How does Topamax (topiramate) induce weight loss?

From the Guidelines

Topamax (topiramate) induces weight loss through several mechanisms affecting the brain and metabolism, including reducing appetite, enhancing feelings of fullness, and increasing energy expenditure, as supported by the most recent study from 2023 1. The exact mechanism of action of topiramate is unknown, but it is thought to alter appetite and decrease energy intake by modulating gamma-aminobutyric acid receptors in relevant CNS structures, as noted in a 2022 study 1. Some key points about topiramate and weight loss include:

• Topiramate has been shown to reduce energy intake in animals and humans, and may increase energy expenditure in rodents, although this effect has not been demonstrated in humans 1.
• The combination of phentermine and topiramate extended-release (ER) has been FDA-approved for the treatment of obesity since 2012, and has been shown to lead to significant weight loss in clinical trials, with a 56-week study showing weight loss of 5.1% with the lower dose and 10.9% with the higher dose of phentermine-topiramate 1.
• Topiramate is typically started at a low dose of 25mg daily and gradually increased to an effective dose of 100-400mg daily, divided into two doses, with weight loss effects usually noticed within the first few months of treatment.
• Side effects of topiramate may include tingling sensations, cognitive slowing, fatigue, and kidney stones, so patients should stay well-hydrated, as noted in the 2022 study 1.
• While not FDA-approved specifically for weight loss, topiramate is sometimes prescribed off-label for this purpose, or in combination with phentermine as the FDA-approved medication Qsymia, as discussed in the 2023 review 1.

From the FDA Drug Label

The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease Table 8: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures Topiramate Dosage (mg/day) Adverse Event Placebo(N=216) 200(N=45) 400(N=68) 600-1,000(N=414) Fatigue 13 11 12 30 Nervousness 7 13 18 19 Difficulty with Concentration/Attention 17 9 14 Confusion 4 9 10 14 Depression 6 9 7 13 Anorexia 4 4 6 12 Language Problems <1 2 9 10 Anxiety 6 2 3 10 Mood Problems 2 0 6 9 Weight Decrease 3 4 9 13

Topamax (topiramate) induces weight loss by causing several side effects that contribute to this outcome, including:

• Anorexia: a decrease in appetite, leading to reduced food intake
• Weight decrease: a direct effect of the medication, with 2.5% to 13% of patients experiencing weight loss in clinical trials 2
• Fatigue: decreased energy levels, which may lead to reduced physical activity and caloric expenditure
• Nervousness: increased anxiety or agitation, potentially leading to decreased appetite or increased energy expenditure These side effects, particularly anorexia and weight decrease, are dose-related and more common at higher dosages of topiramate (200-1,000 mg/day) 2.

From the Research

Mechanism of Weight Loss

• Topiramate, an anticonvulsant drug, has been found to induce weight loss in adults with epilepsy 3.
• The exact mechanism of weight loss is not fully understood, but it is believed to be related to reduced caloric intake, particularly during early treatment 3.
• Weight loss with topiramate is primarily caused by a reduction in body fat mass 3.

Factors Influencing Weight Loss

• Baseline body mass index (BMI) is a significant predictor of weight loss with topiramate, with obese patients experiencing greater weight loss during continued therapy 3.
• Higher baseline BMI is correlated with greater weight loss at 1 year 3.
• Reduced caloric intake is strongly correlated with weight loss at 3 months, but this effect diminishes at 1 year as caloric intake returns to baseline levels 3.

Comparison with Other Antiepileptic Drugs

• Topiramate is one of the few antiepileptic drugs associated with weight loss, whereas others such as gabapentin, pregabalin, valproic acid, and vigabatrin are associated with weight gain 4.
• Topiramate's favorable weight profile makes it an attractive alternative to other antiepileptic drugs that cause weight gain 5.

Clinical Implications

• Topiramate's ability to induce weight loss is a valuable aspect of its therapeutic profile, particularly for patients with epilepsy who are at risk of weight gain due to other antiepileptic drugs 4, 6.
• The use of topiramate as a treatment for obesity has been explored, with some evidence suggesting its effectiveness in promoting long-term weight loss 7.