The goal of typology research is to identify subtypes of alcohol dependent (AD) patients sharing fundamental characteristics and try to match each subtype, with the most precise treatment strategy. This review provides a comprehensive history of the literature on alcohol dependent subtypes starting from the earliest attempt made by Jellinek. The binary models identified most closely with Cloninger and Babor as well as the successively more complex classifications are discussed. Typology classification potentially useful in guiding the treatment of AD patients, especially in the case of the serotonergic medications. Contrasting data suggests that other factors could influence the response to a medication and/or that more complex typologies should be identified. In summary, typology models may assist in the ascertainment criteria for clinical trials performed in behavioral and pharmacotherapeutic interventions. Greater emphasis, however, must be made to more clearly delineate this field of research, while moving toward more standardized typologies.

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Background There is a need to identify novel pharmacological targets to treat alcoholism. Animal and human studies suggest a role of ghrelin in the neurobiology of alcohol dependence and craving. Here, we were the first to test the hypothesis that intravenous administration of exogenous ghrelin acutely increases alcohol craving. Methods This was a double-blind placebo-controlled human laboratory proof-of-concept study. Non-treatment seeking alcohol-dependent heavy drinking individuals were randomized to receive intravenous ghrelin 1mcg/kg, 3 mcg/kg or 0 mcg/kg (placebo), followed by a cuereactivity procedure, during which participants were exposed to neutral (juice) and alcohol cues. The primary outcome variable was the increase in alcohol craving (also called “urge”) for alcohol, assessed by the Alcohol Visual Analogue Scale. Results Out of 103 screenings, 45 individuals received the study drug. Repeated measures of ANCOVA revealed a group effect across ghrelin doses in increasing alcohol craving (p < .05). A dose-specific examination revealed a significant effect of ghrelin 3 mcg/kg vs. placebo in increasing alcohol craving (p < .05) with a large effect size (d = .94). By contrast, no significant ghrelin effect was found in increasing either urge to drink juice or food craving (p: n.s.). No significant differences in side effects were found (p: n.s.). Conclusions Intravenous administration of exogenous ghrelin increased alcohol craving in alcohol-dependent heavy drinking individuals. Although the small sample requires confirmatory studies, these findings provide preliminary evidence that ghrelin may play a role in the neurobiology of alcohol craving, thus demonstrating a novel pharmacological target for treatment.

Animal studies suggest that the gut-brain peptide ghrelin plays an important role in the neurobiology of alcohol dependence (AD). Human studies show an effect of alcohol on ghrelin levels and a correlation between ghrelin levels and alcohol craving in alcoholics. This investigation consisted of two studies. Study 1 was a 12-week study with alcohol-dependent subjects, where plasma ghrelin determinations were assessed four times (T0-T3) and related to alcohol intake and craving [Penn Alcohol Craving Score (PACS) and Obsessive Compulsive Drinking Scale (OCDS)]. Serum growth hormone (GH) levels and assessment of the nutritional/metabolic status were also performed. Study 2 was a pilot case-control study to assess ghrelin gene polymorphisms (Arg51Gln and Leu72Met) in alcohol-dependent individuals. Study 1 showed no significant differences in ghrelin levels in the whole sample, while there was a statistical difference for ghrelin between non-abstinent and abstinent subjects. Baseline ghrelin levels were significantly and positively correlated with the PACS score at T1 and with all craving scores both at T2 and T3 (PACS, OCDS, obsessive and compulsive OCDS subscores). In Study 2, although there was a higher frequency of the Leu72Met ghrelin gene polymorphism in alcohol-dependent individuals, the distribution between healthy controls and alcohol dependent individuals was not statistically significant. This investigation suggests that ghrelin is potentially able to affect alcohol-seeking behaviors, such as alcohol drinking and craving, representing a new potential neuropharmacological target for AD.

Serotonin (5-HT) regulates important biological and psychological processes including mood, and may be associated with the development of several psychiatric disorders. An association between psychopathology and genes that regulate 5-HT neurotransmission is a robust area of research. Identification of the genes responsible for the predisposition, development, and pharmacological response of various psychiatric disorders is crucial to the advancement of our understanding of their underlying neurobiology. This review highlights research investigating 5-HT transporter (5-HTTLPR) polymorphism, because studies investigating the impact of the 5-HTTLPR polymorphism have demonstrated significant associations with many psychiatric disorders. Decreased transcriptional activity of the S allele (“risk allele”) may be associated with a heightened amygdala response leading to anxiety-related personality traits, major depressive disorder, suicide attempts, and bipolar disorder. By contrast, increased transcriptional activity of the L allele is considered protective for depression but is also associated with completed suicide, nicotine dependence, and attention deficit hyperactivity disorder. For some disorders, such as post-traumatic stress disorder and major depressive disorder, the research suggests that treatment response may vary by allele (such as an enhanced response to serotonin specific reuptake inhibitors in patients with major depressive disorder and post-traumatic stress disorder with L alleles), and for alcohol dependence, the association and treatment for S or L alleles may vary with alcoholic subtype. While some studies suggest that 5-HTTLPR polymorphism can moderate the response to pharmacotherapy, the association between 5-HTTLPR alleles and therapeutic outcomes is inconsistent. The discovery of triallelic 5-HTTLPR alleles (LA/LG/S) may help to explain some of the conflicting results of many past association studies, while concurrently providing more meaningful data in the future. Studies assessing 5-HTTLPR as the solitary genetic factor contributing to the etiology of psychiatric disorders continue to face the challenges of statistically small effect sizes and limited replication.

Antipsychotics cause Q-Tc interval prolongation at a higher rate than do antidepressants, and the typical anti-psychotics thioridazine, pimozide, and i.v. haloperidol all have the highest potential for Q-Tc interval prolongation. Tricyclic antidepressants have a higher rate of Q-Tc interval prolongation than do the SSRIs, particularly at higher concentrations and in overdose situations. The frequency of adverse events associated with drug-induced Q-T interval prolongation is unknown.

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