Afflicting 4% of the population worldwide, alcohol dependence is characterized by a sustained period of heavy alcohol use that leads to tolerance and results in withdrawal when consumption is stopped (1). This physical addiction impairs everyday functioning and is associated with negative health effects, including but not limited to high blood pressure, memory disorders, and sleep disturbance. It stands as the third leading cause of preventable death in the United States, and it rightly deserves its status as a major public health challenge because of its chronic, relapsing course (2).
At the core of alcohol dependence is a brain disorder. Thus, to tackle this disorder requires a certain level of respect, which clinicians demonstrate in their willingness to embrace the diverse nature of alcohol dependence cases. Identifying the age of onset is one of the simplest and most effective ways clinicians subtype alcohol dependence. If alcohol use becomes a problem before or after age 25, patients are categorized as early-onset drinkers or late-onset drinkers, respectively (2). This subtle difference now allows researchers to target pharmacological strategies more effectively. By abandoning a one-size-fits all approach to treatment and by recognizing subtypes within this disorder, researchers and clinicians may ultimately arrive at combinations of drug and behavioral interventions with better outcomes.
Some members of the scientific community now herald pharmacogenetics as one way to arriving at these better outcomes. This approach relies on identifying genetic differences to predict more effective drug choices (2). In the case of alcohol dependence, work with three drugs (naltrexone, ondansetron, and LY686017) powers the continued pharmacogenetic push within the field. Whereas naltrexone and ondansetron may be more effective for early-onset drinkers with certain genetic variations, LY686017 has shown promise with late-onset drinkers (1, 3, 4). These findings suggest that subtyping patients based on their history with alcohol and their genetics will unlock targeted treatment strategies for alcohol dependence.
Naltrexone and Early-Onset Drinkers
As one of three FDA-approved drugs for treatment of alcohol dependence, naltrexone has paved the way for pharmacogenetic discoveries. Patients who respond best to naltrexone often fall in the category of early-onset drinkers. Their strong desire to drink is coupled with a family history of alcohol dependence, which has pushed researchers to probe for genetic trends within this subtype (5).
Naltrexone acts on the endogenous opioid system, which is known for inducing euphoria and sedation when activated. Because naltrexone is thought to block alcohol’s feel-good effects by acting as an antagonist at the μ-opioid receptor, preliminary work focused on variations among patients in the gene that encodes for this receptor, OPRM1 (3). Patients with the Asp40 allele of OPRM1 have aspartic acid rather than asparagine at position 40 of this receptor protein, and this shift is suspected to make the receptor bind better to beta-endorphins. This increased affinity for beta-endorphins may lead to a greater euphoric response to alcohol consumption, thereby reinforcing this behavior and facilitating dependence (5).
Oslin and colleagues laid the groundwork by demonstrating that naltrexone treatment resulted in lower relapse rates for individuals with at least one copy of the Asp40 allele (3). This finding validated the potential for treatments that differentiate between genetic subtypes of alcohol dependence, so additional work with Asp40 carriers followed. Naltrexone is now thought to blunt the alcohol-induced euphoria more significantly in Asp40 carriers, and it may elevate GABAergic neurosteroids to help with its inhibition of the endogenous opioid system.
However, other pharmacogenetic studies focusing on this OPRM1 polymorphism and naltrexone have not repeated Oslin’s initial findings (5). Although it may be tempting to label naltrexone as the first successful genetically-targeted therapy for alcohol dependence, clinicians remain divided on this issue while awaiting additional findings.
Ondansetron and Early-Onset Drinkers
Interestingly, the early-onset drinking subtype has also been associated with the serotonergic system. Because of the role the serotonergic system may play in leading to alcohol dependence, genetic differences within this system have yielded additional pharamcogenetic targets. One key genetic difference is found in the serotonin transporter gene (5-HTTPR), which has long (L) and short (S) alleles. The early-onset drinking subtype is more commonly made up of individuals with the L/L genotype. This finding makes sense because the L allele of 5-HTTPR is more transcriptionally active, meaning that more serotonin transporters will be created and likewise found in membranes. Serotonin will be taken back into cells more quickly as a result, and intersynaptic concentrations of serotonin will decrease. Because there is less serotonin available in the synapse, serotonin receptors are up-regulated to counteract this deficit. Upon consuming alcohol, individuals with this up-regulation will have an increase in dopamine release in the nucleus accumbens, a known pleasure center within the brain. This process therefore associates drinking with stronger feelings of pleasure (4). The thought that individuals with the L/L genotype will have more serotonin receptors explains why ondansetron, a serotonin receptor antagonist, would be suspected to work more effectively in these individuals.
Kenna and colleagues initially tested this hypothesis by treating L/L, S/L, and S/S individuals with ondansetron, placebo, and sertraline, a selective serotonin reuptake inhibitor (4). Since subjects with the L/L genotype that received ondansetron drank fewer drinks per day than S/L or S/S subjects also receiving ondansetron, this experiment suggested that ondansetron may be more effective in treating L/L individuals. Work by Johnson and colleagues further validated this strategy with a larger subject pool. L/L variants treated with ondansetron once again drank fewer drinks per day than any other treatment group or genotype (6). In conjunction, these studies provide another potential way to treat individuals with early-onset alcohol dependence more effectively.
LY686017 and Late-Onset Drinkers
In contrast to early-onset alcohol dependence, late-onset alcohol dependence displays less heritability and tends to result from stressful triggers. As a result, the target for treatment shifts toward systems that mediate the stress response. While the stress response is traditionally considered as a cascade that begins with a release of CRH from the hypothalamus and ends with secretion of glucocorticoids from the adrenal glands, other neurotransmitters have been implicated within this response. For example, Substance P is thought to facilitate the stress response by binding neurokinin 1 receptor (NK1R) found in the hypothalamus, amygdala, and nucleus accumbens. Because of its suspected role within the stress response, NK1R has recently become a therapeutic target for alcohol dependence (1).
Initial work with NK1R-deficient mice explains why NK1R would be targeted for alcohol dependence treatment. Mice that did not express the NK1R receptor consumed less alcohol than wild-type controls, especially at higher alcohol concentrations where consumption is motivated by pharmacological rather than taste effects. In addition, NK1R-knockouts displayed increased sensitivity to alcohol relative to wild-type controls (1). Because treatment of alcohol dependence aims to decrease consumption, a drug that could inactivate the effects of this receptor could be clinically relevant in humans.
To recreate this effect in humans, George and colleagues chose a selective NK1R antagonist, LY686017, to treat anxious individuals diagnosed with late-onset alcohol dependence (1). By inactivating this receptor, LY686017 treatment resulted in decreased spontaneous as well as challenge-induced cravings for alcohol. Interestingly, fMRI studies revealed that the treated group had less activation of the insula, a region associated with cravings, in response to negative stimuli. Since the insula may also play a role in maintaining addictive behavior, LY686017’s ability to lead to reduced activation of this region is quite profound. This initial success should propel future studies to reproduce the positive effects of LY686017 on late-onset alcohol dependence, for future insights into NK1R antagonism may lead to efficacious drug development.
Conclusion
Three different drugs have shown promise within either early- or late-onset alcohol dependence. These drugs demonstrate how differentiating between types of alcohol dependence, even with criterion as simple as age of onset, can result in better outcomes for patients. Overlaying this strategy with genetic information further elucidates the correct choice for treatment. Naltrexone may have better outcomes for early-onset drinker with the Asp40 allele of OPRM1, and ondansetron seems to be more beneficial for patients with the L/L genotype for 5-HTTPR. For the late-onset drinkers, LY686017 shows promise. Throughout all of these cases, the findings were encouraging but did not warrant immediate incorporation of these drugs into contemporary treatment strategy. Whereas naltrexone is already approved for treatment, ondansetron and LY686017 must undergo more rigorous clinical trials before being integrated into clinicians’ toolboxes. As the pharmacogenetic trend grows, the work with alcohol dependence may serve as a template for future studies in other forms of addiction. By remembering that brain disorders are the foundation for addiction, pharmacology may come to replace willpower as the public’s choice for a remedy.
References
1. D. George et al., Science 319, 1536-1539 (2008).
2. B. A. Johnson, Am. J. Psychiat. 167, 630-639 (2010).
3. D. W. Oslin et al., Neuropyschopharmacol. 28, 1546-1552 (2003).
4. G. A. Kenna et al., Alcohol. Clin. Exp. Research. 33, 315-322 (2009).
5. L. A. Ray et al., Alcohol. Clin. Exp. Research. In press (2011).
6. B. A. Johnson et al., Am. J. Psychiat. 168, 265-275 (2011).