Anticonvulsants. Several anticonvulsants have been investigated as experimental therapies in AUDs. Johnson and colleagues31 reported the efficacy results of an RCT of topiramate in 2003, which was extended to a multisite study.32 In the extension study, topiramate (up to 300 mg/d over 14 weeks) increased the percentage of abstinent days and decreased the percentage of heavy drinking days; the mean number of daily drinks; and γ-glutamyltransferase level, a laboratory measure of long-term alcohol-related biliary and liver injury. A recent meta-analysis confirmed the effectiveness of topiramate.33 Moreover, topiramate outperformed naltrexone on several drinking-related outcomes, including abstinence, harm-reduced drinking, and psychosocial dysfunction.34
The antiepileptic drug zonisamide also decreased the number of heavy drinking days, the number of drinks per week, and alcohol cravings scores in a single-site, 12-week RCT of alcohol dependence.35 Participants were given escalating doses of zonisamide (up to 500 mg/d) or placebo.
Antiepileptic drug treatment for alcohol dependence appears effective and may be considered in select patients, especially those whose drinking has not adequately responded to FDA-approved medications.
Neuropeptides. Alcohol’s ability to alleviate negative emotional states in stressful situations (eg, social anxiety) has implicated neuropeptidergic systems in the psychopathology of alcoholism. Many preclinical studies have implicated the hypothalamic-pituitary-adrenal axis in stress-induced relapse and cravings, and these findings are presently being translated into humans, especially genetic variation in the corticotropin-releasing factor (CRF) system and alcohol-related endophenotypes.36Although they did not prove to be effective in other stress-related psychiatric disorders (eg, unipolar depression), CRF and other neuropeptide receptor targets are rational thera-pies to decrease stress-induced drinking.
Other treatments and conditions. Although several studies have shown equivocal results with SSRIs, a recent study revealed enhanced response after stratification by age of onset and serotonin transporter genotype (5-HTTLPR).7,37 Carriers of the 5-HTTLPR S allele polymorphism with late-onset (older than 25 years) alcoholism had the best response to sertraline. On the other hand, S' allele carriers with early-onset (younger than 25 years) alcoholism displayed less drinking with placebo than with sertraline.
After findings suggested that the α1-adrenergic receptor antagonist prazosin is effective in reducing alcohol consumption in laboratory animals, a small pilot study was undertaken in humans. Prazosin (16 mg/d for 4 weeks) decreased stress- and cue-induced alcohol cravings, anxiety, and negative emotionality, presumably via its ability to dampen sympathetic activation.38 Given its potential to decrease stress-induced relapse and PTSD-related nightmares, prazosin is currently being evaluated in alcohol dependence as well as in alcohol dependence with comorbid PTSD.
The treatment of comorbid psychiatric disorders and AUDs has been especially fruitful in recent years. In a study of comorbid alcohol dependence and depression, patients were randomized to 200 mg/d of sertraline and 100 mg/d of naltrexone, sertraline alone, naltrexone alone, or double placebo.3 On drinking-related measures, the combination of the SSRI and naltrexone outperformed either treatment alone or double placebo. Interestingly, there was no significant difference in depression scores in the 4 treatment arms at the end of the 14-week study.
Our group has also completed an RCT that compared desipramine with paroxetine in co-occurring PTSD and alcohol dependence. The group that received desipramine had improved drinking-related outcome measures. Naltrex-one offered no additional benefit on drinking outcomes.40
There are several phases in the treatment of AUDs: intoxication, withdrawal, abuse, and dependence. Standard treatments exist to treat alcohol withdrawal, and the FDA-approved medications focus on treatment post-detoxification to prevent relapse. These medications have limitations, so research to evaluate new pharmacological agents is a high clinical priority. Several novel pharmacological mechanisms for AUDs have been evaluated, but more novel targets are needed.