Schizophrenia Research 118 (2010) 218–223

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Schizophrenia Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s

Topiramate for prevention of olanzapine associated weight gain

and metabolic dysfunction in schizophrenia: A double-blind,
placebo-controlled trial
Preeta Kaur Narula a,⁎, H.S. Rehan a, K.E.S. Unni b, Neeraj Gupta b
a
Department of Pharmacology, Lady Hardinge Medical College and Associated S.S.K. Hospitals, New Delhi, India
b
Department of Psychiatry, Lady Hardinge Medical College and Associated S.S.K. Hospitals, New Delhi, India

a r t i c l e i n f o a b s t r a c t

Article history:
Background: Olanzapine associated weight gain (WG) is a major concern in patients with
Received 24 May 2009
schizophrenia. The purpose of this study was to assess the efficacy of topiramate to prevent
Received in revised form 29 January 2010
Accepted 1 February 2010
olanzapine induced WG in these cases. We also studied various metabolic parameters.
Available online 7 March 2010 Methods: In this 12-week, double-blind, parallel group study, seventy-two drug-naïve, first-
episode schizophrenia patients were randomized to receive olanzapine + placebo (olanzapine
Keywords:
group) or olanzapine + topiramate (100 mg/day) (topiramate group). Weight, body mass
Schizophrenia index, fasting glucose, insulin, insulin resistance (IR), leptin, lipids and blood pressure were
Olanzapine assessed at baseline and at 12 weeks. The patients were clinically evaluated using Positive and
Topiramate Negative Syndrome Scale (PANSS) and were monitored for adverse effects.
Weight Results: Topiramate resulted in a weight loss of 1.27 ± 2.28 kg (p b 0.01), decrease in leptin
Metabolic syndrome (p b 0.001), glucose, cholesterol, triglyceride levels and systolic and diastolic blood pressure. In
Leptin the olanzapine group, there was a significant WG, hyperglycemia, hyperinsulinemia, increased
IR, hyperleptinemia, hypercholesterolemia and hypertriglyceridemia (p b 0.001).There was a
greater clinical improvement (PANSS scores) (p b 0.001) in the topiramate group. The adverse
effects were well tolerated.
Conclusions: Topiramate could prevent olanzapine induced weight gain and adverse metabolic
effects. It also results in a greater clinical improvement when used with olanzapine in
schizophrenia.
© 2010 Elsevier B.V. All rights reserved.

1. Introduction a long duration of successful treatment, and low rates of hos-

Management of schizophrenia involves a combination of
pharmacological and behavioral therapies. Pharmacological
treatment is an essential component of clinical management
through the different stages of illness. Among the second
generation antipsychotics, olanzapine is an effective medica-
tion for reduction in psychopathology and disease symptoms,
Abbreviations: WG, Weight gain; BMI, Body mass index; FBG, Fasting
blood glucose; TC, Total cholesterol; IR, Insulin resistance.
⁎ Corresponding author. J – 13/42, Rajouri Garden, New Delhi 110027,
India. Tel: + 91 9811581034.
E-mail address: docpreeta@yahoo.com (P.K. Narula).
pitalizations for an exacerbation of schizophrenia (Jayaram
et al., 2006; Lee et al., 2006; Leucht et al., 2009; Lieberman
et al., 2005). Although olanzapine is a first line agent for
schizophrenia, its use is limited by adverse effects like weight
gain (WG) and other metabolic abnormalities including
hyperglycemia, hyperlipidemia, hyperinsulinemia and meta-
bolic syndrome (Atmaca et al., 2003; Graham et al., 2005;
Hosojima et al., 2006; Lindenmayer et al., 2003; Melkersson
et al., 2000). There is a need to explore agents which can
prevent these treatment associated metabolic changes in
patients with schizophrenia.
Topiramate, a newer anticonvulsant has been associated
with weight loss as a side effect (Ben-Menachem et al., 2003;

0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2010.02.001
 P.K. Narula et al. / Schizophrenia Research 118 (2010) 218–223
Smith et al., 2000). Several case reports have shown
topiramate to control antipsychotic-induced weight gain
without aggravation of their psychotic symptoms (Lin et al.,
2005). A higher dose of topiramate (200 mg/day) was found
to be effective as an adjuvant treatment in patients with
schizophrenia experiencing excess weight gain (Ko et al.,
2005). A recent study by Afshar et al. (2009) concluded that
topiramate could control antipsychotic-induced weight gain
and schizophrenic symptoms. Similar findings were reported
by Kim et al. (2006) in their 12-week open-label study.
However, their study was limited by a small sample size
and lack of placebo control and evaluation of biochemical
parameters. These studies suggest the need for further
rigorous, double-blind, placebo-controlled trials to elucidate
the beneficial effects of topiramate on patients' psychopa-
thology, clinical symptoms and biochemical/metabolic
parameters.
Our comprehensive study was aimed at assessing the
potential of topiramate to prevent olanzapine induced WG
and biochemical/metabolic abnormalities to improve the
patient compliance and decrease the disease morbidity. This
prophylactic role of topiramate was evaluated in drug-naïve,
first-episode schizophrenia patients, thus avoiding the con-
founding effects of prior antipsychotic therapy. We have also
monitored patients for clinical improvement and adverse
effects.
2. Materials and methods
2.1. Subjects
Patients were male and female, 18–65 years of age (both
inclusive) attending the psychiatry clinic at a tertiary care
hospital in New Delhi, India. The first-episode, drug-naïve
patients met the World Health Organization's International
Statistical Classification of Diseases and Related Health
Problems (ICD -10) Diagnostic Criteria for Research for
schizophrenia (ICD-10 DCR WHO, 1994). The patients were
excluded if they had a history of any other neuropsychiatric
illness; they were on Selective Serotonin Reuptake Inhibitors
(SSRIs), mood stabilizers or any other drug which could
potentially influence the weight; positive substance abuse
diagnosis in last 3 months; or a significant medical disorder.
Pregnant and lactating women and women of childbearing
age not using adequate contraception were excluded. The
sample consisted of stable inpatients and outpatients.
The study was approved by The Institutional Review Board.
It was carried out in accordance with The Code of Ethics of
the World Medical Association (Declaration of Helsinki). A
written informed consent was taken from all the patients
and they were free to withdraw their consent to participate at
any time during the study.
2.2. Study design
This was a parallel, double-blind, placebo-controlled 12-
week prospective study where patients were randomly
assigned to either olanzapine + placebo (olanzapine group)
or olanzapine + topiramate (topiramate group) treatment.
The dose of olanzapine ranged from 5 to 20 mg/day in both
the groups and could be increased or decreased (within
219
range) based on the discretion of the physician. Topiramate
was initially started at a dose of 50 mg/day and after 1 week
of therapy, increased to 100 mg/day and maintained on the
same dose throughout the study period. The patients were
followed up for 12 weeks.
2.3. Clinical and biochemical assessments
The patients recruited for the study underwent a complete
physical examination including vitals, weight (kg), and Body
Mass Index (BMI) — weight (kg)/height (m2) at baseline. The
patients were evaluated clinically using the Positive and
Negative Syndrome Scale (PANSS) (Kay et al., 1987).
Laboratory investigations included fasting blood glucose
(FBG) (mg%), fasting serum lipids (mg%) (Total Cholesterol
(TC), Triglycerides, Low Density Lipoprotein (LDL), High
Density Lipoprotein (HDL), Very Low Density Lipoprotein
(VLDL) cholesterol). Serum insulin (µIU/ml) and serum leptin
(ng/ml) were also estimated. Insulin resistance (IR) was
assessed using the homeostasis model assessment (HOMA-
IR) originally described by Matthews et al. (1985). The blood
samples were obtained between 8 AM and 10 AM after over-
night fasting. The first estimates were done in the treatment-
free state (baseline) and the last dose was administered 10–
14 h before the blood samples were withdrawn at the end of
the study period (12 weeks).
2.4. Statistical analysis
Statistical analysis was done using SPSS software for
windows. Independent student's t test was used to compare
parameters between the two groups and paired student's t
test was used to compare the values at baseline and at 12 weeks
in each study group. The significance level was set at p b 0.05,
2-tailed. Results are presented as mean ± S.D. Fisher's exact
test was used to compare the adverse effects. A Pearson's
correlation analysis was done to study the association be-
tween the mean change in weight and change in biochemical
parameters in each group.
3. Results
Ninety-eight patients were screened for the study.
Twenty-six patients were excluded due to various reasons:
twelve patients had a current substance abuse diagnosis; five
patients had a significant medical disorder; seven women
of childbearing age were not using adequate contraceptive
measures and two women were pregnant. Seventy-two
patients were randomly assigned to the two groups. How-
ever, 34 patients (10 inpatients, and 24 outpatients) in the
olanzapine group and 33 patients (8 inpatients, and 25
outpatients) in the topiramate group were included in the
analysis. In the olanzapine group, one patient was lost to
follow up and one was non compliant with treatment. In the
topiramate group, two patients were lost to follow up and one
patient withdrew from the study due to personal reasons.
The baseline characteristics were similar in both the groups
(Table 1). The biochemical parameters including FBG,
TC, triglycerides, LDL, HDL, VLDL, insulin, leptin, and IR
(p = 0.186–0.834) were comparable at baseline. There was no
significant difference in the mean modal dose of olanzapine in
220 P.K. Narula et al. / Schizophrenia Research 118 (2010) 218–223

Table 1 In each treatment group, weight changes were correlated

Comparison of baseline characteristics in the two treatment groups.
Topiramate Olanzapine
(n = 33) (n = 34)
Age in years 31.21 ± 9.70 31 ± 10.09
Sex
Male (%) 22 (66.7) 22 (64.7)
Female (%) 11 (33.3) 12 (35.3)
Marital status 17 (51.5) 15 (44.1)
No. married (%)
Positive family 4 (12.12) 3 (8.82)
history (%)
Body weight (kg) 54 ± 12.9 52.82 ± 12.56
Body mass index 20.56 ± 3.85 20.2 ± 3.92
(kg/m2)
the two groups (11.47 ± 0.4 mg/day and 11.52 ±0.41 mg/day
respectively) (p = 0.936).
There was a decrease in weight (within group p = 0.003;
between group p = 0.05) and BMI (within group, p = 0.004;
between group p = 0.017) with topiramate. Olanzapine
resulted in a significant increase in weight and BMI compared
to baseline (p b 0.001) (Table 2).
There was a decrease in the FBG, TC, triglycerides, HDL and
systolic and diastolic blood pressure in the topiramate group
(p N 0.05). Leptin levels showed a decrease within the group
(p b 0.001). There was a marginal increase in the insulin, LDL
and VLDL levels (p N 0.05). FBG, TC, LDL cholesterol and blood
pressure changes were significant between the groups.
Olanzapine resulted in a significant increase in FBG, insulin,
IR, leptin, TC, triglycerides and LDL cholesterol (p b 0.001)
(Table 3).
The patient population was classified as underweight
patients when the BMI was b18.5 kg/m2 and those with
BMI ≥ 18.5 kg/m2 as normal or above normal BMI (WHO,
1995, 2000, 2004). In the olanzapine group, the WG was
greater in underweight patients (n = 11) when compared to
patients with normal or above normal BMI (n = 23) (6.45 ±
4.41 kg vs. 5.83 ± 3.86 kg respectively) (p = 0.674). The
increase in FBG (13.64 ± 9.34 vs. 9.26 ± 7.32), insulin (1.07 ±
0.81 vs. 0.91 ± 1.51), leptin (2.77± 1.23 vs. 2.3 ± 1.98), TC
(30.45 ± 23.18 vs. 19.35 ± 16.47) and LDL cholesterol (13 ±
15.23 vs. 9.35 ±8.89) was also greater in underweight patients
(p N 0.05). In the topiramate group, eleven patients were
underweight and twenty-two patients had normal or above
normal BMI. The change in weight: underweight vs. normal or
above normal BMI: − 1.27 ± 1.74 kg vs.−1.27 ± 2.55 kg,
change in FBG: 1.45 ± 7.15 vs.1.55 ± 4.29, change in leptin:
0.91 ± 0.94 vs. 0.86 ± 1.36, change in insulin: −0.34 ± 1.69 vs.
−0.03± 0.86, change in TC: 4.64 ± 11.2 vs. 0.59± 10.1 respec-
tively were observed in the topiramate group (p N 0.05).
with change in biochemical parameters. Triglyceride levels
p value
correlated significantly: weight change vs. change in triglyc-
eride: topiramate group: r2 = 0.428, p = 0.013; olanzapine
group: r2 = 0.560, p = 0.001. The change in FBG correlated
0.930
with weight in the olanzapine group (r2 = 0.582, p b 0.001),
0.866 but reached only marginal significance in the topiramate
group (r2 = 0.332, p = 0.059). A significant positive correla-
0.544
tion was observed between weight change and change in TC
0.659 in the olanzapine group (r2 = 0.606) (p b 0.001), but not after
topiramate (r2= 0.307, p = 0.083).
0.706 The clinical improvement assessed with PANSS showed
0.709 significant reduction in the symptom scores in both the
groups. The change in the PANSS (total) and general
psychopathology scale scores was significant between the
two groups (p = 0.001; p b 0.001 respectively) (Table 4).
Weight gain was observed in all the patients with
olanzapine in contrast to only 9 patients in the topiramate
group. A greater number of patients complained of increased
appetite and anticholinergic side effects like dry mouth,
constipation in the olanzapine group (Table 5).
4. Discussion
Antipsychotic-induced WG is one of the major causes of
treatment non-compliance and can lead to chronic diseases
like diabetes, hypertension and dyslipidemias worsening
the morbidity among schizophrenia patients. Cardiovascular
effects also lead to an early mortality in schizophrenia
(Newman and Bland, 1991). Prevention of WG in these
patients has become a priority in clinical practice.
In the topiramate group, the mean weight decreased by
1.27 ± 2.28 kg (p = 0.003) at the end of the study. Similar
findings have been reported by Kim et al. (2006) and Ko et al.
(2005) after 12 weeks of topiramate therapy. Topiramate is
known to have both central and peripheral actions. It is
suggested that the weight reduction with topiramate is due to
the stimulation of energy expenditure and loss of fat rather
than lean body mass (Picard et al., 2000; Richard et al., 2000).
Adverse conditions such as nausea, dyspepsia and diarrhea
may also contribute to weight loss. It is also believed that
the ability of topiramate to inhibit carbonic anhydrase (CAs,
EC 4.2.1.1) enzymes involved in several steps of de novo
lipogenesis, both in the mitochondria and the cytosol of the
cells can result in weight loss (Landmark, 2008; Schneiderhan
and Marvin, 2007; Supuran et al., 2008). Tremblay et al.
(2007) suggest that topiramate results in a decrease in
spontaneous energy/macronutrient intake and can induce a
substantial body energy loss. It decreases the body fat stores
and impacts the energy balance creating a deficit with use.
Klein et al. (2008) also conclude that topiramate induces a

Table 2
Comparison of weight and body mass index in the topiramate and olanzapine groups.

Treatment Baseline 12 weeks Within group t test Between group t test

Weight (kg) Topiramate 54 ± 12.9 52.73 ± 12.9 3.2, p = 0.003 1.9, p = 0.05
Olanzapine 52.82 ± 12.6 58.85 ± 13.1 − 8.8, p b 0.001
Body mass index (kg/m2) Topiramate 20.56 ± 3.9 20.1 ± 4 3.1, p = 0.004 2.4, p = 0.017
Olanzapine 20.2 ± 3.9 22.55 ± 4.1 − 8.7, p b 0.001

Topiramate n = 33; olanzapine n = 34.

 P.K. Narula et al. / Schizophrenia Research 118 (2010) 218–223 221

Table 3
Comparison of glucose, insulin, insulin resistance, leptin, lipids and blood pressure in the topiramate and olanzapine groups.

Treatment Baseline 12 weeks Within group t test Between group t test

FBG (mg%) Topiramate 79.76 ± 9.40 78.24 ± 6.7 1.64, p = 0.11 4.3, p b 0.001
Olanzapine 77.79 ± 7.37 88.47 ± 12.0 − 7.6, p b 0.001
Insulin (µIU/ml) Topiramate 12.33 ± 8.5 12.47 ± 7.9 − 0.6, p = 0.512 0.2, p = 0.981
Olanzapine 11.55 ± 7.2 12.51 ± 7.2 − 4.3, p b 0.001
Insulin resistance Topiramate 2.43 ± 1.77 2.53 ± 1.65 − 2.3, p = 0.03 0.6, p = 0.531
Olanzapine 2.25 ± 1.5 2.8 ± 1.8 − 7.5, p b 0.001
Leptin (ng/ml) Topiramate 17.14 ± 8.9 16.26 ± 8.4 4.12, p b 0.001 1.6, p = 0.114
Olanzapine 17.65 ± 11.04 20.1 ± 11.02 − 8.1, p b 0.001
TC (mg%) Topiramate 135.24 ± 30.1 133.3 ± 30.7 1.06, p = 0.296 2.7, p = 0.008
Olanzapine 132.74 ± 30.7 155.7 ± 5.7 − 6.9, p b 0.001
Triglycerides (mg%) Topiramate 96.61 ± 46.2 94.4 ± 45.2 1.59, p = 0.123 1.5, p = 0.127
Olanzapine 87.71 ± 36.1 110.9 ± 42.3 − 6.2, p b 0.001
LDL cholesterol (mg%) Topiramate 66.42 ± 22.8 66.76 ± 20.7 − 0.27, p = 0.79 2.7, p = 0.009
Olanzapine 72.5 ± 21.9 83.03 ± 28.2 − 5.5, p b 0.001
HDL cholesterol (mg%) Topiramate 43.3 ± 6.1 43 ± 9.36 0.27, p = 0.79 − 4.7, p = 0.64
Olanzapine 40.79 ± 8.96 41.97 ± 8.5 −0.76, p = 0.45
VLDL cholesterol (mg%) Topiramate 25.33 ± 8.46 26.3 ± 9.5 − 1.43, p = 0.163 0.54, p = 0.59
Olanzapine 24.56 ± 10.5 27.6 ± 10.5 − 3.4, p = 0.002
Systolic BP (mm Hg) Topiramate 118.79 ± 7.75 117.88 ± 7 1.5, p = 0.158 2.6, p = 0.012
Olanzapine 119.94 ± 7.12 122.5 ± 7.71 − 2.9, p = 0.007
Diastolic BP (mm Hg) Topiramate 78.61 ± 5.7 77.94 ± 4.8 1.1, p = 0.29 2.5, p = 0.014
Olanzapine 80.18 ± 6.29 81.41 ± 6.2 − 1.5, p = 0.137

Topiramate n = 33; olanzapine n = 34.

general reduction in appetite and hunger; resulting in weight
loss. Lévy et al. (2007) reported that topiramate results in
a decrease in BMI by 3.2 kg/m2 in schizophrenia patients
with antipsychotic-induced WG. In our study, the decrease in
mean BMI was significant with 3 months of continued
therapy (0.46 ± 0.85 kg/m2) (p = 0.004).
Consistent with previous studies, olanzapine resulted in
WG (p b 0.001) (Atmaca et al., 2003; Lindenmayer et al.,
2003). The WG with olanzapine is thought to be primarily
related to its high affinity for serotonin 5HT2c and histamine
H1 receptors. Basson et al. (2001) concluded that the
predictive factors for WG with olanzapine were a non white
race (Indian population), a low baseline BMI and a low initial
body weight. This was corroborated in the present study as it
was observed that underweight patients (BMI b 18.5 kg/m2)
had a greater WG of 6.45 ± 4.41 kg compared to 5.83 ±
3.86 kg in patients with normal or above normal BMI
(BMI ≥ 18.5 kg/m2) (WHO, 1995, 2000, 2004). It is known
that the maximum WG with olanzapine occurs during the
initial therapy (Kinon et al., 2001). Our study highlights that
the concurrent administration of topiramate during this
initial period can prevent such increase in weight even in
high-risk patients (Indian population with low baseline BMI).
In the topiramate group, there was a decrease in the FBG, TC,
triglycerides, HDL cholesterol and leptin. A marginal increase in
the insulin levels was also observed (p N 0.05). Interestingly,
these changes were observed at a low dose (100 mg/day) in
contrast to higher doses used in other studies (Astrup et al.,
2004; Ben-Menachem et al., 2003; Bray et al., 2003). The effects
of topiramate on energy homoeostasis and metabolic param-
eters are diverse and could involve either direct action on the
brain or peripheral mechanisms. It has been observed that
topiramate reduces energy gain in animal models (Picard et al.,
2000; Richard et al., 2000; 2002; York et al., 2000). This may
reflect its ability to stimulate lipoprotein lipase in the adipose
tissue and skeletal muscle with a resultant increase in
thermogenesis (Astrup et al., 2004). In addition, topiramate
enhances the expression of uncoupling proteins 2 and 3 in these
tissues. It also inhibits carbonic anhydrase (CAs, EC 4.2.1.1)
enzymes involved in several steps of de novo lipogenesis, both
in the mitochondria and the cytosol of the cells (Landmark,
2008; Schneiderhan and Marvin, 2007, Supuran et al., 2008). It
is also capable of insulin sensitizing effects; directly enhancing
insulin action in the adipose tissue and secondarily in the
skeletal muscle, lowering glucose and insulin levels (Richard
et al., 2000; 2002; Smith et al., 2000).

Table 4
Comparison of Positive and Negative Syndrome Scale (PANSS) scores in the two treatment groups.

Treatment Baseline 12 weeks Within group t test Between group t test

PANSS (total) Topiramate 102.85 ± 17.5 31.21 ± 2.1 23.5, p b 0.001 3.6, p = 0.001
Olanzapine 103.82 ± 12.7 33.32 ± 2.7 32.9, p b 0.001
Positive scale Topiramate 29.82 ± 7.9 7.18 ± 0.6 16.6, p b 0.001 1.8, p = 0.084
Olanzapine 31.21 ± 5.3 7.47 ± 0.8 26.7, p b 0.001
Negative scale Topiramate 25.0 ± 6.9 7.33 ± 0.8 14.4, p b 0.001 1.5, p = 0.145
Olanzapine 22.73 ± 5.6 7.68 ± 1.1 15.4, p b 0.001
General psychopathology scale Topiramate 48.03 ± 8.1 16.7 ± 1.1 22.2, p b 0.001 4.3, p b 0.001
Olanzapine 49.89 ± 7.2 18.18 ± 1.7 26.8, p b 0.001

Topiramate n = 33; olanzapine n = 34.

222 P.K. Narula et al. / Schizophrenia Research 118 (2010) 218–223

Table 5 In the topiramate group, there was a marginal decrease in

Comparison of adverse drug events in the two treatment groups. the mean systolic and diastolic blood pressure. Astrup et al.
Adverse drug event Topiramate Olanzapine
(2004) and Bray et al. (2003) have also reported a decrease
when topiramate was administered for weight loss. The
WG 9 (27.27) 34 (100)***
olanzapine associated increase in the systolic and diastolic
Increased appetite 2 (6.06) 12 (29.41)**
Somnolence 25 (75.76) 21 (61.77) blood pressure could be prevented by adjunctive topiramate.
Insomnia 1 (3.03) 2 (5.88) The adverse effects were mild to moderate in severity
Asthenia 7 (21.21) 8 (23.53) with no serious adverse effects. There was no treatment
Constipation 1 (3.03) 5 (14.71)
withdrawal due to these side effects. All the patients in the
Dry mouth 4 (12.12) 7 (20.59)
Dizziness 3 (9.09) 8 (23.53) olanzapine group experienced increase in weight (transient/
Fatigue 15 (45.46) 11 (32.35) sustained) during the study in contrast to only nine patients
Paresthesia 3 (9.09) 0 in the topiramate group. Paresthesia, a known adverse effect
Nausea/vomiting/diarrhea 3 (9.09) 1 (2.94) of topiramate was observed in only 9% cases in the topiramate
Concentration/attention difficulty/memory 4 (12.12) 0
group (100 mg/day). This decreased with ongoing treatment
difficulty
Psychomotor slowing 4 (12.12) 0 and did not result in any patient to withdraw from the study.
Astrup et al. (2004) observed paresthesia in 46% of their cases
** p value b0.01; *** p value b0.001.
Values represent number of patients (%) with the adverse event. when 96 mg/day topiramate was used. It was significantly
Topiramate n = 33; olanzapine n = 34. higher (73%) with the 192 mg/day dose. Ko et al. (2005) also
reported that paresthesia was observed in greater number of
subjects when higher doses (200 mg/day) were used.
In line with other studies, we observed hyperglycemia, There are several limitations of our study. The study
hyperinsulinemia, increased IR, hyperleptinemia, hypercholes- population included both inpatients and outpatients which
terolemia and hypertriglyceridemia with olanzapine treatment could affect the dietary intake. The patients were not
(p b 0.001) (Atmaca et al., 2003; Graham et al., 2005; Hosojima controlled for exercise schedule or other lifestyle modifica-
et al., 2006; Lindenmayer et al., 2003; Melkersson et al., 2000). tions. Waist measurements were not performed for the study
The increase in the FBG, insulin, leptin, TC and LDL was greater subjects. This could have strengthened the study in estimat-
in underweight patients. Olanzapine treatment results in ing the effects of the treatment on the occurrence/prevention
increased food intake, WG, IR, hyperinsulinemia and hyperlip- of metabolic syndrome. It is known that other hormones/
idemia (Hester and Thrower, 2005; Hosojima et al., 2006; mediators are involved in the energy homeostasis and
Melkersson et al., 2000). Mechanisms postulated to account for metabolism. This limits the ability of our study to elucidate
antipsychotic-induced metabolic disturbances include primary the mechanisms for observed effects of olanzapine and
damage to the pancreatic islet cells and/or sympathetic ner- topiramate. There is a need for further long-term studies to
vous system dysfunction, and a secondary phenomenon related assess the beneficial effects of topiramate on disease
to weight gain and insulin resistance (Newcomer, 2005). pathology and prevention of complications associated with
Melkersson et al. (2000) also reported a correlation between olanzapine treatment.
hyperlipidemia and hyperinsulinemia. Insulin stimulates leptin
production in adipocytes, and IR with hyperinsulinemia has
been associated with increased leptin levels. Kraus et al. (1999) 5. Conclusion
theorize that olanzapine may alter the feedback mechanism in
the central nervous system regulating leptin levels, resulting The present study demonstrates the ability of low dose
in elevated leptin. We believe that adjunctive topiramate topiramate (100 mg/day) to prevent olanzapine associated
could prevent the increase in leptin leading to maintenance of weight gain. It is noteworthy that it can result in weight loss
baseline levels even during olanzapine administration in high- even in high-risk population (Indian subjects; low baseline
risk population. BMI). It also highlights that it can not only prevent the
The clinical symptoms assessed with PANSS showed development of adverse metabolic profile associated with
significant improvement at follow up visits in both the olanzapine (hyperglycemia, hyperinsulinemia, hyperleptine-
groups. Similar decrease in scores have been reported by mia, hypercholesterolemia and hypertriglyceridemia) but
Mousavi et al. (2007), Kim et al. (2006) and Drapalski et al. also result in greater clinical benefit and improvement of
(2001) in schizophrenic patients. Interestingly, there was a disease symptoms in schizophrenia patients.
greater decrease in the general psychopathology scale and
total scores in the topiramate group which could result in Role of funding source
greater clinical benefit for these patients. Tiihonen et al. None.
(2005) also found topiramate to be superior to placebo in
reducing these symptoms which have a greater impact on the
Contributors
patients' well being and quality of life. This superior effect Dr. Preeta Kaur Narula has made substantial contributions to conception
could be explained by AMPA/KA receptor antagonism by and design, acquisition of data, as well as analysis and interpretation of
topiramate which could blunt the hyperdopaminergic results. She also drafted the manuscript.
mechanisms of disease and excitation resulting from disin- Dr. H.S. Rehan oversaw the entire study process, gone over the
manuscript and has given final approval of the version to be published.
hibited release of glutamate. Thus it could help retard the Dr. K.E.S Unni has been involved in the coordination and monitoring of
disease progression attributed to prolonged stimulation of the various clinical aspects of the study and has given final approval for the
AMPA/KA receptors (Deutsch et al., 2001). version to be published.
 P.K. Narula et al. / Schizophrenia Research 118 (2010) 218–223
Dr Neeraj Gupta was involved in conception of the study, clinical
monitoring and statistical support and has given final approval for the
version to be published.
Conflict of interest
None.
Acknowledgements
We would like to thank Dr Rakesh Goyal and Dr. Shilpee Sorcar of the
psychiatry clinic for their support during the study; and Dr. Anita Chakravarti
and Dr. Alpana Saxena for investigative support.
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