The main finding of the present study is that low-dose topiramate given as a treatment adjunct is well-accepted and effective in reducing craving for alcohol and symptoms of anxiety and depression during the early phase of alcohol withdrawal. Furthermore, topiramate combined with a psychotherapeutic intervention improves abstinence from drinking during the first 16-week post-detoxification period, in comparison with alcohol-dependent individuals receiving psychotherapy alone.
Although topiramate is not currently approved for the treatment of alcohol dependence [27
], several randomized double-blind placebo-controlled trials have demonstrated its efficacy in improving drinking behaviour and maintaining abstinence[28
]. Compared to the standard medications approved for alcohol dependence, topiramate has been found to be inferior to disulfiram in terms of days to relapse [31
] and superior to naltrexone in reducing craving [32
] and improving some other critical measures of drinking behaviour [30
]. The precise mechanism of topiramate's favourable action is unclear. It may be that it modulates GABAergic transmission in the central amygdala, a brain region implicated in the regulation of emotionality and alcohol intake [33
]. Also, it has been shown that GABA receptors undergo allosteric modulation by ethanol and mediate the acute and chronic effects of alcohol, including tolerance, dependence and withdrawal [35
]. On the other hand, topiramate enhances the inhibitory function of GABA, antagonizes excitatory glutamate receptors, and inhibits dopamine release [36
Topiramate has been used for the treatment of alcohol dependence in outpatient settings. Doses ranging from 150 to 300 mg/day have shown promising results, in terms of significant improvement in several dependence-related parameters [3
]. However, a major concern has been topiramate's adverse effects, which are prominent especially during the titration period, appear to be dose-related but usually subside with continued treatment [37
]. Thus, the majority of patients who discontinue topiramate treatment, due to its side effects, do so early in treatment. In this line of thought, a key objective of the present study was to establish the efficacy and side effect profile of low-dose topiramate (up to 75 mg/day) that might improve adherence to treatment. In our sample, a considerable proportion (> 10%) of the topiramate augmentation group had some adverse effects, but no significant difference was recorded compared with the control group. However, these adverse effects were tolerable and there were no dropouts from the study. This was probably due to several reasons such as that the initial detoxification took place in an inpatient basis assuring a high compliance with all treatment interventions, that the study population was highly motivated to withdraw from alcohol, and finally that our sample consisted of individuals with relatively high initial withdrawal symptoms who are usually excluded from most studies of outpatient populations.
Impulsive and compulsive behaviours play a crucial role in alcohol abuse, craving and relapse [39
]; therefore, medications with anticraving properties have been used for prevention of relapse. Several studies have demonstrated topiramate's efficacy in the management of impulsive, aggressive and self-harmful behaviour [42
], gambling [43
], eating disorders [44
], as well as an adjunct to SSRIs in obsessive-compulsive disorder [45
]. Thus, moderation of impulsivity with consequent minimization of craving might be responsible for the lower rates of relapse in the topiramate augmentation group. Moreover, research has consistently documented a strong association between anxiety and/or symptoms of depression and alcohol abuse; these symptoms usually subside following a few weeks of abstinence [46
]. However, mild anxiety [11
] and minor symptoms of depression may persist for several months and various medicines - including tiagabine [47
], mirtazapine and venlafaxine [12
] - have been used adjunctively to standard alcohol detoxification treatment in order to increase patient compliance and improve treatment outcome [10
]. Through such a collateral beneficial action, topiramate could lead to the more favourable outcome observed in the augmentation group of the present study.
The main limitations of the present study are: a) the relatively small sample size, which reduces the statistical significance of our findings, b) the study did not follow a double-blind placebo control design; such a design was not feasible due to the ethical restrictions of our institution, c) assessment of alcohol use during the follow-up period was mostly based on self-reports and periodically cross-checked with an informant and γ-GT measurements, and d) a longer follow-up period would provide important information on the long term efficacy of topiramate in a community setting. Despite the above limitations, our results corroborate previous reports that show the potential usefulness of topiramate in the treatment of alcohol dependence even when administered at low doses.