Suicide rates in the U.S. have increased for the first time in a decade, according to a report published in October by the Johns Hopkins Bloomberg School of Public Health. But what leads a person to commit suicide? Three new studies suggest that the neurological changes in a brain of a suicide victim differ markedly from those in other brains and that these changes develop over the course of a lifetime.

The most common pathway to suicide is through depression, which afflicts two thirds of all people who kill themselves. In October researchers in Canada found that the depressed who commit suicide have an abnormal distribution of receptors for the chemical GABA, one of the most abundant neurotransmitters in the brain. GABA’s role is to inhibit neuron activity. “If you think about the gas pedal and brakes on a car, GABA is the brakes,” explains co-author Michael Poulter, a neuroscientist at the Robarts Research Institute at the University of Western Ontario.

Poulter and his colleagues found that one of the thousands of types of receptors for GABA is underrepresented in the frontopolar cortex of people with major depressive disorder who have committed suicide as compared with nondepressed people who died of other causes. The frontopolar cortex is involved in higher-order thinking, such as decision making. The scientists do not yet know how this abnormality leads to the type of major depression that makes someone suicidal, but “anything that disturbs that system would be predicted to have some sort of important outcome,” Poulter says.

Interestingly, this GABA receptor problem is not the result of abnormal or mutated genes. Rather the change is epigenetic, meaning some environmental influence affected how often the relevant genes were expressed—that is, made into proteins. [For more about epigenetics, see “The New Genetics of Mental Illness,” by Edmund S. Higgins; Scientific American Mind, June/July 2008.] In the frontopolar cortex of suicide brains, the gene for the GABA-A receptor often had a molecule called a methyl group attached to it, the team found. When a methyl group is attached to a gene, it keeps that gene hidden from cells’ protein-building machinery—in this case, preventing the cells from manufacturing GABA-A receptors.

The addition of this methyl tag, called methylation, occurs more extensively in rodents that are handled by humans than in rodents that are not. Less is known about what causes methylation in the human brain, but another recent study suggests it could be related to abuse during childhood. In May researchers at McGill University reported that the gene responsible for creating cells’ protein-building machinery is more frequently methylated in the hippocampus—the brain region responsible for short-term memory and spatial navigation—of depressed suicide victims who suffered child abuse than in the brains of nonsuicide victims who were not abused.

Again, the researchers do not yet know how problems with protein-building machinery lead to depression and suicide. But “it makes sense that if you have some limited capacity for protein synthesis, you gradually are depriving yourself of building critical synapses,” or connections between neurons, which could be important for staying happy, says co-author Moshe Szyf, a pharmacologist at McGill. “Our hypothesis is that there are social events early in life that kind of epigenetically program the brain,” he says. He and his colleagues are now comparing the brains of suicide victims who were abused with those of suicide victims who were not abused to see if their methylation patterns differ.

Even in the womb, epigenetic influences can change the developing brain in ways that increase the risk of eventual suicide. In February 2008 a study revealed that baby boys who are born either short or with low birth weight are more likely to commit violent suicide as adults than longer and heavier babies are, irrespective of their height and weight as adults. Similarly, baby boys born pre­maturely are four times more likely to attempt violent suicide than those born at full term.

The researchers, publishing in the Journal of Epidemiology and Community Health, suggest that the chemical serotonin, which is involved in fetal brain growth, may play a role. A stressful or deprived womb environment may interfere with the development of the fetus and its serotonin system; other studies have shown that the brains of people who exhibit suicidal be­haviors have reduced serotonin activity.

Ultimately, these findings reveal that suicide brains differ from other brains in multiple ways—in other words, “we’re really dealing with some sort of biological imbalance,” Poulter says. “It’s not an attitude problem.” And because epigenetic changes typically occur early in life, it may one day be possible to identify young people at risk for suicide by studying their methylation patterns and then to treat them with drugs that regulate this mechanism, Szyf notes.

Note: This article was originally printed with the title, "The Suicidal Brain".