EXPERT ANALYSIS FROM THE ECNP CONGRESS

PARIS (FRONTLINE MEDICAL NEWS) – Genetic studies are finally making an impact in addiction medicine, as evidenced by the inclusion of three genomewide association studies in one expert’s list of the year’s top 10 developments in the field.

The three genetic studies that made their way onto this admittedly personal top 10 list of advances in addiction medicine include the surprising results of the first-ever genomewide association study of pathological gambling, a methylomic profiling study implicating a gene that regulates low-density lipoprotein cholesterol in the pathogenesis of alcohol use disorder, and a study that identified a specific microRNA as a regulator of motivation for cocaine, Philip Gorwood, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.

The genomewide association study of pathological gambling is particularly timely, because it provides additional supporting evidence of the wisdom of the authors of DSM-5 in placing pathologic gambling within the field of addiction, said Dr. Gorwood , who is professor of psychiatry at Paris Descartes University.

“This was an extremely important development, because it means pathologic gambling is a behavioral addiction,” said Dr. Gorwood, also head of the Clinic for Mental Illness and the Brain at Sainte-Anne Central Hospital in Paris. “This makes a difference to research because it means what we observe in the brain is really due to the patient’s behavior, to his or her choice to gamble, and not because they’re taking alcohol or cocaine or nicotine.”

His list of the year’s top 10 studies in addiction medicine follows:

Deep TMS in AUD

There is a general sense within the field of addiction medicine that transcranial magnetic stimulation (TMS) might have efficacy in some addictive disorders, but it has been hard to make a convincing case for the therapy when the mechanism is unknown.

Italian investigators have brought clarity in a study published in European Psychopharmacology ( 2017 May;27[5]:450-61 ) in which they randomized 11 patients with alcohol use disorder (AUD) to 4 weeks of real or sham deep TMS sessions, coupled with baseline and follow-up single-photon emission computed tomography (SPECT) imaging of dopamine transporter availability in the striatum of the dorsolateral prefrontal cortex. After 4 weeks, the group receiving real TMS showed a clinically important reduction in alcohol intake accompanied by a significant decrease in their elevated strial dopamine transporter availability, while sham-treated controls were unchanged. “This was a small study, but I loved the way the investigators merged a pilot clinical study with a biologic mechanism study,” Dr. Gorwood commented.

Coffee drinking and mortality

Investigators for a prospective cohort study of 521,330 people enrolled in the 10-country European Prospective Investigation into Cancer and Nutrition concluded that, during a mean 16.4 years of follow-up, participants in the top quartile of coffee consumption had a significantly lower risk of all-cause mortality, compared with those who did not drink coffee: a 12% reduction in men and a 7% reduction in women.

Moreover, the risk of mortality tied to digestive disease was reduced by 59% in high– versus non–coffee-consuming men and by 40% in women in this report from the International Agency for Research on Cancer, in Lyon, France . High–coffee-consuming women, but not men, also had a significant 22% reduction in circulatory disease mortality and a 30% lower risk of cerebrovascular disease mortality, compared with those who did not drink coffee.

Of particular interest to psychiatrists, the investigators also examined suicide risk. In a multivariate analysis, men in the third and fourth quartiles of coffee consumption were at 36% and 29% lower risk of death by suicide than those who did not drink coffee. Suicide in women occurred less frequently and was not related to coffee intake.

These various associations did not vary by country, even though coffee preparation methods vary considerably across Europe. And when the investigators excluded participants who died within 8 years of baseline, the results were unchanged, a finding that makes bias tied to reverse causality less likely as explanation for the results, the findings published in the Annals of Internal Medicine ( 2017 Aug 15;167[4]:236-47 ) showed.

“As addiction specialists, our patients often complain that we are forbidding everything. We are the bad guys: Don’t drink too much, don’t eat too much, and so on. The key finding in this European study is that you will not die of coffee drinking, even if you are having 8 cups a day. Yes, we know that coffee has a psychotropic effect, we know that you have a tendency to repeat its consumption, but it is really quite readily distinguishable from other addictive substances,” the psychiatrist said.

Smoking and violence

A few years ago when smoke-free policies were proposed in psychiatric inpatient settings, there was an uproar from staff.

“That was a huge mess,” Dr. Gorwood recalled. “The staff said, ‘Whoa, if you do that, I’m going to be killed by my patients. They are extremely addicted to cigarettes, and if they stop smoking tobacco during their hospitalization – when they already have very high anxiety – we are going to have an increase in violence.’ ”

Not so, as convincingly shown by investigators at King’s College London. They analyzed incident reports of physical assault 30 months before and 12 months after implementation of a no-smoking policy on the inpatient wards of a large London mental health organization. They scrutinized the 4,550 physical assaults that took place during the study period, 4.9% of which were smoking related and found that the number of physical assaults per month fell by 39% after the smoking policy change, according to the study, which was published in the Lancet Psychiatry ( 2017 Jul;4[7]:540-6) .

When an audience member said this reduction in ward violence struck him as counterintuitive and asked for an explanation, Dr. Gorwood noted that the London study wasn’t designed to address the mechanism of benefit. However, he speculated that a reasonable hypothesis prevalent among addiction specialists: Once an addict is no longer being triggered by an addictive substance, he or she will feel better.

“This is why we ask patients with any kind of dependence to stop doing it. They will feel better in terms of mood, well being, and optimistically in terms of violence,” Dr. Gordon said.

Skyrocketing alcohol misuse

The National Epidemiologic Survey on Alcohol and Related Conditions, conducted every 5-6 years by the U.S. National Institute on Alcohol Abuse and Alcoholism, enjoys great respect among addiction medicine specialists worldwide because it surveys tens of thousands of individuals and consistently employs the same methodology and definitions each time. This provides a degree of confidence regarding big-picture trends that’s not often found in European studies. The latest report from the survey is deeply concerning, according to Dr. Gorwood.

Investigators charted changing trends in 12-month rates of alcohol use, high-risk drinking, and AUD between the 2001-2002 survey, which included 43,093 subjects, and the 2012-2013 version, which included 36,309. The rate of alcohol use during the past 12 months increased by 11.2% across this 11-year time span, from 65.4% to 72.7%. Far more troubling: The rate of high-risk drinking climbed by 29.9%, from 9.7% to 12.6%; and the proportion of individuals meeting DSM-IV criteria for AUD jumped by roughly 50%, from 8.5% in 2001-2002 to 12.7% in 2012-2013.

Disproportionate increases in AUD were documented in women, with an 84% jump between the two survey periods; African Americans, with a 93% increase; Asian or Pacific Islanders, 78%; middle-aged individuals ages 45-65, with an 82% increase; and Americans aged 65 or older, with a whopping 107% increase.

These data “constitute a public health crisis,” according to the investigators. “Taken together, these findings portend increases in many chronic comorbidities in which alcohol use has a substantial role,” they added in the article, published in JAMA Psychiatry ( 2017 Sep 1;74[9]:911-23 ).

This unwelcome trend is surely not unique to the United States, in Dr. Gorwood’s view. “We need to figure out why we have such a big increase and what we should be doing about it,” he said.

Smoking cessation in pregnancy

A large Finnish prospective study in which virtually all births in the country’s two northernmost provinces in 1986 have been followed from pregnancy onward provides an optimistic new message regarding prevention of teenage smoking.

The adolescent offspring of Finnish women who quit smoking before becoming pregnant and continued to shun smoking as their child achieved age 15-16 years had the same low rate of daily smoking as those whose mothers never smoked: 10%. If the moms quit smoking during their first trimester, the rate of daily smoking by their teenage offspring at age 15-16 years was higher – 16% – but nonetheless lower than if she continued smoking beyond the first trimester – 25% – even if neither she nor the father smoked during their offspring’s teen years. If the mother continued to smoke after the first trimester and either she or the father smoked as their child grew up, the rate of daily smoking at age 15-16 years climbed to 37%; if both parents smoked, it was 41%, according to results of the study published in the journal Addiction ( 2017 Jan;112[1]:134-43 ).

“A take-home message: If you are a smoker and you quit before pregnancy, you abolish the increased risk, just as if you’d never been smoking in your life. It’s definitely good news,” Dr. Gorwood said.

ADHD medication and SUDs

All physicians who treat patients with attention-deficit/hyperactivity disorder get an earful from parents and patients who fear that the drugs will lead to addiction to stimulants. Reassuring evidence that this isn’t the case comes from a massive study of nearly 3 million adolescent and adult ADHD patients, median age 21, in a U.S. commercial health care claims database. The study endpoint was visits to emergency departments related to substance use disorders during 16 months of follow-up.

In within-individual comparisons, male patients had an adjusted 35% reduction in the likelihood of trips to the ED for substance use events during the months they received stimulant medications or atomoxetine, compared with the months they were off ADHD medication. Females had a 31% reduction during their on-treatment months ( Am J Psychiatry. 2017 Sep 1;174[9]:877-85 ).

“That’s the kind of information I like to share with my patients,” Dr. Gorwood commented. “It’s very easy to understand, and it gives them objective information that – although they may find surprising – treatment protects against addiction rather than leading to addiction.”

Divorce and new AUD

A Swedish national registry study of 942,366 married people born in 1960-1990, none with a history of AUD when they tied the knot, documented that divorce predicted a six- to sevenfold increase in new-onset AUD, compared with that of individuals who stayed married. Remarriage cut that risk by 50%-60% relative to those who did not remarry.

The relationship between marriage, divorce, and AUD was more complex than that, however. The level of drinking actually started to increase several years before divorce.

“A lot of patients will say, ‘Doctor, I’m drinking so much now because I’ve lost my wife, my life is miserable, and the only thing I have now is alcohol to make things feel better.’ But we could propose a different statement: ‘Maybe you got divorced because you drank too much alcohol.’ We wouldn’t say that to patients, of course, but we could help them to recognize their own paradoxical approach,” Dr. Gorwood said.

Widowhood was associated with a roughly fourfold increased risk of new-onset AUD, according to an article in the American Journal of Psychiatry ( 2017 May 1;174[5]:451-8 ).

Study of pathological gambling

A German multicenter team set out to identify genetic pathways involved in pathological gambling. They found a strong association with alcohol dependence, providing novel evidence of genetic overlap between a substance- and non–substance-related addiction. Unexpectedly, they also identified a shared genetic pathway between pathological gambling and Huntington’s disease that will provide a rich new avenue of research. Their results were published in the journal European Psychiatry ( 2016 Aug;36:38-46 ).

Gene implicated in alcohol use disorder

For several years, cardiologists have been agog over the unprecedented LDL cholesterol–lowering ability of a novel class of medications that inhibit the protein produced by the PCSK9 (proprotein convertase subtilisin/kexin 9) gene, which slows removal of LDL from the circulation. Ongoing studies of the PCSK9 inhibitors evolocumab and alirocumab are widely expected to report reductions in cardiovascular event rates far beyond what is achievable with statins.

Now investigators at the U.S. National Institute on Alcohol Abuse and Alcoholism have conducted a genomewide methylomic variation study that showed PCSK9 expression in the liver is dysregulated in patients with alcohol use disorder. They coupled this finding with a translational study in a mouse model of alcohol use disorder in which they demonstrated that alcohol exposure leads to PCSK9 downregulation, with resultant lowering of LDL.

Taken together, the results, published in Molecular Psychiatry (2017 Aug 29. doi: 10.1038/mp.2017.168), suggest that epigenetic regulation of PCSK9 by alcohol is a dynamic process in which exposure to small amounts of alcohol leads to less PCSK9 gene expression, less methylation, and lower LDL, while chronic heavy use leads to greater gene expression, unfavorable lipid levels, and eventually to low PCSK9 protein levels as a result of hepatotoxicity.

MicroRNA-495 and cocaine

Using genomewide sequencing techniques, investigators zeroed in on a specific microRNA known as miR-495 as an important posttranscriptional regulator of the expression of genes included in KARG , the Knowledgebase for Addiction Related Genes database. This small RNA is highly expressed in the nucleus accumbens, a key area of the brain involved in motivation and reward.

In rodent studies, the researchers showed that administration of cocaine rapidly downregulated miR-495 expression in the nucleus accumbens with an accompanying increase in expression of addiction-related genes known to be involved in specific substance use disorder–related biologic pathways. Moreover, when the investigators induced miR-495 overexpression in the nucleus accumbens, the animals lost motivation to seek and self-administer cocaine without having any effect on food-seeking, suggesting miR-495 selectively affects addiction-related behaviors, according to results of a study published in Molecular Psychiatry (2017 Jan 3. doi: 10.1038/mp.2016.238).

“I found this really convincing. There is converging evidence that we’re going to hear a lot more about miR-495 later on,” Dr. Gorwood said.

He reported having no financial conflicts of interest regarding his presentation.

bjancin@frontlinemedcom.com

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