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Review
. 2010;16(19):2103-12.
doi: 10.2174/138161210791516404.

Topiramate in the New Generation of Drugs: Efficacy in the Treatment of Alcoholic Patients

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Free PMC article
Review

Topiramate in the New Generation of Drugs: Efficacy in the Treatment of Alcoholic Patients

Bankole A Johnson et al. Curr Pharm Des. .
Free PMC article

Abstract

Predicated upon a neuropharmacological conceptual model, there is now solid clinical evidence to support the efficacy of topiramate for the treatment of alcohol dependence. Topiramate treatment can be initiated whilst the alcohol-dependent individual is still drinking - just when crisis intervention is most likely to be needed by a patient with or without his or her family asking the health practitioner for assistance. Because topiramate can be paired with a brief intervention, there is now the exciting possibility of treating most alcohol- dependent individuals in office-based practice or generic treatment settings. Topiramate's additional effects on other impulsedyscontrol disorders make it a particularly interesting compound for the treatment of other comorbid drug or psychiatric disorders. Additionally, future studies should explore whether topiramate can be combined with other putative therapeutic agents to increase its efficacy. One notable clinical challenge in the development of topiramate as a pharmacotherapy to treat alcohol dependence is the determination of the smallest dose that can result in efficacy, thereby achieving the optimum balance between therapeutic benefit and adverse event profile. Animal data do provide support for topiramate's general anti-drinking effects but also indicate that its mechanisms of action might rely on several complex pharmacobehavioral changes. Additional preclinical studies are needed to elucidate more clearly the basic mechanistic processes that underlie topiramate's efficacy as a treatment for alcohol dependence. Preclinical information that topiramate may have differential effects based on genetic vulnerability opens up the possibility of future methods to optimize treatment.

Figures

Figure (1)
Figure (1)
Schematic illustration of the hypothesized effects of acute and chronic alcohol, both with and without topiramate, on the cortico-mesolimbic dopamine (DA) reward circuit [57]. (Upper left) Acute alcohol suppresses the firing rate of ventral tegmental area (VTA) gamma-aminobutyric acid (GABA) neurons, which leads to less suppression of VTA DA neuronal activity. This disinhibition leads to VTA DA neuronal firing and DA release in the nucleus accumbens (N Acc.) [57]. (Lower left) With chronic drinking, VTA GABA neurons are hyperexcitable, mainly because of increased glutamatergic input, less GABA tone from the N Acc., and rebound firing of GABA neurons because of their long-term suppression from repeated alcohol ingestion. This leads to VTA DA hypofunction and decreased release (compared with the acute condition) of DA in the N Acc. [57]. (Upper right) During acute drinking, the GABAergic influence of topiramate probably predominates, particularly in the N Acc. This leads to greater inhibition of N Acc. DA neurons, and greater GABA tone from the N Acc. to the VTA suppresses VTA DA cell firing. Topiramate concomitantly inhibits the excitatory effects of glutamatergic neurons on DA neurons in the VTA and N Acc. These combined actions of topiramate should lead to profound suppression of DA neuronal activity and DA release in the N Acc. Hence, topiramate reduces the DA-mediated reinforcing effects of acute alcohol [57]. (Lower right) During chronic drinking, the predominant neuronal activity resides with the hyperexcitable state of VTA GABA neurons. Because of GABA-mediated inhibition and glutamatergic blockade of these neurons, topiramate “normalizes” VTA GABA neuronal activity. Although this would, at first, suggest that DA release in the N Acc. would be enhanced, this does not occur, and DA release in the N Acc. is most likely reduced because these N Acc. terminals are contemporaneously inhibited by GABA inhibition and blockade of glutamate (GLU). In the chronic drinker, the anti-glutamatergic and L-type calcium channel effects of topiramate to block sensitization might predominate. Hence, topiramate would make it easier for a chronic alcoholic to withdraw from alcohol because rebound DA release would not occur (if drinking were ceased abruptly), and topiramate would aid in relapse prevention because alcohol's reinforcing effects would be decreased [57]. Line weights represent relative strengths of neuronal activity (heavy, medium, and light). The broken line represents decreased tone. VP, ventral pallidum. Reprinted from Johnson [57] with the permission of John Wiley & Sons, Inc.

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