Topamax (topiramate), oddly enough, is a derivative of fructose. It is strange that one of the very few psychotropics to cause weight loss is closely related to sugar, but there you have it. It is only approved as adjunctive therapy for seizure treatment by the FDA. Like many of the newer generation of putative mood stabilizers, Topamax enhances the activity of the neurotransmitter GABA, and monkeys around with sodium channels in the neurons, limiting repetitive firing. But authorities are quick to admit that we haven't a clue as to how Topamax actually works.

Before wading into the muddy waters of whether Topamax is effective for bipolar disorder, let's look at one thing that everybody can agree on: Topamax causes weight loss. Both the more extensive epilepsy literature and the recent psychiatric studies consistently report average weight losses from 5 to 15 lbs., depending on the length of the study and the dose of the drug. In the bipolar disorder studies, significant weight loss occurred pretty quickly, often within 5 to 10 weeks. In this sense, Topamax is a definite crowd-pleaser for our patients, whether it helps to stabilize their mood or not.

In terms of efficacy, TCR's reading of the literature is that Topamax is probably not effective as monotherapy for acute mania, but that it works pretty well as adjunctive therapy for treatment resistant bipolar disorder. All of the published studies have been open-label, either retrospective chart reviews or prospective open-label trials. While TCR often slams drugs that have no better quality of evidence than this, we have to admit that there is an impressive number of published trials, and that the results are pretty consistently positive for Topamax (1). The typical result is that Topamax add-on results in improvement in 50-60% of patients. These trials are usually pretty short, in the range of 4 to 10 weeks, which is a problem because we all know that treatment-resistant bipolar patients basically require life-long treatment, so a couple of months is a drop in the bucket.

One longer term study is worth describing, because it was done well and it provides some potential clinical guidelines for our use of Topamax. Susan McElroy and her colleagues at the University of Cinncinatti devised a study to see whether adding Topamax to the existing regimens of bipolar patients would make any difference (2). All of the 56 subjects had failed prior mood stabilizer trials. Topamax was added gingerly to their regimens, starting with 25 to 50 mg QD and was increased by 25 to 50 mg every 3 to 14 days. These patients were then regularly assessed with standard rating scales, and the mean duration of treatment was about 7 months; the average final dose of Topamax was 245 mg QD.

The results were fairly dramatic, in that adjunctive Topamax worked great for the 63% of patients who entered the study with hypomanic, manic, or mixed symptoms, but it didn't do much of anything for most of the patients with bipolar depression. One irksome finding, however, was that there was a 54% drop-out rate. Most of these patients did not drop out because of side effects but rather because they weren't getting better quickly enough. As any clinician knows who works with the bipolar population, long-term stick-to-itiveness with a given medication is not a cardinal feature: the disease simply causes too much suffering to allow for patience.

The bottom-line from the McElroy study: use Topamax as add-on for your bipolar patients when they have some manic component to their presentation; it's unlikely to be helpful when they are depressed.

A nice chart review published by Marcotte and colleagues reviewed the results of adding Topamax to the regimens of 58 treatment refractory patients, most of whom had either bipolar disorder or schizoaffective disorder, and 44 of whom were rapid cyclers (3). Topamax was started at 25 mg BID, and was increased by 50 mg every 7 days, with an eventual mean dose of 100 mg BID. The response was good, with 62% improving moderately or markedly. Interestingly, most responders noted improvement within 3 days of starting the medication, although other studies have reported longer kick-in periods.

Thus, Topamax appears to deserve a niche in our armamentarium, especially for treatment-refractory patients. What are its problems? Its biggest ones have earned it the nickname “Dopamax:”side effects of cognitive slowing and sedation. The PDR lists rates of psychomotor slowing, memory loss, and confusion as 13%, 12%, and 11%, respectively, and a 29% prevalence of somnolence. Anecdotally, real world office practice figures are probably higher than these. The "Dopamax" effects tend to be dose-related, so titrate slowly, and be prepared to stop at the first sign of a response. Most clinicians shoot for a dose range of 100-200 mg QD to maximize response while minimizing side effects.

An odd side effect of Topamax is the development of kidney stones in 1-2% of patients taking it, which is about 3 times higher than the rate in the general population. This is apparently caused by the fact that Topamax is a weak carbonic anhydrase inhibitor. Also, Topamax is a weak 3A4 inducer, and can decrease the levels of oral contraceptives dangerously.

As a final note, these days, you can't really discuss Topamax without mentioning Zonegram (zonisamide). This is because Zonegram, like Topamax, is a novel anticonvulsant with some data for efficacy in bipolar disorder (3) and which is great for weight loss. A recent JAMA study of obese, psychiatrically healthy, patients documented a whopping average weight loss of 20 pounds on Zonegram after 8 months, vs. only 4 pounds on placebo. Like Topamax, Zonegram can cause fatigue, cognitive impairment, and kidney stones. Unlike Topamax, however, Zonegram is a sulfa, so be wary of using it in patients with sulfa allergies.

TCR VERDICT: When you need to add-on, think Topamax.

<sub>1. McElroy SL, Suppes T, Keck PE, et. al. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry. 2000; 47:1025-33.
2. Marcotte D. Use of topiramate, a new anti-epileptic as a mood stabilizer. J Affect Disord. 1998; 50:245-51.
3. Kanba S, Yagi G, Kamijima K. The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18:707-715.
4. Gadde KM, Franciscy DM, Wagner HR II, et al. Zonisamide for weight loss in obese adults. JAMA. 2003;289:1820-1825</sub>