ANN ARBOR, MICHIGAN— A new brain study finds major differences between women with serious depression and those who are healthy, in a brain-chemical system that is crucial to stress and emotions.

Research shows that depression has its roots in alterations within the brain—specifically, in the endogenous opioid system that is a central part of the brain’s natural pain and stress-reduction systems. The findings also show significant variation between individuals with depression; such variation seems to be linked to whether the patient’s condition responds to an antidepressant medication.

The study, performed by researchers at the University of Michigan Medical School Depression Center in Ann Arbor, is published in the November Archives of General Psychiatry. The results are based on brain imaging, blood chemistry, and other data from 14 women with major depression and 14 healthy women of about the same age and background. When the study began, the women with depression were not taking antidepressants.

"This work gives further evidence of individual differences in brain mechanisms that are altered in major depression," said senior author Jon-Kar Zubieta, MD, PhD, the Jenkins Research Professor of Depression and Associate Professor of Psychiatry and Radiology. "We found these differences in the response of the endogenous opioid system. Some women, but not others, with major depression, showed exaggerated responses in this system when undergoing an emotional challenge."

That emotional challenge was the summoning of memories of a very sad event in women’s lives, which the researchers asked them to recall while they were undergoing positron emission tomography (PET) of the brain. The women recalled the death or serious illness of a friend or family member, a past divorce or breakup with a boyfriend, or other major difficulties. They also underwent brain imaging during a neutral emotional state.

Just before the brain scans, the women also had their blood assayed to measure levels of two hormones that are released in response to stress. An antidepressant was prescribed for the depressed women, who then reported regularly about their depressive symptoms for the next 10 weeks. Those whose depression had not eased by the end of the first month received a prescription for an increased dose of antidepressant.

"Women who had more pronounced responses in stress response mechanisms during brain imaging also showed alterations in hormones, like cortisol, that are sometimes oversecreted in depression," Dr. Zubieta explained. "In addition, these women responded poorly to treatment with medication."

The research builds on previous studies that found differences in the body’s and brain’s stress-response systems among people with depression. But this is the first time that specific differences in the mu-opioid system have been shown between people with depression and those without.

Dr. Zubieta performed the work with Susan Kennedy, PhD, who is first author on the new paper. They used a brain-imaging technique that the research team had previously used to see how the brain responds to pain and to placebo treatment of pain.

The technique involves a form of the drug carfentanil, which binds to the same receptors on the surface of brain cells that mu-opioids bind. Mu-opioids reduce or block the spread of messages related to pain, stress, and emotional distress between the body and the brain. They have been called the body’s "natural painkillers." The drug is modified to allow it to be "seen" by the PET scanner, so that the researchers can create maps of the specific brain areas where the natural mu-opioids are more or less active at any given time.

In the new study, the researchers also found that the mu-opioid system was overactive in women with depression, even at baseline, when they were not being asked to recall sad memories.

During the "sadness challenge," the nondepressed women did not show any activation of their mu-opioid system, but the depressed women had a significant activation of that system, and the level of that activation correlated with the intensity of their negative emotional state brought on by the sad memories. Among the nondepressed women, the mu-opioid system was actually less active in some parts of the brain than it had been before they recalled sad memories.

The researchers found differences among the depressed women, too, in some areas of the brain. In the rostral anterior cingulate, which is involved in mood regulation and the integration of sensations and emotions, women whose depression responded to antidepressant treatment had lower mu-opioid responses than did women whose depression was unresponsive to medication.

The new findings add the mu-opioid system to the list of brain systems that appear to be altered in depression. Others include the corticotropin-releasing hormone system and those involved in noradrenaline, dopamine, and serotonin production.

"Further research on these differences, and their relationship to patients’ responses to various depression treatments, is crucial to the continued improvement in the understanding of depression and the development of better treatment strategies for patients," Dr. Zubieta said.

Return to table of contents