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Placebo, Antidepressant May Lift Depression Via Common Mechanism

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Whether it's a widely prescribed medication or a placebo, a successful treatment for depression must trigger a common pattern of brain activity changes, suggests a team of researchers funded by the National Institute of Mental Health.

Using functional brain imaging, Helen Mayberg, M.D., and colleagues at the University of Texas Health Science Center, San Antonio, have found increased activity in the cortex accompanied by decreases in limbic regions in patients who responded to either the popular antidepressant fluoxetine or to a placebo. They propose that this pattern of changes may be necessary for therapeutic response. However, patients who responded to fluoxetine also experienced unique changes in lower areas—brainstem, striatum, and hippocampus—thought to confer additional advantage in sustaining the response long term and preventing relapse. The researchers report on their Positron Emission Tomography (PET scan) study in the May 2002 American Journal of Psychiatry.

"Our findings do not support the notion that antidepressants work merely via a placebo effect," cautioned Mayberg, who has since moved to the Rotman Research Institute at the University of Toronto. "Patients on active medication who failed to improve did not sustain the brainstem, striatal, and hippocampus changes unique to antidepressant responders."

In the randomized, double-blind trial, 17 middle-aged men, hospitalized for unipolar depression, received either fluoxetine or placebo for 6 weeks. Rating scales revealed that 4 of the men responded to placebo and another 4 showed comparable improvement with the active medication. Nine patients failed to get better.

"Treatment with placebo is not absence of treatment, just absence of active medication," note the researchers, citing possible therapeutic benefits of a change in environment and the supportive, therapeutic milieu of an inpatient psychiatric ward.

PET scans traced the destination of a radioactive form of glucose—the brain's fuel—to detect brain activity patterns. After 6 weeks, brains of men who responded to either treatment showed "remarkable concordance." Activity increased in prefrontal cortex, posterior cingulate, premotor, parietal cortex, and posterior insula. Activity decreased in subgenual cingulate, parahippocampus, thalamus and hypothalamus.

Men who responded to fluoxetine, in addition, showed changes in certain lower brain areas—brainstem, hippocampus, striatum and anterior insula. Brain areas activated in the fluoxetine responders were also somewhat larger. The brainstem and hippocampus appear to have important input in sustaining the cortical/limbic changes, suggest the researchers, who note that absence of changes in these lower brain areas in placebo responders may render them at higher risk for relapse, which several previous clinical studies have shown.

Although both placebo and antidepressant responders showed increased activity in the posterior cingulate (see graphic) at 6 weeks, this change had already occurred in placebo responders at 1 week. Together with other evidence, this suggests that the ability to increase activity in the posterior cingulate may be an early indicator of a brain's capacity to change and respond to treatment, says Mayberg. Medications that take a "bottom up" approach or non-drug, cognitive "top-down" interventions should work equally well. However, a need for progressively more aggressive treatments could signal "poor adaptive capacity" in the cortex/limbic network found to change in responders, say the researchers.

Also participating in the study were: J. Arturo Silva, M.D., Steven Brannan, M.D., Janet Tekell, M.D., Roderick Mahurin, Ph.D., Scott McGinnis, Paul Jerabek, Ph.D. In addition to an NIMH grant, the study was also supported by a grant from Eli Lilly and Company.

The National Institute of Mental Health (NIMH) is part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

Composite PET scan data

Composite PET (positron emission tomography) scan data, superimposed on MRI (magnetic resonance imaging) scans, show brain areas that increased (red) or decreased (yellow) in activity in men who responded to placebo (top row) and fluoxetine (bottom row). Both groups shared a pattern of increased activity in the cortex (e.g., prefrontal, posterior cingulate) and decreased activity in limbic regions (e.g., subgenual cingulate), which the researchers suggest is necessary for therapeutic response. Men who responded to the active medication, in addition, experienced decreased activity in certain lower brain areas (e.g., hippocampus, anterior insula) thought to sustain the cortical/limbic changes and prevent relapse.

Source: Helen Mayberg, M.D., University of Toronto

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About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website .