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British Journal of Clinical

Pharmacology

DOI:10.1111/j.1365-2125.2010.03783.x

Metformin for
olanzapine-induced weight
gain: a systematic review
and meta-analysis
Samir Kumar Praharaj,1 Amlan Kusum Jana,2 Nishant Goyal1 &
Vinod Kumar Sinha1

Correspondence
Dr Samir Kumar Praharaj MD, DPM,
Central Institute of Psychiatry, Kanke,
Ranchi, Jharkhand 834006, India.
Tel.: + 91 94 3134 5765
Fax: + 91 65 1223 1689
E-mail: samirpsyche@yahoo.co.in
----------------------------------------------------------------------

Keywords
meta-analysis, metformin, olanzapine,
systematic review, weight gain
----------------------------------------------------------------------

Received
30 May 2010

Accepted
6 August 2010

Central Institute of Psychiatry, Kanke, Ranchi 834006, India and 2Department of Psychiatry, KPC

Medical College and Hospital, Jadavpur, Kolkata 700032, India

WHAT IS ALREADY KNOWN ABOUT


THIS SUBJECT
Olanzapine in an atypical antipsychotic
agent which is associated with significant
weight gain.
Metformin, an anti-hyperglycaemic agent,
has been used to treat or prevent weight
gain associated with olanzapine.
Meta-analyses on studies that have
examined the use of metformin for
treatment of antipsychotic-induced weight
gain report significant heterogeneity.

WHAT THIS STUDY ADDS


Systematic review and meta-analysis
showed that metformin is useful for the
short-term treatment of olanzapine-induced
weight gain.

Olanzapine is an atypical antipsychotic that is useful in schizophrenia


and bipolar affective disorder, but its use is associated with
troublesome weight gain and metabolic syndrome. A variety of
pharmacological agents has been studied in the efforts to reverse
weight gain induced by olanzapine, but current evidence is insufficient
to support any particular pharmacological approach. We conducted a
systematic review and meta-analysis of randomized controlled trials of
metformin for the treatment of olanzapine-induced weight gain.
Systematic review of the literature revealed 12 studies that had
assessed metformin for antipsychotic-induced weight gain. Of these,
four studies (n = 105) met the review inclusion criteria and were
included in the final analysis. Meta-analysis was performed to see the
effect size of the treatment on body weight, waist circumference and
body-mass index (BMI). Weighted mean difference (WMD) for body
weight was 5.02 (95% CI 3.93, 6.10) kg lower with metformin as
compared with placebo at 12 weeks. For waist circumference, the test
for heterogeneity was significant (P = 0.00002, I2 = 85.1%). Therefore, a
random effects model was used to calculate WMD, which was 1.42
(95% CI 0.29, 3.13) cm lower with metformin as compared with placebo
at 12 weeks. For BMI, WMD was 1.82 (95% CI 1.44, 2.19) kg m-2 lower
with metformin as compared with placebo at 12 weeks. Existing data
suggest that short term modest weight loss is possible with metformin
in patients with olanzapine-induced weight gain.

Introduction
Body weight gain and metabolic alterations are clinically
relevant side effects of atypical antipsychotics which are
evident after approximately 10 weeks of treatment [1].
Olanzapine is linked to clinically significant body weight
gain ranging from 0.9 kg month-1 up to 6 to 10 kg or
more after 1 year of treatment [2]. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study
2011 The Authors
British Journal of Clinical Pharmacology 2011 The British Pharmacological Society

found that 30% of olanzapine-treated schizophrenia


patients gained >7% of their baseline body weight [3].
Weight gain with olanzapine has been found to be significantly higher than with other atypical antipsychotics,
except for clozapine [4]. It is hypothesized that appetite
stimulation and insulin resistance are the underlying
mechanisms for olanzapine-induced weight gain [5, 6].
A possible cause of appetite stimulation has been
suggested to involve serotonin 5-HT2C and histamine
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S. K. Praharaj et al.

H1-receptor antagonism, resulting in food craving and


binge eating [7].
Therefore, effective pharmacological and nonpharmacological strategies are urgently required for optimal body
weight control during olanzapine treatment [8]. Various
medications such as amantadine, nizatidine, ranitidine,
famotidine, topiramate, fenfluramine, reboxetine, fluoxetine, fluvoxamine, sibutramine, dextroamphetamine,
d-fenfluramine, orlistat, phenylpropanolamine, rosiglitazone and metformin have been reported to counteract
effectively antipsychotic-induced body weight gain [911].
The antidiabetic agent metformin, a biguanide, is particularly attractive because of its dual mechanism of decreasing body weight gain and improving insulin sensitivity,
both of which are affected by olanzapine. Metformin has
been demonstrated to improve glycaemic control and promotes a moderate weight loss in both diabetic and nondiabetic subjects [12, 13]. Studies that have assessed
metformin for olanzapine-induced weight gain report
weight loss, though the effect varies across studies. In the
systematic review by Bushe et al. [14], studies that have
evaluated the effect of metformin on antipsychoticinduced weight gain were included. They were not able to
combine studies for meta-analysis due to the high level of
heterogeneity. Further, they noted that the effect of dietary
and lifestyle interventions could not be teased out. In
another recent systematic review and meta-analysis [15],
metformin treatment caused a significant body weight
reduction in adult non-diabetic patients treated with
atypical antipsychotics (4.8%, 95% CI 1.6, 8.0) and in children (4.1%, 95% CI 2.2, 6.0) compared with placebo. Ehret
et al. [16] in their meta-analysis on six studies (n = 336)
reported that metformin significantly reduced weight
(WMD 3.16 kg, P = 0.0002), BMI (WMD 1.21 kg m-2; P =
0.0001), waist circumference (WMD 1.99 cm; P = 0.005), and
HOMA-IR (WMD 1.71; P = 0.004) as compared with placebo
in those receiving atypical antipsychotics. Maayan et al.
[11] in their meta-analysis comparing 15 agents for
antipsychotic-induced weight gain, reported metformin
producing greatest weight loss (seven studies, n = 334,
-2.94 kg, 95% CI -4.89, -0.99), that remained significant
when metformin was initiated after occurrence of weight
gain, but not when started concomitantly with antipsychotics. As the weight gain pattern is different for olanzapine as compared with other atypical antipsychotics and it
is one of the most commonly used antipsychotics, we conducted a systematic review and meta-analysis with an
objective to determine the effects of metformin for reducing or preventing weight gain associated with olanzapine.

Methods
Data sources and search strategy
Studies were identified using online searches of PUBMED/
MEDLINE and Cochrane database (CENTRAL). Searches
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were conducted using the combination of terms atypical


antipsychotics, olanzapine, body weight gain, obesity and
metformin. We inspected the reference list of all identified
studies, including existing reviews for relevant citations.
The search was restricted to publications in the English
language.

Study selection: inclusion criteria


One reviewer (SKP) initially evaluated the abstracts from
the literature search. The following criteria were used to
identify the studies:
1 Randomized, double-blind clinical trials comparing
metformin with placebo for olanzapine-induced weight
gain,
2 Outcome measures to include body weight, waist circumference and BMI,
3 Study duration of at least 12 weeks.

Data extraction
Two reviewers (SKP and NG) decided, independently,
whether individual studies met the inclusion criteria. Disagreements were resolved by discussion with a third
reviewer (AKJ).We used a standardized form, and extracted
data which included patient and study characteristics,
outcome measures and study results.

Assessment of methodological quality


of studies
The methodological quality of included trials in this review
was done using the Jadad Scale [17]. It includes three
items: (i) Was the study described as randomized? (ii) Was
the study described as double-blind? (iii) Was there a
description of withdrawals and drop outs? Scoring was
done as follows: one point for a positive answer and one
point deducted if either the randomization or the
blinding/masking procedures were inadequate. Cut-off of
two points on the Jadad scale was considered.

Quantitative data synthesis


Meta-analyses were undertaken to estimate overall treatment effects where the trials were considered to be similar
enough to combine using Rev Man 4.2 version. This decision was based on assessing similarity of trial characteristics as well as results. Separate meta-analyses were
undertaken for each outcome (body weight, waist circumference and BMI). Treatment effects were expressed as
weighted mean differences as outcomes were continuous
with 95% confidence intervals (95% CI). Homogeneity
among studies was tested using Cochrans Q-test and I2
statistic, in which greater than 50% indicates a moderate
amount of heterogeneity [18]. If significant statistical heterogeneity was detected (Cochran Q-test P < 0.1 or I2 value
> 50%), random effects estimates were calculated using

Metformin for olanzapine-induced weight gain

Table 1
Characteristics of included studies

Study

Methods

Paticipants

Intervention

Outcome

Baptista et al. [26]

Allocation: randomized
Blinding: double
Duration: 14 weeks
Allocation: randomized
Blinding: double
Duration: 12 weeks

Diagnosis: schizophrenia and


schizoaffective
n = 40
Diagnosis: schizophrenia and
bipolar disorder
n = 80

1. Olanzapine 10 mg plus metformin 850


to 1750 mg daily, n = 19
2. Olanzapine 10 mg plus placebo, n = 18
1. Olanzapine 520 mg plus metformin
850 to 2550 mg daily. n = 36
2. Olanzapine plus placebo, n = 36

Body weight, WC, BMI, BPRS

Allocation: randomized
Blinding: double
Duration: 12 weeks
Allocation: randomized
Blinding: double
Duration: 12 weeks

Diagnosis: schizophrenia
n = 40

1. Olanzapine 15 mg plus
750 mg daily, n = 20
2. Olanzapine 15 mg plus
1. Olanzapine 15 mg plus
750 mg daily, n = 32
2. Olanzapine 15 mg plus

metformin

Body weight, WC, BMI, waist-to-hip ratio

placebo, n = 20
metformin

Body weight, WC, BMI, glucose, insulin,

Baptista et al. [27]

Wu et al. [24]

Wu et al. [25]

Diagnosis: schizophrenia
n = 64

Body weight, WC, BMI, glucose, insulin,


HOMA-R, leptin, cortisol, growth
hormone, lipid profile

placebo, n = 32

WC, Waist circumference; BMI, Body-mass index; HOMA-R, Homeostatic model assessment for insulin resistance.

DerSimonian & Laird methods [19]. Otherwise, a fixedeffect model was used for analysis.

Results
Studies included
The combined search strategies identified 12 papers on
use of metformin in olanzapine-induced weight gain.
Three studies were excluded because of the following
reasons: Baptista et al. [20] used a metformin and sibutramine combination, whereas Klein et al. [21] and Shin et al.
[22] had reported combined results for atypical antipsychotics. Four other papers were commentaries on other
studies, whereas Morrison et al. [23] conducted an openlabel study. Finally, four studies met the review inclusion
criteria (total 105 subjects) and were included in the final
analysis [2427]. Characteristics of included studies are
summarized in Table 1. One of the included studies [25]
had results from four groups (metformin only, metformin
and lifestyle intervention, lifestyle intervention only or
placebo), of which only comparison between metformin
and placebo was included and the other two groups were
excluded in our meta-analysis. In the study of Baptista et al.
[26], 14 week values were included in the meta-analysis.

Study quality
All of the four studies were described as randomized. Two
studies [24, 25] were randomly assigned in blocks of four/
eight to ensure approximately equal numbers of participants within the two treatment groups. Concealment of
allocation was adequately reported in two studies [24, 25].
All the studies were double-blind.The dropout rate ranged
from 7.5 to 10% across these studies.

Meta-analysis
Forest plots for meta-analyses for body weight gain, waist
circumference and BMI are presented in Figures 13. For

body weight gain, the test for heterogeneity was not significant (P = 0.45, I2 = 0%). Weighted mean difference for
body weight was 5.02 (95% CI 3.93, 6.10) kg lower with
metformin as compared with placebo at 12 weeks. For
waist circumference, the test for heterogeneity was significant (P = 0.00002, I2 = 85.1%). Therefore, a random effects
model was used to calculate WMD, which was 1.42 (95% CI
0.29, 3.13) cm lower with metformin as compared with
placebo at 12 weeks. For BMI, the test for heterogeneity
was not significant (P = 0.52, I2 = 0%) and WMD was 1.82
(95% CI 1.44, 2.19) kg m-2 lower with metformin as compared with placebo at 12 weeks.

Discussion
Existing data suggest that short term modest weight loss is
possible with metformin in patients with olanzapineinduced weight gain. In our meta-analysis, weight reduction was 5.02% with metformin, which was higher that for
the approved drugs for weight reduction such as orlistat
and sibutramine, which reduced body weight by only 2.9%
and 4.3%, respectively [28]. The adverse events reported
with metformin were similar to placebo groups. These
results encourage additional studies in more homogenous
populations on the potential use of metformin in assisting
olanzapine-treated patients in the long-term control of
body weight and BMI. Baseline screening and a monitoring
plan must be initiated on commencement of antipsychotic
treatment [29]. With significant weight gain or emerging
metabolic effects, the risks and benefits of antipsychotic
choice and concomitant medications should be
re-evaluated. Although metformin may not be routinely
indicated for all patients on olanzapine as prophylaxis
based on the current evidence, its use is justified in
patients having olanzapine-induced weight gain with no
contraindication to metformin.
Our study is limited by the number of studies included
for meta-analysis. The small number of studies did not
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S. K. Praharaj et al.

Review:
Comparison:
Outcome:

METFORMIN FOR OLANZAPINE-INDUCED WEIGHT GAIN


01 Metformin vs. Placebo
01 Body weight at 12 weeks

Study
or sub-category

Metformin
Mean (SD)

Baptista et al. (2006) [26]


Baptista et al. (2007) [27]
Wu et al. (2008) [24]
Wu et al. (2008) [25]

19
36
18
32

Placebo
Mean (SD)

n
18
36
19
32

63.80 (10.20)
64.80 (14.60)
1.90 (2.72)
61.90 (2.60)

WMD (fixed)
95% Cl

Weight
%
3.21
2.08
22.54
72.16

1.80 [7.84, 4.24]


0.60 [8.10, 6.90]
4.97 [7.25, 2.69]
5.30 [6.57, 4.03]

100.00

5.02 [6.10, 3.93]

65.60 (8.50)
65.40 (17.70)
6.87 (4.23)
67.20 (2.60)

105
Total (95% Cl)
105
Test for heterogeneity: Chi2 = 2.62, df = 3 (P = 0.45), I2 = 0%
Test for overall effect: Z = 9.08 (P < 0.00001)
10

WMD (fixed)
95% Cl

10

Favours treatment Favours control

Figure 1
Forest Plot showing body weight (kg) at 12 weeks in randomized controlled trials comparing metformin and placebo for olanzapine-induced weight gain

Review:
Comparison:
Outcome:

METFORMIN FOR OLANZAPINE-INDUCED WEIGHT GAIN


01 Metformin vs. Placebo
02 Waist circumference at 12 weeks

Study
or sub-category

Metformin
Mean (SD)

Baptista et al. (2006) [26]


Baptista et al. (2007) [27]
Wu et al. (2008) [24]
Wu et al. (2008) [25]

19
36
18
32

91.20 (9.10)
89.50 (11.80)
0.46 (0.12)
82.70 (1.72)

Placebo
Mean (SD)

WMD (random)
95% Cl

Weight
%

87.80 (7.60)
91.80 (13.30)
1.37 (0.62)
85.50 (1.72)

18
36
19
32

105
105
Total (95% Cl)
Test for heterogeneity: Chi2 = 20.18, df = 3 (P = 0.0002), I2 = 85.1%
Test for overall effect: Z = 1.63 (P = 0.10)
10

WMD (random)
95% Cl

8.18
7.23
44.22
40.36

3.40 [1.98, 8.79]


2.30 [8.11, 3.51]
0.91 [1.19, 0.63]
2.80 [3.64, 1.96]

100.00

1.42 [3.13, 0.29]

10

Favours treatment Favours control

Figure 2
Forest plot showing waist circumference (cm) at 12 weeks in randomized controlled trials comparing metformin and placebo for olanzapine-induced weight
gain

METFORMIN FOR OLANZAPINE-INDUCED WEIGHT GAIN


Review:
Comparison: 01 Metformin vs. Placebo
03 BMI at 12 weeks
Outcome:
Study
or sub-category

Metformin
Mean (SD)

Baptista et al. (2006) [26]


Baptista et al. (2007) [27]
Wu et al. (2008) [24]
Wu et al. (2008) [25]

19
36
18
32

25.30 (2.90)
24.50 (4.90)
0.54 (0.92)
23.50 (0.86)

n
18
36
19
32

Placebo
Mean (SD)

WMD (fixed)
95% Cl

Weight
%

25.50 (3.90)
26.10 (5.90)
2.26 (1.92)
25.40 (0.86)

105
105
Total (95% Cl)
Test for heterogeneity: Chi2 = 2.25, df = 3 (P = 0.52), I2 = 0%
Test for overall effect: Z = 9.47 (P < 0.00001)
10

WMD (fixed)
95% Cl

2.86
2.25
15.27
79.62

0.20 [2.42, 2.02]


1.60 [4.11, 0.91]
1.70 [2.68, 0.76]
1.90 [2.32, 1.48]

100.00

1.82 [2.19, 1.44]

10

Favours treatment Favours control

Figure 3
Forest plot showing BMI (kg m-2) at 12 weeks in randomized controlled trials comparing metformin and placebo for olanzapine-induced weight gain
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Metformin for olanzapine-induced weight gain

allow us to conduct tests for publication bias. Also, sensitivity analysis was not performed in our study. Nevertheless, heterogeneity was not seen for body weight gain and
BMI in the studies. For waist circumference, a random
effects model was used to curb the problem of heterogeneity. Although, statistically homogenous, there were differences in the study population in four studies. Weight
loss in the Wu et al. studies [24, 25] was greater than that in
the Baptista et al. studies [26, 27], which may be because of
younger participants in the former who responded better
than the older persons [30]. Furthermore, two of the
studies [24, 26] have evaluated prevention of olanzapineinduced weight gain, whereas the other two [25, 27] have
studied reversal of weight gain. Although these studies
were combined in our review, it has been suggested that
metformin appears to benefit more when started early in
the course of treatment [30]. Nevertheless, the mechanism
of action of metformin does not seem to vary in both these
situations, which justifies the combination of these studies
in our meta-analysis. We suggest that all future studies
should respect standards of measuring outcomes and of
reporting data in order to enhance the comparability of
study results. Also, binary outcomes (number of patients
losing >7% initial body weight as in CATIE study [3]) should
also be reported as they are easier to interpret and clinically relevant.

Competing interests
There are no competing interests to declare.

Sources of funding
None.

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