Genes May Play Key Role In Impulsive Aggression in BPD

Recent research suggests that people with borderline personality disorder may be genetically predisposed to the disorder and impulsive aggression.

“Impulsive acts of verbal and/or physical aggression are associated with domestic violence, workplace violence, and crimes involving physical assaults. Impulsive aggression has also been associated with personality disorders and is a major research focus because of the dire social consequences,” said Antonia New, M.D., an assistant professor of psychiatry at Mount Sinai School of Medicine/Bronx VA Medical Center.

New presented the research at a conference on borderline personality disorder last month in Bethesda, Md. The conference was organized by the Treatment and Research Advancements Association for Personality Disorder.

Twin studies have shown that the genetic contribution to borderline personality disorder is about 60 percent. The genetic contribution to impulsive aggression is estimated to be between 20 percent and 62 percent, said New.

She looked for candidate genes in the serotonergic system based on previous findings from studies that have consistently shown a decreased neuroendocrine response to serotonergic agents in impulsive aggression. In one study involving the serotonergic agent d,l-fenfluramine, there was a decreased prolactin response in patients with impulsive aggression, suggesting abnormal functioning of serotonin receptors, according to New.

However, a decreased prolactin response to fenfluramine was found most often in people with personality disorder who had attempted suicide and engaged in self-destructive behaviors, according to a study by New and other researchers published in the March 1997 Psychiatry Research. New told Psychiatric News that suicide attempts and self-injurious behaviors represent self-directed aggression.

In addition, the results of a brain imaging study by New and colleagues at Mount Sinai/Bronx VA showed that regions of the brain that inhibit aggression were not activated by a serotonergic agent, meta-chloropiperazine, in impulsive aggressive patients with personality disorders in contrast to normal controls (see story on Original article: page 29). The study was published in the July 2002 Archives of General Psychiatry.

New hypothesized that multiple genes and environmental factors contributed to the susceptibility involved in the complex behavior of impulsive aggression. “In this model, each gene provides a small contribution toward the susceptibility to impulsive aggression.”

She studied two candidate serotonin genes in large samples of patients with personality disorders. The first study looked at HTR1B, a gene with a presynaptic receptor that regulates and synthesizes serotonin. The study, published in the July 1, 2001, issue of Biological Psychiatry, had a sample size of about 90 subjects with personality disorders.

“Previous studies of mice found that the ones lacking HTR1B displayed more aggressive behaviors than the mice with HTR1B,” said New.

She did not find a similar association between HTR1B and impulsive aggression in human subjects. She found, however, that subjects with a G-allele variant of the gene had a higher number of suicide attempts compared with subjects with a C-allele variant of the gene.

An unpublished second study by New looked at HTR2A, a gene with a postsynaptic serotonin receptor that is widely distributed in the neocortex of the brain. The study involved nearly 140 subjects with personality disorders, she said.

“The results showed that subjects with an unexpressed variant of the gene had higher rates of self-injurious acts than subjects with an expressed variant of the gene,” said New.

“These preliminary findings show how subtle genetic variations of a serotonin receptor gene can increase or decrease susceptibility to behaviors associated with borderline personality disorder,” said New.

She emphasized that the gene candidate association findings are preliminary and need to be replicated.

“We plan to look at brain responses to provocation in patients with impulsive aggression to determine whether there are a smaller number of underlying genes that create susceptibility. This means that when we do candidate gene studies, genotyping of patients, and relating those genotypes to brain imaging results, we are more likely to find a reproducible finding,” said New. ▪