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Research News . . . . Topiramate in Bipolar Disorder Topiramate (Topamax®), a new novel anticonvulsant, is increasingly being used in the treatment of refractory mood disorders. A number of recent open-label (non-blind) studies have suggested that topiramate is an effective adjunctive treatment in bipolar disorder. A recent excellent review by Chengappa et al. (2001)1 points out many of the unique structural, pharmacological, and clinical properties of topiramate that have led to its increasing use in bipolar illness. We will summarize these characteristics of topiramate, review the published studies of topiramate in mood disorders, and note the adverse side effects that may occur when using this new treatment. We highlight the conundrum that while topiramate looks promising in open adjunctive studies, four recent placebo-controlled studies in acute mania have shown the drug to be ineffective in monotherapy and less effective than lithium. I. Structure and Pharmacology2 Topiramate is a sulfamate-substituted monosaccharide that was FDA-approved in 1996 for use in the United States in refractory partial-onset seizures as an adjunctive treatment. Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet formulation is about 80% compared to a solution. The bioavailability of topiramate is not affected by food. Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). The precise mechanism by which topiramate exerts its anti-seizure effect is unknown; however, electrophysiological and biochemical studies of the effects of topiramate on cultured neurons have revealed three properties that may contribute to its antiepileptic efficacy. First, action potentials elicited repetitively by a sustained depolarization of the neurons are blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action (shared by valproate, carbamazepine, and lamotrigine). Second, topiramate increases the frequency at which (gamma)-aminobutyric acid (GABA) activates GABAA receptors, and enhances the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter (like valproate). Third, topiramate antagonizes the ability of kainate to activate the kainate/AMPA ([alpha]-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; non-NMDA) subtype of excitatory amino acid (glutamate) receptor, but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate are concentration-dependent within the range of 1 µM to 200 µM. Topiramate also inhibits some isoenzymes of carbonic anhydrase (CA-II and CA-IV). This pharmacologic effect is generally weaker than that of acetazolamide, a known carbonic anhydrase inhibitor (more widely used for treatment of altitude sickness than for affective or seizure disorders). This action of topiramate (on carbonic anhydrase) contributes to its side-effects profile of renal calculi (kidney stones) and paresthesias (unusual tingling sensations). Topiramate is also a calcium channel inhibitor at the L-, N-, and possibly T-type channels as well. 1Chengappa KNR, Gershon S, and Levine J (2001). The evolving role of topiramate among other mood stablizers in the management of bipolar disorder. Bipolar Disorders 3: 215-232. 2 Topamax (topiramate) tablets. Physicians' Desk Reference (2002), Medical Economics Inc., Montvale, NJ. Click here to go to Ortho-McNeil Pharmaceutical Topiramate website Click here to see table of topiramate studies in mood disorders |