Zonisamide for Attenuation of Weight Gain in a Morbidly-Obese Adolescent on an Antipsychotic

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Zonisamide for Attenuation of Weight Gain in a Morbidly-Obese Adolescent on an Antipsychotic
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Nguyen, Mathew L.
Shapiro, Michael A.
Rahmani, Mariam
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Obesity is a growing problem in the child and adolescent population. Particularly concerning is the trend of overweight children being increasingly prescribed antipsychotic medications that can lead to further weight gain. We present a case of a morbidly obese adolescent male who had made strides in weight loss with psychopharmacologic aide who was started on an antipsychotic. Weight loss plateaued, and zonisamide was added to further help with weight loss. We discuss the possible risks and benefits of this medication in aiding in preventing weight gain associated with antipsychotic medication.
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Publication of this article was funded in part by the University of Florida Open- Access Publishing Fund.

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The International Open Access Journal of Obesity & W eight Loss TherapyExecutive EditorsReza Hakkak University of Arkansas for Medical Sciences, USA M Yamaguchi Emory University School of Medicine, USA Ion C. Baianu University of Illinois at Urbana-Champaign, USA U Gruntmanis University of Texas, USA M E. Shomali University of Maryland School of Medicine, USA This article was originally published in a journal by OMICS Publishing Group, and the attached copy is provided by OMICS Publishing Group for the authors benefit and for the benefit of the authors institution, for commercial/research/educational use including without limitation use in instruction at your institution, sending it to specific colleagues that you know, and providing a copy to your institutions administrator. All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institutions website or repository, are requested to cite properly.Available online at: OMICS Publishing Group ( www .omicsonline.org ) ISSN: 2165-7904Journal of Obesity & Weight Loss Ther apy

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Obesity & Weight Loss Therapy Nguyen et al., J Obes Wt Loss Ther 2012, 2:4 http://dx.doi.org/10.4172/2165-7904.1000134 J Obes Wt Loss Ther Open Access Case Report Mathew L. Nguyen1, Michael A. Shapiro2* and Mariam Rahmani21Assistant Professor, Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Florida, PO Box 100234, Gainesville, FL 32610, USA2Department of Psychiatry, University of Florida, PO Box 100234, Gainesville, FL 32610, USA *Corresponding author: Michael A. Shapiro, MD, Department of Psychiatry, University of Florida, PO Box 100234, Gainesville, FL 32610, USA, Tel: 352-8706234; Fax: 352-265-7053; E-mail: Received May 14, 2012; Accepted May 24, 2012; Published May 28, 2012 Citation: Nguyen ML, Shapiro MA, Rahmani M (2012) Zonisamide for Attenuation of Weight Gain in a Morbidly-Obese Adolescent on an Antipsychotic. J Obes Wt Loss Ther 2:134. doi:10.4172/2165-7904.100013 4 Copyright: 2012 Nguyen ML, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Keywords: Zonisamide; Adolescent; Obesity; AntipsychoticIntroductionIn recent years there has been an increase in the number of antipsychotics prescribed to children and adolescents [1]. Associated with this, there has also been much discussion about metabolic syndrome and its connection with this medication class, especially in this population. In the adult population, metabolic syndrome is dened by the following parameters: abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance, and prothrombotic and proinammatory states [2]. In children, the parameters for dening metabolic syndrome have been more widely debated. e International Diabetes Federation recently published its guideline criteria [3]: 1. For children ages 6 9 years old, obesity is dened as > 90 th percentile of waist circumference. 2. For children and adolescents ages 10 16 years old, obesity is dened as waist circumference > 90th percentile, followed by adult criteria for triglycerides, high-density lipoprotein cholesterol (HDL-C), blood pressure, and glucose. Among other factors, insulin resistance is thought to play a central role in the pathogenesis of metabolic syndrome, though beyond the scope of this article, insulin resistance can lead to increased cardiovascular risks aecting morbidity and mortality rates [3]. A more easily measured parameter is obesity (mean body mass index [BMI] > 33.4 kg/m2), which has been strongly associated with insulin resistance. One report indicates that the worldwide prevalence of childhood obesity has increased from 4.2% in 1990 to 6.7% in 2010 [4], with another study indicating that the rates in the United States have tripled in the last 25 years [5]. In addition to insulin resistance, childhood obesity has been associated with elevated blood pressure, elevated triglycerides, low HDL-C, and abnormal glucose metabolism [3]. A major player in the increasing trends of weight gain and obesity in children and adolescents is the use of antipsychotic medications for a wider variety of mental illnesses in this population. As the rates of childhood obesity have increased, so have the rates of antipsychotic prescribing in the child and adolescent population. One study looking at the Texas medicaid population of children and adolescents between 1996 to 2000 showed that, during that 5-year time interval, an additional 12 .25 children and adolescents per 1000 enrollees were prescribed antipsychotics (+160%), and the prevalence of atypical antipsychotics increased by 13.29 per 1000 enrollees (+494%) during that same time period [5]. More recent associations between long-term use of antipsychotics and metabolic abnormalities in children and adolescents have begun to become clearer. Calarge et al. [6] looked at the eects of long-term risperidone in medically healthy children ages 7 to 17. Compared to lean children, overweight and obese children had higher odds of metabolic abnormalities, including increased waist circumference, hypertriglyceridemia, and low, high-density lipoprotein cholesterol (HDL-C) [6]. ere is an area for debate whether some or many of these children need to be on long-term antipsychotic medications; however, for those that require antipsychotic treatment, the adverse eects of weight gain and its potential sequelae need to be addressed. In this case, we report on a morbidly obese adolescent who carries the diagnosis of Mood Disorder, Not Otherwise Specied (NOS) and Disruptive Behavior Disorder, NOS. Case Report Johnny, a 14 year-old Caucasian male weighing 301 kg, was admitted to the Pediatrics Hospital to evaluate for pseudotumor cerebri. His home medication of uoxetine 20 mg prescribed for depression was continued. Child and Adolescent Psychiatry were consulted to help with management of depression and morbid obesity. On day 2 of the hospitalization, we added topiramate for appetite suppression and eventually titrated it to 100 mg qAM and 300 mg qhs by day 50. We also began methylphenidate for appetite suppression, which was ultimately changed and increased to Concerta 54 mg qAM by day 51. Johnny had a previous psychiatric history of mood lability AbstractObesity is a growing problem in the child and adolescent population. Particularly concerning is the trend of overweight children being increasingly prescribed antipsychotic medications that can lead to further weight gain. We present a case of a morbidly obese adolescent male who had made strides in weight loss with psychopharmacologic aide who was started on an antipsychotic. Weight loss plateaued, and zonisamide was added to further help with with antipsychotic medication.

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Citation: Nguyen ML, Shapiro MA, Rahmani M (2012) Zonisamide for Attenuation of Weight Gain in a Morbidly-Obese Adolescent on an Antipsychotic. J Obes Wt Loss Ther 2:134. doi:10.4172/2165-7904.1000134 Page 2 of 3 J Obes Wt Loss Ther and irritability, so the decision to not increase Concerta to 72 mg was made so as to minimize the potential for stimulant-induced agitation. Over the course of 3 months during the hospitalization, Johnnys weight decreased to 213.4 kg. On day 61, aripiprazole 5 mg BID was added to the regimen to address ongoing and worsening mood lability, irritability, and physical agitation with periods of physical aggression. ere were periods during which Johnny would yell and tantrum. Other times, he would hit the nurses hand, causing medication to spill. On rarer occasions, he would barricade himself in his room, not allowing sta to enter. Aripiprazole was added because there is some evidence that antipsychotics are helpful with these behaviors, especially with regard to physical agitation and aggression [7]. Aripiprazole was chosen as it is thought of as one of the more weight-neutral of the SecondGeneration Antipsychotics (SGAs) [8]. Over the course of the next month, Johnnys weight plateaued around 210 kg. He had lost in excess of 80 kgs during the rst three months of hospitalization, and the plateau was partially attributed to the addition of the SGA. With his history of aggression and current symptoms, the decision was made to continue the aripiprazole despite its potential negative eect on ongoing weight loss. On day 90, aer about one month of no further weight loss, zonisamide 50 mg was added with the hopes that it might facilitate further weight loss. Zonisamide was eventually increased to 100 mg. We titrated the zonisamide up slowly, monitoring for the potential for Anti-Epileptic Drug (AED)-induced agitation [9]. e previously noted episodes of agitation and physical aggression had been signicantly tempered with the addition of aripiprazole. Johnny was in the hospital only for another full month aer the dose was increased to 100 mg, and he saw his weight decrease to 202.76 kg at the time of discharge. DiscussionMore literature regarding the connection between secondgeneration antipsychotics and obesity and other components of metabolic syndrome (particularly glucose and lipid metabolism) is emerging. One study showed that, in children and adolescents ages 4 19 that were treated with SGAs, within the rst three months of treatment, the majority showed signicant weight gain (> 7% of baseline weight): 58% with aripiprazole, 64% with risperidone, 56% with quetiapine, and 84% with olanzapine [10]. Khan reviewed the eects of olanzapine and risperidone on patients (mean age of 13) over a 27-day duration. ey showed that the study group had a signicant increase in Body Mass Index (BMI) for both medications with mean increases in weight being 9.1 lbs and 7.4 lbs, respectively [11]. ough the amount of weight gained varies with each SGA and may be person-specic, it is becoming clearer that weight gain in children and adolescents on SGAs is the trend and not the exception. Eorts to use medications in combination with SGAs to attenuate or ameliorate weight gain have produced modest results at best. Maayan reviewed data on the eectiveness of 15 dierent medications, looking primarily at their eect on body weight and BMI in adult patients. Results were most robust for metformin, but they were modest and heterogeneous. is analysis did include popular weight loss medications such as topiramate and psychostimulants, which had less of an impact. None of the agents were able to entirely reverse weight gain from antipsychotics [12]. is study did not include zonisamide. Wellmer et al. did a retrospective chart review analyzing weight changes aer beginning zonisamide. Patients ages were 17-68. Aer about 13 months of treatment, 35% of patient showed > 5% weight loss, and weight loss was more prominent in patients who were overweight prior to beginning treatment. e weight loss was reversible aer discontinuation of zonisamide [13]. is analysis demonstrated the usefulness of zonisamide for weight loss in patients but did not specically consider patients whose weight gain had been a consequence of SGA use. In another study, Yang cited three cases of patients with Schizophrenia, ages 28, 31, and 48, each of whom carried the diagnosis of Schizophrenia and treated with multiple antipsychotic medications (both rst and second generation). Zonisamide was started at 50 mg daily and titrated up to either 150 mg or 200 mg daily over a period of 16 weeks. Each patient showed a decrease in BMI and waist circumference [14]. A further review of the literature yielded no articles, either anecdotal or evidence-based that commented on the eects of zonisamide augmentation on the parameters of metabolic syndrome. Zonisamide is an antiseizure medication approved as adjunctive treatment for partial seizures in adults [9]. It currently does not have an indication in children or adolescents, though there have been some studies touting its eectiveness in this population [15]. ere are also some reports of oligohydrosis and fever in pediatric patients, leading to hospitalization, though these cases are rare and listed at 13 cases per 10,000 pediatric-years of exposure [16]. e actual mechanism of action for weight attenuation with zonisamide is still unclear. Wallingford attempted to look at this question in looking at the concomitant use of zonisamide with olanzapine, measuring the eects on body weight and feeding behaviors in the Sprague-Dawley rat. ey concluded that while olanzapine induced hyperphagia, weight gain, and elevated blood glucose, these outcomes were attenuated and reversed with the concomitant use of zonisamide [17]. For our case, we have a morbidly obese adolescent male who had remarkable weight loss during his rst 3 months of hospitalization, going from 301 kg to 213.4 kg. is loss of 87.6 kg could be attributed to many factors, including the addition of appetite suppressing medications (topiramate and methylphenidate) as well as a structured environment and monitored nutritional intake, among other factors. We started with Topiramate and Methylphenidate as they have more data associated with weight loss [12]. Aripiprazole was added to help control episodes of agitation when Johnny would occasionally barricade himself in his room; it was not felt this agitation was due to medication eects. With the addition of the SGA, Johnnys weight loss appeared to plateau. We cannot with certainty make this connection, and the timing of the weight plateau and the addition of the SGA may have been coincidental; however, a review of the chart shows no other major changes that could have explained the halt in weight loss. e addition of zonisamide seemed to promote further weight loss over the course of the subsequent month, with a nal discharge weight of 202.76 kg. We do not know if his weight loss continued aer discharge or if it would have continued had he been in the hospital longer. More research regarding the use of zonisamide as either a single or adjunct agent for weight loss is needed, especially in light of the escalating rates of childhood obesity and antipsychotic prescribing. It should be noted that the zonisamide package insert warns of three potential neuropsychiatric side eects: ) psychiatric symptoms, including depression and psychosis, 2) psychomotor slowing, diculty with concentration, and speech or language problems, in particular,

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Citation: Nguyen ML, Shapiro MA, Rahmani M (2012) Zonisamide for Attenuation of Weight Gain in a Morbidly-Obese Adolescent on an Antipsychotic. J Obes Wt Loss Ther 2:134. doi:10.4172/2165-7904.1000134 Page 3 of 3 J Obes Wt Loss Ther word-nding diculties, and 3) somnolence or fatigue. In placebocontrolled trials, 2.2% of patients discontinued Zonegran or were hospitalized for depression compared to 0.4% of placebo patients, while 1.1% of Zonegran and 0.4% of placebo patients attempted suicide [9]. is is particularly important in the child and adolescent population, especially given the FDA warning on Anti-Epileptic Drugs (AED) in patients aged 24 and younger [18]. Johnny did not experience any worsening aggression or agitation with the addition of the zonisamide.FundingPublication of this article was funded in part by the University of Florida OpenAccess Publishing Fund.References 1. Patel NC, Sanchez RJ, Johnsrud MT, Crismon ML (2002) Trends in antipsychotic use in a Texas population of children and adolescents: 1996 to 2000. J Child Adolesc Psychopharmacol 12: 221-229. 2. (2002) Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report, National Institutes of Health 02-5215. 3. Steinberger J, Daniels SR, Eckel RH, Hayman L, Lustiq RH, et al. (2009) Progress and challenges in metabolic syndrome in children and adolescents: Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation 119: 628647. 4. de Onis M, Blssner M, Borghi E (2010) Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr 92: 12571264. 5. Skelton JA, Cook SR, Auinger P, Klein JD, Barlow SE (2009) Prevalence and trends of severe obesity among US children and adolescents. Acad Pediatr 9: 322-329. 6. Calarge CA, Acion L, Kuperman S, Tansey M, Schlechte JA (2009) Weight gain and metabolic abnormalities during extended risperidone treatment in children and adolescents. J Child Adolesc Psychopharmacol 19: 101-109. Submit your next manuscript and get advantages of OMICS Group submissionsUnique features: User friendly/feasible website-translation of your paper to 50 worlds leading languages Audio Version of published paper Digital articles to share and explore Special features: 200 Open Access Journals 15,000 editorial team 21 days rapid review process Quality and quick editorial, review and publication processing Indexing at PubMed (partial), Scopus, DOAJ, EBSCO, Index Copernicus and Google Scholar etc Sharing Option: Social Networking Enabled Better discount for your subsequent articles Submit your manuscript at: http://www.omicsonline.org/submission 7. Schur SB, Sikich L, Findling RL, Malone RP, Crismon ML, et al. (2003) Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part 1: a review. J Am Acad Child Adolesc Psychiatry 42: 132-144. 8. Fraguas D, Correll CU, Merchn-Naranjo J, Rapado-Castro M, Parellada M, et and adolescents with psychotic and bipolar spectrum disorders: Comprehensive review of prospective head-to-head and placebo-controlled comparisons. Eur Neuropsychopharmacol 21: 621-645. 9. Angus A Wilfong, L James Willmore (2006) Zonisamide a review of experience and use in partial seizures. Neuropsychiatr Dis Treat 2: 269. 10. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, et al. (2009) Cardiometabolic risk of second-generation antipsychotic medications during 11. Khan RA, Mican LM, Suehs BT (2009) Effects of olanzapine and risperidone on metabolic factors in children and adolescents: A retrospective evaluation. J Psychiatr Pract15: 320-328. 12. Maayan L, Vakhrusheva J, Correll CU (2010) Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis. Neuropsychopharmacology 35: 15201530. 13. Wellmer J, Wellmer S, Bauer J (2009) The impact of zonisamide on weight. A clinical study in 103 patients with epilepsy. Acta Neurol Scand 119: 233-238. 14. Yang J, Lee MS, Joe SH, Jung IK, Kim SH (2010) Zonisamide-induced weight loss in schizophrenia: case series. Clin Neuropharmacol 33: 104-106. 15. Shinnar S, Pellock JM, Conry JA (2009) Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy. Eur J Paediatr Neurol 13: 3-9. 16. Knudsen JF, Thambi LR, Kapcala LP, Racoosin JA (2003) Oligohydrosis and fever in pediatric patients treated with zonisamide. Pediatr Neurol 28: 184-189. 17. Wallingford NM, Sinnayah P, Bymaster FP, Gadde KM, Krishnan RK, et al. (2008) Zonisamide prevents olanzapine-associated hyperphagia, weight gain, and elevated blood glucose in rats. Neuropsychopharmacology 33: 2922-2933. 18. (2009) Suicidal behavior and ideation and antiepileptic drugs. US Department of Health and Human Services FDA.