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Responders to Fast-Acting Antidepressant can be Identified by Brain Signal

by Kathy Jones on August 7, 2012 at 7:33 PM
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 Responders to Fast-Acting Antidepressant can be Identified by Brain Signal

A biological marker that may help identify patients who will respond to an experimental, rapid-acting antidepressant has been discovered by scientists.

The brain signal, detectable by noninvasive imaging, also holds clues to the agent's underlying mechanism, which are vital for drug development, say National Institutes of Health researchers.

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The signal is among the latest of several such markers, including factors detectable in blood, genetic markers, and a sleep-specific brain wave, recently uncovered by the NIH team and grantee collaborators. They illuminate the workings of the agent, called ketamine, and may hold promise for more personalized treatment.

"These clues help focus the search for the molecular targets of a future generation of medications that will lift depression within hours instead of weeks," explained Carlos Zarate, M.D., of the NIH's National Institute of Mental Health (NIMH). "The more precisely we understand how this mechanism works, the more narrowly treatment can be targeted to achieve rapid antidepressant effects and avoid undesirable side effects."
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Zarate, Brian Cornwell, Ph.D., and NIMH colleagues report on their brain imaging study online in the journal Biological Psychiatry.

Previous research had shown that ketamine can lift symptoms of depression within hours in many patients. But side effects hamper its use as a first-line medication. So researchers are studying its mechanism of action in hopes of developing a safer agent that works similarly.

Ketamine works through a different brain chemical system than conventional antidepressants. It initially blocks a protein on brain neurons, called the NMDA receptor, to which the chemical messenger glutamate binds. However, it is not known if the drug's rapid antidepressant effects are a direct result of this blockage or of downstream effects triggered by the blockage, as suggested by animal studies.

To tease apart ketamine's workings, the NIMH team imaged depressed patients' brain electrical activity with magnetoencephalography (MEG). They monitored spontaneous activity while subjects were at rest, and activity evoked by gentle stimulation of a finger, before and 6.5 hours after an infusion of ketamine.

It was known that by blocking NMDA receptors, ketamine causes an increase in spontaneous electrical signals, or waves, in a particular frequency range in the brain's cortex, or outer mantle. Hours after ketamine administration—in the timeframe in which ketamine relieves depression - spontaneous electrical activity in people at rest was the same whether or not the drug lifted their depression.

Electrical activity evoked by stimulating a finger, however, was different in the two groups. MEG imaging made it possible to monitor excitability of the somatosensory cortex, the part of the cortex that registers sensory stimulation. Those who responded to ketamine showed an increased response to the finger stimulation, a greater excitability of the neurons in this part of the cortex.

Such a change in excitability is likely to result, not from the immediate effects of blocking the receptor, but from other processes downstream, in the cascade of effects set in motion by NMDA blockade, say the researchers. Evidence points to changes in another type of glutamate receptor, the AMPA receptor, raising questions about whether the blocking of NMDA receptors is even necessary for ketamine's antidepressant effect. If NMDA blockade is just a trigger, then targeting AMPA receptors may prove a more direct way to effect a lifting of depression.

A separate study of ketamine biomarkers by the NIMH group adds to evidence that the drug may work, in part, by strengthening neural connections. Thirty treatment resistant depressed patients who received ketamine showed increased sleep-specific slow brainwave activity (SWA) - a marker of such strengthened synapses and of increased synchronization of networks in the cortex. They also had higher blood levels of a key neural growth chemical, brain-derived neurotrophic factor (BDNF), previously linked, in animal studies, to ketamine's action. Intriguingly, the boosts in BDNF were proportional to those in SWA only among 13 participants whose depressions significantly lifted - suggesting a potential marker of successful treatment.

"Linked SWA and BDNF may represent correlates of mood improvement following ketamine treatment," said Zarate. "These may be part of the mechanism underlying the rapid antidepressant effects and prove useful in testing potential new therapies that target the glutamate system."

The increases in SWA, detected via electroencephalography (EEG), were also reflected in increased slope and amplitude of individual brainwaves - additional indicators of neural health and adaptability.



Source: Eurekalert
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