PET shows link between endorphins and depression

With the help of PET, researchers at the University of Michigan Medical School have found more evidence that depression has its roots in specific alterations within the brain, particularly in the endorphin system that is a central part of the brain's natural pain and stress reduction capability.

The researchers also found significant variation among individuals with depression that seems to be linked to whether the patients respond to an antidepressant medication.

Previous studies have found differences in the stress response system of both the body and the brain among people with depression. But this is the first time that specific differences in the μ-opioid system have been shown between people with depression and those without, according to the study (Arch Gen Psych 2006:63;1199-1206).

Susan Kennedy, Ph.D., a member of the U-M Molecular and Behavioral Neuroscience Institute, and colleagues evaluated 14 women with major depression and 14 healthy women. The women with depression were not taking antidepressants when the study began.

Each subject was asked to recall a very sad event in her life while undergoing PET imaging with radiolabeled carfentanil. Carfentanil is a drug that binds to the same receptors on the surface of brain cells that μ-opioids, or endorphins, bind to. The women also were scanned during a neutral emotional state.

Just before the PET imaging, subjects had their blood tested to measure levels of two hormones that are released in response to stress.

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

Researchers also found that the μ-opioid system was overactive in women with depression even at baseline, when they weren't being asked to recall sad memories.

"This work gives further evidence of individual differences in brain mechanisms that are altered in major depression," said senior author Dr. Jon-Kar Zubieta, an associate professor of psychiatry and radiology at U-M. "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."

The depressed women were then prescribed an antidepressant drug and reported regularly about their depression symptoms for the next 10 weeks. Those whose depression hadn't eased by the end of the first month received a prescription for an increased dose of antidepressant.

Compared with women who did not respond to medication, those who did had far lower μ-opioid responses in the rostral anterior cingulate, which is involved in mood regulation and the integration of sensations and emotions.

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

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

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