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ANN ARBOR, Mich. - Numerous studies have shown that the brain molecule

neuropeptide Y (NPY) helps to restore calm after stressful events. A team of

University of Michigan-led researchers has now found that people whose genes

predispose them to produce lower levels of NPY are more responsive to negative

stimuli in key brain circuits related to emotion - and are therefore less

resilient in the face of stress and may be at higher risk for developing a major

depressive disorder.

The scientists hope the research will eventually help with early diagnosis

and intervention for depression and other psychiatric illnesses, and in the

development of therapies that can be tailored to individuals based on their

genetic profiles. The findings were published Feb. 7 in the Archives of

General Psychiatry.

"This is what we mean when we talk about 'personalized medicine,' " says the

study's lead author, Brian Mickey, M.D., Ph.D., an assistant professor in the

Department of Psychiatry at the University of Michigan Medical School and

researcher at the U-M Molecular and Behavioral Neurosciences Institute. "These

are genetic features that can be measured in any person. We hope they can guide

us toward assessing an individual's risk for developing depression and

anxiety."

The findings also help fill in new areas on the genetic "map" of depression,

says the study's senior author Jon-Kar Zubieta, M.D., Ph.D., a professor of

psychiatry and radiology and research professor at the Molecular and Behavioral

Neurosciences Institute.

"We've identified a biomarker - in this case genetic variation - that is

linked with increased risk of major depression," Zubieta says. "This appears to

be another mechanism, independent of previous targets in depression research,

such as serotonin, dopamine and norepinephrine."

Using three separate approaches, researchers found that individuals with the

genotype that produces lower amounts of NPY had measurably stronger brain

responses to negative stimuli and psychological responses to physical pain. They

were also overrepresented in a population diagnosed with a major depressive

disorder.

Three approaches

Using three separate approaches, each with a varying number of research

subjects ranging from 58 to 152, U-M researchers and their partners studied the

link between NPY gene expression and emotional processing.

U-M researchers recruited and characterized participants, performed

neuroimaging, and conducted the pain challenge. Their partners at the Laboratory

of Neurogenetics at the National Institute on Alcohol Abuse and Alcoholism in

Bethesda, Md. performed the genotyping.

The research subjects were classified according to whether they had low,

medium or high NPY gene expression.

Using functional magnetic resonance imaging (fMRI), the scientists observed

the brain activity of each subject as he or she viewed neutral words (such as

"material") negatively charged words (like "murderer"), and positively charge

words (like "hopeful").

In response to negative words, subjects in the low NPY group showed strong

activation in the prefrontal cortex, which is involved with processing emotion,

while subjects with high NPY demonstrated a much smaller response.

"This tells us 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," says Mickey.

In a second test, healthy subjects reported their emotional experiences

during a stress challenge. Saline solution was injected into the jaw muscle,

which produces moderate pain for 20 minutes, but no lasting harm. The level of

pain was adjusted for each person to until it was, for them, a 4 on a scale of 1

to 10.

These subjects rated the positivity or negativity of their feelings both

before and after the pain challenge. Those in the low NPY group were more

negative both before and after the pain - meaning they were more emotionally

affected while anticipating the pain and while reflecting on their experience

immediately afterward.

Lastly, scientists compared the NPY genotypes of subjects with major

depressive disorder with control subjects to see if there was an association

between the condition and low expression of NPY.

Subjects with low-expression NPY genotypes were overrepresented in the group

with depression.

"We're not just associating a particular gene with a particular illness,"

Zubieta says. "We're expanding the understanding of the physiology of

depression." Funding: The research was supported by grants 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.

Disclosures: Zubieta has acted as consultant for Eli Lilly and Co, Merck and

Johnson & Johnson over the last year.

Additional U-M authors: Mary M. Heitzeg, Ph.D.; David T. Hsu, Ph.D.; Scott A.

Langenecker, Ph.D.; Tiffany M. Love, Ph.D., Marta Peciña, M.D., Ph.D.; Tal

Shafir, Ph.D.

Other authors: Laboratory of Neurogenetics at the National Institute on

Alcohol Abuse and Alcoholism, Bethesda, Md.: Zhifeng Zhou, Ph.D.; Colin A.

Hodgkinson, Ph.D.; David Goldman, M.D.; Elizabeth Heinz

University of Maryland Dental School: Christian S. Stohler, D.M.D.

Reference: "Emotion Processing, Major Depression, and Functional Genetic

Variation of Neuropeptide Y," Archives of General Psychiatry, Feb. 7,

2011