Liam Davenport

September 27, 2016

VIENNA — New research into the anesthetic ketamine may provide fresh insight into the drug's rapid antidepressant effects.

Two studies presented here at the 29th European College of Neuropsychopharmacology (ECNP) Congress show that in contrast to other N-Methyl-D-aspartate (NMDA) antagonists, ketamine appears to have the opposite effect on the brain's thalamocortical networks, a finding that may provide insight into the drug's antidepressant effects.

In the first study, lead investigator Maria Amat Foraster, a PhD student from the University of Copenhagen, Denmark, and Institut d'Investigacions Biomèdiques de Barcelona, Spain, noted that currently available drugs to treat depression, including selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors, have delayed onset of therapeutic action and low efficacy.

Consequently, there has been increased interest in novel strategies, including the use of ketamine, a noncompetitive NMDA receptor antagonist that has rapid and long-lasting antidepressant effects. However, it also has psychotomimetic actions that increase its potential for abuse.

Previous studies have shown that phencyclidine (PCP) activates thalamocortical networks via NMDA receptor blockade in the reticular nucleus of the thalamus. Moreover, it decreases delta oscillations, an effect that is reversed by antipsychotic medications.

Hypothesizing that ketamine acts in the same way, the researchers conducted single-unit and local field potential recordings in the reticular and mediodorsal/centromedial nuclei of the thalamus and in the medial prefrontal cortex of anesthetized rats given cumulative intravenous ketamine doses of 1, 2, and 5 mg/kg or saline.

The results showed that in the reticular nucleus, ketamine significantly reduced the firing activity of neurons and dose-dependently decreased delta oscillations compared with baseline (P < .05 for both).

In the mediodorsal/centromedial nuclei of the thalamus, ketamine dose-dependently reduced the firing activity of neurons (P < .05). In addition, the drug evolved a short-lasting decrease in delta oscillations and a long-lasting increase in high-frequency low-gamma oscillations vs baseline (P < .05).

The researchers also found that in the medial prefrontal cortex, ketamine dose-dependently reduced the firing activity of antidromically driven corticothalamic neurons (P < .05). It also evoked short-lasting decreases in delta oscillations and a long-lasting increase in high-frequency gamma and beta oscillations compared with baseline (P < .05).

"In conclusion, ketamine induces a decrease in activity of the thalamocortical circuits, unlike PCP, which activates the cortical circuits. Similarly to PCP, ketamine evoked a short-lasting decrease in delta oscillations, which might underlie its psychotomimetic effects," said Foraster.

"On the other hand, ketamine evolved a long-lasting increase in gamma oscillations, which could be due to the activation of other cortical layers. This increase in activity might be a reflection of its antidepressantlike effects. However, further work is needed to understand the contributions of the observed effects," she added.

Impact on Gray Matter Volume

A second study, presented by Rob Chesters, a PhD student at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, the United Kingdom, underlined the difficulties of understanding the impact of ketamine on the brain, revealing that the drug appears to have opposite effects on gray matter volumes in humans and in mice.

In his presentation, Chesters pointed out that although ketamine has been associated with a number of brain changes on structural MRI, it is not clear whether they may be due to concomitant use of other drugs, such as nicotine, alcohol, ecstasy, methamphetamine, and cocaine.

To compare the effects of ketamine on brain structure in long-term users and a mouse model of long-term ketamine use, the researchers recruited 14 long-term ketamine users and 13 poly–drug using control individuals. They gave 20 mg/kg ketamine or saline to mice either once per day every 3 days for 30 days or once per day every day for 14 days.

Region-of-interest analysis on MRI showed that in humans who used ketamine on a long-term basis, there was a decrease in gray matter volume across the frontal cortex (P < .05). In contrast, mice that underwent intermittent administration of ketamine experienced increases in gray matter volume in the left frontal cortex (P < .05). The changes in mice that underwent continuous ketamine administration were not significant.

The researchers believe the disparity in the brain effects of ketamine between humans and mice are most likely due to combined use of other drugs in humans. Chester concluded that more work is needed to determine the effects of ketamine on the human brain.

Research Gaps

Commenting on the studies for Medscape Medical News, session cochair Marin Jukic, PhD, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden, said that there is still a long way to go in understanding ketamine's mechanism of action and that there were two main gaps in the presented research.

The first relates to the time at which the effect of ketamine was measured, "because people just measure after half an hour in animals, and they don't really look to the protracted effect of ketamine, which is quite important.

"The second point is the specificity of neural circuits involved in ketamine mode of action." Noting that there have been a number of preclinical and clinical studies in this area, he added, "It's very important to dissect the circuits and to also see how they behave in a chronic manner."

He emphasized that this is especially important with ketamine, as the impairments that occur with long-term administration mean that it cannot currently be used in an outpatient setting to treat depression.

Dr Jukic believes future research may be able to isolate the antidepressant effects of ketamine.

"The true molecular targets, I believe, are still missing, and with this research into specific alterations in the brain, and with specific molecular targets in those specific regions, we might be able to tease out a compound which affects only that.

"That would probably get rid of most of the unspecificity [of ketamine], and then we could more freely work with this drug, because it won't have such dangerous side effects."

The study was financially supported by Lundbeck A/S, Innovation Fund Denmark, and Instituto de Salud Carlos III. The researches have disclosed no relevant financial relationships.

29th European College of Neuropsychopharmacology (ECNP) Congress. Abstracts S.16.04 and S.16.06. Presented September 19, 2016.

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