Topiramate in Bipolar Disorder and Comorbidities: The Myths and the Evidence

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BIPOLAR UPDATE

There appears to be some confusion regarding the efficacy of topiramate in bipolar disorder. Some prescribers think it is effective for mania, depression, or simply for “mood.” The evidence does not support this: all studies found no efficacy.¹ Also, topiramate has a significant adverse effect burden, including the infrequent but serious problems of kidney stones (in more than 2% of patients),² glaucoma, and suicidal ideation, and the more common problems (disliked by patients) of cognitive and memory impairment, numbness and tingling in the extremities, and hyperchloremic acidosis (present in up to 40% of patients²—check electrolytes and you will see) which can give a variety of non-specific symptoms that include dizziness, nausea, and fatigue. Topiramate is FDA approved for seizures and for migraine prophylaxis.

There are some off-label proposed uses for topiramate in comorbidities that are common in patients with bipolar disorder. It has been used as an adjunct to olanzapine to mitigate or even prevent weight gain.³ This is not recommended as something to do routinely (because of all those adverse effects), but at times this can be helpful and worth the risks. Topiramate in low doses (up to 92 mg) is a component of a weight loss combination product (with phentermine) that is on the market.

Some patients with bipolar disorder who experience weight gain also have binge eating disorder (BED). There is only one FDA-approved medication for this: lisdexamfetamine. However, patients with bipolar disorder not currently on a good dose of a mood stabilizer and who have comorbid BED would likely not benefit from lisdexamfetamine or any other stimulant (nor with any antidepressant, some of which also have positive studies in BED).⁴ Topiramate has 2 positive studies in BED with good results so you might think of it for them.

Some substance abuse disorders (SUDs) may benefit from topiramate for prevention of relapse. There may be mild benefit in alcohol use disorder,⁵ and there are 2 positive studies of patients with cocaine use disorder, only 1 of which showed benefit at end point—at doses up to 300 mg daily.⁶ Note that all of these studies used substantial doses of topiramate. One encounters patients on low doses like 25 mg twice a day. These may be placebo-level doses for any of the possible SUD indications.

Several trials have examined the effect of topiramate on posttraumatic stress disorder (PTSD). In 2 studies, there was no difference from placebo, but 1 study conducted in Brazil on 70 civilian patients found a good effect size. The reduction in the Clinician-Administered PTSD scale was 58 on topiramate and 32 on placebo, p = 0.008.⁷

Three small placebo-controlled trials of topiramate at up to 200 mg daily in patients with borderline personality disorder (BPD) are all from the same research group in Germany/Austria. Large improvements in hostility, interpersonal sensitivity, and anxiety symptoms were reported, larger than have been seen in other psychopharmacology studies of BPD.⁸ Although the papers identify no funding source, the UK NICE Guideline Development Group (GDG), suspicious about the large effect sizes, attempted without success to get more information about the funding from the authors and the publishing journals. Their interesting conclusion was “. . . as the GDG were unable to gain clarity in this regard, they took the decision not to consider their trials when drawing up their conclusions.”⁹ Clearly, these studies need replication.

Dr Osser is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA. The author reports no conflicts of interest concerning the subject matter of this article.

References

1. Pigott K, Galizia I, Vasudev K, et al. Topiramate for acute affective episodes in bipolar disorder in adults. Cochrane Database Syst Rev. 2015; 9(9): CD003384. PMID: 27591453

2. Dell’Oro VG, Belotti EA, Simonetti BG, et al. Metabolic disturbances and renal stone promotion on topiramate: a systematic review. Br J Clin Pharmacol. 2013;70(6):958-964

3. Narula PK, Rehan HS, Unni KES, Gupta N. Topiramate for the prevention of olanzapine associated weight gain and metabolic dysfunction in schizophrenia: a double-blind, placebo-controlled trial. Schizophr Res. 2010:118:218-223.

4. McElroy S, Hudson JI, Capece JA, et al. Topiramate for the Treatment of Binge Eating Disorder Associated With Obesity: A Placebo-Controlled Study. Biol Psychiatry. 2007;61(9):1039-1048.

5. Palpacuer C, Duprez R, Huneau A, et al. Pharmacologically Controlled Drinking in the Treatment of Alcohol Dependence or Alcohol Use Disorders: A Systematic Review with Direct and Network Meta-Analyses on Nalmefene, Naltrexone, Acamprosate, Baclofen and Topiramate. Addiction. 2018;113(2):220-237.

6. Singh M, Keer D, Klimas J, et al. Topiramate for Cocaine Dependence: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Addiction. 2016;111(8):1137-1146.

7. Yeh MSL, Mari JJ, Costa MCP, et al. A double-blind, randomized controlled trial to study the efficacy of topiramate in a civilian sample of PTSD. CNS Neurosci Ther. 2010;175:305-310.

8. Loew TH, Nickel MK, Muehlbacher M, et al. Topiramate treatment for women with borderline personality disorder: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2006;25:61-66.

9. National Institute for Clinical Excellence (NICE). Borderline Personality Disorder: Treatment and Management. January 28, 2009. Accessed July 13, 2020. www.nice.org.uk/CG78❒