Topiramate (Topamax)

Topiramate in Brief
  • Generic name : Topiramate
  • Brand names: Topamax®, Trokendi XR®, Qudexy XR®
  • Therapeutic class: Anti-epileptic, Anticonvulsant
  • Pharmacologic class: Sulfamate-substituted monosaccharide derivative
  • FDA Approved: 24 December 1996
  • Chemical Formula: C12H21NO8S
  • Pregnancy Category: D (increased risk for oral clefts)
  • Habit forming? No
  • Originally discovered: 1979, McNeil Pharmaceutical, USA USA

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD


Topiramate was invented by Ortho-McNeil scientist Dr. Bruce Maryanoff during a search for new antidiabetic pharmaceutical 41. Topiramate has a singular chemical structure. It was synthesized during a research project to discover substances analogous to fructose 1.6-diphosphate inhibitors of the glyconeogenic process.

Unexpectedly, Dr. Maryanoff discovered that this agent had powerful anticonvulsant properties.   Topiramate's structural chain resembles a chemical radical in the acetazolamide molecule, which raised the possibility of antiepileptic properties.


After extensive testing, clinical trials, and substantial investment, Ortho-McNeil showed that the compound was safe and effective leading to FDA approval as anti-epileptic agent.

The first studies demonstrating the efficacy and tolerability of topiramate in the migraine prevention emerged in the late 1990s 12. U.S. FDA approved Topamax for the prophylaxis (prevention) of migraine headaches in adults in August 2004.

On August 2013 FDA approved Trokendi XR -- once-daily extended-release formulation of topiramate. Trokendi XR utilizes Microtrol® Technology. Once-daily Trokendi XR is bioequivalent to twice-daily Topamax.

FDA approved indications

  • Monotherapy or adjunctive therapy for partial onset seizures
  • Monotherapy or adjunctive therapy for primary generalized tonic-clonic seizures
  • Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome
  • Prophylaxis of migraine headache

Off-label & Investigational uses

  • bipolar disorder 2, 3, 4, 10, 15
  • weight loss and obesity 7, 13, 14, 21, 24
  • alcohol dependence 8, 27
  • binge eating disorder 5, 29
  • cocaine dependence 28
  • bulimia nervosa 6, 30
  • cluster headaches 23
  • chronic daily headache 43
  • infantile spasms 31, 32, 33
  • smoking cessation 26, 34, 35
  • post-traumatic stress disorder 20, 36
  • neuropathic pain 37, 38
  • sleep-related eating disorder (SRED) and nocturnal eating syndrome (NES) 9, 39
  • scar therapy 40
  • migraine prevention in children 19
  • pathologic gambling 42
  • painful diabetic neuropathy 44

The putative efficacy of topiramate in the treatment of alcohol dependence is based on reversing chronic changes induced by alcohol resulting in dopamine-facilitated neurotransmission in the midbrain. Topiramate might antagonise alcohol's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of GABA activity and inhibition of glutamate function.

Studies have shown that topiramate (up to 300 mg per day) is more efficacious than placebo as an adjunction to standardized management of alcohol dependence. Topiramate can reduce consumption and craving in alcohol-dependent patients 8. Double-blind, randomized, controlled study indicated that topiramate also can increase overall well-being and quality of life and lessen dependence severity and its harmful consequences of alcohol-dependent individuals 27.

Also, topiramate is a promising treatment of cigarette smoking in alcoholic individuals 25.

Binge eating disorder
Topiramate is efficacious and relatively well tolerated in the short-term treatment of binge eating disorder associated with obesity 5. In the study topiramate was associated with a significantly higher rate of reduction in binge frequency, binge day frequency, body mass index, weight, and scores on the Clinical Global Impression severity scale and the Yale-Brown Obsessive Compulsive Scale (modified for binge eating) than placebo.

Bipolar disorder
Topiramate may represent a valuable alternative to existing mood stabilizers, either as an adjunct or as monotherapy in patients with bipolar or schizoaffective disorder. Preliminary open observations suggest that it may have antimanic or anticycling effects in bipolar disorder 19.

Preliminary findings provide support for a modest efficacy of topiramate, especially as monotherapy, in the treatment of acute mania 16.

Results of four double-blind placebo-controlled trials do not support the efficacy of topiramate as monotherapy in acute mania or mixed episodes in adults with bipolar I disorder. Topiramate is not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression 18.

Topiramate as adjunctive treatment appears to have efficacy for the manic and mixed phases of bipolar illness 17.

Topiramate lacks efficacy in the treatment of acute mania. Increasing evidence, based on controlled studies, supports the use of topiramate in bipolar disorders in depressive phase 15.

Results from these trials suggest topiramate may be efficacious in BD subtypes, particularly in rapid-cycling patients and those refractory to conventional treatment.

Adjunctive topiramate may be useful in treating bipolar II disorder.


Weight loss and obesity
The evidence of a strong weight-reducing potential of topiramate is indisputable and clinically significant.

Randomized, double-blind, placebo-controlled study investigated the long-term efficacy and safety of topiramate in obese persons 24. Topiramate treatment over the course of 1 year resulted in clinically significant weight reduction. Improvements were also observed in blood pressure and glucose tolerance:

96 mg/day
192 mg/day
256 mg/day
Percentage of lost body weight at 60 weeks 7.0% 9.1% 9.7% 1.7%
The loss of more that 5% of baseline weight was (% of participants) 54% 61% 67% 18%
Weight loss of 10% and more (% of participants) 29% 40% 44% 6%
Improvements in blood pressure (systolic/diastolic changes) -3.1/-1.3 mmHg -5.7/-3.4 mmHg -4.6/-2.4 mmHg +0.4/+1.0 mmHg

The most common adverse events more frequently observed in topiramate group occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration, attention or memory, language problems, nervousness, and psychomotor slowing.

In a study 14 focusing on topiramate-related weight loss, 15 patients who had gained weight after using SSRIs for anxiety disorder received topiramate, starting at a dose of 50 mg and titrating up to a target dose of 100-250 mg daily. Participants' weights were measured at baseline and after 5 and 10 weeks of treatment. Before topiramate treatment, these participants had gained a mean of 13.0 ± 8.4 kg. After starting topiramate therapy for approximately 10 weeks, patients lost a mean of 4.2 ± 6.0 kg.

However, Topamax is not considered a first choice for weight loss due to high rate of side effects, such as cognitive impairment, anxiety, memory loss or difficulty concentrating, which can be intolerable.

Neuropathic pain
Antiepileptics are useful in the treatment of neuropathic pain. There are good theoretical explanations how topiramate can alleviate neuropathic pain. Topiramate acts on neuronal transmission in several ways: by modulating voltage-gated sodium ion channels, potentiating gamma-aminobutyric acid inhibition, blocking excitatory glutamate neurotransmission, modulating voltage-gated calcium ion channels, and by inhibiting carbonic anhydrase.

There are good reasons for a trial of topiramate in persons with neuropathic pain where conventional treatments have failed. Although not currently licensed for treating pain, topiramate should be considered before invasive methods of pain relief are contemplated 37.

Topiramate may reduce chronic sciatica but causes frequent side effects 38.

In randomized, double-blind trial topiramate reduced pain visual analog score, worst pain intensity and sleep disruption in patients with painful diabetic neuropathy 44.

Topiramate "pros" and "cons"


  • Effective in a variety of different seizure types
  • May be effective for patients who have failed to respond to antidepressants or mood stabilizers
  • Adjunctive topiramate effective for treatment-resistant bipolar-spectrum disorders 10
  • Potential for weight loss and a reduction in BMI (often, weight loss is highly desired by patients) 11
  • One of the few FDA-approved medications for migraine prevention
  • May be taken without regard to meals
  • Advantages over neuroleptics in that it carries no risk of tardive dyskinesia
  • Does not appear to destabilize mood in patients with comorbid bipolar disorder
  • Minimal interactions with other medications
  • Pharmacological advantages: low protein binding, high therapeutic index, minimal hepatic metabolism and mainly unchanged renal excretion
  • Blood pressure lowering effect 25


  • Pregnancy Category D -- increased risk for the development of oral clefts in infants born to women treated with topiramate.
  • Nephrolithiasis -- risk of developing kidney stones (about 1.5%); an explanation for this risk may lie in the fact that topiramate is a carbonic anhydrase inhibitor 1
  • Ophthalmological side effects -- risk of acute myopia and angle-closure glaucoma 1, 3
  • Can decrease efficacy of hormonal contraceptives 1
  • Cognitive disturbances, abnormal thinking, memory difficulty1
  • Very slow titration until the effective dose is reached.

Mechanism of action

The precise mechanisms by which topiramate exerts its anticonvulsant and migraine prevention effects are unknown. However, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and migraine prophylaxis. Topiramate at pharmacologically relevant concentrations 22:

  • blocks voltage-dependent sodium channels
  • potentiates the activity of gamma-amino-butyric acid (GABA), an inhibitory neurotransmitter (activate GABA postsynaptic receptors)
  • blocks the action of glutamate (excitatory neurotransmitter)
  • inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV (weakly inhibits carbonic anhydrase)
  • negatively modulates high-voltage-activated calcium channels.

Time to clear out of the system

The mean plasma elimination half-life is 21 hours 1. Topiramate is excreted from the body within 4-5 days.

Onset of action

Steady state is reached in about 4 days in persons with normal renal function 1.

Initial side effects

CNS side effects may be minimized by initial slow titration or small reductions in other medications with sedative effects. These effects usually diminish over time.

Topiramate withdrawal

Gradually withdraw therapy to minimize potential of increased seizure frequency.

Further reading


  • 1. Physicians’ Desk Reference, 59th ed; Thomson PDR: Montvale, NJ; 2005.
  • 2. Calabrese JR, Keck PE, McElroy SL, Shelton MD. A pilot study of topiramate as monotherapy in the treatment of acute mania. J Clin Psychopharmacol. 2001 Jun;21(3):340-2 PubMed
  • 3. Banta JT, Hoffman K, Budenz DL, Ceballos E, Greenfield DS. Presumed topiramate-induced bilateral acute angle-closure glaucoma. Am J Ophthalmol. 2001 Jul;132(1):112-4. PubMed
  • 4. Vieta E, Goikolea JM, Olivares JM, Gonzalez-Pinto A, Rodriguez A, Colom F, Comes M, Torrent C, Sanchez-Moreno J. 1-year follow-up of patients treated with risperidone and topiramate for a manic episode. J Clin Psychiatry. 2003 Jul;64(7):834-9. PubMed
  • 5. McElroy SL, Arnold LM, Shapira NA, Keck PE, Rosenthal NR, Karim MR, Kamin M, Hudson JI. Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. Am J Psychiatry. 2003 Feb;160(2):255-61.
  • 6. Hedges DW, Reimherr FW, Hoopes SP, Rosenthal NR, Kamin M, Karim R, Capece JA. Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 2: improvement in psychiatric measures. J Clin Psychiatry. 2003 Dec;64(12):1449-54. PubMed
  • 7. Carpenter LL, Leon Z. Do obese depressed patients respond to topiramate? J Affect Disord. 2002 May;69(1-3):251-5. PubMed
  • 8. Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD, Lawson K, Javors MA, Ma JZ. Topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003 May 17;361(9370):1677-85.
  • 9. Winkelman JW. Treatment of nocturnal eating syndrome and sleep-related eating disorder with topiramate. Sleep Med. 2003 May;4(3):243-6. PubMed
  • 10. Vieta E, Torrent C, Garcia-Ribas G, Gilabert A, Garcia-Pares G, Rodriguez A, Cadevall J, Garcia-Castrillon J, Lusilla P, Arrufat F. Use of topiramate in treatment-resistant bipolar spectrum disorders. J Clin Psychopharmacol. 2002 Aug;22(4):431-5. PubMed
  • 11. Chengappa KN, Chalasani L, Brar JS, Parepally H, Houck P, Levine J. Changes in body weight and body mass index among psychiatric patients receiving lithium, valproate, or topiramate: an open-label, nonrandomized chart review. Clin Ther. 2002 Oct;24(10):1576-84. PubMed
  • 12. Schuaib A, Ahmed F, Muratoglu M, Kochanski P. Topiramate in migraine prophylaxis: a pilot study. Cephalalgia. 1999;19:379-380.
  • 13. Husum H, Van Kammen D, Termeer E, Bolwig G, Mathe A. Topiramate normalizes hippocampal NPY-LI in flinders sensitive line 'depressed' rats and upregulates NPY, galanin, and CRH-LI in the hypothalamus: implications for mood-stabilizing and weight loss-inducing effects. Neuropsychopharmacology. 2003;28:1292-1299.
  • 14. Van Ameringen M, Mancini C, Pipe B, Campbell M, Oakman J. Topiramate treatment for SSRI-induced weight gain in anxiety disorders. J Clin Psychiatry. 2002;63:981-984.
  • 15. Arnone D. Review of the use of Topiramate in psychiatric disorders. Ann Gen Psychiatry. 2005 Feb 16;4(1):5. Full Text
  • 16. Bozikas VP, Petrikis P, Kourtis A, Youlis P, Karavatos A. Treatment of acute mania with topiramate in hospitalized patients. Prog Neuropsychopharmacol Biol Psychiatry. 2002 Oct;26(6):1203-6. PubMed
  • 17. Chengappa KN, Rathore D, Levine J, Atzert R, Solai L, Parepally H, Levin H, Moffa N, Delaney J, Brar JS. Topiramate as add-on treatment for patients with bipolar mania. Bipolar Disord. 1999 Sep;1(1):42-53. PubMed
  • 18. Kushner SF, Khan A, Lane R, Olson WH. Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord. 2006 Feb;8(1):15-27. PubMed
  • 19. Winner P, Pearlman EM, Linder SL, Jordan DM, Fisher AC, Hulihan J. Topiramate for migraine prevention in children: a randomized, double-blind, placebo-controlled trial. Headache. 2005 Nov-Dec;45(10):1304-12. PubMed
  • 20. Berlant J, van Kammen DP. Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry. 2002 Jan;63(1):15-20. PubMed
  • 21. Husum H, Van Kammen D, Termeer E, Bolwig G, Mathe A. Topiramate normalizes hippocampal NPY-LI in flinders sensitive line 'depressed' rats and upregulates NPY, galanin, and CRH-LI in the hypothalamus: implications for mood-stabilizing and weight loss-inducing effects. Neuropsychopharmacology. 2003 Jul;28(7):1292-9.
  • 22. Textbook of Psychopharmacology. American Psychiatric Publishing 4th Ed. 2009, p. 797.
  • 23. Lainez MJ, Pascual J, Pascual AM, Santonja JM, Ponz A, Salvador A. Topiramate in the prophylactic treatment of cluster headache. Headache. 2003 Jul-Aug;43(7):784-9 PubMed
  • 24. Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M; OBES-002 Study Group. 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. 2004 Nov;28(11):1399-410.
  • 25. Tonstad S, Tykarski A, Weissgarten J, Ivleva A, Levy B, Kumar A, Fitchet M. Efficacy and safety of topiramate in the treatment of obese subjects with essential hypertension. Am J Cardiol. 2005 Jul 15;96(2):243-51. PubMed
  • 26. Johnson BA, Ait-Daoud N, Akhtar FZ, Javors MA. Use of topiramate to promote smoking abstinence among alcohol-dependent smokers: a randomized controlled trial. Arch Intern Med. 2005 Jul 25;165(14):1600-5.
  • 27. Johnson BA, Ait-Daoud N, Akhtar FZ, Ma JZ. Topiramate reduces the consequences of drinking and improves the quality of life of alcohol-dependent individuals: a randomized controlled trial. Arch Gen Psychiatry. 2004 Sep;61(9):905-12.
  • 28. Kampman KM, Pettinati H, Lynch KG, Dackis C, Sparkman T, Weigley C, O'Brien CP. A pilot trial of topiramate for the treatment of cocaine dependence. Alcohol Depend. 2004 Sep 6;75(3):233-40. PubMed
  • 29. McElroy SL, Hudson JI, Capece JA, Beyers K, Fisher AC, Rosenthal NR. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007 May 1;61(9):1039-48. PubMed
  • 30. Nickel C, Tritt K, Muehlbacher M, Pedrosa Gil F, Mitterlehner FO, Kaplan P, Lahmann C, Leiberich PK, Krawczyk J, Kettler C, Rother WK, Loew TH, Nickel MK. Topiramate treatment in bulimia nervosa patients: a randomized, double-blind, placebo-controlled trial. Int J Eat Disord. 2005 Dec;38(4):295-300. PubMed
  • 31. Glauser TA, Clark PO, Strawsburg R. A pilot study of topiramate in the treatment of infantile spasms. Epilepsia. 1998 Dec;39(12):1324-8. PubMed
  • 32. Zou LP, Ding CH, Fang F, Sin NC, Mix E. Prospective study of first-choice topiramate therapy in newly diagnosed infantile spasms. Clin Neuropharmacol. 2006 Nov-Dec;29(6):343-9. PubMed
  • 33. Hsieh MY, Lin KL, Wang HS, Chou ML, Hung PC, Chang MY. Low-dose topiramate is effective in the treatment of infantile spasms. Chang Gung Med J. 2006 May-Jun;29(3):291-6. PubMed
  • 34. Oncken C, Arias AJ, Feinn R, Litt M, Covault J, Sofuoglu M, Kranzler HR. Topiramate for smoking cessation: a randomized, placebo-controlled pilot study. Nicotine Tob Res. 2014 Mar;16(3):288-96. PubMed
  • 35. Reid MS, Palamar J, Raghavan S, Flammino F. Effects of topiramate on cue-induced cigarette craving and the response to a smoked cigarette in briefly abstinent smokers. PubMed
  • 36. Tucker P, Trautman RP, Wyatt DB, Thompson J, Wu SC, Capece JA, Rosenthal NR. Efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007 Feb;68(2):201-6. PubMed
  • 37. Chong MS, Libretto SE. The rationale and use of topiramate for treating neuropathic pain. Clin J Pain. 2003 Jan-Feb;19(1):59-68. PubMed
  • 38. Khoromi S, Patsalides A, Parada S, Salehi V, Meegan JM, Max MB. Topiramate in chronic lumbar radicular pain. J Pain. 2005 Dec;6(12):829-36.
  • 39. Winkelman JW. Efficacy and tolerability of open-label topiramate in the treatment of sleep-related eating disorder: a retrospective case series. J Clin Psychiatry. 2006 Nov;67(11):1729-34.
  • 40. Shapira NA, Lessig M, Murphy TK, Annis AM, Lazoritz M. Evaluation of open-label topiramate for scar therapy. Dermatol J. 2003 Dec;9(5):3. PubMed
  • 41. Anticonvulsant sulfamate derivatives. US Patent 4513006.
  • 42. Berlin HA, Braun A, Simeon D, Koran LM, Potenza MN, McElroy SL, Fong T, Pallanti S, Hollander E. A double-blind, placebo-controlled trial of topiramate for pathological gambling. World J Biol Psychiatry. 2011 Apr 12. PubMed
  • 43. Mosek A, Dano M. Topiramate in the treatment of refractory chronic daily headache. An open trial. J Headache Pain. 2005 Apr;6(2):77-80.
  • 44. Raskin P, Donofrio PD, Rosenthal NR, Hewitt DJ, Jordan DM, Xiang J, Vinik AI; CAPSS-141 Study Group. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology. 2004 Sep 14;63(5):865-73.

Published: March 31, 2008
Last updated: January 27, 2017

Interesting facts
Topiramate facts
  • Topiramate, a fructopyranose derivative, possesses a chemical structure unlike that of other anticonvulsants.
  • It was originally designed as a hypoglycaemic agent subsequently approved as anticonvulsant.

More Facts
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