Gene variants that cause low expression of the brain chemical NPY are linked to negative emotional processing and higher risk of developing some major depressive disorders said US scientists in a new study published this week.

The team of University of Michigan-led researchers used three different approaches to show that people with a genotype that produces lower levels of neuropeptide Y (NPY) had measurably stronger brain responses to negative stimuli and psychological responses to physical pain and were more likely to be found among groups diagnosed with a major depressive disorder.

They hope their discovery will help doctors diagnose and treat depression and other psychiatric conditions earlier and help developers create therapies that can be adapted to suit the genetic profile of individual patients.

You can read how they arrived at their findings in the paper they wrote that was published online on 7 February in the Archives of General Psychiatry.

Previous studies have shown that NPY restores calm after stressful events.

With this study, senior author Dr Jon-Kar Zubieta, a professor of psychiatry and radiology and research professor at the Molecular and Behavioral Neurosciences Institute at the University of Michigan in Ann Arbor, and colleagues, discovered what happens when people don’t have enough of the brain chemical and what the reason might be.

They found that people with genes that cause lower levels of NPY are more responsive to negative stimuli in parts of the brain linked to emotion and this makes them less resilient to stress and more likely to develop a major depressive disorder.

Lead author Dr Brian Mickey, an assistant professor in the Department of Psychiatry at the University of Michigan Medical School and researcher at the university’s Molecular and Behavioral Neurosciences Institute, told the media that these genetic features can be assessed in any person and they hope they and other scientists will be able to use them to work out a person’s individual risk of developing depression and anxiety:

“This is what we mean when we talk about ‘personalized medicine’,” he explained.

The researchers also hope the discovery will add another piece of vital information to the “genetic map” of depression.

“This appears to be another mechanism, independent of previous targets in depression research, such as serotonin, dopamine and norepinephrine,” said Zubieta, whose disclosure information in the article shows he has acted as consultant to three major drug companies in the last year.

For their study, Zubieta and colleagues recruited a total of 179 participants: 44 individuals with major depressive disorder and 137 healthy controls.

With the help of genotyping by colleagues at the Laboratory of Neurogenetics at the National Institute on Alcohol Abuse and Alcoholism in Bethesda, Maryland, they established that 84% of the participants (152 individuals) had either low, intermediate or high expression of NPY.

They then used three approaches to examine the link between NPY gene expression and emotional processing.

For the first, they invited each participant to look at words with neutral, negative and positive emotional connotations (eg “material”, “murder”, “hopeful”) while they watched their brain activity using functional magnetic resonance imaging (fMRI).

They observed that in response to the negative words, participants with low NPY showed stronger activity in the prefrontal cortex than participants with high NPY. This part of the brain plays a key role in emotional processing.

Mickey said this observation shows that:

“… individuals with the risk-associated NPY gene variant tend to activate this key brain region more than other people, even in the absence of stress and before psychiatric symptoms are present.”

For the second approach, Zubieta and colleagues invited each participant to undergo a pain stress test where they received an injection of saline solution into a jaw muscle. The pain lasted about 20 minutes and there was no lasting harm from the procedure. The researchers adjusted the level of the pain until it registered a 4 on a scale of 1 to 10 for each participant.

The participants described how positive or negative their feelings were before and after the pain challenge.

The results showed that those with low NPY expression reported more negative feelings both before and after the pain challenge, which the researchers said suggests they were more emotionally affected while anticipating the stress challenge and also when they thought about it afterwards.

And in the third approach, they compared NPY genotypes in the two groups and found that the group with major depressive disorder had a higher proportion of participants with low expression of NPY.

They concluded that:

“These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices.”

“These genetically influenced neural response patterns appear to mediate risk for some forms of MDD [major depressive disorder],” they added.

Zubieta said these findings go further than just linking a gene to an illness:

“We’re expanding the understanding of the physiology of depression,” he said.

Funds from from the National Institutes of Mental Health, National Institute on Drug Abuse, the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, and the Phil F Jenkins Research Fund helped pay for the study.

“Emotion Processing, Major Depression, and Functional Genetic Variation of Neuropeptide Y.”
Brian J. Mickey, Zhifeng Zhou, Mary M. Heitzeg, Elizabeth Heinz, Colin A. Hodgkinson, David T. Hsu, Scott A. Langenecker, Tiffany M. Love, Marta Peciña, Tal Shafir, Christian S. Stohler, David Goldman, Jon-Kar Zubieta.
Arch Gen Psychiatry, Vol 68, No 2, pp 158-166, Published online 7 Feb 2011.
DOI:10.1001/archgenpsychiatry.2010.197

Additional source: University of Michigan Health System (press release, 7 Feb 2011).

Written by: Catharine Paddock, PhD