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National Institute of Mental Health (NIMH)

For Immediate Release
Thursday, October 2, 2008


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Jules Asher
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Millisecond Brain Signals Predict Response to Fast-Acting Antidepressant
Electromagnetic Biomarker Could Minimize Trial-and-Error Prescribing

Images of the brainís fastest signals reveal an electromagnetic marker that predicts a patientís response to a fast-acting antidepressant, researchers have discovered.

"Such biomarkers that identify who will benefit from a new class of antidepressants could someday minimize trial-and-error prescribing and speed delivery of care for what can be a life-threatening illness," said Carlos Zarate, M.D., of the National Institute of Mental Health (NIMH), Mood and Anxiety Disorders Program.

In the new study at the National Institutes of Health in Bethesda, MD, depressed patients showed increasing activity in a mood-regulating hub near the front of the brain while viewing flashing frightful faces & the more the increase, the better their response to an experimental fast-acting medication called ketamine. By contrast, healthy controls showed decreasing activity in this brain area under the same conditions.

Zarate, Giacomo Salvadore, M.D., Brian Cornwell, Ph.D., and NIMH colleagues report on their discovery online in Biological Psychiatry September 25, 2008.

Two years ago, Zarate and colleagues reported that ketamine, which targets the brain chemical glutamate (http://www.nimh.nih.gov/science-news/2008/faster-acting-medications-for-bipolar-disorders-manic-phase-may-be-feasible.shtml), can lift depressions in just hours (http://www.nimh.nih.gov/science-news/2006/experimental-medication-kicks-depression-in-hours-instead-of-weeks.shtml) instead of the weeks it takes conventional antidepressants, which work through the brain chemical serotonin. Evidence suggests that glutamate likely acts closer to the source of the depression than serotonin, and is not dependant on slower mechanisms, such as the synthesis of new neurons (http://www.nimh.nih.gov/science-news/2003/creation-of-new-neurons-critical-to-antidepressant-action-in-mice.shtml).

Earlier imaging studies with conventional antidepressants had hinted that increased activity of the mood-regulating hub, called the anterior cingulate cortex (ACC), signals a better response.

To find out if ACC activity might also forecast response to glutamate-targeting medications, the NIMH researchers imaged the brain activity of 11 depressed patients and 11 healthy participants, using magnetoencephalography (MEG). This imaging technology can non-invasively detect brain electromagnetic activity lasting only milliseconds & the speed of communications in neural circuits & whereas other functional brain imaging techniques can only capture activity that last seconds or minutes, and some involve radiation exposure. This precise timing enabled the MEG scanner to capture the brainís split-second responses to rapidly flashing pictures of fearful faces, a task known to activate the ACC.

While healthy participantsí ACC activity dropped off as they quickly habituated to the faces, patientsí ACC activity showed an opposite trend. The more robust this increase, the more symptoms improved just four hours after a patient received a single infusion of ketamine.

ďThe ACC may be slow to respond, but not completely impaired, in patients who respond to ketamine,Ē explained Cornwell.

The lag in ACC activity could be a window into the dysfunctional workings of the glutamate-related circuitry targeted by the medication, the researchers suggest. Ketamineís side effects make it a poor candidate for becoming a practical antidepressant, but the new findings are helping to focus the search for new treatments that work through the same mechanism, they say.

ACC activity predicts treatment response
The degree of increased activity in a mood regulating hub called the anterior cingulate (arrow) in response to flashing frightful faces predicted a patientsí response to a fast-acting antidepressant mechanism. MEG data superimposed on anatomical MRI image of the brain. Source: NIMH Mood and Anxiety Disorders Program.
Carlos Zarate, M.D., and MEG scanner
Carlos Zarate, M.D., (left) NIMH Mood and Anxiety Disorders Program, with MEG scanner. Source: NIMH .

The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. More information is available at the NIMH website, http://www.nimh.nih.gov.

The National Institutes of Health (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. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
References:
Salvadore G, Cornwell BR, Colon-Rosario V, Coppola R, Grillon C, Zarate CA, Manji H. Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biol Psychiatry. 2008 Sept. 25. [Epub ahead of print]

Tottenham, N., Tanaka, J., Leon, A.C., McCarry, T., Nurse, M., Hare, T.A., Marcus, D.J., Westerlund, A., Casey, B.J., Nelson, C.A. (in press). The NimStim set of facial expressions: judgments from untrained research participants. Psychiatry Research.

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