Topiramate (Topamax)

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

History

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

Alcoholism
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:

	Topiramate 96 mg/day	Topiramate 192 mg/day	Topiramate 256 mg/day	Placebo
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"

Advantages:

• 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

Disadvantages:

• 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

• Topiramate (Topamax) vs Divalproex (Depakote)

References

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