Topiramate for prevention of olanzapine associated weight gain and metabolic dysfunction in schizophrenia: A double-blind, placebo-controlled trial

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 b

Department of Pharmacology, Lady Hardinge Medical College and Associated S.S.K. Hospitals, New Delhi, India 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

Article history: Received 24 May 2009 Received in revised form 29 January 2010 Accepted 1 February 2010 Available online 7 March 2010 Keywords: Schizophrenia Olanzapine Topiramate Weight Metabolic syndrome Leptin

a b s t r a c t Background: Olanzapine associated weight gain (WG) is a major concern in patients with schizophrenia. The purpose of this study was to assess the efficacy of topiramate to prevent olanzapine induced WG in these cases. We also studied various metabolic parameters. Methods: In this 12-week, double-blind, parallel group study, seventy-two drug-naïve, firstepisode schizophrenia patients were randomized to receive olanzapine + placebo (olanzapine group) or olanzapine + topiramate (100 mg/day) (topiramate group). Weight, body mass index, fasting glucose, insulin, insulin resistance (IR), leptin, lipids and blood pressure were assessed at baseline and at 12 weeks. The patients were clinically evaluated using Positive and Negative Syndrome Scale (PANSS) and were monitored for adverse effects. Results: Topiramate resulted in a weight loss of 1.27 ± 2.28 kg (p b 0.01), decrease in leptin (p b 0.001), glucose, cholesterol, triglyceride levels and systolic and diastolic blood pressure. In 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 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 medication 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: [email protected] (P.K. Narula). 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.02.001

a long duration of successful treatment, and low rates of hospitalizations 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 metabolic 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;

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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.

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' psychopathology, 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 confounding effects of prior antipsychotic therapy. We have also monitored patients for clinical improvement and adverse effects.

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 (HOMAIR) originally described by Matthews et al. (1985). The blood samples were obtained between 8 AM and 10 AM after overnight fasting. The first estimates were done in the treatmentfree 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. Materials and methods

2.4. Statistical analysis

2.1. Subjects

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 between the mean change in weight and change in biochemical parameters in each group.

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 12week 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

2.3. Clinical and biochemical assessments

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. However, 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

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Table 1 Comparison of baseline characteristics in the two treatment groups.

Age in years Sex Male (%) Female (%) Marital status No. married (%) Positive family history (%) Body weight (kg) Body mass index (kg/m2)

Topiramate (n = 33)

Olanzapine (n = 34)

p value

31.21 ± 9.70

31 ± 10.09

0.930

22 (66.7) 11 (33.3) 17 (51.5)

22 (64.7) 12 (35.3) 15 (44.1)

0.866 0.544

4 (12.12)

3 (8.82)

0.659

54 ± 12.9 20.56 ± 3.85

52.82 ± 12.56 20.2 ± 3.92

0.706 0.709

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 respectively were observed in the topiramate group (p N 0.05).

In each treatment group, weight changes were correlated with change in biochemical parameters. Triglyceride levels correlated significantly: weight change vs. change in triglyceride: topiramate group: r2 = 0.428, p = 0.013; olanzapine group: r2 = 0.560, p = 0.001. The change in FBG correlated with weight in the olanzapine group (r2 = 0.582, p b 0.001), but reached only marginal significance in the topiramate group (r2 = 0.332, p = 0.059). A significant positive correlation was observed between weight change and change in TC in the olanzapine group (r2 = 0.606) (p b 0.001), but not after topiramate (r2= 0.307, p = 0.083). The clinical improvement assessed with PANSS showed 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.

Weight (kg) Body mass index (kg/m2)

Treatment

Baseline

12 weeks

Within group t test

Between group t test

Topiramate Olanzapine Topiramate Olanzapine

54 ± 12.9 52.82 ± 12.6 20.56 ± 3.9 20.2 ± 3.9

52.73 ± 12.9 58.85 ± 13.1 20.1 ± 4 22.55 ± 4.1

3.2, − 8.8, 3.1, − 8.7,

1.9, p = 0.05

Topiramate n = 33; olanzapine n = 34.

p = 0.003 p b 0.001 p = 0.004 p b 0.001

2.4, p = 0.017

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

FBG (mg%) Insulin (µIU/ml) Insulin resistance Leptin (ng/ml) TC (mg%) Triglycerides (mg%) LDL cholesterol (mg%) HDL cholesterol (mg%) VLDL cholesterol (mg%) Systolic BP (mm Hg) Diastolic BP (mm Hg)

Treatment

Baseline

12 weeks

Within group t test

Between group t test

Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine

79.76 ± 9.40 77.79 ± 7.37 12.33 ± 8.5 11.55 ± 7.2 2.43 ± 1.77 2.25 ± 1.5 17.14 ± 8.9 17.65 ± 11.04 135.24 ± 30.1 132.74 ± 30.7 96.61 ± 46.2 87.71 ± 36.1 66.42 ± 22.8 72.5 ± 21.9 43.3 ± 6.1 40.79 ± 8.96 25.33 ± 8.46 24.56 ± 10.5 118.79 ± 7.75 119.94 ± 7.12 78.61 ± 5.7 80.18 ± 6.29

78.24 ± 6.7 88.47 ± 12.0 12.47 ± 7.9 12.51 ± 7.2 2.53 ± 1.65 2.8 ± 1.8 16.26 ± 8.4 20.1 ± 11.02 133.3 ± 30.7 155.7 ± 5.7 94.4 ± 45.2 110.9 ± 42.3 66.76 ± 20.7 83.03 ± 28.2 43 ± 9.36 41.97 ± 8.5 26.3 ± 9.5 27.6 ± 10.5 117.88 ± 7 122.5 ± 7.71 77.94 ± 4.8 81.41 ± 6.2

1.64, p = 0.11 − 7.6, p b 0.001 − 0.6, p = 0.512 − 4.3, p b 0.001 − 2.3, p = 0.03 − 7.5, p b 0.001 4.12, p b 0.001 − 8.1, p b 0.001 1.06, p = 0.296 − 6.9, p b 0.001 1.59, p = 0.123 − 6.2, p b 0.001 − 0.27, p = 0.79 − 5.5, p b 0.001 0.27, p = 0.79 −0.76, p = 0.45 − 1.43, p = 0.163 − 3.4, p = 0.002 1.5, p = 0.158 − 2.9, p = 0.007 1.1, p = 0.29 − 1.5, p = 0.137

4.3, p b 0.001 0.2, p = 0.981 0.6, p = 0.531 1.6, p = 0.114 2.7, p = 0.008 1.5, p = 0.127 2.7, p = 0.009 − 4.7, p = 0.64 0.54, p = 0.59 2.6, p = 0.012 2.5, p = 0.014

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 parameters 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.

PANSS (total) Positive scale Negative scale General psychopathology scale Topiramate n = 33; olanzapine n = 34.

Treatment

Baseline

12 weeks

Within group t test

Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine Topiramate Olanzapine

102.85 ± 17.5 103.82 ± 12.7 29.82 ± 7.9 31.21 ± 5.3 25.0 ± 6.9 22.73 ± 5.6 48.03 ± 8.1 49.89 ± 7.2

31.21 ± 2.1 33.32 ± 2.7 7.18 ± 0.6 7.47 ± 0.8 7.33 ± 0.8 7.68 ± 1.1 16.7 ± 1.1 18.18 ± 1.7

23.5, 32.9, 16.6, 26.7, 14.4, 15.4, 22.2, 26.8,

p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001

Between group t test 3.6, p = 0.001 1.8, p = 0.084 1.5, p = 0.145 4.3, p b 0.001

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Table 5 Comparison of adverse drug events in the two treatment groups. Adverse drug event

Topiramate

Olanzapine

WG Increased appetite Somnolence Insomnia Asthenia Constipation Dry mouth Dizziness Fatigue Paresthesia Nausea/vomiting/diarrhea Concentration/attention difficulty/memory difficulty Psychomotor slowing

9 (27.27) 2 (6.06) 25 (75.76) 1 (3.03) 7 (21.21) 1 (3.03) 4 (12.12) 3 (9.09) 15 (45.46) 3 (9.09) 3 (9.09) 4 (12.12)

34 (100)*** 12 (29.41)** 21 (61.77) 2 (5.88) 8 (23.53) 5 (14.71) 7 (20.59) 8 (23.53) 11 (32.35) 0 1 (2.94) 0

4 (12.12)

0

** p value b0.01; *** p value b0.001. Values represent number of patients (%) with the adverse event. Topiramate n = 33; olanzapine n = 34.

In line with other studies, we observed hyperglycemia, hyperinsulinemia, increased IR, hyperleptinemia, hypercholesterolemia and hypertriglyceridemia with olanzapine treatment (p b 0.001) (Atmaca et al., 2003; Graham et al., 2005; Hosojima et al., 2006; Lindenmayer et al., 2003; Melkersson et al., 2000). The increase in the FBG, insulin, leptin, TC and LDL was greater in underweight patients. Olanzapine treatment results in increased food intake, WG, IR, hyperinsulinemia and hyperlipidemia (Hester and Thrower, 2005; Hosojima et al., 2006; Melkersson et al., 2000). Mechanisms postulated to account for antipsychotic-induced metabolic disturbances include primary damage to the pancreatic islet cells and/or sympathetic nervous system dysfunction, and a secondary phenomenon related to weight gain and insulin resistance (Newcomer, 2005). Melkersson et al. (2000) also reported a correlation between hyperlipidemia and hyperinsulinemia. Insulin stimulates leptin production in adipocytes, and IR with hyperinsulinemia has been associated with increased leptin levels. Kraus et al. (1999) theorize that olanzapine may alter the feedback mechanism in the central nervous system regulating leptin levels, resulting in elevated leptin. We believe that adjunctive topiramate could prevent the increase in leptin leading to maintenance of baseline levels even during olanzapine administration in highrisk population. The clinical symptoms assessed with PANSS showed significant improvement at follow up visits in both the groups. Similar decrease in scores have been reported by Mousavi et al. (2007), Kim et al. (2006) and Drapalski et al. (2001) in schizophrenic patients. Interestingly, there was a greater decrease in the general psychopathology scale and total scores in the topiramate group which could result in greater clinical benefit for these patients. Tiihonen et al. (2005) also found topiramate to be superior to placebo in reducing these symptoms which have a greater impact on the patients' well being and quality of life. This superior effect could be explained by AMPA/KA receptor antagonism by topiramate which could blunt the hyperdopaminergic mechanisms of disease and excitation resulting from disinhibited release of glutamate. Thus it could help retard the disease progression attributed to prolonged stimulation of AMPA/KA receptors (Deutsch et al., 2001).

In the topiramate group, there was a marginal decrease in the mean systolic and diastolic blood pressure. Astrup et al. (2004) and Bray et al. (2003) have also reported a decrease when topiramate was administered for weight loss. The olanzapine associated increase in the systolic and diastolic blood pressure could be prevented by adjunctive topiramate. The adverse effects were mild to moderate in severity with no serious adverse effects. There was no treatment withdrawal due to these side effects. All the patients in the olanzapine group experienced increase in weight (transient/ sustained) during the study in contrast to only nine patients in the topiramate group. Paresthesia, a known adverse effect of topiramate was observed in only 9% cases in the topiramate group (100 mg/day). This decreased with ongoing treatment and did not result in any patient to withdraw from the study. Astrup et al. (2004) observed paresthesia in 46% of their cases when 96 mg/day topiramate was used. It was significantly 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. There are several limitations of our study. The study population included both inpatients and outpatients which could affect the dietary intake. The patients were not controlled for exercise schedule or other lifestyle modifications. Waist measurements were not performed for the study subjects. This could have strengthened the study in estimating the effects of the treatment on the occurrence/prevention of metabolic syndrome. It is known that other hormones/ mediators are involved in the energy homeostasis and metabolism. This limits the ability of our study to elucidate the mechanisms for observed effects of olanzapine and topiramate. There is a need for further long-term studies to assess the beneficial effects of topiramate on disease pathology and prevention of complications associated with olanzapine treatment. 5. Conclusion The present study demonstrates the ability of low dose topiramate (100 mg/day) to prevent olanzapine associated weight gain. It is noteworthy that it can result in weight loss even in high-risk population (Indian subjects; low baseline BMI). It also highlights that it can not only prevent the development of adverse metabolic profile associated with olanzapine (hyperglycemia, hyperinsulinemia, hyperleptinemia, hypercholesterolemia and hypertriglyceridemia) but also result in greater clinical benefit and improvement of disease symptoms in schizophrenia patients. Role of funding source None.

Contributors Dr. Preeta Kaur Narula has made substantial contributions to conception and design, acquisition of data, as well as analysis and interpretation of results. She also drafted the manuscript. Dr. H.S. Rehan oversaw the entire study process, gone over the manuscript and has given final approval of the version to be published. Dr. K.E.S Unni has been involved in the coordination and monitoring of the various clinical aspects of the study and has given final approval for the 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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