Over two years ago, the Chair of the DSM-5, David Kuyper admitted that despite telling patients for decades that they anticipated finding biomarkers for psychiatric disorders, that discovery continues to be “disappointingly” out of reach. The hope is that at some future time, the promise will become a reality. “In the future, we hope to be able to identify disorders using biological and genetic markers that provide precise diagnoses that can be delivered with complete reliability and validity.”
In “What are Biomarkers?”, Strimbu and Tavel said by definition, biomarkers are objective, quantifiable characteristics of biological processes. The WHO said a biomarker is almost any measurement that reflects the interaction between a biological system and a potential hazard. “The measured response may be functional and physiological, biochemical at the cellular level, or a molecular interaction.” They cautioned that the overreliance on biomarkers “presents a serious and persistent risk of producing misleading, and in some cases dangerous, erroneous conclusions.” And yet, in many areas of research, it appears this warning is ignored. Keep this in mind as we review here three different studies into biomarkers for—of all things—binge drinking.
A recent press release announced that a biomarker distinguishing binger drinkers from moderate drinkers among young adults has been found by researchers at the University of Illinois at Chicago. The press release suggested the biomarker, “called phosphatidyl ethanol (PEth), could be used to screen young adults for harmful or heavy drinking such as binge drinking.” The lead author for the study, Mariann Piano, said: “Using a biomarker of heavy alcohol consumption such as PEth along with self-reporting could provide an objective measure for use in research, screening and treatment of hazardous alcohol use among young adults.” But I’m not convinced that it would be an appropriate or even helpful screening tool as suggested.
The association of PEth to alcohol consumption has been known for some time, so the suggestion this was a “groundbreaking” research study examining “the relationship between biomarkers and alcohol consumption” by Brent McCluskey in The Fix was a bit misleading. McClusky later clarified that the study was “groundbreaking” because this was the first study to investigate PEth levels in young adults. A search of just the journal Alcohol and Alcoholism, where the Piano et al. study was published, indicated there were 34 total articles meeting the search criteria of “PEth.”
Dr. Lena Gustavsson was the winner of the ESBRA Award in 1994 for her work on phosphatidyl ethanol (PEth). Aradottir et al. reported in 2006 that PEth was a promising new marker for ethanol abuse. They found that blood concentrations of PEth were highly correlated to alcohol intake. “Its diagnostic sensitivity is higher than that for previously established alcohol markers.”
In 2011, Isaksson et al. noted that since the formation of PEth was specifically dependent upon ethanol, “the diagnostic specificity of PEth as an alcohol biomarker is theoretically 100%.” They added that the half-life of PEth in blood is around four days.
Helender et al. (2012) concluded that PEth was the most sensitive biomarker of current alcohol consumption and prior drinking because the PEth test can detect lower consumption levels.
Jain et al. in 2014 found strong associations between PEth and self-reported measures of alcohol consumption among young injection drug users. They suggested PEth may be a useful marker “in settings where alcohol consumption is difficult to assess,” or to confirm or refute self-reported measures of alcohol consumption.
Kechagias et al. (2015) concluded that PEth was the only marker that could discriminate between abstinence and a moderate daily consumption of alcohol.
So the PEth biomarker would help to confirm whether or not someone is honestly reporting their recent consumption of alcohol. It would NOT be a biomarker to identify at risk binge drinkers. And it seems to have little application for treatment other than as an “honesty test” in treatment to affirm or rule out recent alcohol consumption. It may be a more accurate or sensitive test than a breathalyzer, but that doesn’t strike me as groundbreaking news.
Biological Psychiatry had another study in its in June 2015 issue by Warnault et al. that suggested a gene variant, Met68BDNF, reduced the release of brain-derived neurotrophic factor (BDNF) in mice. These mice would consume excessive amounts of alcohol and continue to drink despite negative consequences. An NIH news release said the researchers treated the alcohol with bitter-tasting quinine. “This suggests Met68BDNF carriers compulsively drink alcohol despite aversive consequences.”
The implication is that in humans, this gene variant may put an individual at greater risk of developing an alcohol use disorder. By administering a pharmaceutical compound developed to mimic the action of BDNF, the researchers were able to stop the compulsive drinking behavior in the mice. “This compound (LM22A-4) may have potential as a therapeutic for humans. It appears to reduce compulsive drinking without a generalized effect on motivation.”
BDNF is a protein in humans that is encoded by the BDNF gene. It acts on certain neurons, “helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.” In the brain, it is active in areas vital to memory, learning and higher thinking. The BDNF gene may play a role in the regulation of stress response and in the biology of mood disorders. The expression of BDNF is reduced in Alzheimer’s and Huntingdon disease. Linda Gabriel described BDNF as Miracle-Gro for the brain.” If you’re interested, Alomone Labs is offering a free sample of human BDNF.
Although an interesting finding, it has only been demonstrated within mice at this point in time. If further research were to show that Met68BDNF in humans was associated with a higher risk of alcohol use disorders, compounds like LM22A-4 may help in reducing the neurochemical element in craving or compulsive drinking. But there’s more to compulsive drinking than just biology and neurochemistry.
The most interesting study to me was reported in News & Views for The Scripps Research Institute. Herman et al. reported that the deletion of GIRK3 subunits (G-protein-gated inwardly rectifying potassium) in mice. They compared “knockout” mice, ones missing GIRK3, with normal mice. During a simulated “happy hour” when access to alcohol was limited to two hours a day, GIRK3 knockout mice consumed significantly more alcohol than the control group of normal mice. When mice were given continuous access to alcohol, conditions where mice do not get intoxicated, the effect was not evident.
There was no difference found between the GIRK3 and control mice in how alcohol was metabolized. Both groups also experienced a similar loss of balance, sleepiness and reduced body temperature in response to alcohol. The researchers thought there were two possibilities. Mice without GIRK3 could be drinking more because they felt more pleasure from alcohol, so they wanted to drink more. Or they felt less pleasure and thus needed to drink more to reach the same level of pleasure as normal mice.
In order to answer this question, they looked at the mesocorticolimbic dopaminergic pathway (the reward pathway in the brain) and found that the pathway was completely insensitive to alcohol without GIRK3. Even at high doses, alcohol did not alter the firing of neurons missing GIRK3. Alcohol also failed to trigger the release of dopamine in the ventral striatum of GIRK3 mice. The results suggested that mice drink more alcohol to boost the engagement of other neural pathways mediating alcohol’s rewarding effects.
By reintroducing GIRK3 in the knockout mice, the researchers were able to alter the binge drinking down to normal levels. Normal mice with increased GIRK3 drank even less. “This has led the researchers to believe that a compound selectively targeting GIRK3-containing channels may hold promise for reducing alcohol consumption in heavy binge drinkers.” An abstract for the study published in the Proceedings of the National Academy of Sciences can be found here.
PEth, BDNF, and GIRK3 are all biomarkers of some sort that are being applied to the potential hazard of “binge drinking.” As Strimbu and Tavel observed, the key issue is determining the relationship between any given biomarker and the relevant clinical endpoints, which in this case is binge drinking. In some cases, biomarkers may be shown to measure the process of a key pathway stage in reaching the clinical endpoint of binge drinking. But assuming this relationship risks mistaking correlation for causation. PEth seems to be an example of a correlational biomarker. And caution needs to be exercised at this point with any conclusions drawn from the findings of studies with BDNF and GIRK3.
While there is growing evidence of a genetic connection with alcoholism, the evidence is not conclusive at this time. Following Carleton Erickson, I’d say that while alcohol dependence runs in families, it is not purely a genetic disease. “Rather, the tendency to become alcoholic is inherited. Thus alcoholism can skip generations, or affect only certain individuals in an alcoholic family.” See “The Genetic Connection” for more discussion on genetic research into alcohol dependence.