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Why are people who recover from major depression never really out of the woods?

New study finds unique brain marker of 'vulnerability'

Baycrest Centre for Geriatric Care

Recovering from a major depression is only half the battle. Staying well and avoiding a recurrence can be an even tougher challenge.

Now a new study, published in the November issue of the American Journal of Psychiatry, has identified an apparent 'depression trait marker' in the brain that may explain why recovered patients remain vulnerable to another depressive episode. The finding could have important implications for developing more targeted treatments that help patients stay well longer AND identifying family members at risk before they have even experienced a major depression.

Co-investigators Drs. Mario Liotti and Helen Mayberg conducted the study at the University of Texas Health Science Center in San Antonio. Dr. Liotti now works within the Department of Psychology, at the University of Aberdeen, Scotland, and Dr. Mayberg works within The Rotman Research Institute at Baycrest Centre for Geriatric Care in Toronto.

"We know that depressed patients, even after they've become well, have a tendency to remain highly sensitive to emotional stress," says Dr. Mayberg, who also holds the Sandra A. Rotman Chair in Neuropsychiatry at the University of Toronto and Baycrest Centre. Related research has shown that this emotional sensitivity may be a risk factor for depression recurrence. "This phenomenon is seen in recovered patients -- whether they're on maintenance medication or not, there remains a persistent vulnerability for further episodes. Now we've found a clue using brain imaging that may point to a depression trait marker that underlies this vulnerability."

This 'depression trait marker' involves two brain regions: the subgenual cingulate and the medial frontal cortex. These brain regions are located in a band that runs deep within the frontal lobes, down the midline. The subgenual cingulate is an area previously identified as critical to the acute experience of intense sadness in healthy volunteers as well as a target of anti-depressant action in depressed patients. The medial frontal regions have been previously linked to the cognitive aspects of emotional processing involving self-reference, reward and positive reinforcement. In both the recovered depressed patients as well as the acutely depressed patients, these brain areas show changes in response to intense negative emotional stimuli in a way that is markedly different from that of healthy subjects.

In the study, 25 adults underwent a temporary mood provocation technique -- memory induced sadness. The participants comprised three groups:

  • An experimental group of 10 women who had recovered from a major depression (nine of the 10 were on a maintenance anti-depressant, one was medication free);
  • An acute depression group of seven women who were actively suffering from a major depression (all, except one, were medication free during the study); and
  • A healthy group of eight women with no personal or family history of depression.

At the same time as they were recalling an extremely sad experience in their life (for example, the death of a loved one), their brains were scanned using positron emission tomography (PET), which consists of computerized multi-colored images showing where maximum activity (blood flow) is occurring.

As first reported in May 1999, also in the American Journal of Psychiatry, Mayberg, Liotti and colleagues at the University of Texas identified a "see-saw" relationship -- increases in one set of regions with simultaneous decreases in the others -- between the emotional (limbic) and cognitive (cortical) areas of the brain when healthy subjects go from a neutral to an acute sad state. The reverse pattern -- limbic decreases, cortical increases -- was seen as depressed patients were successfully treated with anti-depressants.

In this latest extension of this work, fully recovered depressed patients (who had been well for over a year) and actively depressed patients -- while showing similar changes in many regions seen in healthy subjects -- also show several 'significant differences'. Unlike never-depressed control subjects, depressed patients fail to show the expected increases in the subgenual cingulate. More interesting, there were additional, unique decreases in activity in the medial frontal cortex seen in the depressed subjects, that did not occur in the control group. These medial frontal decreases in brain activity in the fully recovered patients mimic the more chronic metabolic abnormalities previously described in severely depressed patients who are not responsive to medication.

This discovery, says Drs. Mayberg and Liotti, is helping to zero in on the subtleties of depression recovery and the brain regions that remain vulnerable to acute environmental stressors, despite highly effective anti-depressant treatment. "We think of these abnormal change patterns as a snapshot of the initial brain responses to acute stress in depressed patients -- a pattern that appears similar whether patients are currently ill or fully recovered -- suggesting a more general depression trait marker," adds Dr. Liotti.

This information may prove critical in helping researchers and clinicians in their quest to find new drug, cognitive and combination therapies for patients that will prevent recurrence of depression. It may also help to identify patients' family members at risk of major depression, so they can be treated before they become sick.

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The study was funded by the American-based Charles A. DANA Foundation.

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