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Metabolic syndrome is common in patients of schizophrenia. It can add to morbidity, loss of functionality and discontinuation of antipsychotic medication. Apart from metformin, there are limited treatment options as add on-s to antipsychotics for treatment of metabolic syndrome. There have been placebo-controlled studies of Topiramate as an adjuvant but the present study would be the first head-on trial between these drugs for treatment of metabolic syndrome in patients of schizophrenia.
If the outcome measures show a significant improvement with add on topiramate when compared with Metformin, then add on Topiramate can be a preferred treatment for metabolic syndrome in patients with schizophrenia on atypical antipsychotics. The adverse effects of Metformin can be side-stepped and Topiramate can also be given in conditions which are contraindications for Metformin. Thus, Topiramate can be a good alternative to metformin especially in conditions like liver, cardiac and renal impairment where metformin use should be avoided. Topiramate can not only improve metabolic parameters but can also have a beneficial effect on the symptom severity of schizophrenia. Thus, it can be a good augmentation drug to be used along with antipsychotics in these patients.
Study Design: The proposed study will be a randomised, parallel arm, active controlled, open label, clinical trial.
Study Setting: The proposed study will be conducted at the out-patient (OP) and the in-patient (IP) settings of the Department of Psychiatry, All India Institute of Medical Sciences, Bhubaneswar.
Study Groups: The study population will comprise of 60 patients with schizophrenia (F20 according to ICD 10 DCR) on atypical antipsychotics for more than 3 months diagnosed with metabolic syndrome.
Sample size: Sample size calculation has been done based on the expected difference in the cardiovascular risk scoring (QRISK3), the primary outcome measure of our study. Sample size of 23 per group will achieve a power of 80%, to detect the difference of 5% in cardiovascular risk scoring (QRISK3) between the groups with standard deviation as 6.0 and a level of significance 0.05. Assuming an attrition rate of 25%, 30 patients will be recruited per group.
Details of Control(s): It is an active controlled study where the control group will receive add-on metformin along with the ongoing atypical antipsychotic.
Details of intervention:
The patients who are randomized to Topiramate group will be receiving Topiramate at a stable dose of 50 mg/day during the study period that is for 8 weeks along with the ongoing atypical antipsychotic.
The patients who are randomized to Metformin group will be receiving Metformin at dose of 500 mg/day twice a day, a total of 1000 mg/day for 8 weeks along with the ongoing atypical antipsychotic.
Duration of study: The study will be conducted for a period of 18 months
Investigation specifically related to Protocols:
The following Psychiatric scales will be used:
a) QRISK3 b) Lipid profile c)Fasting serum insulin by ELISA for insulin resistance (HOMA-IR) d)Fasting blood glucose for insulin resistance (HOMA-IR)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin arm | Active Comparator | 1000mg for 8 weeks |
|
| Topiramate arm | Experimental | 50mg for 8 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug | 1000mg for 8 weeks |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in the QRISK3 score. | QRISK3 (QRESEARCH cardiovascular risk algorithm)2018 algorithm- used for calculating the cardiovascular risk in the upcoming 10 years. It is measured for the age group of 25 to 84 years using information like age, weight, height, BMI, Lipid profile, past history of CKD, angina, migraine etc. Higher score indicates higher risk. | 8 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the LDL/HDL ratio(Low density lipoprotein/High density lipoprotein).Higher ratio indicates higher risk | Calculated from the lipid profile | 8 weeks |
| Change in Insulin Resistance (HOMA-IR)(homeostasis model assessment-estimated insulin resistance ). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Biswa Ranjan Mishra, MD, DPM | All India Institute of Medical Sciences, Bhubaneswar | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dept of Psychiatry, Aiims, Bhubaneswar | Bhubaneswar | Odisha | 751019 | India |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17909124 | Background | Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007 Oct;64(10):1123-31. doi: 10.1001/archpsyc.64.10.1123. | |
| 19293950 | Background | DE Hert M, Schreurs V, Vancampfort D, VAN Winkel R. Metabolic syndrome in people with schizophrenia: a review. World Psychiatry. 2009 Feb;8(1):15-22. doi: 10.1002/j.2051-5545.2009.tb00199.x. |
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| ID | Term |
|---|---|
| D024821 | Metabolic Syndrome |
| D012559 | Schizophrenia |
| ID | Term |
|---|---|
| D007333 | Insulin Resistance |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
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Not provided
| ID | Term |
|---|---|
| D008687 | Metformin |
| D000077236 | Topiramate |
| C079516 | Topaz resin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D005632 |
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| Topiramate | Drug | 50mg for 8 weeks |
|
|
Calculated from serum insulin level and fasting glucose level according to the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) |
| 8 weeks |
| Change in Positive and negative syndrome scale | Positive and negative syndrome scale, a scale used to measure the symptom severity in patients of schizophrenia including positive, negative and general psychopathology.Higher scores indicate more severity of illness.Maximum score 30 and maximum 210 | 8 weeks |
| Change in Clinical Global Impression-Schizophrenia scale | Scale that is used to measure the baseline severity, change in severity of illness with treatment and global improvement. More score indicates more impairment. | 8 weeks |
| 20692814 | Background | Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, Kissling W, Davis JM, Leucht S. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010 Nov;123(2-3):225-33. doi: 10.1016/j.schres.2010.07.012. Epub 2010 Aug 7. |
| 26280837 | Background | Zheng W, Li XB, Tang YL, Xiang YQ, Wang CY, de Leon J. Metformin for Weight Gain and Metabolic Abnormalities Associated With Antipsychotic Treatment: Meta-Analysis of Randomized Placebo-Controlled Trials. J Clin Psychopharmacol. 2015 Oct;35(5):499-509. doi: 10.1097/JCP.0000000000000392. |
| 31009043 | Background | Flory J, Lipska K. Metformin in 2019. JAMA. 2019 May 21;321(19):1926-1927. doi: 10.1001/jama.2019.3805. |
| 29557263 | Background | Goh KK, Chen CH, Lu ML. Topiramate mitigates weight gain in antipsychotic-treated patients with schizophrenia: meta-analysis of randomised controlled trials. Int J Psychiatry Clin Pract. 2019 Mar;23(1):14-32. doi: 10.1080/13651501.2018.1449864. Epub 2018 Mar 20. |
| 23694688 | Background | Lawrence D, Hancock KJ, Kisely S. The gap in life expectancy from preventable physical illness in psychiatric patients in Western Australia: retrospective analysis of population based registers. BMJ. 2013 May 21;346:f2539. doi: 10.1136/bmj.f2539. |
| 10553730 | Background | Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999 Nov;156(11):1686-96. doi: 10.1176/ajp.156.11.1686. |
| 21284696 | Background | Praharaj SK, Jana AK, Goyal N, Sinha VK. Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis. Br J Clin Pharmacol. 2011 Mar;71(3):377-82. doi: 10.1111/j.1365-2125.2010.03783.x. |
| 18082302 | Background | Chen CH, Chiu CC, Huang MC, Wu TH, Liu HC, Lu ML. Metformin for metabolic dysregulation in schizophrenic patients treated with olanzapine. Prog Neuropsychopharmacol Biol Psychiatry. 2008 May 15;32(4):925-31. doi: 10.1016/j.pnpbp.2007.11.013. Epub 2007 Nov 17. |
| 27716110 | Background | de Silva VA, Suraweera C, Ratnatunga SS, Dayabandara M, Wanniarachchi N, Hanwella R. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016 Oct 3;16(1):341. doi: 10.1186/s12888-016-1049-5. |
| 20207521 | Background | Narula PK, Rehan HS, Unni KE, Gupta N. Topiramate for prevention of olanzapine associated weight gain and metabolic dysfunction in schizophrenia: a double-blind, placebo-controlled trial. Schizophr Res. 2010 May;118(1-3):218-23. doi: 10.1016/j.schres.2010.02.001. Epub 2010 Mar 7. |
| 17873679 | Background | Egger C, Muehlbacher M, Schatz M, Nickel M. Influence of topiramate on olanzapine-related weight gain in women: an 18-month follow-up observation. J Clin Psychopharmacol. 2007 Oct;27(5):475-8. doi: 10.1097/jcp.0b013e31814b98e5. |
| 20233913 | Background | Ellinger LK, Ipema HJ, Stachnik JM. Efficacy of metformin and topiramate in prevention and treatment of second-generation antipsychotic-induced weight gain. Ann Pharmacother. 2010 Apr;44(4):668-79. doi: 10.1345/aph.1M550. Epub 2010 Mar 16. |
| 33454933 | Background | Ince B, Altinbas K. [Ten-Year Risk of Cardiovascular Disease in Patients with Bipolar Disorder]. Turk Psikiyatri Derg. 2020 Winter;31(4):225-231. doi: 10.5080/u25270. Turkish. |
| 26781921 | Background | Tang Q, Li X, Song P, Xu L. Optimal cut-off values for the homeostasis model assessment of insulin resistance (HOMA-IR) and pre-diabetes screening: Developments in research and prospects for the future. Drug Discov Ther. 2015 Dec;9(6):380-5. doi: 10.5582/ddt.2015.01207. |
| 3616518 | Background | Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76. doi: 10.1093/schbul/13.2.261. |
| D009750 |
| Nutritional and Metabolic Diseases |
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
| Fructose |
| D006601 | Hexoses |
| D009005 | Monosaccharides |
| D000073893 | Sugars |
| D002241 | Carbohydrates |
| D007661 | Ketoses |