Day # 59: Topiramate

Welcome back to our current theme of bipolar disorder. We are continuing our conversation on the medications classified as "mood stabilizers" and today we will discuss topiramate.


Today's content level: Beginner; Intermediate



INTRODUCTION AND MECHANISM OF ACTION


•Topiramate = Topamax, Topomac


•Topiramate is an anti-epileptic drug (AED) used for seizure disorders, but also can be used for mood stabilization in bipolar disorder as well as other indications we will cover below.


Mechanism of action includes:

  • Blocks voltage-dependent sodium channels.

  • Inhibits release of glutamate.

  • Potentiates GABA.

  • Inhibits carbonic anhydrase (important for ophthalmologic side effect discussed below)

  • Delayed onset of action (weeks) for all indications.



INDICATIONS


Topiramate

  • Epilepsy: FDA-approved to treat partial onset seizures, generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut Syndrome. It can also be used as adjunctive treatment in a variety of other seizure types.

  • Bipolar disorder (off-label): It has been historically used for mood stabilization along with other AEDs (valproic acid, carbamazepine, etc...), although recent meta-analysis was unable to show effectiveness in acute manic or depressive episodes. There is also little evidence to support maintenance monotherapy. May consider use as an adjunct. Of note, the manufacturer has dropped topiramate from further development as a mood stabilizer. 1

  • Migraine prophylaxis: Approved for migraine prophylaxis. May take up to one month of daily use to see a decline in frequency of headaches.

  • Weight management: Used for weight loss as an adjunct to reduced calorie diet and increased exercise. Approve in adults with initial BMI of ≥30 in the presence of at least one weight-related comorbid condition. Often used in combination with phentermine. Also used in psychotropic drug-induced weight gain (off-label): Statistically significant weight loss among patients prescribed second generation antipsychotics by ~3kg greater than placebo. 2

  • Binge-eating disorder (off-label): Compared with placebo, topiramate is associated with a significantly greater rate of reduction in binge frequency, binge day frequency, and BMI in those with binge-eating disorder. 3

  • Potential for use in other issues with impulse-control to include decreased self-mutilatory behavior in patients with borderline personality disorder.

  • Drug use disorder (off-label): Data supports reduction in cravings, overall use, and lengthened time to relapse in patients with alcohol use disorder, tobacco use disorder, and cocaine use disorder. 4, 5.



SIDE EFFECTS


Common side effects include:

  • Sedation

  • GI upset

  • Weight LOSS

  • Ataxia

  • Paresthesia -> especially numbness and tingling in finger tips and peripheral extremities. Sometimes improved by QHS dosing.

  • Cognitive slowing -> This is often the most limiting side effect of topiramate. Most studies agree this occurs in around 10% of patients. Symptoms include reductions in verbal fluency, processing speed, attention, and memory. 6


Serious side effects include:

  • Metabolic acidosis: May cause a hyperchloremic non- anion gap metabolic acidosis. Suggest obtaining baseline and periodic serum bicarbonate levels.

  • Kidney stones: Increases risk for development of calcium phosphate kidney stones. Encourage patients to stay adequately hydrated.

  • Spontaneous glaucoma: Inhibition of carbonic anhydrase may lead to secondary narrow angle-closure glaucoma. This is, essentially, blocked drainage canals in the eye, resulting in a sudden rise in intra-ocular pressure. Warn patients to seek immediate care from an eye specialist if these symptoms occur.

  • Increased risk for suicidality

  • Overdose-> characterized by altered mental status, GI upset, ataxia, and metabolic disturbances. No fatalities reported.


METABOLISM


•Topiramate increases phenytoin and valproic acid levels.


•Topiramate will decrease levels of oral contraceptives, so recommend use of an additional form of birth control (eg, condoms, spermicide).


Carbamazepine and phenytoin decreases topiramate levels.


Avoid the use of topiramate in combination with other medications that are carbonic anhydrase inhibitors (ex. acetazolamide) as this further increases the risks for kidney stones, metabolic acidosis, and spontaneous glaucoma.



CONCLUSIONS


Great work today. You have now finished the third theme in the Bullet Psych curriculum. Congratulations! We have now covered the psychotic disorders theme, the depressive disorders theme, and the bipolar disorders theme. Next up: Anxiety disorders!



Resources for today's post include the Maudsley Prescribers Guide, Stahl's Essentials for Psychopharmacology, and Pocket Psychiatry.


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