Genetic Markers May Predict Drug Dependence

Deborah Brauser

September 12, 2012

September 12, 2012 — Although specific endophenotypes may be associated with an increased risk of developing cocaine or amphetamine dependence, some siblings may be more resilient to these genetic factors, new research suggests.

Investigators assessed 50 people addicted to a stimulant, 50 nonaddicted biological siblings, and 50 unrelated healthy peers (control group). They found that both the addicted and nonaddicted sibling participants showed significant deficits in their executive functioning, slower response speeds, and increased presence of anxious-impulsive personality traits compared with the control group.

"I was somewhat surprised to see that the siblings shared such a high number of vulnerability factors with their dependent brother or sister, such as a lack of self-control, high levels of impulsive and compulsive behaviors, and a traumatic childhood. Yet they did not abuse drugs," lead author Karen D. Ersche, PhD, from the Department of Psychiatry Brain Mapping Unit at the University of Cambridge, United Kingdom, told Medscape Medical News.

Dr. Karen Ersche

"Now we need to understand what makes the siblings resilient against addiction," said Dr. Ersche.

She noted that the takeaway message for clinicians is that the deficits commonly seen in drug-dependent individuals, such difficulty with attention and self-control and a tendency to form habits quickly, are not necessarily a result of their drug use. Instead, these factors may be present before individuals start using drugs.

"Consequently, when these people stop taking drugs, it is likely that their problems will persist. The strategies that unaffected siblings successfully apply to overcome these problems in their daily lives may provide vital clues to help those trying to beat their addiction."

The study is published in the September issue of the American Journal of Psychiatry.

Reducing Stigma

"I feel very strongly about the widespread stigma attached to people who have become dependent on drugs," said Dr. Ersche.

"I believe that a better understanding of the underlying mechanisms involved in drug addiction has the potential to clarify the factors that put an individual at risk for dependence, and to facilitate more rational developments of effective interventions," she added.

As reported earlier this year by Medscape Medical News, Dr. Ersche and colleagues published a study in Molecular Psychiatry that showed that cocaine "ages the brain" and leads to more brain volume loss per year than is seen in people who have never used the substance.

And last year, the investigators found that individuals who are cocaine dependent have "abnormal structure of corticostriatal brain systems," which may help explain their compulsion to use the stimulant.

Dr. Ersche noted that the current study is important because relatively little is known about why people with a family history of addiction have an 8-fold higher risk of becoming dependent on drugs if they start experimenting with addictive substances.

"We wanted to understand the factors that may mediate this increased risk for addiction in people with a family history," she explained.

Shared Abnormalities

A total of 50 individuals addicted to either cocaine (94%) or amphetamines (6%), 50 biological siblings who had no history of substance abuse, and 50 healthy unrelated peers comprising the control group were included in this study.

All 150 participants were between the ages of 18 and 55 years; and the group of addicted individuals used stimulants for a mean of 16 years. A variety of neurocognitive and personality tests were administered to all.

"Measures of trait-anxiety, stress-sensitivity, and trauma history were used as markers of psychological stress or vulnerability," report the investigators.

Results showed that the 2 familial groups had significant differences in executive functioning tasks compared with the control group (P < .001) and compared with each other (also P < .001).

These tasks included assessments of working memory and mental planning.

The addicted group and the siblings group also showed significant differences in response control, as well as in emotional functioning, impulsivity-compulsivity, and self-evaluation vs the control group (all, P < .001).

Compared just with each other, the addicted group differed significantly from their siblings in the emotional, psychosocial, impulsivity-compulsivity, and self-evaluation domains (all, P < .005).

"We found that the sibling pairs shared a number of abnormalities that have been associated with addiction, despite only 1 of the pair-members developing the disorder," said Dr. Ersche.

However, "we cannot discriminate genetic from common environmental causes for their emergence," write the investigators. "Nevertheless, the distinction this affords between predisposing factors and drug-induced changes is still valuable."

Resilience Studies Needed

"Among the findings that appear salient in terms of mechanisms and consequences of substance use disorders, impulsive behavior...was strongly related to stimulant dependence," Alan C. Swann, MD, from the Department of Psychiatry and Behavioral Sciences at the University of Texas Health Science Center in Houston, writes in an accompanying editorial.

"Impulsivity is multifaceted, and one of the strengths of the Ersche et al. study was that the authors used laboratory-, behavioral-, and personality-based measures of traits related to impulsivity," writes Dr. Swann.

He notes that the role of early-life environmental disruptions was another "notable finding," but he also pointed out several study limitations.

"Probands and their siblings were exposed to stressful environments that could have had appreciable epigenetic consequences," he writes.

Also, the differences found in anxiety and impulsive traits, and in response control, between these 2 groups "may reflect previously inherited characteristics associated with susceptibility to substance use or may be the later epigenetic consequences of stimulant exposure."

He adds that, as mentioned by the investigators, the study also did not address why unaffected siblings were resilient to substance abuse.

"Our efforts have aimed at illness more than resilience, but a better understand of resilience mechanisms could provide new strategies for prevention and treatment," concludes Dr. Swann.

The study was supported by a grant from the Medical Research Council. Dr. Ersche and 1 of the study authors have disclosed no relvant financial relationships. The other 4 study authors and Dr. Swann report several relationships, which are listed in the original article.

Am J Psychiatry. 2012;169:926-936, 888-890. Abstract, Editorial