Magnetoencephalography Imaging Shows How the Brain Reacts to Fast-Acting Antidepressant

The brain signal, detectable by noninvasive imaging called magnetoencephalography (MEG), also provides insights into to the agent’s underlying processes, which are critical for drug development.

The signal is one the latest identified of several such markers, including factors detectable in blood, genetic markers, and a sleep-specific brain wave, recently uncovered by the US National Institutes of Health (NIH; Bethesda, MD, USA) team and grantee collaborators. They reveal the workings of the agent, called ketamine, and may hold potential 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, MD, 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.”

Dr. Zarate, Brian Cornwell, PhD, and NIMH colleagues reported on their brain imaging study online July 5, 2012, in the journal Biological Psychiatry. Earlier studies had shown that ketamine can lift symptoms of depression within hours in many patients. But side effects hinder its use as a first-line medication. Therefore, researchers are evaluating 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 (N-methyl-D-aspartate receptor) 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 break down ketamine’s mechanisms, 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 revealed an increased response to the finger stimulation, a greater excitability of the neurons in this part of the cortex.

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 associated, 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 Dr. 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--further signs of neural health and adaptability. Before the discovery of ketamine’s antidepressant effects, the only fast-acting antidepressant therapies were sleep deprivation and electroconvulsive therapy (ECT), both of which are also thought to work, at least in part, by stimulating BDNF.

Ketamine also recently generated the fastest, strongest, and longest-lasting antisuicidal intervention ever demonstrated in a controlled trial, according to Dr. Zarate and colleagues. In a replication of an earlier study, the researchers validated that ketamine not only lifts depression, but also reduces suicidal thoughts in bipolar patients. The effects were identifiable as soon as 40 minutes after a single infusion in 15 treatment resistant patients taking mood stabilizers, and remained significant for at least a few days. Three-fourths of the patients responded to ketamine, with none responding to a placebo. The findings add reduced suicidal thinking to the list of potential therapeutic advantages of targeting the brain's glutamate system.

While the research on biologic markers and processes have potential for development of more practical medications in the long term, questions remain about whether there might be a limited role for ketamine itself in the short term. In a recent assessment of the state of the science, Dr. Zarate and American and European colleagues propose that intravenous ketamine may prove useful for acutely suicidal patients who receive treatment in hospital emergency rooms. It may also offer an alternative to ECT, long considered the treatment of last resort for treatment resistant depression, but burdened with worries about cognitive side effects.

“We are investigating ketamine in multiple ways--studying genes, gene expression, synapses, cells, circuits, and symptoms with neuroimaging, genetics, electrophysiological measures and other techniques,” explained Dr. Zarate. “These studies hold hope for predicting the likelihood of response and for gaining insights into mechanisms of action.”

Related Links:
US National Institutes of Health
US National Institute of Mental Health