Novel Compound May Help Stress-Related Alcohol Abuse

Fran Lowry

October 12, 2016

The novel compound ABT-436, a V1b receptor antagonist, may be particularly useful for treating people with alcohol use disorder who also have high anxiety and stress levels, new research shows.

"Vasopressin plays a significant role in regulating various complex behaviors, including compulsive alcohol consumption," first author Megan Ryan, clinical program director, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland, told Medscape Medical News.

"The compound that we studied appears to impact the withdrawal negative effect stage of the addiction cycle, reducing the frequency of drinking but not the consumption once drinking is initiated," Ryan said.

Megan Ryan

Funded by the National Institutes of Health, the study was published online September 23 in Neuropsychopharmacology.

Led by Raye Litten, PhD, acting director of the NIAAA's Division of Medications Development, the study included 150 men and women who met DSM-IV diagnostic criteria for alcohol dependence. The patients were randomly allocated to receive either ABT-436 or placebo, plus a computerized behavioural intervention, for 12 weeks.

"This computerized intervention consisted of seven different educational modules that are used to give people feedback on how much they are drinking and ways to stop drinking or reduce alcohol consumption," said Ryan, one of the program developers.

Dr Raye Litten

"Study participants would sit down at a computer when they came in for each clinic visit and play the module, which was 10 minutes long," she added.

ABT-436 is designed to block the effects of vasopressin, a neuropeptide produced in the hypothalamus of the brain.

"Vasopressin helps to regulate the pituitary adrenal axis and other brain circuits involved in emotion, and as such, it plays a role in regulating stress, anxiety, and their interaction with alcohol use disorder," Dr Litten said.

The primary outcome of the study was percentage of days of heavy drinking.

Overall, the percentage of heavy drinking days was lower for participants receiving ABT-436 than for those receiving placebo (31.3 vs 37.6), but the difference was not statistically significant (P = .172).

However, participants who received ABT-436 had a significantly greater percentage of abstinence days than those receiving placebo (51.2 vs 41.6; P = .37).

A similar result was shown for ABT-436 in smokers, the researchers say.

Smokers who received ABT-436 smoked significantly fewer cigarettes per week than those who received placebo (P = .046).

ABT-436 was well tolerated, with diarrhea being the most common side effect.

In a subgroup analysis, ABT-436 was more successful on curbing drinking in people with higher baseline levels of stress.

Among those individuals, those who received placebo reported heavy drinking 40% of the time, whereas among those who took ABT-436, the percentage of heavy drinking days was 29%.

"This drug does seem to show promise among the group with high anxiety, and so we believe that it has potential in these patients," Ryan said.

"We are hoping that someone else will take up where we left off. Our program's mission is to get initial findings out there and either hope that the pharmaceutical companies take over or even another grantee or another company that has a similar compound," she said.

"Disappointing" Results

"The study is very well done by a group of well-seasoned investigators and investigates a current hypothesis linking stress reduction and drinking with a relevant medication for reducing vasopressin activity, ABT-436," Thomas Kosten, MD, Waggoner Chair and professor of psychiatry, neuroscience, pharmacology, immunology, and pathology, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, told Medscape Medical News.

"The effect size is moderate, d = 0.3, for ABT-436 producing a greater percentage of days abstinent, which is somewhat disappointing, and the failure of the primary outcome, percentage of heavy drinking days to be significantly reduced with the treatment, is doubly disappointing, considering the hypothesized mechanism of action for ABT-436," Dr Kosten said.

"The subject selection may have reduced the ability to detect a more robust effect by its exclusion of all axis I disorders, since this V1b antagonist is expected to reduce anxiety and depression, and both of these disorders are common comorbidities with alcohol use disorder. The inclusion of panic disorder seemed unjustified, and I would have expected that if any specific disorder were included, PTSD [posttraumatic stress disorder] might be included among all the anxiety disorders," he said.

"Already stressed patients with PTSD plus alcohol use disorder would seem to align with the hypothesis for this trial of ABT-436 reducing stress-related drinking," he said.

"In the discussion, good reasons are given for selecting this more targeted population for future work. However, this study showed that ABT-436 did not reduce a direct and measurable anxiolytic effect in these anxious, 'normal' alcohol use disorder patients," Dr Kosten said.

"My final concern is a recurrent lack of validation for self-reported alcohol use and medication compliance. This validation seems of some concern because more participants discontinued medication related to AEs [adverse events] in the ABT-436 group than in the placebo group, minus eight vs zero, with half of these discontinuations due to diarrhea.

"Furthermore, diarrhea was more common and occurred in half the patients getting ABT-436. This might complicate commercial use of this medication, even if a next clinical trial shows similar or better efficacy by changing both the patient sample and the primary target outcome measure from heavy drinking to days of alcohol use," he said.

Neuropsychopharmacology. Published online September 23, 2016. Abstract

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