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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
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