assigned to receive either
haloperidol, olanzapine or risperidone. We used a sim-
ple randomization procedure. A computer-generated
randomization list was drawn up by a statistician. Treat-
ment dose ranges were 3–9 mg/day for haloperidol, 5–
20 mg/day for olanzapine and 3–6 mg/day for
risperidone. Doses could be adjusted as clinically in-
dicated within the prescribed range in an attempt to
target the lowest effective dose. Certain concomitant
medications (lormetazepam and clonazepam) were
permitted for the management of agitation, general
behavior disturbances and/or insomnia. Only if clini-
cally significant extrapyramidal signs occurred was
anticholinergic medication (biperiden at a dose of up to
 ARTICLE IN PRESS
R. Perez-Iglesias et al. / Schizophrenia Research xx (2007) xxx–xxx 3

8 mg/day) allowed. Antidepressants (sertraline) and
mood stabilizers (lithium) were permitted if clinically
needed. Those patients who did not respond after
6 weeks of treatment (b30% total improvement
measured by SAPS (Andreasen, 1984), SANS (Andrea-
sen, 1983) scales) or who had significant side effects
(measured by UKU scale (Lingjaerde et al., 1987)) were
changed to a different antipsychotic. All patients were
informed about potential weight gain and exercise and
dietary recommendations were given.
The study's main outcome measures were changes in
body weight and body mass index at 1 year after the
enrolment. The sample size of our study provides 80%
power to detect a half standard deviation difference
between treatment means using a 2-sided test at a 0.05
significance level.

Fig. 1. Participant flow in the randomized clinical trial.

Please cite this article as: Perez-Iglesias, R., et al., Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a
randomized clinical trial in a drug-naïve population, Schizophr. Res. (2007), doi:10.1016/j.schres.2007.10.022
 ARTICLE IN PRESS
4 R. Perez-Iglesias et al. / Schizophrenia Research xx (2007) xxx–xxx

2.3. Assessments
Patients' height was measured at the time of en-
rolment in the study. Patients' weight was determined
at baseline, at 12-weeks and at 1 year follow-up.
Body weight was measured with subjects wearing light
clothing. Body mass index was computed as body
weight (kg) divided by height in meters squared. A BMI
of 18.5 to 24.9 was considered normal, a BMI of 25 to
29.9 was considered overweight, and a BMI above than
30 was considered to indicate obesity.
2.4. Statistical analysis
The analysis has been performed on a “per protocol”
or “on-treatment” basis (only participants who fulfilled
the protocol were included: N = 95 completers) as well
as according to the intention to treat basis (all patients
were included in the treatment group to which they were
initially assigned, no matter how long they adhered to
the protocol: N = 144).
To ensure group comparability, baseline sociodemo-
graphic and clinical characteristics were tested by one-
way analysis of variance (ANOVA) for continuous
variables and by chi-square test for categorical vari-
ables. The relationship between main outcomes
(changes in weight and BMI) and antipsychotic
medication was investigated by analysis of covariance
(ANCOVA). Change in each parameter between base-
line and endpoint was used as the dependent variable,
type of medication (treatment group) was used as the
independent variable and BMI at baseline, sex and age
were used as covariates. When the analysis revealed
significant between group effects, additional post hoc
analysis (Sidak test) was conducted.
The Statistical Package for Social Science (SPSS),
version 12.0 was used for statistical analyses. All sta-
tistical tests were two-tailed and significance was de-
termined at the 0.05 level.
3. Results
Mean age was 27.0 years (range 15.4–48.3), 62.2%
were men and 84.8% were unmarried. Ninety six per-
cent were Caucasian. Most patients were living with
their family (83.5%). The percentage of unemployment
was 47%. Sixty four percent of the sample was di-
agnosed as having schizophrenia. The mean duration of
psychosis was 13.7 months, with a median duration of
4 months. A total of 103 subjects required hospitaliza-
tion after initial contact.
The mean BMI at baseline was 23.1 kg/m2 (± 3.5 SD).
After 12 weeks of treatment the mean weight gain was
5.8 kg (SD:5.4) and after 1 year follow-up the mean
weight gain was 10.5 kg (SD:8.2). At intake, 27.1% had
excess weight (22.6% were overweight and 4.5% were
obese). At 3 months this number rose to 47.6% (38.6%
were overweight and 9% were obese) and at 1 year the
percentage of population with excessive body weight
was 60.4% (34.7% overweight and 25.7% obese). The
mean percentage of weight gain was 15.04% of their
baseline weight.
Baseline sociodemographic and clinical data for each
group of treatment are listed in Table 2. There were no
significant differences between the three groups with
regard to sex, age, educational level, socioeconomic
status, diagnosis, severity of illness and drug consump-
tion. Mean doses of antipsychotics at different moments
are listed in Table 2. Treatment-emergent extrapyrami-
dal signs and symptoms were more frequent and more
severe in the haloperidol-treated group and a signifi-
cantly higher percentage of patients required antic-
holinergic treatment in this group.
Table 1
Discontinuation rates
HAL = 52 OLZ = 54 RISP = 58 Total
(N = 164)
Completed study 24 36 35 95
(same protocol)
Discontinued 28 18 23 69

Reasons for discontinuation

3.1. Enrolment and characteristics of study population Lost to follow-up 2 5 11 18
Rejected to be 1 1 2
Two hundred and twenty five subjects were screened. evaluated at end point
Of these, 59 were excluded for not meeting the inclusion Changed to another 25 13 11 49
treatment
criteria and two refused to participate in the study. A
Reasons
total of 164 patients were included and randomized to – Inefficacy 7 7 3
receive (Fig. 1): haloperidol (52), olanzapine (54) and – Side effects: total 17 6 8
risperidone (58). In all, 49 needed treatment switch (Side effect: weight (0) (3) (1)
(29.9%), 18 were lost to follow up (11%) and 2 patients gain)
– No adherence 2
rejected to be evaluated at end point (Table 1).

Please cite this article as: Perez-Iglesias, R., et al., Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a
randomized clinical trial in a drug-naïve population, Schizophr. Res. (2007), doi:10.1016/j.schres.2007.10.022
 ARTICLE IN PRESS
R. Perez-Iglesias et al. / Schizophrenia Research xx (2007) xxx–xxx 5

Table 2
Comparison baseline demographic and clinical characteristics between treatment groups
Haloperidol N = 52 Olanzapine N = 54 Risperidone N = 58 F df p
Mean (SD) Mean (SD) Mean (SD)
Age at admission, years 27.4 (7) 27.6 (6.9) 26 (7) 0.895 2, 161 0.411
Age at illness onset, years 26.1 (6.4) 26.6 (6.8) 24.9 (6.4) 1.088 2, 161 0.339
Duration of Untreated Psychosis 15.3 (30.9) 12.1 (29.4) 13.9 (22.6) 0.175 2, 161 0.839
(DUP), months
SANS-SAPS at intake 20.7 (7.9) 20 (7.6) 19.9 (6.7) 0.177 2, 161 0.838
Weight at intake 69 (13.5) 65.4 (13) 66.7 (12.1) 1.059 2, 161 0.349
BMI at intake 24 (4) 22.8 (2.9) 22.7 (3.4) 2.330 2, 161 0.101

N (%) N (%) N (%) χ2 df p

Sex (male) 35 (67.3) 32 (59.3) 36 (62.1) 0.860 2 0.650
Education level (secondary or lower) 25 (48.1) 27 (50) 31 (53.4) 0.328 2 0.849
Family socioeconomic status (not/low 15 (28.8) 15 (27.8) 21 (38.2) 1.647 2 0.439
qualified worker)
Unmarried 45 (86.5) 42 (77.8) 52 (89.7) 3.241 2 0.198
Living with family 41 (78.8) 46 (85.2) 50 (86.2) 1.239 2 0.538
Student 13 (25) 9 (16.7) 9 (15.5) 1.871 2 0.392
Unemployed 23 (44.2) 23 (42.6) 31 (53.4) 1.549 2 0.461
Drug consumption
Smoking 30 (57.7) 32 (59.3) 35 (60.3) 0.080 2 0.961
Cannabis 25 (48.1) 26 (48.1) 27 (46.6) 0.037 2 0.982
Alcohol 32 (61.5) 25 (47.2) 32 (55.2) 2.198 2 0.333
Diagnosis
Schizophrenia 40 (76.9) 29 (54.7) 34 (63) 5.791 2 0.055
Others
Schizophreniform disorder 10 (19.2) 16 (30.2) 12 (22.2)
Psychosis NOS 1 (1.9) 5 (9.4) 5 (9.3)
Brief psychosis 1 (1.9) 3 (5.7) 3 (5.6)

Only completers (N = 95)

mg/d (SD) mg/d (SD) mg/d (SD)
Mean dose (mg/d) per protocol
At 6 weeks (N = 164) 5.2 (2.1) 15.3 (4.8) 4.2 (1.5)
At 3 months (N = 156) 4.7 (2.0) 13.3 (4.7) 4 (1.6)
At 1 year (N = 95) 2.9 (1.4) 10.1 (3.9) 3.6 (1.9)

N (%) N (%) N (%) χ2 df p

Concomitant treatments
Benzodiazepines 6 weeks 18 (34.6) 13 (25.5) 12 (22.2) 2.183 2 0.336
Benzodiazepines 3 months 11 (23.9) 8 (16.3) 12 (23.1) 1.012 2 0.603
Benzodiazepines 1 year 1 (4.2) 3 (8.3) 5 (14.3) 1.788 2 0.409
Anticholinergics 6 weeks 38 (73.1) 2 (3.9) 18 (33.3) 53.320 2 0.000⁎
Anticholinergics 3 months 35 (76.1) 2 (4.1) 20 (38.5) 51.821 2 0.000⁎
Anticholinergics 1 year 11 (45.8) 0 (0) 11 (31.4) 19.129 2 0.000⁎
Hypnotics 6 weeks 10 (19.2) 4 (7.8) 5 (9.3) 3.764 2 0.152
Hypnotics 3 months 8 (17.4) 2 (4.1) 4 (7.7) 5.191 2 0.075
Hypnotics 1 year 2 (8.3) 0 (0) 2 (5.7) 2.790 2 0.248
Antidepressants 6 weeks 1 (1.9) 1 (2.0) 1 (1.9) 0.002 2 0.999
Antidepressants 3 months 2 (4.3) 3 (6.1) 2 (3.8) 0.314 2 0.855
Antidepressants 1 year 3 (12.5) 3 (8.3) 8 (22.9) 3.107 2 0.211
Mood stabilizers 6 weeks 0 (0) 1 (2.0) 0 (0) 2.092 2 0.351
Mood stabilizers 3 months 0 (0) 1 (4.0) 0 (0) 2.014 2 0.365
Mood stabilizers 1 year 0 (0) 2 (5.6) 0 (0) 3.348 2 0.187

Please cite this article as: Perez-Iglesias, R., et al., Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a
randomized clinical trial in a drug-naïve population, Schizophr. Res. (2007), doi:10.1016/j.schres.2007.10.022
 ARTICLE IN PRESS
6 R. Perez-Iglesias et al. / Schizophrenia Research xx (2007) xxx–xxx

3.2. Comparison between groups 4. Discussion

As shown in Table 3 differences between groups
were observed in weight gain and BMI change at
3 months. In both analyses, per protocol (PP) and in-
tention to treat (ITT) post hoc tests revealed a significant
difference in weight gain between the haloperidol and
olanzapine group (ITT: p = 0.018; PP: p = 0.001). Be-
tween the olanzapine and risperidone group only a BMI
change in a PP analysis reached statistical significance
(PP: p = 0.031).
No significant differences among groups in weight
gain or BMI change were detected after 1 year of
treatment (Table 4). In an ITT analysis the mean increase
in weight was 10.7 kg (SD: 7.7) for haloperidol, 11.2 kg
(SD: 8.0) for olanzapine and 9.5 kg (SD: 9.0) for the
risperidone group. The results did not differ substan-
tially in a PP basis analysis: 9.7 kg (SD:5.7) for hal-
operidol, 10.9 kg for olanzapine (SD: 7.2) and 8.9 kg
(SD: 8.8) for risperidone treatment.
When we compare the three groups according to their
percentage of weight gain we don't find statistically
significant differences (Table 5), but there are more
patients in the olanzapine group with a higher increase
in baseline weight.
In Fig. 2 it is possible to appreciate the different slope
of weight gain for the three treatments. Olanzapine
treated patients showed a rapid weight gain pattern
during the first 12 weeks followed by a flattening in the
rate of weight increase. On the contrary, the haloperidol
group experienced a constant rate of weight gain over
the first year of treatment. Risperidone treatment oc-
cupied an intermediate position.
Weight gain induced by antipsychotics in a drug-
naïve population is a larger and more frequent problem
than described in most earlier studies based on research
on chronic patients previously exposed to antipsychotics
(Allison et al., 1999; Conley and Mahmoud, 2001;
Lieberman et al., 2005; Simpson et al., 2005). After
12 months of treatment 93.8% of our population ex-
perienced an increase in their body weight and, of those
77.1% gained more than 7% of their initial weight. Sixty
percent of this population fell into an overweight or
obese category and subsequently they will be more
likely to suffer health problems associated with this
condition. The greater magnitude of weight gain ob-
served in our study can be explained by the baseline
characteristics of our population (young people with a
low prevalence of obesity (4%); never exposed to an-
tipsychotic treatment) and by presumably good treat-
ment compliance (good social/family support, good
attendance in regular visits, low rate of drop-outs). Only
a few studies based on first episode psychotic patients
with nil or limited exposure to antipsychotic medica-
tion have described comparable results.(Schooler et al.,
2005; Strassnig et al., 2007; Zipursky et al., 2005).
Schooler et al. (2005) in a double blind randomized trial
reported a weight gain of 6.5 kg (SD: 8.9) for hal-
operidol and 7.5 kg (SD: 9.3) for risperidone, slightly
inferior to our findings. Zipursky et al. (2005) compared
the weight gain with haloperidol and olanzapine treat-
ment in a randomized double-blind study and they
found for the olanzapine-group a mean weight gain of
15.5 kg (SD: 9.6) and for the haloperidol-group 7.1 kg

Table 3
Weight gain and BMI change after 3 months of treatment with haloperidol, olanzapine or risperidone in a population of drug-naïve psychotic patients
Haloperidol Olanzapine Risperidone F df p† p‡
Mean (SD) Mean (SD) Mean (SD)
HAL vs OLZ HAL vs RISP OLZ vs RISP
Mean (SE) Mean (SE) Mean (SE)
Intention to treat analysis (N = 144)
Weight gain (kg) raw 4.18 (5.49) 7.19 (5.26) 6.03 (5.00)
Weight gain (kg) adjusted 4.38 (0.69) 7.16 (0.70) 5.85 (0.71) 3.912 2 0.022 0.018 0.376 0.477
BMI change (kg/m2) raw 1.43 (1.84) 2.51 (1.78) 2.00 (1.60)
BMI change (kg/m2) adjusted 1.52 (0.23) 2.50 (0.24) 1.94 (0.24) 4.364 2 0.015 0.011 0.518 0.263

Per protocol analysis (N = 95)

Weight gain (kg) raw 3.75 (4.08) 8.37 (5.00) 5.90 (5.11)
Weight gain (kg) adjusted 3.92 (0.91) 8.28 (0.75) 5.88 (0.74) 7.045 2 0.001 0.001 0.272 0.075
BMI change (kg/m2) raw 1.31 (1.40) 2.89 (1.68) 1.95 (1.61)
BMI change (kg/m2) adjusted 1.39 (0.31) 2.86 (0.25) 1.93 (0.25) 7.412 2 0.001 0.001 0.449 0.031
†ANCOVA model: parameter change was used as the dependent variable, treatment group was the fixed factor and baseline BMI, age and sex were
used as covariates.
‡Pairwise comparisons based on estimated marginal means; Sidak adjustment for multiple comparisons.

Please cite this article as: Perez-Iglesias, R., et al., Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a
randomized clinical trial in a drug-naïve population, Schizophr. Res. (2007), doi:10.1016/j.schres.2007.10.022
 ARTICLE IN PRESS
R. Perez-Iglesias et al. / Schizophrenia Research xx (2007) xxx–xxx 7

Table 4
Weight gain and BMI change after 1 year of treatment with haloperidol, olanzapine or risperidone in a population of drug-naïve psychotic patients
Haloperidol Olanzapine Risperidone F df p† p‡
Mean (SD) Mean (SD) Mean (SD)
HAL vs OLZ HAL vs RISP OLZ vs RISP
Mean (SE) Mean (SE) Mean (SE)
Intention to treat analysis (N = 144)
Weight gain (kg) raw 10.65 (7.66) 11.22 (7.99) 9.46 (8.99)
Weight gain (kg) adjusted 10.64 (1.17) 11.33 (1.16) 9.35 (1.21) 0.718 2 0.490 0.967 0.829 0.558
BMI change (kg/m2) raw 3.74 (2.60) 3.97 (2.79) 3.25 (3.07)
BMI change (kg/m2) adjusted 3.76 (0.41) 4.01 (0.40) 3.19 (0.42) 1.050 2 0.353 0.961 0.700 0.402

Per protocol analysis (N = 95)

Weight gain (kg) raw 9.67 (5.65) 10.94 (7.18) 8.94 (8.79)
Weight gain (kg) adjusted 9.68 (1.52) 11.05 (1.23) 8.82 (1.25) 0.817 2 0.445 0.863 0.962 0.504
BMI change (kg/m2) raw 3.36 (1.85) 3.81 (2.53) 3.05 (2.96)
BMI change (kg/m2) adjusted 3.39 (0.52) 3.86 (0.42) 2.98 (0.43) 1.051 2 0.354 0.871 0.904 0.388
†ANCOVA model: parameter change was used as the dependent variable, treatment group was the fixed factor and baseline BMI, age and sex were
used as covariates.
‡Pairwise comparisons based on estimated marginal means; Sidak adjustment for multiple comparisons.

(SD: 6.7) after 1 year, using an observed-cases analysis. olanzapine (Lieberman et al., 2005)), 3) no previous
It is worth pointing out that the haloperidol treatment is research has been performed with 100% drug-naïve
not neutral. In the three randomized studies performed patients, so the potential effect of these drugs on weight
in first episode psychotic populations the weight gain gain have not been well established.
was superior to 7 kg after 12 months. The weight gain A similar pattern of weight gain has been described
described in the olanzapine group was higher than the in a chronic schizophrenic population treated with
results we have found. However, the proportion of pa- olanzapine and risperidone during 1 year (Alvarez
tients who discontinued the study at 1 year was very et al., 2006). The total amount of weight gain was
high, 64.1% in the olanzapine group and 73.5% in the substantially different to our results, but the timing of
haloperidol group, so the results are based on the small weight increase was similar: olanzapine treated patients
proportion of patients who remained in the study and experienced a more rapid increase in weight finding
these could not be representative of the population at significant differences compared with the risperidone
baseline. In a recent study, Strassnig and colleagues group at 8, 12 and 16 weeks but not later on. In another
(2007) reported a weight increase of 4.1 kg (SD: 5.6) for study including first episode psychotic patients the au-
haloperidol and 17.0 kg (SD: 12.6) for olanzapine at thors did not find a statistically significant difference
1 year. The treatments were not randomized and the between FGA (chlorpromazine) and SGA (clozapine) at
sample size was very small in the olanzapine group (11 the end of the first year (Lieberman et al., 2003). More
patients).
At the end point we did not find differences in weight Table 5
gain among treatments — neither between first and Weight gain after 1 year of treatment (per protocol analysis; N = 95)
second generation antipsychotics nor between olanza-
Haloperidol Olanzapine Risperidone χ2 p
pine and risperidone. This finding, contrary to that re- % (n) % (n) % (n)
ported in most previous studies, could be attributed to
N7% 87.5 (21) 75.0 (27) 71.4 (25) 2.177 0.337
differences in methodology: 1) most data about weight baseline
gain induced by antipsychotics are based on short-term weight
studies, consequently the likelihood of finding differ- N10% 70.8 (17) 66.7 (24) 54.3 (19) 1.982 0.371
ences is higher due to the different rate of weight gain baseline
weight
caused by antipsychotics during the first weeks, 2) it is
N15% 29.2 (7) 52.8 (19) 37.1 (13) 3.667 0.160
not rare to find high-drop out rates in experimental baseline
studies and it is not unusual to use LOCF (last obser- weight
vation carried forward) imputation strategy, penalizing N20% 20.8 (5) 41.7 (15) 28.6 (10) 3.125 0.210
antipsychotics with a more rapid weight increase and baseline
weight
with better compliance (as it has been described with

Please cite this article as: Perez-Iglesias, R., et al., Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a
randomized clinical trial in a drug-naïve population, Schizophr. Res. (2007), doi:10.1016/j.schres.2007.10.022
 ARTICLE IN PRESS
8 R. Perez-Iglesias et al. / Schizophrenia Research xx (2007) xxx–xxx

Fig. 2. Different patterns of weight gain after 1 year of treatment with haloperidol, olanzapine or risperidone in a population of drug-naïve psychotic
patients.

long-term studies in first episode patients are necessary
to confirm these specific patterns of weight gain for
different antipsychotics but these findings suggest that
the weight gain profile should not be an issue of par-
ticular concern when we prescribe antipsychotics for
long term. However the magnitude and frequency of this
side effect represents an important health problem for
this particular population.
Limitations:
• The lack of blindness is the major limitation of this
study but we do not think that our results can be
affected by it because treatment changes were not
related to the outcome variable (weight gain).
• Given the sample size of our study we were not able to
detect statistically significant small differences among
treatments. Olanzapine-treated patients experienced
the higher mean weight gain, the higher BMI increase,
and the higher body weight increase (as a percentage of
baseline weight), but the magnitude of the effect size
was not big enough to be detected in our study.
• As the study was conducted in the context of the real
world the only method used to monitor the treatment
compliance was self-reported. However this is still a

Please cite this article as: Perez-Iglesias, R., et al., Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a
randomized clinical trial in a drug-naïve population, Schizophr. Res. (2007), doi:10.1016/j.schres.2007.10.022
 ARTICLE IN PRESS
R. Perez-Iglesias et al. / Schizophrenia Research xx (2007) xxx–xxx
good estimation of the weight gain induced by anti-
psychotic in regular clinical practice and in a situation
with perfect treatment compliance we would even
expect a bigger effect of antipsychotic on weight gain.
• This is an estimation of weight gain for patients with
schizophrenia or schizophrenia-related disorders,
not previously exposed to antipsychotics. These results
can not be generalisable to chronic populations or
patients previously exposed to antipsychotic medication.
Role of the funding source
The present study was performed at the Hospital Marques de
Valdecilla, University of Cantabria, Santander, Spain, under the
following grant support: Instituto de Salud Carlos III, FIS 00/3095 and
SENY Fundatio Research Grant CI 2005-0308007, Fundacion
Marques de Valdecilla A/02/07.
No pharmaceutical company supplied financial support.
Contributors
All the authors have participated and have made substantial
contributions to this paper:
Rocio Perez-Iglesias: design, analysis and interpretations of data and,
drafting the article. Benedicto Crespo-Facorro and Jose Luis Vazquez-
Barquero: conception, design and revising. Obdulia Martinez-Garcia,
Maria Luz Ramirez-Bonilla, Mario Alvarez-Jimenez, Jose Maria Pelayo-
Teran: collection and interpretation of data.
Jose Antonio Amado and Maria Teresa Garcia-Unzueta: inter-
pretation of data and revising. They have read and approved the final
version of the article.
Conflict of interest
All authors declare they have NO conflicts of interest.
We have no affiliation or financial or other relationships with any
organization or entity with a financial interest in or in financial
competition with the subject matter or materials discussed in the
manuscript.
Acknowledgements
We wish to thank the PAFIP researchers who helped with data
collection and assistance during the investigations. In addition, we
acknowledge the study participants and their families for enrolling in
this study.
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Please cite this article as: Perez-Iglesias, R., et al., Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a
randomized clinical trial in a drug-naïve population, Schizophr. Res. (2007), doi:10.1016/j.schres.2007.10.022