Skip to main content

Weight-Reducing Side Effects of the Antiepileptic Agents Topiramate and Zonisamide

Part of the Handbook of Experimental Pharmacology book series (HEP,volume 209)

Abstract

Drug-induced weight alteration can be a serious side effect that applies to several therapeutic agents and must be referred to in the respective approved labeling texts. The side effect may become health threatening in case of significant weight change in either direction. Several antiepileptic drugs (AEDs) are associated with weight gain such as gabapentin, pregabalin, valproic acid, and vigabatrin and to some extent carbamazepine. Others are weight neutral such as lamotrigine, levetiracetam, and phenytoin or associated with slight weight loss as, e.g., felbamate. The focus of this chapter is on the two AEDs causing strong weight loss: topiramate and zonisamide. For both drugs, several molecular mechanisms of actions are published. We provide a review of these potential mechanisms, some of which are based on in vivo studies in animal models for obesity, and of clinical studies exploring these two drugs as single entities or in combinations with other agents.

Keywords

  • AED
  • AMPA
  • Animal models
  • Anticonvulsant
  • Antiepileptic
  • Binge eating
  • Bupropion
  • Carbonic anhydrase
  • Clinical studies
  • Clozapine
  • Drug combinations
  • Drug induced
  • Empatic®
  • GABA
  • Ion channels
  • Mechanism of action
  • Molecular mechanism
  • Olanzapine
  • Phentermine
  • Potassium channel
  • QNEXA®
  • Side effect
  • Sodium channel
  • Topamax®
  • Topiramate
  • Weight gain
  • Weight loss
  • Weight modification
  • Weight reducing
  • Zonegran®
  • Zonisamide

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-642-24716-3_20
  • Chapter length: 34 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   299.00
Price excludes VAT (USA)
  • ISBN: 978-3-642-24716-3
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   379.99
Price excludes VAT (USA)
Hardcover Book
USD   449.99
Price excludes VAT (USA)
Fig. 1

References

  • Angehagen M, Ben-Menachem E, Rönnbäck L, Hansson E (2003a) Topiramate protects against glutamate- and kainate-induced neurotoxicity in primary neuronal-astroglial cultures. Epilepsy Res 54(1):63–71

    PubMed  CAS  CrossRef  Google Scholar 

  • Angehagen M, Ben-Menachem E, Rönnbäck L, Hansson E (2003b) Novel mechanisms of action of three antiepileptic drugs, vigabatrin, tiagabine, and topiramate. Neurochem Res 28(2):333–340

    PubMed  CAS  CrossRef  Google Scholar 

  • Angehagen M, Ben-Menachem E, Shank R, Rönnbäck L, Hansson E (2004) Topiramate modulation of kainate-induced calcium currents is inversely related to channel phosphorylation level. J Neurochem 88(2):320–325

    PubMed  CrossRef  CAS  Google Scholar 

  • Angehagen M, Rönnbäck L, Hansson E, Ben-Menachem E (2005) Topiramate reduces AMPA-induced Ca(2+) transients and inhibits GluR1 subunit phosphorylation in astrocytes from primary cultures. J Neurochem 94(4):1124–1130

    PubMed  CrossRef  CAS  Google Scholar 

  • Antel J, Weber A, Sotriffer CA, Klebe G (2004) Multiple binding modes observed in X-ray structures of carbonic anhydrase-inhibitor complexes and other systems: consequences for structure-based drug design. In: Supuran CT, Scozzafava A, Conway J (eds) Carbonic anhydrase: its inhibitors and activators, CRC enzyme inhibitors series. CRC Press, Boca Raton

    Google Scholar 

  • Antel J, Gregory PC, Nordheim U (2006) CB1 cannabinoid receptor antagonists for treatment of obesity and prevention of comorbid metabolic disorders. J Med Chem 49(14):4008–4016

    PubMed  CAS  CrossRef  Google Scholar 

  • Arbaizar B, Gómez-Acebo I, Llorca J (2008) Efficacy of topiramate in bulimia nervosa and binge-eating disorder: a systematic review. Gen Hosp Psychiatry 30(5):471–475

    PubMed  CrossRef  Google Scholar 

  • Aribi AM, Stringer JL (2002) Effects of antiepileptic drugs on extracellular pH regulation in the hippocampal CA1 region in vivo. Epilepsy Res 49:143–151

    PubMed  CAS  CrossRef  Google Scholar 

  • Astrup A, Toubro S (2004) Topiramate: a new potential pharmacological treatment for obesity. Obes Res 12(Suppl):167S–173S

    PubMed  CAS  CrossRef  Google Scholar 

  • Atli A, Dogra S (2005) Zonisamide in the treatment of painful diabetic neuropathy: a randomized, double-blind, placebo-controlled pilot study. Pain Med 6:225–234

    PubMed  CrossRef  Google Scholar 

  • Baptista T, ElFakih Y, Uzcátegui E, Sandia I, Tálamo E, Araujo de Baptista E, Beaulieu S (2008) Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs 22(6):477–495

    PubMed  CAS  CrossRef  Google Scholar 

  • Bays H (2010) Phentermine, topiramate and their combination for the treatment of adiposopathy (‘sick fat’) and metabolic disease. Expert Rev Cardiovasc Ther 8(12):1777–1801

    PubMed  CAS  CrossRef  Google Scholar 

  • Ben-Menachem E (2007) Weight issues for people with epilepsy–a review. Epilepsia 48(Suppl 9):42–45

    PubMed  CrossRef  Google Scholar 

  • Ben-Menachem E, Axelsen M, Johanson EH, Stagge A, Smith U (2003) Predictors of weight loss in adults with topiramate-treated epilepsy. Obes Res 11(4):556–562

    PubMed  CAS  CrossRef  Google Scholar 

  • Berghöfer A, Pischon T, Reinhold T, Apovian CM, Sharma AM, Willich SN (2008) Obesity prevalence from a European perspective: a systematic review. BMC Public Health 8:200

    PubMed  CrossRef  Google Scholar 

  • Bischofs S, Zelenka M, Sommer C (2004) Evaluation of topiramate as an anti-hyperalgesic and neuroprotective agent in the peripheral nervous system. J Peripher Nerv Syst 9:70–78

    PubMed  CAS  CrossRef  Google Scholar 

  • Biton V (2004) Zonisamide: newer antiepileptic agent with multiple mechanisms of action. Expert Rev Neurother 4:935–943

    PubMed  CAS  CrossRef  Google Scholar 

  • Biton V (2007) Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol 30:230–240

    PubMed  CAS  Google Scholar 

  • Bray GA, Hollander P, Klein S, Kushner R, Levy B, Fitchet M, Perry BH (2003) A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 11:722–733

    PubMed  CAS  CrossRef  Google Scholar 

  • Bussone G, Usai S, D'Amico D (2006) Topiramate in migraine prophylaxis: data from a pooled analysis and open-label extension study. Neurol Sci 27(Suppl 2):S159–S163

    PubMed  CrossRef  Google Scholar 

  • Campistol J, Campos J, Casas C, Herranz JL (2005) Topiramate in the prophylactic treatment of migraine in children. J Child Neurol 20:251–253

    PubMed  Google Scholar 

  • Capuano A, Vollono C, Mei D, Pierguidi L, Ferraro D, Di Trapani G (2004) Antiepileptic drugs in migraine prophylaxis: state of the art. Clin Ter 155:79–87

    PubMed  CAS  Google Scholar 

  • Casini A, Antel J, Abbate F, Scozzafava A, David S, Waldeck H, Schafer S, Supuran CT (2003) Carbonic anhydrase inhibitors: SAR and X-ray crystallographic study for the interaction of sugar sulfamates/sulfamides with isozymes I, II and IV. Bioorg Med Chem Lett 13:841–845

    PubMed  CAS  CrossRef  Google Scholar 

  • Catterall WA (1999) Molecular properties of brain sodium channels: an important target for anticonvulsant drugs. Adv Neurol 79:441–456

    PubMed  CAS  Google Scholar 

  • Chengappa KN, Gershon S, Levine J (2001) The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder. Bipolar Disord 3:215–232

    PubMed  CAS  CrossRef  Google Scholar 

  • Chong MS, Libretto SE (2003) The rationale and use of topiramate for treating neuropathic pain. Clin J Pain 19:59–68

    PubMed  CAS  CrossRef  Google Scholar 

  • Costa C, Tozzi A, Luchetti E, Siliquini S, Belcastro V, Tantucci M, Picconi B, Ientile R, Calabresi P, Pisani F (2010) Electrophysiological actions of zonisamide on striatal neurons: selective neuroprotection against complex I mitochondrial dysfunction. Exp Neurol 221:217–224

    PubMed  CAS  CrossRef  Google Scholar 

  • Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, Heimburger DC, Lucas CP, Robbins DC, Chung J, Heymsfield SB (1999) Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 281:235–242

    PubMed  CAS  CrossRef  Google Scholar 

  • De Simone G, Di Fiore A, Menchise V, Pedone C, Antel J, Casini A, Scozzafava A, Wurl M, Supuran CT (2005) Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies. Bioorg Med Chem Lett 15:2315–2320

    PubMed  CrossRef  CAS  Google Scholar 

  • Dhellemmes P, Defoort S, Vinchon M (2008) Benign intracranial hypertension: the role of medical treatment. Neurochirurgie 54:717–720

    PubMed  CAS  CrossRef  Google Scholar 

  • Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784

    PubMed  CrossRef  CAS  Google Scholar 

  • Dodgson SJ, Shank RP, Maryanoff BE (2000) Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 41(Suppl 1):S35–S39

    PubMed  CAS  CrossRef  Google Scholar 

  • Drake ME Jr, Greathouse NI, Renner JB, Armentbright AD (2004) Open-label zonisamide for refractory migraine. Clin Neuropharmacol 27:278–280

    PubMed  CAS  CrossRef  Google Scholar 

  • Dursun SM, Devarajan S (2000) Clozapine weight gain, plus topiramate weight loss. Can J Psychiatry 45(2):198

    PubMed  CAS  Google Scholar 

  • Elterman RD, Glauser TA, Wyllie E, Reife R, Wu SC, Pledger G (1999) A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group. Neurology 52:1338–1344

    PubMed  CAS  Google Scholar 

  • Fakhoury T, Murray L, Seger D, McLean M, Abou-Khalil B (2002) Topiramate overdose: clinical and laboratory features. Epilepsy Behav 3:185–189

    PubMed  CrossRef  Google Scholar 

  • Flegal KM, Carroll MD, Ogden CL, Curtin LR (2010) Prevalence and trends in obesity among us adults, 1999–2008. JAMA 303(3):235–241

    PubMed  CAS  CrossRef  Google Scholar 

  • Fountaine RJ, Taylor AE, Mancuso JP, Greenway FL, Byerley LO, Smith SR, Most MM, Fryburg DA (2010) Increased food intake and energy expenditure following administration of olanzapine to healthy men. Obesity (Silver Spring) 18:1646–1651

    CAS  CrossRef  Google Scholar 

  • Francis J, Burnham WM (1992) [3H]Phenytoin identifies a novel anticonvulsant-binding domain on voltage-dependent sodium channels. Mol Pharmacol 42(6):1097–1103

    PubMed  CAS  Google Scholar 

  • Fung EL, Nelson EA (2007) Oligohydrosis underestimated side effect with topiramate treatment. Indian J Pediatr 74(7):694

    PubMed  CrossRef  Google Scholar 

  • Gadde KM, Franciscy DM, Wagner HR 2nd, Krishnan KR (2003) Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA 289:1820–1825

    PubMed  CAS  CrossRef  Google Scholar 

  • Gadde KM, Yonish GM, Foust MS, Wagner HR (2007) Combination therapy of zonisamide and bupropion for weight reduction in obese women: a preliminary, randomized, open-label study. J Clin Psychiatry 68:1226–9

    PubMed  CAS  CrossRef  Google Scholar 

  • Gaspari CN, Guerreiro CA (2010) Modification in body weight associated with antiepileptic drugs. Arq Neuropsiquiatr 68(2):277–281

    PubMed  CrossRef  Google Scholar 

  • Gebhardt S, Theisen FM, Haberhausen M, Heinzel-Gutenbrunner M, Wehmeier PM, Krieg JC, Kühnau W, Schmidtke J, Remschmidt H, Hebebrand J (2010) Body weight gain induced by atypical antipsychotics: an extension of the monozygotic twin and sib pair study. J Clin Pharm Ther 35(2):207–211

    PubMed  CAS  CrossRef  Google Scholar 

  • Ghelardoni S, Bazinet RP, Rapoport SI, Bosetti F (2005) Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism. Psychopharmacology (Berl) 180:523–529

    CAS  CrossRef  Google Scholar 

  • Gibbs JW III, Sombati S, DeLorenzo RJ, Coulter DA (2000) Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia 41(Suppl 1):S10–S16

    PubMed  CAS  CrossRef  Google Scholar 

  • Gryder DS, Rogawski MA (2003) Selective antagonism of GluR5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons. J Neurosci 23(18):7069–7074

    PubMed  CAS  Google Scholar 

  • Hahn MK, Remington G, Bois D, Cohn T (2010) Topiramate augmentation in clozapine-treated patients with schizophrenia: clinical and metabolic effects. J Clin Psychopharmacol 30(6):706–710

    PubMed  CAS  CrossRef  Google Scholar 

  • Hasegawa H (2004) Utilization of zonisamide in patients with chronic pain or epilepsy refractory to other treatments: a retrospective, open label, uncontrolled study in a VA hospital. Curr Med Res Opin 20:577–580

    PubMed  CAS  CrossRef  Google Scholar 

  • Hebebrand J, Volckmar AL, Knoll N, Hinney A (2010) Chipping away the ‘missing heritability’: GIANT steps forward in the molecular elucidation of obesity – but still lots to go. Obes Facts 3:294–303

    PubMed  CrossRef  Google Scholar 

  • Herrero AI, Del Olmo N, Gonzalez-Escalada JR, Solis JM (2002) Two new actions of topiramate: inhibition of depolarizing GABA(A)-mediated responses and activation of a potassium conductance. Neuropharmacology 42:210–220

    PubMed  CAS  CrossRef  Google Scholar 

  • Hord AH, Denson DD, Chalfoun AG, Azevedo MI (2003) The effect of systemic zonisamide (Zonegran) on thermal hyperalgesia and mechanical allodynia in rats with an experimental mononeuropathy. Anesth Analg 96:1700–1706; table of contents

    PubMed  CAS  CrossRef  Google Scholar 

  • Houseknecht KL, Robertson AS, Zavadoski W, Gibbs EM, Johnson DE, Rollema H (2007) Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology 32(2):289–297

    PubMed  CAS  CrossRef  Google Scholar 

  • TOP Institute Pharma; Project T2-105 (2006–2011) Investigation of drug-induced weight alterations to identify novel therapeutic strategies for the treatment of obesity, dyslipidemia and diabetes. Principal investigator: Elwin Verheij; partners: Abbott (formerly Solvay Pharmaceuticals), Danone Research (formerly Numico), Leiden University Medical Center, Netherlands Institute for Neurosciences, PRA International, TNO, University Medical Center Groningen http://www.tipharma.com/projects/cardiovascular-diseases/drug-induced-weight-alteration.html

  • Jackson HC, Cheetham SC, Gregory PC, Antel J (2007). Effect of chronic administration of topiramate and phentermine, alone and in combination, in an animal model of dietary-induced obesity. Neuroscience Program No 629.15, Society for Neuroscience: San Diego, CA

    Google Scholar 

  • Jain KK (2000) An assessment of zonisamide as an anti-epileptic drug. Expert Opin Pharmacother 1:1245–1260

    PubMed  CAS  CrossRef  Google Scholar 

  • James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rössner S, Saris WH, Van Gaal LF (2000) Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM study group. Sibutramine trial of obesity reduction and maintenance. Lancet 356(9248):2119–2125

    PubMed  CAS  CrossRef  Google Scholar 

  • James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL, Investigators SCOUT (2010) Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 363(10):905–917

    PubMed  CAS  CrossRef  Google Scholar 

  • Johannessen Landmark C (2008) Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs 22(1):27–47

    PubMed  CrossRef  Google Scholar 

  • Jones MW (1998) Topiramate – safety and tolerability. Can J Neurol Sci 25(3):S13–S15

    PubMed  CAS  Google Scholar 

  • Jones D (2008) End of the line for cannabinoid receptor 1 as an anti-obesity target? Nat Rev Drug Discov 7(12):961–962

    PubMed  CAS  CrossRef  Google Scholar 

  • Kelly KM (1998) Gabapentin. Antiepileptic mechanism of action. Neuropsychobiology 38(3):139–144

    PubMed  CAS  CrossRef  Google Scholar 

  • Kennett GA, Clifton PG (2010) New approaches to the pharmacological treatment of obesity: can they break through the efficacy barrier? Pharmacol Biochem Behav 97(1):63–83

    PubMed  CAS  CrossRef  Google Scholar 

  • Kim CS (2003) Zonisamide effective for weight loss in women. J Fam Pract 52:600–601

    PubMed  Google Scholar 

  • Kim JH, Yim SJ, Nam JH (2006) A 12-week, randomized, open-label, parallel-group trial of topiramate in limiting weight gain during olanzapine treatment in patients with schizophrenia. Schizophr Res 82(1):115–117

    PubMed  CrossRef  Google Scholar 

  • Klein KM, Hamer HM, Reis J, Schmidtke J, Oertel WH, Theisen FM, Hebebrand J, Rosenow F (2005) Weight change in monozygotic twins treated with valproate. Obes Res 13(8):1330–1334

    PubMed  CAS  CrossRef  Google Scholar 

  • Knudsen JF, Thambi LR, Kapcala LP, Racoosin JA (2003) Oligohydrosis and fever in pediatric patients treated with zonisamide. Pediatr Neurol 28(3):184–189

    PubMed  CrossRef  Google Scholar 

  • Kuo RL, Moran ME, Kim DH, Abrahams HM, White MD, Lingeman JE (2002) Topiramate-induced nephrolithiasis. J Endourol 16:229–231

    PubMed  CrossRef  Google Scholar 

  • Kushner SF, Khan A, Lane R, Olson WH (2006) Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord 8:15–27

    PubMed  CAS  CrossRef  Google Scholar 

  • Kuzmiski JB, Barr W, Zamponi GW, MacVicar BA (2005) Topiramate inhibits the initiation of plateau potentials in CA1 neurons by depressing R-type calcium channels. Epilepsia 46(4):481–489

    PubMed  CAS  CrossRef  Google Scholar 

  • Kuzniecky R, Ho S, Pan J, Martin R, Gilliam F, Faught E, Hetherington H (2002) Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults. Neurology 58:368–372

    PubMed  CAS  Google Scholar 

  • Leniger T, Wiemann M, Bingmann D, Widman G, Hufnagel A, Bonnet U (2002) Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons. Epilepsia 43:469–74

    PubMed  CAS  CrossRef  Google Scholar 

  • Leniger T, Thöne J, Wiemann M (2004) Topiramate modulates pH of hippocampal CA3 neurons by combined effects on carbonic anhydrase and Cl-/HCO3-exchange. Br J Pharmacol 142(5):831–842

    PubMed  CAS  CrossRef  Google Scholar 

  • Leppik IE (2004) Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure 13(Suppl 1):S5–S9; discussion S10

    PubMed  CrossRef  Google Scholar 

  • Levy E, Margolese HC, Chouinard G (2002) Topiramate produced weight loss following olanzapine-induced weight gain in schizophrenia. J Clin Psychiatry 63:1045

    PubMed  CrossRef  Google Scholar 

  • Lévy E, Agbokou C, Ferreri F, Chouinard G, Margolese HC (2007) Topiramate-induced weight loss in schizophrenia: a retrospective case series study. Can J Clin Pharmacol 14(2):e234–e239

    PubMed  Google Scholar 

  • Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC (2005) Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 142:532–546

    PubMed  CAS  Google Scholar 

  • Liang Y, She P, Wang X, Demarest K (2006) The messenger RNA profiles in liver, hypothalamus, white adipose tissue, and skeletal muscle of female Zucker diabetic fatty rats after topiramate treatment. Metabolism 55:1411–1419

    PubMed  CAS  CrossRef  Google Scholar 

  • Linne Y, Hemmingsson E, Adolfsson B, Ramsten J, Rössner S (2002) Patient expectations of obesity treatment—the experience from a day-care unit. Int J Obes 26:739–741

    CAS  CrossRef  Google Scholar 

  • 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 35:1520–1530

    PubMed  CAS  CrossRef  Google Scholar 

  • Martins PJF, Haas M, Obici S (2010) Central nervous system delivery of the antipsychotic olanzapine induces hepatic insulin resistance. Diabetes 59(10):2418–2425

    PubMed  CAS  CrossRef  Google Scholar 

  • Maryanoff BE (2009) 2009 Edward E Smissman Award. Pharmaceutical “gold” from neurostabilizing agents: topiramate and successor molecules. J Med Chem 52:3431–3440

    PubMed  CAS  CrossRef  Google Scholar 

  • Maryanoff BE, Nortey SO, Gardocki JF, Shank RP, Dodgson SP (1987) Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-d-fructopyranose sulfamate and related compounds. J Med Chem 30:880–887

    PubMed  CAS  CrossRef  Google Scholar 

  • Maryanoff BE, Costanzo MJ, Nortey SO, Greco MN, Shank RP, Schupsky JJ, Ortegon MP, Vaught JL (1998) Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives. J Med Chem 41:1315–1343

    PubMed  CAS  CrossRef  Google Scholar 

  • Masereel B, Rolin S, Abbate F, Scozzafava A, Supuran CT (2002) Carbonic anhydrase inhibitors: anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties. J Med Chem 45:312–320

    PubMed  CAS  CrossRef  Google Scholar 

  • McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J, Baskin M, Benca RM, Biggio J, Boggiano MM, Eisenmann JC, Elobeid M, Fontaine KR, Gluckman P, Hanlon EC, Katzmarzyk P, Pietrobelli A, Redden DT, Ruden DM, Wang C, Waterland RA, Wright SM, Allison DB (2009) Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr 49(10):868–913

    PubMed  CrossRef  Google Scholar 

  • McElroy SL, Kotwal R, Hudson JI, Nelson EB, Keck PE (2004) Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial. J Clin Psychiatry 65:50–56

    PubMed  CAS  CrossRef  Google Scholar 

  • McIntyre RS, Riccardelli R, Binder C, Kusumakar V (2005) Open-label adjunctive topiramate in the treatment of unstable bipolar disorder. Can J Psychiatry 50:415–422

    PubMed  Google Scholar 

  • McLean MJ, Bukhari AA, Wamil AW (2000) Effects of topiramate on sodium-dependent action-potential firing by mouse spinal cord neurons in cell culture. Epilepsia 41(Suppl 1):S21–S24

    PubMed  CAS  CrossRef  Google Scholar 

  • McNaughton NC, Davies CH, Randall A (2004) Inhibition of alpha(1E) Ca(2+) channels by carbonic anhydrase inhibitors. J Pharmacol Sci 95(2):240–247

    PubMed  CAS  CrossRef  Google Scholar 

  • Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H (1990a) Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain. Med J Osaka Univ 39(1–4):13–17

    PubMed  CAS  Google Scholar 

  • Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H (1990b) [3H]Zonisamide binding in rat brain. Med J Osaka Univ 39(1–4):19–22

    PubMed  CAS  Google Scholar 

  • Nathan PJ, O'Neill BV, Napolitano A, Bullmore ET (2011) Neuropsychiatric Adverse Effects of Centrally Acting Antiobesity Drugs. CNS Neurosci Ther. 17:490–505

    PubMed  CAS  CrossRef  Google Scholar 

  • NCT00203450 (2003) Zonegran for the treatment of weight gain associated with psychotropic medication use: a placebo-controlled trial; Sponsor: Tuscaloosa Research & Education Advancement Corporation; Study Start Date: May 2003

    Google Scholar 

  • NCT00363376 (2008) A double-blind, placebo-controlled study of zonisamide to prevent olanzapine-associated weight gain; Sponsor: Lindner Center of HOPE; Study Start Date: January 2008

    Google Scholar 

  • NCT00401973 (2006) The assessment of the safety, efficacy, and practicality of an algorithm including amantadine, metformin and zonisamide for the prevention of olanzapine-associated weight gain in outpatients with schizophrenia; Sponsor: Eli Lilly and Company; Study Start Date: November 2006

    Google Scholar 

  • NCT00734435 (2008) A proof of concept, multi-center, randomized, double-blind, parallel, placebo-controlled, study of zonisamide sustained release (SR) 360 mg versus placebo in the prevention of weight gain associated with olanzapine therapy for psychosis; Sponsor: Orexigen Therapeutics, Inc.; Study Start Date: September 2008

    Google Scholar 

  • Nickel MK, Nickel C, Muehlbacher M, Leiberich PK, Kaplan P (2005) Influence of topiramate on olanzapine-related adiposity in women: a random, double-blind, placebo-controlled study. J Clin Psychopharmacol 25:211–217

    PubMed  CAS  CrossRef  Google Scholar 

  • Ohtahara S (2006) Zonisamide in the management of epilepsy – Japanese experience. Epilepsy Res 68(Suppl 2):S25–S33

    PubMed  CAS  CrossRef  Google Scholar 

  • Oommen KJ, Mathews S (1999) Zonisamide, a new anti-epileptic drug. Clin Neuropharmacol 22:192–200

    PubMed  CAS  Google Scholar 

  • Perucca E (1997) A pharmacological and clinical review on topiramate, a new antiepileptic drug. Pharmacol Res 35:241–256

    PubMed  CAS  CrossRef  Google Scholar 

  • Picard F, Deshaies Y, Lalonde J, Samson P, Richard D (2000) Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obes Res 8:656–663

    PubMed  CAS  CrossRef  Google Scholar 

  • Post RM, Ketter TA, Uhde T, Ballenger JC (2007) Thirty years of clinical experience with carbamazepine in the treatment of bipolar illness: principles and practice. CNS Drugs 21(1):47–71

    PubMed  CAS  CrossRef  Google Scholar 

  • Raskin P, Donofrio PD, Rosenthal NR, Hewitt DJ, Jordan DM, Xiang J, Vinik AI (2004) Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology 63:865–873

    PubMed  CAS  Google Scholar 

  • Reis J, Tergau F, Hamer HM, Muller HH, Knake S, Fritsch B, Oertel WH, Rosenow F (2002) Topiramate selectively decreases intracortical excitability in human motor cortex. Epilepsia 43:1149–1156

    PubMed  CAS  CrossRef  Google Scholar 

  • Ribacoba Montero R, Salas Puig X (2002) Efficacy and tolerability of long term topiramate in drug resistant epilepsy in adults. Rev Neurol 34:101–105

    PubMed  CAS  Google Scholar 

  • Richard D, Ferland J, Lalonde J, Samson P, Deshaies Y (2000) Influence of topiramate in the regulation of energy balance. Nutrition 16:961–966

    PubMed  CAS  CrossRef  Google Scholar 

  • Richard D, Picard F, Lemieux C, Lalonde J, Samson P, Deshaies Y (2002) The effects of topiramate and sex hormones on energy balance of male and female rats. Int J Obes Relat Metab Disord 26:344–353

    PubMed  CAS  CrossRef  Google Scholar 

  • Rinaldi-Carmona M, Barth F, Congy C, Martinez S, Oustric D, Pério A, Poncelet M, Maruani J, Arnone M, Finance O, Soubrié P, Le Fur G (2004) SR147778 [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization. J Pharmacol Exp Ther 310:905–914

    PubMed  CAS  CrossRef  Google Scholar 

  • Rogawski MA (2006) Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 69(3):273–294

    PubMed  CAS  CrossRef  Google Scholar 

  • Rogawski MA, Löscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5(7):553–564

    PubMed  CAS  CrossRef  Google Scholar 

  • Rosenfeld WE (1997) Topiramate: a review of preclinical, pharmacokinetic, and clinical data. Clin Ther 19:1294–1308

    PubMed  CAS  CrossRef  Google Scholar 

  • Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39(1):32–41

    PubMed  CAS  CrossRef  Google Scholar 

  • Russo E, Constanti A, Ferreri G, Citraro R, De Sarro G (2004) Nifedipine affects the anticonvulsant activity of topiramate in various animal models of epilepsy. Neuropharmacology 46(6):865–878

    PubMed  CAS  CrossRef  Google Scholar 

  • Scheen AJ (2010) Cardiovascular risk-benefit profile of sibutramine. Am J Cardiovasc Drugs 10(5):321–334

    PubMed  CAS  CrossRef  Google Scholar 

  • Schubert S, Brandl U, Brodhun M, Ulrich C, Spaltmann J, Fiedler N, Bauer R (2005) Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets. Brain Res 1058(1–2):129–136

    PubMed  CAS  CrossRef  Google Scholar 

  • Seino M (2004) Review of zonisamide development in Japan. Seizure 13(Suppl 1):S2–S4

    PubMed  CrossRef  Google Scholar 

  • Shank RP, Gardocki JF, Vaught JL, Davis CB, Schupsky JJ, Raffa RB, Dodgson SJ, Nortey SO, Maryanoff BE (1994) Topiramate: preclinical evaluation of structurally novel anticonvulsant. Epilepsia 35:450–460

    PubMed  CAS  CrossRef  Google Scholar 

  • Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE (2000) An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 41(Suppl 1):S3–S9

    PubMed  CAS  CrossRef  Google Scholar 

  • Sills GJ, Leach JP, Kilpatrick WS, Fraser CM, Thompson GG, Brodie MJ (2000) Concentration-effect studies with topiramate on selected enzymes and intermediates of the GABA shunt. Epilepsia 41(Suppl 1):S30–S34

    PubMed  CAS  CrossRef  Google Scholar 

  • Skradski S, White HS (2000) Topiramate blocks kainate-evoked cobalt influx into cultured neurons. Epilepsia 41(Suppl 1):S45–S47

    PubMed  CAS  CrossRef  Google Scholar 

  • Stringer JL (2000) A comparison of topiramate and acetazolamide on seizure duration and paired-pulse inhibition in the dentate gyrus of the rat. Epilepsy Res 40:147–153

    PubMed  CAS  CrossRef  Google Scholar 

  • Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7:168–181

    PubMed  CAS  CrossRef  Google Scholar 

  • Supuran CT, Di Fiore A, De Simone G (2008) Carbonic anhydrase inhibitors as emerging drugs for the treatment of obesity. Expert Opin Emerg Drugs 13(2):383–392

    PubMed  CAS  CrossRef  Google Scholar 

  • Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh N, Masuzaki H, Mori K, Tamura N, Hosoda K, Nakao K (1996) Molecular cloning of rat leptin receptor isoform complementary DNAs – identification of a missense mutation in Zucker fatty (fa/fa) rats. Biochem Biophys Res Commun 225(1):75–83

    PubMed  CAS  CrossRef  Google Scholar 

  • Tanabe M, Sakaue A, Takasu K, Honda M, Ono H (2005) Centrally mediated antihyperalgesic and antiallodynic effects of zonisamide following partial nerve injury in the mouse. Naunyn Schmiedebergs Arch Pharmacol 372:107–114

    PubMed  CAS  CrossRef  Google Scholar 

  • Taverna S, Sancini G, Mantegazza M, Franceschetti S, Avanzini G (1999) Inhibition of transient and persistent Na+ current fractions by the new anticonvulsant topiramate. J Pharmacol Exp Ther 288:960–968

    PubMed  CAS  Google Scholar 

  • Theisen FM, Cichon S, Linden A, Martin M, Remschmidt H, Hebebrand J (2001) Clozapine and weight gain. Am J Psychiatry 158(5):816

    PubMed  CAS  CrossRef  Google Scholar 

  • Theisen FM, Haberhausen M, Firnges MA, Gregory P, Reinders JH, Remschmidt H, Hebebrand J, Antel J (2007) No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation. Pharmacogenomics J 7:275–281

    PubMed  CAS  CrossRef  Google Scholar 

  • Thone J, Leniger T, Splettstosser F, Wiemann M (2008) Antiepileptic activity of zonisamide on hippocampal CA3 neurons does not depend on carbonic anhydrase inhibition. Epilepsy Res 79:105–111

    PubMed  CrossRef  CAS  Google Scholar 

  • Tonstad S, Tykarski A, Weissgarten J, Ivleva A, Levy B, Kumar A, Fitchet M (2005) Efficacy and safety of topiramate in the treatment of obese subjects with essential hypertension. Am J Cardiol 96:243–251

    PubMed  CAS  CrossRef  Google Scholar 

  • Toplak H, Hamann H, Moore R, Masson E, Gorska M, Vercruysse F, Sun X, Fitchet M (2007) Efficacy and safety of topiramate in combination with metformin in the treatment of obese subjects with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Int J Obes 31(1):138–146

    CAS  CrossRef  Google Scholar 

  • Ueda Y, Doi T, Tokumaru J, Willmore LJ (2003) Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures. Brain Res Mol Brain Res 116(1–2):1–6

    PubMed  CAS  CrossRef  Google Scholar 

  • Van Gaal L, Pi-Sunyer X, Després JP, McCarthy C, Scheen A (2008) Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the Rimonabant in Obesity (RIO) program. Diabetes Care 31(Suppl 2):S229–S240

    PubMed  CrossRef  CAS  Google Scholar 

  • Van Passel L, Arif H, Hirsch LJ (2006) Topiramate for the treatment of epilepsy and other nervous system disorders. Expert Rev Neurother 6:19–31

    PubMed  CrossRef  Google Scholar 

  • Vasudev K, Macritchie K, Geddes J, Watson S, Young A (2006) Topiramate for acute affective episodes in bipolar disorder. Cochrane Database Syst Rev CD003384

    Google Scholar 

  • VI-0521(QNEXA®) Briefing document (2010) http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm218821.pdf

  • Vinik A (2005) Clinical review: use of antiepileptic drugs in the treatment of chronic painful diabetic neuropathy. J Clin Endocrinol Metab 90:4936–4945

    PubMed  CAS  CrossRef  Google Scholar 

  • Vohora D, Saraogi P, Yazdani MA, Bhowmik M, Khanam R, Pillai KK (2010) Recent advances in adjunctive therapy for epilepsy: focus on sodium channel blockers as third-generation antiepileptic drugs. Drugs Today (Barc) 46(4):265–277

    CAS  CrossRef  Google Scholar 

  • Walker RM, DiFonzo CJ, Barsoum NJ, Smith GS, Macallum GE (1988) Chronic toxicity of the anticonvulsant zonisamide in beagle dogs. Fundam Appl Toxicol 11:333–342

    PubMed  CAS  CrossRef  Google Scholar 

  • Wallingford NM, Sinnayah P, Bymaster FP, Gadde KM, Krishnan RK, McKinney AA, Landbloom RP, Tollefson GD, Cowley MA (2008) Zonisamide prevents olanzapine-associated hyperphagia, weight gain, and elevated blood glucose in rats. Neuropsychopharmacology 33(12):2922–2933

    PubMed  CAS  CrossRef  Google Scholar 

  • Wang PW, Yang YS, Chandler RA, Nowakowska C, Alarcon AM, Culver J, Ketter TA (2008) Adjunctive zonisamide for weight loss in euthymic bipolar disorder patients: a pilot study. J Psychiatr Res 42:451–7

    PubMed  CrossRef  Google Scholar 

  • Weiergräber M, Henry M, Krieger A, Kamp M, Radhakrishnan K, Hescheler J, Schneider T (2006) Altered seizure susceptibility in mice lacking the Ca(v)2.3 E-type Ca2+ channel. Epilepsia 47(5):839–850

    PubMed  CrossRef  Google Scholar 

  • Wenzel RG, Schwarz K, Padiyara RS (2006) Topiramate for migraine prevention. Pharmacotherapy 26:375–387

    PubMed  CAS  CrossRef  Google Scholar 

  • Wieczorkiewicz-Plaza A, Plaza P, Maciejewski R, Czuczwar M, Przesmycki K (2004) Effect of topiramate on mechanical allodynia in neuropathic pain model in rats. Pol J Pharmacol 56:275–278

    PubMed  CAS  Google Scholar 

  • Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M (2004) A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord 28:1399–1410

    PubMed  CAS  CrossRef  Google Scholar 

  • Wilkes JJ, Nelson E, Osborne M, Demarest KT, Olefsky JM (2005a) Topiramate is an insulin-sensitizing compound in vivo with direct effects on adipocytes in female ZDF rats. Am J Physiol Endocrinol Metab 288:E617–E624

    PubMed  CAS  CrossRef  Google Scholar 

  • Wilkes JJ, Nguyen MT, Bandyopadhyay GK, Nelson E, Olefsky JM (2005b) Topiramate treatment causes skeletal muscle insulin sensitization and increased Acrp30 secretion in high-fat-fed male Wistar rats. Am J Physiol Endocrinol Metab 289:E1015–E1022

    PubMed  CAS  CrossRef  Google Scholar 

  • Yagi K (2004) Overview of Japanese experience-controlled and uncontrolled trials. Seizure 13(Suppl 1):S11–S15; discussion S16

    PubMed  CrossRef  Google Scholar 

  • Yamamura S, Hamaguchi T, Ohoyama K, Sugiura Y, Suzuki D, Kanehara S, Nakagawa M, Motomura E, Matsumoto T, Tanii H, Shiroyama T, Okada M (2009) Topiramate and zonisamide prevent paradoxical intoxication induced by carbamazepine and phenytoin. Epilepsy Res 84(2–3):172–186

    PubMed  CAS  CrossRef  Google Scholar 

  • York DA, Singer L, Thomas S, Bray GA (2000) Effect of topiramate on body weight and body composition of osborne-mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAs. Nutrition 16(10):967–975

    PubMed  CAS  CrossRef  Google Scholar 

  • Zullino DF, Krenz S, Besson J (2003) AMPA blockade may be the mechanism underlying the efficacy of topiramate in PTSD. J Clin Psychiatry 64:219–220

    PubMed  CrossRef  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J. Antel .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Antel, J., Hebebrand, J. (2012). Weight-Reducing Side Effects of the Antiepileptic Agents Topiramate and Zonisamide. In: Joost, HG. (eds) Appetite Control. Handbook of Experimental Pharmacology, vol 209. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-24716-3_20

Download citation